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3,000 |
Wie lange dauert eine Langzeitanwendung?
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3,001 |
A prospective observational study on critically ill children with diaphragmatic dysfunction: clinical outcomes and risk factors
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BACKGROUND: Diaphragmatic dysfunction (DD) has a great negative impact on clinical outcomes, and it is a well-recognized complication in adult patients with critical illness. However, DD is largely unexplored in the critically ill pediatric population. The aim of this study was to identify risk factors associated with DD, and to investigate the effects of DD on clinical outcomes among critically ill children. METHODS: Diaphragmatic function was assessed by diaphragm ultrasound. According to the result of diaphragmatic ultrasound, all enrolled subjects were categorized into the DD group (n = 24) and the non-DD group (n = 46). Collection of sample characteristics in both groups include age, sex, height, weight, primary diagnosis, complications, laboratory findings, medications, ventilatory time and clinical outcomes. RESULTS: The incidence of DD in this PICU was 34.3%. The level of CRP at discharge (P = 0.003) in the DD group was higher than the non-DD group, and duration of elevated C-reactive protein (CRP) (P < 0.001), sedative days (P = 0.008) and ventilatory treatment time (P < 0.001) in the DD group was significantly longer than the non-DD group. Ventilatory treatment time and duration of elevated CRP were independently risk factors associated with DD. Patients in the DD group had longer PICU length of stay, higher rate of weaning or extubation failure and higher mortality. CONCLUSION: DD is associated with poorer clinical outcomes in critically ill childern, which include a longer PICU length of stay, higher rate of weaning or extubation failure and a higher mortality. The ventilatory treatment time and duration of elevated CRP are main risk factors of DD in critically ill children. TRIAL REGISTRATION: Current Controlled Trials ChiCTR1800020196, Registered 01 Dec 2018.
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3,002 |
Towards harmonization of microscopy methods for malaria clinical research studies
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Microscopy performed on stained films of peripheral blood for detection, identification and quantification of malaria parasites is an essential reference standard for clinical trials of drugs, vaccines and diagnostic tests for malaria. The value of data from such research is greatly enhanced if this reference standard is consistent across time and geography. Adherence to common standards and practices is a prerequisite to achieve this. The rationale for proposed research standards and procedures for the preparation, staining and microscopic examination of blood films for malaria parasites is presented here with the aim of improving the consistency and reliability of malaria microscopy performed in such studies. These standards constitute the core of a quality management system for clinical research studies employing microscopy as a reference standard. They can be used as the basis for the design of training and proficiency testing programmes as well as for procedures and quality assurance of malaria microscopy in clinical research.
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3,003 |
FLAVi: An Enhanced Annotator for Viral Genomes of Flaviviridae
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Responding to the ongoing and severe public health threat of viruses of the family Flaviviridae, including dengue, hepatitis C, West Nile, yellow fever, and Zika, demands a greater understanding of how these viruses emerge and spread. Updated phylogenies are central to this understanding. Most cladograms of Flaviviridae focus on specific lineages and ignore outgroups, hampering the efficacy of the analysis to test ingroup monophyly and relationships. This is due to the lack of annotated Flaviviridae genomes, which has gene content variation among genera. This variation makes analysis without partitioning difficult. Therefore, we developed an annotation pipeline for the genera of Flaviviridae (Flavirirus, Hepacivirus, Pegivirus, and Pestivirus, named “Fast Loci Annotation of Viruses” (FLAVi; http://flavi-web.com/), that combines ab initio and homology-based strategies. FLAVi recovered 100% of the genes in Flavivirus and Hepacivirus genomes. In Pegivirus and Pestivirus, annotation efficiency was 100% except for one partition each. There were no false positives. The combined phylogenetic analysis of multiple genes made possible by annotation has clear impacts over the tree topology compared to phylogenies that we inferred without outgroups or data partitioning. The final tree is largely congruent with previous hypotheses and adds evidence supporting the close phylogenetic relationship between dengue and Zika.
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3,004 |
Recent Progress in the Detection of Bacteria Using Bacteriophages: A Review
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Bacteria will likely become our most significant enemies of the 21st century, as we are approaching a post-antibiotic era. Bacteriophages, viruses that infect bacteria, allow us to fight infections caused by drug-resistant bacteria and create specific, cheap, and stable sensors for bacteria detection. Here, we summarize the recent developments in the field of phage-based methods for bacteria detection. We focus on works published after mid-2017. We underline the need for further advancements, especially related to lowering the detection (below 1 CFU/mL; CFU stands for colony forming units) and shortening the time of analysis (below one hour). From the application point of view, portable, cheap, and fast devices are needed, even at the expense of sensitivity.
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3,005 |
Nephrotic syndrome in The Netherlands: a population-based cohort study and a review of the literature
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Nephrotic syndrome (NS) is a clinical diagnosis with proteinuria, hypoalbuminaemia and oedema. NS is rare in children, and its incidence in The Netherlands is unknown. The aim of this study was to estimate the incidence of idiopathic NS in the Netherlands. All paediatric patients (age 0–18 years) with a newly diagnosed NS in the Netherlands were registered by the Dutch Pediatric Surveillance Unit during the years 2003 until 2006, secondary NS was excluded. All paediatricians filled out questionnaires about the first clinical findings of the patients and incidences were calculated. A literature review on incidences of childhood NS was conducted. The incidence of NS in children in the Netherlands in the years 2003 until 2006 was 1.52/ 100, 000 children/ year. The median age at diagnosis was 3.88 years with a mean age of 5.08 years. A significant male:female ratio of 2.04:1 was found. This prospective study of NS in the Netherlands revealed an incidence of 1.52:100, 000 children/year, and is similar to the incidences found all over the world.
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3,006 |
Sighting characteristics and photo-identification of Cuvier’s beaked whales (Ziphius cavirostris) near San Clemente Island, California: a key area for beaked whales and the military?
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The relationship between beaked whales and certain anthropogenic sounds remains poorly understood and of great interest. Although Cuvier’s beaked whales (Ziphius cavirostris) are widely distributed, little is known of their behavior and population structure throughout much of their range. We conducted a series of five combined visual-acoustic marine mammal surveys from 2006 to 2008 in the southern San Nicolas Basin, a site of frequent naval activity off the southern California coast, west of San Clemente Island. The study area was defined by a 1,800 km(2) array of 88 bottom-mounted hydrophones at depths up to 1,850 m. The array was used to vector visual observers toward vocalizing marine mammal species. Thirty-seven groups of Cuvier’s beaked whales were encountered during the study period. The overall encounter rate was one group for every 21.0 h of survey effort, and was as high as one group per 10.2 h of effort during the October 2007 survey. Whales were encountered in the deepest portion of the study area, at a mean bottom depth of 1,580 m (SD 138). The average group size was 3.8 individuals (SD 2.4), which was higher than has been reported from other studies of this species. Twenty-four groups were observed over multiple surfacings (median = 4 surfacings, range 2–15). The mean encounter duration of extended sightings was 104 min (SD 98, range 12–466 min) and the mean distance moved over the course of sightings was 1.66 km (SD 1.56, range 0.08–6.65 km). Temporal surfacing patterns during extended encounters were similar to dive behavior described from Cuvier’s beaked whales carrying time-depth recording tags. Seventy-eight photographic identifications were made of 58 unique individuals, for an overall resighting rate of 0.26. Whales were sighted on up to 4 days, with duration from first to last sighting spanning 2–79 days. For those whales sighted on subsequent days, the mean distance between subsequent sightings was 8.6 km (SD 7.9). Individuals resighted over 2–3 days were usually in association with previous group members. Approximately one-third of groups contained more than one adult male, and many of the repeated associations involved adult males. These observations suggest the basin west of San Clemente Island may be an important region for Cuvier’s beaked whales, and also one which affords an unusual opportunity to collect detailed data on this species. Given its status as an active military range, it can also provide the ability to monitor the behavior of individuals in the presence of naval sonar, a critical step in the management of this and other beaked whale populations worldwide.
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3,007 |
Recruitment and ontogenetic habitat shifts of the yellow snapper (Lutjanus argentiventris) in the Gulf of California
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We examined recruitment and ontogenetic habitat shifts of the yellow snapper Lutjanus argentiventris in the Gulf of California, by conducting surveys and collections in multiple mangrove sites and major marine coastal habitats from 1998 to 2007. Over 1,167 juvenile individuals were collected and 516 otoliths were aged to describe the temporal pattern of the settlement. L. argentiventris recruits in mangroves, where juveniles remain until they are approximately 100 mm in length or 300-days-old. Back-calculated settlement dates and underwater surveys indicated a major recruitment peak during September and October, around 8 days before and after the full moon. The majority of mangrove sites in the Gulf of California had a similar L. argentiventris average size at the beginning of the settlement season for the cohort of 2003; although there were significant differences in individual sizes at the end of the nursery stage. When sub-adults leave mangroves, they live in shallow rocky reefs and later become abundant in deeper rocky reefs. The density of migratory individuals (10–20 cm SL) decreased exponentially as the distance between a reef and a nearby mangrove site increased. This finding has important implications for local fishery regulations and coastal management plans. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1007/s00227-009-1271-5) contains supplementary material, which is available to authorized users.
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3,008 |
Implementation and experiments for interactive lyrics transcreation system
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The evolution of the Internet has enabled us to enjoy the music created in various countries. But still, it is often difficult to understand the lyrics written in foreign languages. Professional translators have published many international songs with lyrics that fit the melody so that the ordinary people can enjoy the lyrics of such international songs. This paper discusses lyrics transcreation into the Japanese language. Also, the paper presents an interactive visual lyrics transcreation system and describes the details of its implementation. This system allows users to select temporary lyrics from a set of tentative translations and then freely modify the lyrics with a real-time visualization mechanism. We also propose a lyrics translation algorithm that solves an essential problem of lyrics translation into Japanese. In this study, we interviewed two experts regarding problems with lyrics translation and received reviews of our presented system. We also conducted preliminary experiments with 19 participants to determine the best combination of user interface components for our system. We performed additional user experiments inviting 12 participants to compare lyrics transcreation using the presented system to manual lyrics transcreation. Lyrics transcreation by the presented system brought better results against those of manual transcreation.
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3,009 |
Restoration of renal function in zebrafish models of ciliopathies
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The ciliopathies are a class of rare human genetic disease whose aetioligies lie in defective primary cilia. Typical ciliopathies include Bardet–Biedl syndrome (BBS), nephronophthisis (NPHP), Jeune, Joubert, oro-facial-digital (OFD1) and Meckel (MKS) syndromes. All ciliopathies have the common denominator of renal disease, often including tubular cysts. In this study, we have modelled a range of ciliopathies in zebrafish and shown in all cases that knocking down these genes causes cystic lesions in the kidney. We have identified two drugs, rapamycin and roscovitine, which ameliorate the renal phenotype, both morphologically and functionally. This is the first study in which zebrafish has been used to identify potential therapeutic modalities for ciliopathic renal disease, and the results pave the way for further investigations in mammalian models.
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3,010 |
Distribution and phylogenetic analysis of Dabieshan tick virus in ticks collected from Zhoushan, China
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Dabieshan tick virus (DBV) belongs to Phlebovirus and its pathogenicity to human and animals is unknown. To investigate the presence of Dabieshan tick virus in Zhoushan, 353 ticks were collected from May 2018 to October 2019. The detection result showed that the average prevalence rate among these samples was 30.3% (107 positives out of 353 samples), which means DBVs are widely distributed in tick populations in Zhoushan of China. In a phylogenetic analysis based on the nucleotide sequences of the L and S segments of the virus (ZS-DBS-2018 tick virus) in the study, it clustered with Dabieshan tick virus (KM817666.1, KM817733.1) with a 97.1% and 99.6% nucleotide identity, respectively. Further studies involving virus isolation are required to characterize Dabieshan tick virus and to expand the geographical distribution of the sampled ticks.
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3,011 |
A Novel Virus Alters Gene Expression and Vacuolar Morphology in Malassezia Cells and Induces a TLR3-Mediated Inflammatory Immune Response
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Most fungal viruses have been identified in plant pathogens, whereas the presence of viral particles in human-pathogenic fungi is less well studied. In the present study, we observed extrachromosomal double-stranded RNA (dsRNA) segments in various clinical isolates of Malassezia species. Malassezia is the most dominant fungal genus on the human skin surface, and species in this group are considered etiological factors of various skin diseases including dandruff, seborrheic dermatitis, and atopic dermatitis. We identified novel dsRNA segments, and our sequencing results revealed that the virus, named MrV40, belongs to the Totiviridae family and contains an additional satellite dsRNA segment encoding a novel protein. The transcriptome of virus-infected Malassezia restricta cells was compared to that of virus-cured cells, and the results showed that transcripts involved in ribosomal biosynthesis were downregulated and those involved in energy production and programmed cell death were upregulated. Moreover, transmission electron microscopy revealed significantly larger vacuoles in virus-infected M. restricta cells, indicating that MrV40 infection dramatically altered M. restricta physiology. Our analysis also revealed that viral nucleic acid from MrV40 induced a TLR3 (Toll-like receptor 3)-mediated inflammatory immune response in bone marrow-derived dendritic cells, suggesting that a viral element contributes to the pathogenicity of Malassezia.
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3,012 |
Dimethyl fumarate alleviates the nitroglycerin (NTG)-induced migraine in mice
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BACKGROUND: Oxidative stress and inflammatory pathways are involved in migraine and endogenous antioxidant defense system has a role in the prevention of hyperalgesia in migraine. In this study, we aimed to evaluate the role of the most pharmacologically effective molecules among the fumaric acid esters (FAEs), dimethyl fumarate, nuclear factor E2-related factor 2/antioxidant response element (Nrf-2/ARE) pathway-mediated, in regulating the hypersensitivity in a mouse model of nitroglycerine (NTG)-induced migraine. METHODS: Mice were orally administered with DMF at the doses of 10, 30, and 100 mg/kg, 5 min after NTG intraperitoneal injections. We performed histological and molecular analysis on the whole brain and behavioral tests after 4 h by NTG-migraine induction. The expression of nuclear factor kappa-light-chain-enhancer of activated B cells (NF-кB) subunit p65, nuclear factor of kappa light polypeptide gene enhancer in B-cells inhibitor alpha (IκBα), inducible nitrite oxide synthase (iNOS), cyclooxygenase 2 (COX-2), Nrf-2, manganese superoxide dismutase (Mn-SOD), and heme-oxygenase-1 (HO-1) were detected by Western blot. Tail flick, hot plate, orofacial formalin, and photophobia tests were used to evaluate migraine-like pain and migraine-related light sensitivity. Moreover, we evaluate Nrf-2-dependent mechanism by the in vitro stimulation of cells extracted by trigeminal ganglia with diethylenetriamine/nitric oxide (DETA/NO), a nitric oxide (NO) donor. The cells were pre-treated with DMF and an antagonist of Nrf-2, trigonelline (TR) 2 h before DETA/NO stimulation. RESULTS: DMF treatment notably reduced histological damage as showed by cresyl violet staining; also, regulating both NF-κB and Nrf-2 pathway, DMF treatment decreased the severity of inflammation and increased the protective antioxidant action. Moreover, the headache was significantly reduced. The protective effect of DMF treatment, via Nrf-2, was confirmed in in vitro studies, through inhibition of Nrf-2 by trigonelline. Cytotoxicity, iNOS, and MnSOD expression were evaluated. CONCLUSION: These results provided the evidence that DMF, by Nrf-2 modulation, has a protective effect on central sensitization induced by NTG, suggesting a new insight into the potential application of DMF as novel candidates in drug development for migraine.
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3,013 |
Methylmercury toxic mechanism related to protein degradation and chemokine transcription
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Methylmercury is an environmental pollutant that causes neurotoxicity. Recent studies have reported that the ubiquitin-proteasome system is involved in defense against methylmercury toxicity through the degradation of proteins synthesizing the pyruvate. Mitochondrial accumulation of pyruvate can enhance methylmercury toxicity. In addition, methylmercury exposure induces several immune-related chemokines, specifically in the brain, and may cause neurotoxicity. This summary highlights several molecular mechanisms of methylmercury-induced neurotoxicity.
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3,014 |
Mechanical circulatory support in refractory cardiogenic shock due to influenza virus-related myocarditis
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BACKGROUND: There is scarce evidence for mechanical circulatory support (MCS) in patients with influenza-related myocarditis complicated by refractory cardiogenic shock (rCS). We sought to investigate the impact of MCS using combined veno-arterial extracorporeal membrane oxygenation (VA-ECMO) and micro-axial flow pumps (the ECMELLA concept) in influenza-related myocarditis complicated by rCS. METHODS: This is a prospective, observational analysis from the single centre HAnnover Cardiac Unloading REgistry (HACURE) from two recent epidemic influenza seasons. We analysed patients with verified influenza-associated myocarditis complicated by rCS who were admitted to our intensive care unit (ICU) on MCS. Subsequently, we performed a propensity score (PS) matched analysis to patients with acute myocardial infarction (AMI) complicated by rCS and non-ischaemic cardiomyopathy (DCM) related rCS. RESULTS: We describe a series of seven patients with rCS-complicated influenza-related myocarditis (mean age 56±10 years, 58% male, influenza A (n=2)/influenza B (n=5)). No patient had been vaccinated prior to the influenza season. MCS was provided using combined VA-ECMO and Impella micro-axial flow pump. In two patients with out-of-hospital cardiac arrest, VA-ECMO had been implanted for extracorporeal cardiopulmonary resuscitation. All patients died within 18 days of hospital admission. By PS-based comparison to patients with AMI- or DCM-related rCS and combined MCS, 30-day mortality was significantly higher in influenza-related rCS. CONCLUSION: Despite initial stabilisation with combined MCS in patients with rCS-complicated influenza-related myocarditis, the detrimental course of shock could not be stopped and all patients died. Influenza virus infection potentially critically affects other organs besides the heart, leading to irreversible end-organ damage that MCS cannot compensate for and, therefore, results in a devastating outcome.
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3,015 |
Timing of surgery after recovery from coronavirus disease 2019 (COVID-19) infection
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3,016 |
Will there be any more classical scrapie cases in sheep in Great Britain? A modelling study to predict future cases
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The aim of this study was to apply a back-calculation model to Great Britain (GB) classical scrapie surveillance data, and use this model to estimate how many more cases might be expected, and over what time frame these cases might occur. A back-calculation model was applied to scrapie surveillance data between 2005 and 2019 to estimate the annual rate of decline of classical scrapie. This rate was then extrapolated to predict the number of future cases each year going forward. The model shows that there may be yet further cases of classical scrapie in GB. These will most likely occur in the fallen stock scheme, with approximately a 25% probability of at least 1 further scrapie positive, with a very low probability (~0.2%) of having up to three additional scrapie positives. This highlights the difficulty of completely eliminating all further cases, even in the presence of very effective control measures.
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3,017 |
Myocardial infarction evaluation from stopping time decision toward interoperable algorithmic states in reinforcement learning
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BACKGROUND: The Elliot wave principle commonly characterizes the impulsive and corrective wave trends for both financial market trends and electrocardiograms. The impulsive wave trends of electrocardiograms can annotate several wave components of heart-beats including pathological heartbeat waveforms. The stopping time inquires which ordinal element satisfies the assumed mathematical condition within a numerical set. The proposed work constitutes several algorithmic states in reinforcement learning from the stopping time decision, which determines the impulsive wave trends. Each proposed algorithmic state is applicable to any relevant algorithmic state in reinforcement learning with fully numerical explanations. Because commercial electrocardiographs still misinterpret myocardial infarctions from extraordinary electrocardiograms, a novel algorithm needs to be developed to evaluate myocardial infarctions. Moreover, differential diagnosis for right ventricle infarction is required to contraindicate a medication such as nitroglycerin. METHODS: The proposed work implements the stopping time theory to impulsive wave trend distribution. The searching process of the stopping time theory is equivalent to the actions toward algorithmic states in reinforcement learning. The state value from each algorithmic state represents the numerically deterministic annotated results from the impulsive wave trend distribution. The shape of the impulsive waveform is evaluated from the interoperable algorithmic states via least-first-power approximation and approximate entropy. The annotated electrocardiograms from the impulsive wave trend distribution utilize a structure of neural networks to approximate the isoelectric baseline amplitude value of the electrocardiograms, and detect the conditions of myocardial infarction. The annotated results from the impulsive wave trend distribution consist of another reinforcement learning environment for the evaluation of impulsive waveform direction. RESULTS: The accuracy to discern myocardial infarction was found to be 99.2754% for the data from the comma-separated value format files, and 99.3579% for those containing representative beats. The clinical dataset included 276 electrocardiograms from the comma-separated value files and 623 representative beats. CONCLUSIONS: Our study aims to support clinical interpretation on 12-channel electrocardiograms. The proposed work is suitable for a differential diagnosis under infarction in the right ventricle to avoid contraindicated medication during emergency. An impulsive waveform that is affected by myocardial infarction or the electrical direction of electrocardiography is represented as an inverse waveform.
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3,018 |
Intravenous calcium as a pressor in a swine model of hypoxic pseudo-pulseless electrical mechanical activity—a preliminary report
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BACKGROUND: Pseudo-pulseless electrical activity (pseudo-PEA) is a lifeless form of profound cardiac shock characterized by measurable cardiac mechanical activity without clinically detectable pulses. Pseudo-PEA may constitute up to 40% of reported cases of cardiac arrest. Resuscitation from pseudo-PEA is often associated with hypotension refractory to catecholamine pressors. We hypothesized that this post-resuscitation state may be associated with hypocalcemic hypotension responsive to intravenous calcium. METHODS: Using pre-existing data from our hypoxic swine pseudo-PEA model, we measured blood pressure, hemodynamics, and electrolytes. Physiological data were analyzed on a heartbeat by heartbeat basis. The midpoint of the calcium response was defined using change of curvature feature detection. Hemodynamic parameters were shifted such that the value at the midpoint was equal to zero. RESULTS: In 9 animals with refractory hypotension, we administered 37 boluses of intravenous calcium in the dosage range of 5-20 mg. Comparisons were made between the average values in the time period 40-37 s before the midpoint and 35-40 s after the midpoint. Of the 37 administered boluses, 34 manifested a change in the blood pressure, with mean aortic pressure, systolic and diastolic pressures all increasing post bolus administration. CONCLUSIONS: Administration of intravenous calcium may be associated with a pressor-like response in refractory hypotension after resuscitation from pseudo-PEA. Relative ionized hypocalcemia may cause hypotension after resuscitation from pseudo-PEA. Therapy with intravenous calcium should be further investigated in this setting.
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3,019 |
Outbreak of multi-drug-resistant (MDR) Shigella flexneri in northern Australia due to an endemic regional clone acquiring an IncFII plasmid
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Epidemiological surveillance of Shigella spp. in Australia is conducted to inform public health response. Multi-drug resistance has recently emerged as a contributing factor to sustained local transmission of Shigella spp. All data were collected as part of routine public health surveillance, and strains were whole-genome sequenced for further molecular characterisation. 108 patients with an endemic regional Shigella flexneri strain were identified between 2016 and 2019. The S. flexneri phylogroup 3 strain endemic to northern Australia acquired a multi-drug resistance conferring bla(DHA) plasmid, which has an IncFII plasmid backbone with virulence and resistance elements typically found in IncR plasmids. This is the first report of multi-drug resistance in Shigella sp. in Australia that is not associated with men who have sex with men. This strain caused an outbreak of multi-drug-resistant S. flexneri in northern Australia that disproportionality affects Aboriginal and Torres Strait Islander children. Community controlled public health action is recommended. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (10.1007/s10096-020-04029-w) contains supplementary material, which is available to authorized users.
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3,020 |
Neurally adjusted ventilatory assist in acute respiratory failure: a randomized controlled trial
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PURPOSE: We hypothesized that neurally adjusted ventilatory assist (NAVA) compared to conventional lung-protective mechanical ventilation (MV) decreases duration of MV and mortality in patients with acute respiratory failure (ARF). METHODS: We carried out a multicenter, randomized, controlled trial in patients with ARF from several etiologies. Intubated patients ventilated for ≤ 5 days expected to require MV for ≥ 72 h and able to breathe spontaneously were eligible for enrollment. Eligible patients were randomly assigned based on balanced treatment assignments with a computerized randomization allocation sequence to two ventilatory strategies: (1) lung-protective MV (control group), and (2) lung-protective MV with NAVA (NAVA group). Allocation concealment was maintained at all sites during the trial. Primary outcome was the number of ventilator-free days (VFDs) at 28 days. Secondary outcome was all-cause hospital mortality. All analyses were done according to the intention-to-treat principle. RESULTS: Between March 2014 and October 2019, we enrolled 306 patients and randomly assigned 153 patients to the NAVA group and 153 to the control group. Median VFDs were higher in the NAVA than in the control group (22 vs. 18 days; between-group difference 4 days; 95% confidence interval [CI] 0 to 8 days; p = 0.016). At hospital discharge, 39 (25.5%) patients in the NAVA group and 47 (30.7%) patients in the control group had died (between-group difference − 5.2%, 95% CI − 15.2 to 4.8, p = 0.31). Other clinical, physiological or safety outcomes did not differ significantly between the trial groups. CONCLUSION: NAVA decreased duration of MV although it did not improve survival in ventilated patients with ARF. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (10.1007/s00134-020-06181-5) contains supplementary material, which is available to authorized users.
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3,021 |
Insulin Injection Practices in a Population of Canadians with Diabetes: An Observational Study
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INTRODUCTION: Proper insulin injection technique has demonstrated positive clinical outcomes in patients with diabetes. A Canadian-based practice reflective was undertaken to evaluate the current state of understanding of injection technique practices by patients administering insulin, and the importance physicians place on proper injection technique. METHODS: Twenty-four sites across Canada completed a practice profile survey and enrolled adult non-pregnant patients with either type 1 or type 2 diabetes injecting insulin using an insulin pen. Seven areas of proper injection technique to be evaluated were identified by the study steering committee: size of injection site, use of a skin lift, needle reuse, length of the needle, duration of the needle in the skin, injection into lipohypertrophic tissue, and applied injection force. During a scheduled visit, each patient filled out the Injection Technique Survey and the physician documented the answers via an electronic database. RESULTS: Almost all physicians surveyed agreed (96%) that proper insulin injection technique is important or very important and 80% indicated they were either completely confident or fairly confident in discussing overall insulin injection technique. All patients surveyed were making at least one insulin injection technique error within the following categories: applied injection force (76%), area size of injection site (64%), duration of pen needle in skin (61%), pen needle reuse (39%), performs a skin lift with a 4 or 5 mm needle (38%), uses a longer pen needle than required (34%), and injection of insulin into lipohypertrophic tissue (37%). CONCLUSION: Patients commonly make insulin injection errors. Patient and physician education on optimal insulin injection technique continues to be an unmet medical need for the treatment of patients with diabetes. Prospective trials examining the impact of new technology, diabetes educational teams, and e-learning as educational interventions are potential avenues to explore in future studies to support improved insulin injection technique. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (10.1007/s13300-020-00913-y) contains supplementary material, which is available to authorized users.
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3,022 |
Ultrasonographic assessment of parasternal intercostal muscles during mechanical ventilation
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Although mechanical ventilation is a lifesaving treatment, abundant evidence indicates that its prolonged use (1 week or more) promotes respiratory muscle weakness due to both contractile dysfunction and atrophy. Along with the diaphragm, the intercostal muscles are one of the most important groups of respiratory muscles. In recent years, muscular ultrasound has become a useful bedside tool for the clinician to identify patients with respiratory muscle dysfunction related to critical illness and/or invasive mechanical ventilation. Images obtained over the course of illness can document changes in muscle dimension and can be used to estimate changes in function. Recent evidence suggests the clinical usefulness of ultrasound imaging in the assessment of intercostal muscle function. In this narrative review, we summarize the current literature on ultrasound imaging of the parasternal intercostal muscles as used to assess the extent of muscle activation and muscle weakness and its potential impact during discontinuation of mechanical ventilation. In addition, we proposed a practical flowchart based on recent evidence and experience of our group that can be applied during the weaning phase. This approach integrates multiple predictive parameters of weaning success with respiratory muscle ultrasound.
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3,023 |
Cessation of breastfeeding and associated factors in the era of elimination of mother to child transmission of HIV at Ndejje health center, Uganda: a retrospective cohort study
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BACKGROUND: Breastfeeding an infant exposed to Human Immunodeficiency Virus (HIV) carries the risk of HIV acquisition whilst not breastfeeding poses a higher risk of death from malnutrition, diarrhea, and pneumonia. In Uganda, mothers living with HIV are encouraged to discontinue breastfeeding at 12 months but data are limited. We examined the frequency and factors associated with cessation of breastfeeding at 1 year among mothers living with HIV at Ndejje Health Center IV, a large peri-urban health facility in Uganda. METHODS: This retrospective cohort study involved all mothers living with HIV and enrolled in HIV care for ≥12 months between June 2014 and June 2018. We abstracted data from registers, held focus group discussions with mothers living with HIV and key informant interviews with healthcare providers. Cessation of breastfeeding was defined as the proportion of mothers living with HIV who had discontinued breastfeeding at 1 year. We summarized quantitative data descriptively, tested differences in outcome using Chi-square and t - tests, and established independently associated factors using modified Poisson regression analysis at 5% statistical significance level. We thematically analyzed qualitative data to enrich and triangulate the quantitative results. RESULTS: Of 235 participants, 150 (63.8%) had ceased breastfeeding at 1 year and this was independently associated with the infant being male (Adjusted Risk Ratio [aRR] 1.25, 95% confidence interval [CI] 1.04, 1.50), the mother being multiparous (aRR 1.26, 95% CI 1.04–1.53), and the initiation of breastfeeding being on the same-day as birth (aRR 0.06, 95% CI 0.01–0.41). The reasons for ceasing breastfeeding included male infants over breastfeed than females, maternal literacy and knowledge adequacy about breastfeeding, support and reminders from the partner, and boys can bite once they get teeth. CONCLUSION: Suboptimal proportion of infants were ceased from breastfeeding at 1 year and this might increase the risk of mother to child transmission of HIV. Cessation of breastfeeding was more likely among male infants and multiparous mothers but less likely when breastfeeding was initiated on the same-day as birth. Interventions to enhance cessation of breastfeeding should target none multiparous mothers and those with female infants.
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3,024 |
A limbic circuit selectively links active escape to food suppression
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Stress has pleiotropic physiologic effects, but the neural circuits linking stress to these responses are not well understood. Here, we describe a novel population of lateral septum neurons expressing neurotensin (LS(Nts)) in mice that are selectively tuned to specific types of stress. LS(Nts) neurons increase their activity during active escape, responding to stress when flight is a viable option, but not when associated with freezing or immobility. Chemogenetic activation of LS(Nts) neurons decreases food intake and body weight, without altering locomotion and anxiety. LS(Nts) neurons co-express several molecules including Glp1r (glucagon-like peptide one receptor) and manipulations of Glp1r signaling in the LS recapitulates the behavioral effects of LS(Nts) activation. Activation of LS(Nts) terminals in the lateral hypothalamus (LH) also decreases food intake. These results show that LS(Nts) neurons are selectively tuned to active escape stress and can reduce food consumption via effects on hypothalamic pathways.
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3,025 |
Predicting the treatment response of certolizumab for individual adult patients with rheumatoid arthritis: protocol for an individual participant data meta-analysis
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BACKGROUND: A model that can predict treatment response for a patient with specific baseline characteristics would help decision-making in personalized medicine. The aim of the study is to develop such a model in the treatment of rheumatoid arthritis (RA) patients who receive certolizumab (CTZ) plus methotrexate (MTX) therapy, using individual participant data meta-analysis (IPD-MA). METHODS: We will search Cochrane CENTRAL, PubMed, and Scopus as well as clinical trial registries, drug regulatory agency reports, and the pharmaceutical company websites from their inception onwards to obtain randomized controlled trials (RCTs) investigating CTZ plus MTX compared with MTX alone in treating RA. We will request the individual-level data of these trials from an independent platform (http://vivli.org). The primary outcome is efficacy defined as achieving either remission (based on ACR-EULAR Boolean or index-based remission definition) or low disease activity (based on either of the validated composite disease activity measures). The secondary outcomes include ACR50 (50% improvement based on ACR core set variables) and adverse events. We will use a two-stage approach to develop the prediction model. First, we will construct a risk model for the outcomes via logistic regression to estimate the baseline risk scores. We will include baseline demographic, clinical, and biochemical features as covariates for this model. Next, we will develop a meta-regression model for treatment effects, in which the stage 1 risk score will be used both as a prognostic factor and as an effect modifier. We will calculate the probability of having the outcome for a new patient based on the model, which will allow estimation of the absolute and relative treatment effect. We will use R for our analyses, except for the second stage which will be performed in a Bayesian setting using R2Jags. DISCUSSION: This is a study protocol for developing a model to predict treatment response for RA patients receiving CTZ plus MTX in comparison with MTX alone, using a two-stage approach based on IPD-MA. The study will use a new modeling approach, which aims at retaining the statistical power. The model may help clinicians individualize treatment for particular patients. SYSTEMATIC REVIEW REGISTRATION: PROSPERO registration number pending (ID#157595).
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3,026 |
A multi-omics supervised autoencoder for pan-cancer clinical outcome endpoints prediction
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BACKGROUND: With the rapid development of sequencing technologies, collecting diverse types of cancer omics data become more cost-effective. Many computational methods attempted to represent and fuse multiple omics into a comprehensive view of cancer. However, different types of omics are related and heterogeneous. Most of the existing methods do not consider the difference between omics, so the biological knowledge of individual omics may not be fully excavated. And for a given task (e.g. predicting overall survival), these methods prefer to use sample similarity or domain knowledge to learn a more reasonable representation of omics, but it’s not enough. METHODS: For the purpose of learning more useful representation for individual omics and fusing them to improve the prediction ability, we proposed an autoencoder-based method named MOSAE (Multi-omics Supervised Autoencoder). In our method, a specific autoencoder were designed for each omics according to their size of dimension to generate omics-specific representations. Then, a supervised autoencoder was constructed based on specific autoencoder by using labels to enforce each specific autoencoder to learn both omics-specific and task-specific representations. Finally, representations of different omics that generate from supervised autoencoders were fused in a traditional but powerful way, and the fused representation was used for subsequent predictive tasks. RESULTS: We applied our method over TCGA Pan-Cancer dataset to predict four different clinical outcome endpoints (OS, PFI, DFI, and DSS). Compared with traditional and state-of-the-art methods, MOSAE achieved better predictive performance. We also tested the effects of each improvement, which all have a positive effect on predictive performance. CONCLUSIONS: Predicting clinical outcome endpoints are very important for precision medicine and personalized medicine. And multi-omics fusion is an effective way to solve this problem. MOSAE is a powerful multi-omics fusion method, which can generate both omics-specific and task-specific representation for given endpoint predictive tasks and improve the predictive performance.
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3,027 |
Hepatitis a virus infection in Central-West Tunisia: an age structured model of transmission and vaccination impact
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BACKGROUND: The epidemiological pattern of hepatitis A infection has shown dynamic changes in many parts of the world due to improved socio-economic conditions and the accumulation of seronegative subjects, which leads to possible outbreaks and increased morbidity rate. In Tunisia, the epidemiological status of hepatits A virus is currently unknown. However, over the past years higher numbers of symptomatic hepatitis A virus infection in school attendants and several outbreaks were reported to the Ministry of Health, especially from regions with the lowest socio-economic levels in the country. The aim of this study was to investigate the current seroprevalence of hepatitis A virus antibodies in central-west Tunisia and assess the impact of hepatitis A virus vaccination on hepatitis A epidemiology. METHODS: Serum samples from 1379 individuals, aged 5–75 years, were screened for hepatitis A virus antibodies. Adjusted seroprevalence, incidence and force of infection parameters were estimated by a linear age structured SEIR (Susceptible-Exposed-Infectious-Recovered) compartmental model. A vaccine model was then constructed to assess the impact on hepatitis A virus epidemiology of 3 scenarios of vaccination strategies: one dose at 12-months of age, one dose at 6-years and one dose at 12-months and another at 6-years of age during 6 years. RESULTS: A rapid increase in anti-hepatitis A virus seroprevalence was noted during infancy and adolescence: 47% of subjects under 10-years-old are infected; the prevalence increases to 77% at 15-years and reaches 97% in subjects aged 30-years. The force of infection is highest between 10 and 30-years of age and the incidence declines with increasing age. The vaccine model showed that the 3-scenarios lead to a significant reduction of the fraction of susceptibles. The two doses scenario gives the best results. Single-dose vaccination at 6-years of age provides more rapid decrease of disease burden in school-aged children, as compared to single-dose vaccination at 12-months, but keeps with a non-negligible fraction of susceptibles among children < 6-years. CONCLUSIONS: Our study confirms the epidemiological switch from high to intermediate endemicity of hepatitis A virus in Tunisia and provides models that may help undertake best decisions in terms of vaccinations strategies.
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3,028 |
Long-read-based human genomic structural variation detection with cuteSV
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Long-read sequencing is promising for the comprehensive discovery of structural variations (SVs). However, it is still non-trivial to achieve high yields and performance simultaneously due to the complex SV signatures implied by noisy long reads. We propose cuteSV, a sensitive, fast, and scalable long-read-based SV detection approach. cuteSV uses tailored methods to collect the signatures of various types of SVs and employs a clustering-and-refinement method to implement sensitive SV detection. Benchmarks on simulated and real long-read sequencing datasets demonstrate that cuteSV has higher yields and scaling performance than state-of-the-art tools. cuteSV is available at https://github.com/tjiangHIT/cuteSV.
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3,029 |
Designing a novel hybrid healthcare teleconsultation network: a benchtop study of telepathology in Iran and a systematic review
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BACKGROUND: Growing demand for medical services has increased patient waiting time due to the limited number or unbalanced distribution of healthcare centers. Healthcare teleconsultation networks are one of the potentially powerful systems to overcome this problem. Medical pathology can hugely benefit from teleconsultation networks because having second opinions is precious for many cases; however, resource planning (i.e., assignment and distribution of pathology consultation requests) is challenging due to bulky medical images of patients. This results in high setup and operational costs. The aim of this study is to design an optimal teleconsultation network for pathology labs under the supervision of medical sciences universities in Tehran, Iran. METHODS: To avoid the setup cost, we first propose a modified hybrid peer-to-peer (P2P) overlay architecture for our telepathology network, using Iran’s National Healthcare Information Network (SHAMS) as the underlying infrastructure. Then we apply optimization techniques to solve the request assignment and distribution problems in the network. Finally, we present a novel mathematical model with the objective of minimizing the variable operational costs of the system. RESULTS: The efficiency of the proposed method was evaluated by a set of practical-sized network instances simulated based on the characteristics of SHAMS. The results show that the presented model and architecture can obtain optimal solutions for network instances up to 350 nodes, which covers our target network. CONCLUSIONS: We believe that the proposed method can be beneficial for designing large-scale medical teleconsultation networks by adjusting the constraints according to the rules and conditions of each country. Our findings showed that teleconsultation networks in countries with strong information technology (IT) infrastructures are under the influence of consultation fees, while in countries with weak IT infrastructure, the transmission costs are more critical. To the best of our knowledge, no research has so far addressed resource planning in medical teleconsultation networks using optimization techniques. Besides, the target network, i.e., pathology labs under the supervision of medical sciences universities in Tehran and the SHAMS network, are discussed for the first time in this work.
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3,030 |
Improved RIDIT statistic approach provides more intuitive and informative interpretation of EQ-5D data
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BACKGROUND: EQ-5D is generic measure of health-related quality of life. Studies using EQ-5D generate ordinal data that are interpreted as categories ordered by severity. New analytic approaches taking into account the ordinal nature of the health dimension severity and leading to a better interpretation of EQ-5D data are needed to better elucidate differences in health-related quality of life. We propose utilizing the Improved RIDIT statistical method to analyze EQ-5D outcomes. METHODS: 556 Moroccan participants aged over 18 years representing four chronic diseases: back pain (n = 158), renal insufficiency (n = 56), diabetes (n = 82) or hypertension (n = 80) and healthy subjects (n = 180). All participants received the two EQ-5D versions. Two other published data sets were included. The first was extracted from a diabetic Spain study and the second was extracted from a clinical trial study. The Improved RIDIT analyses were carried out using an R statistic program we developed. RESULTS: Applying the Improved RIDIT on the EQ-5D data allowed estimating for the first time the ordinal odds, the Absolute Risk Reduction (ARR) or the Absolute Risk Increase (ARI) and the Number Needed to Treat. The ARI values estimated for Moroccan patients showed that (i) hypertension increased anxiety/depression by 66% and reduced mobility by 65%; (ii) back pain increased pain/discomfort by 69%; (iii) renal insufficiency impacts mobility (ARI = 57%, odds(ordinal) = 9.95) and usual activities (ARI = 44%, odds(ordinal) = 6.41) and (iv) diabetes acts only on anxiety/depression (ARI = 50%, odds(ordinal) = 4.8). Also, we demonstrated that the approach works well in clinical trials. CONCLUSIONS: Improved RIDIT provides more intuitive and informative interpretation of the EQ-5D data by (1) taking into account the level severity; estimating (2) the odds ordinal, (3) the ARR/ARI and the NNT; (4) analyzing the five dimensions of the EQ-5D separately, which gives clinical teams more precision in understanding the treatment/pathology impacts on the health status and completes the EQ-5D data analysis based on score utilities.
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3,031 |
Thrombomodulin facilitates peripheral nerve regeneration through regulating M1/M2 switching
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BACKGROUND: Excessive inflammation within damaged tissue usually leads to delayed or insufficient regeneration, and nerves in the peripheral nervous system (PNS) generally do not recover fully following damage. Consequently, there is growing interest in whether modulation of the inflammatory response could help to promote nerve regeneration in the PNS. However, to date, there are no practical therapeutic strategies for manipulating inflammation after nerve injury. Thrombomodulin (TM) is a transmembrane glycoprotein containing five domains. The lectin-like domain of TM has the ability to suppress the inflammatory response. However, whether TM can modulate inflammation in the PNS during nerve regeneration has yet to be elucidated. METHODS: We investigated the role of TM in switching proinflammatory type 1 macrophages (M1) to anti-inflammatory type 2 macrophages (M2) in a human monocytic cell line (THP-1) and evaluated the therapeutic application of TM in transected sciatic nerve injury in rats. RESULTS: The administration of TM during M1 induction significantly reduced the expression levels of inflammatory cytokines, including TNF-a (p < 0.05), IL-6 (p < 0.05), and CD86 (p < 0.05), in THP-1 cells. Simultaneously, the expression levels of M2 markers, including IL-10 (p < 0.05) and CD206 (p < 0.05), were significantly increased in TM-treated THP-1 cells. Inhibition of IL-4R-c-Myc-pSTAT6-PPARγ signaling abolished the expression levels of IL-10 (p < 0.05) and CD206 (p < 0.05). The conditioned medium (CM) collected from M1 cells triggered an inflammatory response in primary Schwann cells, while CM collected from M1 cells treated with TM resulted in a dose-dependent reduction in inflammation. TM treatment led to better nerve regeneration when tested 6 weeks after injury and preserved effector muscle function. In addition, TM treatment reduced macrophage infiltration at the site of injury and led to potent M1 to M2 transition, thus indicating the anti-inflammatory capacity of TM. CONCLUSIONS: Collectively, our findings demonstrate the anti-inflammatory role of TM during nerve regeneration. Therefore, TM represents a potential drug for the promotion and modulation of functional recovery in peripheral nerves that acts by regulating the M1/M2 ratio.
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3,032 |
A semi-supervised approach for extracting TCM clinical terms based on feature words
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BACKGROUND: A semi-supervised model is proposed for extracting clinical terms of Traditional Chinese Medicine using feature words. METHODS: The extraction model is based on BiLSTM-CRF and combined with semi-supervised learning and feature word set, which reduces the cost of manual annotation and leverage extraction results. RESULTS: Experiment results show that the proposed model improves the extraction of five types of TCM clinical terms, including traditional Chinese medicine, symptoms, patterns, diseases and formulas. The best F1-value of the experiment reaches 78.70% on the test dataset. CONCLUSIONS: This method can reduce the cost of manual labeling and improve the result in the NER research of TCM clinical terms.
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3,033 |
Characterization and genomic analysis of a diesel-degrading bacterium, Acinetobacter calcoaceticus CA16, isolated from Canadian soil
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BACKGROUND: With the high demand for diesel across the world, environmental decontamination from its improper usage, storage and accidental spills becomes necessary. One highly environmentally friendly and cost-effective decontamination method is to utilize diesel-degrading microbes as a means for bioremediation. Here, we present a newly isolated and identified strain of Acinetobacter calcoaceticus (‘CA16’) as a candidate for the bioremediation of diesel-contaminated areas. RESULTS: Acinetobacter calcoaceticus CA16 was able to survive and grow in minimal medium with diesel as the only source of carbon. We determined through metabolomics that A. calcoaceticus CA16 appears to be efficient at diesel degradation. Specifically, CA16 is able to degrade 82 to 92% of aliphatic alkane hydrocarbons (C(n)H(n + 2); where n = 12–18) in 28 days. Several diesel-degrading genes (such as alkM and xcpR) that are present in other microbes were also found to be activated in CA16. CONCLUSIONS: The results presented here suggest that Acinetobacter strain CA16 has good potential in the bioremediation of diesel-polluted environments.
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3,034 |
Simulating transmission of ESKAPE pathogens plus C. difficile in relevant clinical scenarios
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BACKGROUND: The prevalence of healthcare-acquired infections (HAI) and rising levels of antimicrobial resistance places significant economic and public health burdens on modern healthcare systems. A group of highly drug resistant pathogens known as the ESKAPE pathogens, along with C. difficile, are the leading causes of HAIs. Interactions between patients, healthcare workers, and environmental conditions impact disease transmission. Studying pathogen transfer under varying contact scenarios in a controlled manner is critical for understanding transmission and disinfectant strategies. In lieu of human subject research, this method has the potential to contribute to modeling the routes of pathogen transmission in healthcare settings. METHODS: To overcome these challenges, we have developed a method that utilizes a synthetic skin surrogate to model both direct (skin-to-skin) and indirect (skin-to fomite-to skin) pathogen transfer between infected patients and healthy healthcare workers. This surrogate material includes a background microbiome community simulating typical human skin flora to more accurately mimic the effects of natural flora during transmission events. RESULTS: We demonstrate the ability to modulate individual bacterial concentrations within this microbial community to mimic bacterial concentrations previously reported on the hands of human subjects. We also explore the effect of various decontamination approaches on pathogen transfer between human subjects, such as the use of handwashing or surface disinfectants. Using this method, we identify a potential outlier, S. aureus, that may persist and retain viability in specific transfer conditions better than the overall microbial community during decontamination events. CONCLUSIONS: Our work describes the development of an in vitro method that uses a synthetic skin surrogate with a defined background microbiota to simulate skin-to-skin and skin-to fomite-to skin contact scenarios. These results illustrate the value of simulating a holistic microbial community for transfer studies by elucidating differences in different pathogen transmission rates and resistance to common decontamination practices. We believe this method will contribute to improvements in pathogen transmission modeling in healthcare settings and increase our ability to assess the risk associated with HAIs, although additional research is required to establish the degree of correlation of pathogen transmission by skin or synthetic alternatives.
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3,035 |
The psychosis analysis in real-world on a cohort of large-scale patients with schizophrenia
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BACKGROUND: With China experiencing unprecedented economic development and social change over the past three decades, Chinese policy makers and health care professionals have come to view mental health as an important outcome to monitor. Our study conducted an epidemiological study of psychosis in Guangdong province, with 20 million real-world follow-up records in the last decade. METHODS: Data was collected from Guangdong mental health information platform from 2010 to 2019, which had standardized disease registration and follow-up management for nearly 600,000 patients with six categories of mental diseases and 400,000 patients with schizophrenia. We conducted clinical staging for the disease course of the patients and divided the data with various factors into different stages of disease. Quantitative analysis was utilized to investigate the high relevant indicators to the disease. The results were projected on geography map for regional distribution analysis. RESULTS: The majority cases of mental disease incidence were between the age of 15 and 29, while the peak age for both male and female was between 20 to 24 years old. The disease course with the largest number of patients’ cases was between 5 to 10 years. The therapeutic effect of patients gradually decreased with the development of disease course, while the risk increased with the disease course. The analysis of influencing factors showed that poor economic conditions incurred higher risk scores, and good medication adherence was effective in improving treatment outcomes. In addition, receiving good education contributed to the reduction of the risk of schizophrenia and the improvement of the efficiency of early treatment. Through the analysis of regional distribution of schizophrenia disease, developed economic conditions and favorable resource conditions could promote the reduction of disease risk, while in economically backward regions, it often accompanied with lower therapeutic effect and higher disease risk. CONCLUSIONS: Certain demographic factors had a relatively prominent impact on the therapeutic effect and risk of schizophrenia, such as high-quality medication adherence. Therapeutic effect and risk were highly correlated. Backward economic conditions often associated with poor efficacy and higher risk assessment, and the developed economy and better medical resource are beneficial for the treatment of psychotic.
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3,036 |
Simulation-based assessment of model selection criteria during the application of benchmark dose method to quantal response data
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BACKGROUND: To employ the benchmark dose (BMD) method in toxicological risk assessment, it is critical to understand how the BMD lower bound for reference dose calculation is selected following statistical fitting procedures of multiple mathematical models. The purpose of this study was to compare the performances of various combinations of model exclusion and selection criteria for quantal response data. METHODS: Simulation-based evaluation of model exclusion and selection processes was conducted by comparing validity, reliability, and other model performance parameters. Three different empirical datasets for different chemical substances were analyzed for the assessment, each having different characteristics of the dose-response pattern (i.e. datasets with rich information in high or low response rates, or approximately linear dose-response patterns). RESULTS: The best performing criteria of model exclusion and selection were different across the different datasets. Model averaging over the three models with the lowest three AIC (Akaike information criteria) values (MA-3) did not produce the worst performance, and MA-3 without model exclusion produced the best results among the model averaging. Model exclusion including the use of the Kolmogorov-Smirnov test in advance of model selection did not necessarily improve the validity and reliability of the models. CONCLUSIONS: If a uniform methodological suggestion for the guideline is required to choose the best performing model for exclusion and selection, our results indicate that using MA-3 is the recommended option whenever applicable.
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3,037 |
High-yield expression of recombinant soybean agglutinin in plants using transient and stable systems
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Soybean agglutinin (SBA) is a specific N-acetylgalactosamine-binding plant lectin that can agglutinate a wide variety of cells. SBA has great potential for medical and biotechnology-focused applications, including screening and treatment of breast cancer, isolation of fetal cells from maternal blood for genetic screening, the possibility as a carrier system for oral drug delivery, and utilization as an affinity tag for high-quality purification of tagged proteins. The success of these applications, to a large degree, critically depends on the development of a highly efficient expression system for a source of recombinant SBA (rSBA). Here, we demonstrate the utility of transient and stable expression systems in Nicotiana benthamiana and potato, respectively, for the production of rSBA, with the transgenic protein accumulated to 4% of total soluble protein (TSP) in Nicotiana benthamiana leaves and 0.3% of TSP in potato tubers. Furthermore, we show that both plant-derived rSBAs retain their ability to induce the agglutination of red blood cells, are similarly glycosylated when compared with native SBA, retained their binding specificity for N-acetylgalactosamine, and were highly resistant to degradation in simulated gastric and intestinal fluids. Affinity column purification using N-acetylgalactosamine as a specific ligand resulted in high recovery and purity of rSBA. This work is the first step toward use of rSBA for various new applications, including the development of rSBA as a novel affinity tag for simplified purification of tagged proteins and as a new carrier molecule for delivery of oral drugs. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1007/s11248-010-9419-0) contains supplementary material, which is available to authorized users.
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3,038 |
The role of vegetative cell fusions in the development and asexual reproduction of the wheat fungal pathogen Zymoseptoria tritici
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BACKGROUND: The ability of fungal cells to undergo cell-to-cell communication and anastomosis, the process of vegetative hyphal fusion, allows them to maximize their overall fitness. Previous studies in a number of fungal species have identified the requirement of several signaling pathways for anastomosis, including the so far best characterized soft (So) gene, and the MAPK pathway components MAK-1 and MAK-2 of Neurospora crassa. Despite the observations of hyphal fusions’ involvement in pathogenicity and host adhesion, the connection between cell fusion and fungal lifestyles is still unclear. Here, we address the role of anastomosis in fungal development and asexual reproduction in Zymoseptoria tritici, the most important fungal pathogen of wheat in Europe. RESULTS: We show that Z. tritici undergoes self-fusion between distinct cellular structures, and its mechanism is dependent on the initial cell density. Contrary to other fungi, cell fusion in Z. tritici only resulted in cytoplasmic mixing but not in multinucleated cell formation. The deletion of the So orthologous ZtSof1 disrupted cell-to-cell communication affecting both hyphal and germling fusion. We show that Z. tritici mutants for MAPK-encoding ZtSlt2 (orthologous to MAK-1) and ZtFus3 (orthologous to MAK-2) genes also failed to undergo anastomosis, demonstrating the functional conservation of this signaling mechanism across species. Additionally, the ΔZtSof1 mutant was severely impaired in melanization, suggesting that the So gene function is related to melanization. Finally, we demonstrated that anastomosis is dispensable for pathogenicity, but essential for the pycnidium development, and its absence abolishes the asexual reproduction of Z. tritici. CONCLUSIONS: We demonstrate the role for ZtSof1, ZtSlt2, and ZtFus3 in cell fusions of Z. tritici. Cell fusions are essential for different aspects of the Z. tritici biology, and the ZtSof1 gene is a potential target to control septoria tritici blotch (STB) disease.
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3,039 |
MCC-SP: a powerful integration method for identification of causal pathways from genetic variants to complex disease
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BACKGROUND: Genome-wide association studies (GWAS) have successfully identified genetic susceptible variants for complex diseases. However, the underlying mechanism of such association remains largely unknown. Most disease-associated genetic variants have been shown to reside in noncoding regions, leading to the hypothesis that regulation of gene expression may be the primary biological mechanism. Current methods to characterize gene expression mediating the effect of genetic variant on diseases, often analyzed one gene at a time and ignored the network structure. The impact of genetic variant can propagate to other genes along the links in the network, then to the final disease. There could be multiple pathways from the genetic variant to the final disease, with each having the chain structure since the first node is one specific SNP (Single Nucleotide Polymorphism) variant and the end is disease outcome. One key but inadequately addressed question is how to measure the between-node connection strength and rank the effects of such chain-type pathways, which can provide statistical evidence to give the priority of some pathways for potential drug development in a cost-effective manner. RESULTS: We first introduce the maximal correlation coefficient (MCC) to represent the between-node connection, and then integrate MCC with K shortest paths algorithm to rank and identify the potential pathways from genetic variant to disease. The pathway importance score (PIS) was further provided to quantify the importance of each pathway. We termed this method as “MCC-SP”. Various simulations are conducted to illustrate MCC is a better measurement of the between-node connection strength than other quantities including Pearson correlation, Spearman correlation, distance correlation, mutual information, and maximal information coefficient. Finally, we applied MCC-SP to analyze one real dataset from the Religious Orders Study and the Memory and Aging Project, and successfully detected 2 typical pathways from APOE genotype to Alzheimer’s disease (AD) through gene expression enriched in Alzheimer’s disease pathway. CONCLUSIONS: MCC-SP has powerful and robust performance in identifying the pathway(s) from the genetic variant to the disease. The source code of MCC-SP is freely available at GitHub (https://github.com/zhuyuchen95/ADnet).
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3,040 |
Frequency of congenital cytomegalovirus infections in newborns in the Sao Paulo State, 2010-2018
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Human cytomegalovirus (HCMV) infections remain a neglected public health issue. The aim of the present study was to evaluate the frequency of HCMV congenital infections in newborns up to 1 month in the Sao Paulo State, from 2010 to 2018. The molecular characterization of HCMV-positive samples was also undertaken. Urine samples from 275 potential congenital HCMV-infected patients were tested by real-time Polymerase Chain Reaction (qPCR). HCMV-positive samples were amplified by conventional PCR targeting the UL89 gene, sequenced and searched for mutations. A total of 32 (11.6%) positive-HCMV cases were detected (mean Ct 30.59); mean and median age of 10.3 and 6 days old, respectively. Children aged between 0-3 weeks had higher HCMV detection rates (84.4%; 27/32). UL89 gene was successfully sequenced in two samples, both classified as the human betaherpesvirus 5. No described resistance-associated mutations were identified. A routine screening in newborns coupled with the genetic characterization of key viral genes is vital to decrease sequels associated with congenital HCMV infections.
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3,041 |
Effects and safety of tanreqing injection on viral pneumonia: A protocol for systematic review and meta-analysis
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BACKGROUND: Viral pneumonia is a common respiratory disease that leads to high mortality around the world. Tanreqing (TRQ) injection has been widely used to treat viral pneumonia in China. However, the efficiency and safety of TRQ injection for viral pneumonia have not been scientifically and methodically evaluated up to now. Thus, this protocol describes a plan of performing a systematic review and meta-analysis to evaluate the efficacy and safety of TRQ injection on patients with viral pneumonia. METHODS: Only randomized controlled trials will be enrolled in our study, and we will search eligible studies in the following electronic databases: PubMed, Embase, Cochrane Central Register of Controlled Trials, Clinical Trials, China National Knowledge Infrastructure, the Wanfang database, the Chinese Scientific Journal Database, and the Sinomed. The total effective rate of clinical efficacy will be used as primary outcome. Time to relieve symptoms, incidence of adverse reactions, and the laboratory parameters will be used as secondary outcomes. Any side effects and adverse events will be recorded and assessed as safety outcomes. Study inclusion, data extraction, and quality assessment will be performed independently by 2 reviewers, and any disagreement will be resolved by a third reviewer. After that, data synthesis and subgroup analysis will be conducted with the Review Manager V.5.3.3 software. RESULTS: This review will provide a high-quality synthesis to assess the effectiveness and safety of TRQ injection for viral pneumonia patients. CONCLUSION: Our study will provide comprehensive evidence to decide whether TRQ injection is effective and safe for viral pneumonia patients. PROSPERO REGISTRATION NUMBER: PROSPERO CRD42020164164
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3,042 |
A comparison of COVID-19 mortality rates between European and Asian States
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3,043 |
Metabolic Dysregulation in Idiopathic Pulmonary Fibrosis
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Idiopathic pulmonary fibrosis (IPF) is a fibroproliferative disorder limited to the lung. New findings, starting from our proteomics studies on IPF, suggest that systemic involvement with altered molecular mechanisms and metabolic disorder is an underlying cause of fibrosis. The role of metabolic dysregulation in the pathogenesis of IPF has not been extensively studied, despite a recent surge of interest. In particular, our studies on bronchoalveolar lavage fluid have shown that the renin–angiotensin–aldosterone system (RAAS), the hypoxia/oxidative stress response, and changes in iron and lipid metabolism are involved in onset of IPF. These processes appear to interact in an intricate manner and to be related to different fibrosing pathologies not directly linked to the lung environment. The disordered metabolism of carbohydrates, lipids, proteins and hormones has been documented in lung, liver, and kidney fibrosis. Correcting these metabolic alterations may offer a new strategy for treating fibrosis. This paper focuses on the role of metabolic dysregulation in the pathogenesis of IPF and is a continuation of our previous studies, investigating metabolic dysregulation as a new target for fibrosis therapy.
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3,044 |
Naturally-Occurring Alkaloids of Plant Origin as Potential Antimicrobials against Antibiotic-Resistant Infections
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Antibiotic resistance is now considered a worldwide problem that puts public health at risk. The onset of bacterial strains resistant to conventional antibiotics and the scarcity of new drugs have prompted scientific research to re-evaluate natural products as molecules with high biological and chemical potential. A class of natural compounds of significant importance is represented by alkaloids derived from higher plants. In this review, we have collected data obtained from various research groups on the antimicrobial activities of these alkaloids against conventional antibiotic-resistant strains. In addition, the structure–function relationship was described and commented on, highlighting the high potential of alkaloids as antimicrobials.
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3,045 |
Should Networks Supplant Tree Building?
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Recent studies suggested that network methods should supplant tree building as the basis of genealogical analysis. This proposition is based upon two arguments. First is the observation that bacterial and archaeal lineages experience processes oppositional to bifurcation and hence the representation of the evolutionary process in a tree like structure is illogical. Second is the argument tree building approaches are circular—you ask for a tree and you get one, which pins a verificationist label on tree building that, if correct, should be the end of phylogenetic analysis as we currently know it. In this review, we examine these questions and suggest that rumors of the death of the bacterial tree of life are exaggerated at best.
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3,046 |
Antibacterial Activity of Manganese Dioxide Nanosheets by ROS-Mediated Pathways and Destroying Membrane Integrity
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Manganese dioxide (MnO(2)) nanosheets have shown exciting potential in nanomedicine because of their ultrathin thickness, large surface area, high near-infrared (NIR) absorbance and good biocompatibility. However, the effect of MnO(2) nanosheets on bacteria is still unclear. In this study, MnO(2) nanosheets were shown for the first time to possess highly efficient antibacterial activity by using Salmonella as a model pathogen. The growth curve and surface plate assay uncovered that 125 μg/mL MnO(2) nanosheets could kill 99.2% of Salmonella, which was further verified by fluorescence-based live/dead staining measurement. Mechanism analysis indicated that MnO(2) nanosheet treatment could dramatically induce reactive oxygen species production, increase ATPase activity and cause the leakage of electrolytes and protein contents, leading to bacterial death. These results uncover the previously undefined role of MnO(2) nanosheets and provide novel strategies for developing antimicrobial agents.
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3,047 |
Graphene Oxide-Linezolid Combination as Potential New Anti-Tuberculosis Treatment
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Global pandemic management represents a serious issue for health systems. In some cases, repurposing of existing medications might help find compounds that have the unexpected potential to combat microorganisms. In the same way, changing cell–drug interaction by nanotechnology could represent an innovative strategy to fight infectious diseases. Tuberculosis (TB) remains one of the most alarming worldwide infectious diseases and there is an urgent need for new drugs and treatments, particularly for the emergence and spread of drug-resistant Mycobacterium tuberculosis (Mtb) strains. New nanotechnologies based on carbon nanomaterials are now being considered to improve anti-TB treatments, and graphene oxide (GO) showed interesting properties as an anti-TB drug. GO, which preferentially accumulates in the lungs and is degraded by macrophagic peroxidases, can trap Mycobacterium smegmatis and Mtb in a dose-dependent manner, reducing the entry of bacilli into macrophages. In this paper, combinations of isoniazid (INH), amikacin (AMK) and linezolid (LZD) and GO anti-mycobacterial properties were evaluated against Mtb H37Rv by using a checkerboard assay or an in vitro infection model. Different GO effects have been observed when incubated with INH, AMK or LZD. Whereas the INH and AMK anti-mycobacterial activities were blocked by GO co-administration, the LZD bactericidal effect increased in combination with GO. GO-LZD significantly reduced extracellular mycobacteria during infection and was able to kill internalized bacilli. GO-LZD co-administration is potentially a new promising anti-TB treatment at the forefront in fighting emerging antibiotic-resistant Mtb strains where LZD administration is suggested. This innovative pharmacological approach may lead to reduced treatment periods and decreased adverse effects. More importantly, we demonstrate how nanomaterials–drugs combinations can represent a possible strategy to quickly design drugs for pandemics treatment.
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3,048 |
The effect of copartisan justice ministers on human rights in presidential democracies
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A body of literature suggests that states with independent courts are more likely to protect human rights. A recent article challenges this notion by arguing that when both the president and his or her justice minister share the same party—i.e., they are copartisans—that state is less likely to protect human rights, as justice ministers may value their loyalty to the president over their duty to enforce court decisions. In this article, I estimate government respect for human rights accounting for both copartisan justice ministers and an independent judiciary. In the end, I find copartisan justice ministers to be negatively associated with high government respect for human rights, even after controlling for judicial independence. Many constitutions already seek to ensure an independent judiciary, but if copartisan justice ministers increase the likelihood that governments repress, then perhaps constitutional engineers should also consider options that would reduce the likelihood that both the president and his or her justice minister share the same party.
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3,049 |
Sensitivity optimisation of tuberculosis bioaerosol sampling
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INTRODUCTION: Detection of Mycobacterium tuberculosis (Mtb) in patient-derived bioaerosol is a potential tool to measure source case infectiousness. However, current bioaerosol sampling approaches have reported low detection yields in sputum-positive TB cases. To increase the utility of bioaerosol sampling, we present advances in bioaerosol collection and Mtb identification that improve detection yields. METHODS: A previously described Respiratory Aerosol Sampling Chamber (RASC) protocol, or “RASC-1”, was modified to incorporate liquid collection of bioaerosol using a high-flow wet-walled cyclone (RASC-2). Individuals with GeneXpert-positive pulmonary TB were sampled pre-treatment over 60-minutes. Putative Mtb bacilli were detected in collected fluid by fluorescence microscopy utilising DMN-Trehalose. Exhaled air and bioaerosol volumes were estimated using continuous CO(2) monitoring and airborne particle counting, respectively. Mtb capture was calculated per exhaled air volume sampled and bioaerosol volume for RASC-1 (n = 35) and for RASC-2 (n = 21). Empty chamber samples were collected between patients as controls. RESULTS: The optimised RASC-2 protocol sampled a median of 258.4L (IQR: 226.9–273.6) of exhaled air per patient compared with 27.5L (IQR: 23.6–30.3) for RASC-1 (p<0.0001). Bioaerosol volume collection was estimated at 2.3nL (IQR: 1.1–3.6) for RASC-2 compared with 0.08nL (IQR: 0.05–0.10) for RASC-1 (p<0.0001). The detection yield of viable Mtb improved from 43% (median 2 CFU, range: 1–14) to 95% (median 20.5 DMN-Trehalose positive bacilli, range: 2–155). These improvements represent a lowering of the limit of detection in the RASC-2 platform to 0.9 Mtb bacilli per 100L of exhaled air from 3.3 Mtb bacilli per 100L (RASC-1). CONCLUSION: This study demonstrates that technical improvements in particle collection together with sensitive detection enable rapid quantitation of viable Mtb in bioaerosols of sputum positive TB cases. Increased sampling sensitivity may allow future TB transmission studies to be extended to sputum-negative and subclinical individuals, and suggests the potential utility of bioaerosol measurement for rapid intervention in other airborne infectious diseases.
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3,050 |
Detection of latent forms of Mycobacterium avium subsp. paratuberculosis infection using host biomarker-based ELISAs greatly improves paratuberculosis diagnostic sensitivity
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Bovine paratuberculosis (PTB) is a chronic granulomatous enteritis, caused by Mycobacterium avium subsp. paratuberculosis (MAP), responsible for important economic losses in the dairy industry. Current diagnostic methods have low sensitivities for detection of latent forms of MAP infection, defined by focal granulomatous lesions and scarce humoral response or MAP presence. In contrast, patent infections correspond to multifocal and diffuse types of enteritis where there is increased antibody production, and substantial mycobacterial load. Our previous RNA-Seq analysis allowed the selection of five candidate biomarkers overexpressed in peripheral blood of MAP infected Holstein cows with focal (ABCA13 and MMP8) and diffuse (FAM84A, SPARC and DES) lesions vs. control animals with no detectable PTB-associated lesions in intestine and regional lymph nodes. The aim of the current study was to assess the PTB diagnostic potential of commercial ELISAs designed for the specific detection of these biomarkers. The ability of these ELISAs to identify animals with latent and/or patent forms of MAP infection was investigated using serum from naturally infected cattle (n = 88) and non-infected control animals (n = 67). ROC analysis revealed that the ABCA13-based ELISA showed the highest diagnostic accuracy for the detection of infected animals with focal lesions (AUC 0.837, sensitivity 79.25% and specificity 88.06%) and with any type of histological lesion (AUC 0.793, sensitivity 69.41% and specificity 86.57%) improving on the diagnostic performance of the popular IDEXX ELISA and other conventional diagnostic methods. SPARC and MMP8 showed the highest diagnostic accuracy for the detection of animals with multifocal (AUC 0.852) and diffuse lesions (AUC 0.831), respectively. In conclusion, our results suggest that quantification of ABCA13, SPARC and MMP8 by ELISA has the potential for implementation as a diagnostic tool to reliably identify MAP infection, greatly improving early detection of MAP latent infections when antibody responses and fecal shedding are undetectable using conventional diagnostic methods.
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3,051 |
Erratum: Vol. 69, No. 32
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3,052 |
EDF1 coordinates cellular responses to ribosome collisions
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Translation of aberrant mRNAs induces ribosomal collisions, thereby triggering pathways for mRNA and nascent peptide degradation and ribosomal rescue. Here we use sucrose gradient fractionation combined with quantitative proteomics to systematically identify proteins associated with collided ribosomes. This approach identified Endothelial differentiation-related factor 1 (EDF1) as a novel protein recruited to collided ribosomes during translational distress. Cryo-electron microscopic analyses of EDF1 and its yeast homolog Mbf1 revealed a conserved 40S ribosomal subunit binding site at the mRNA entry channel near the collision interface. EDF1 recruits the translational repressors GIGYF2 and EIF4E2 to collided ribosomes to initiate a negative-feedback loop that prevents new ribosomes from translating defective mRNAs. Further, EDF1 regulates an immediate-early transcriptional response to ribosomal collisions. Our results uncover mechanisms through which EDF1 coordinates multiple responses of the ribosome-mediated quality control pathway and provide novel insights into the intersection of ribosome-mediated quality control with global transcriptional regulation.
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3,053 |
Metatranscriptomic Analysis of Virus Diversity in Urban Wild Birds with Paretic Disease
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Wild birds are major natural reservoirs and potential dispersers of a variety of infectious diseases. As such, it is important to determine the diversity of viruses they carry and use this information to help understand the potential risks of spillover to humans, domestic animals, and other wildlife. We investigated the potential viral causes of paresis in long-standing, but undiagnosed, disease syndromes in wild Australian birds. RNA from diseased birds was extracted and pooled based on tissue type, host species, and clinical manifestation for metagenomic sequencing. Using a bulk and unbiased metatranscriptomic approach, combined with clinical investigation and histopathology, we identified a number of novel viruses from the families Astroviridae, Adenoviridae, Picornaviridae, Polyomaviridae, Paramyxoviridae, Parvoviridae, and Circoviridae in common urban wild birds, including Australian magpies, magpie larks, pied currawongs, Australian ravens, and rainbow lorikeets. In each case, the presence of the virus was confirmed by reverse transcription (RT)-PCR. These data revealed a number of candidate viral pathogens that may contribute to coronary, skeletal muscle, vascular, and neuropathology in birds of the Corvidae and Artamidae families and neuropathology in members of the Psittaculidae. The existence of such a diverse virome in urban avian species highlights the importance and challenges in elucidating the etiology and ecology of wildlife pathogens in urban environments. This information will be increasingly important for managing disease risks and conducting surveillance for potential viral threats to wildlife, livestock, and human health. IMPORTANCE Wildlife naturally harbor a diverse array of infectious microorganisms and can be a source of novel diseases in domestic animals and human populations. Using unbiased RNA sequencing, we identified highly diverse viruses in native birds from Australian urban environments presenting with paresis. This research included the clinical investigation and description of poorly understood recurring syndromes of unknown etiology: clenched claw syndrome and black and white bird disease. As well as identifying a range of potentially disease-causing viral pathogens, this study describes methods that can effectively and efficiently characterize emergent disease syndromes in free-ranging wildlife and promotes further surveillance for specific pathogens of potential conservation and zoonotic concern.
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3,054 |
Coumarin carbonic anhydrase inhibitors from natural sources
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Coumarins constitute a relatively new class of inhibitors of the zinc enzyme carbonic anhydrase (CA, EC 4.2.1.1), possessing a unique inhibition mechanism, acting as “prodrug inhibitors.” They undergo the hydrolysis of the lactone ring mediated by the esterase activity of CA. The formed 2-hydroxy-cinnamic acids thereafter bind within a very particular part of the enzyme active site, at its entrance, where a high variability of amino acid residues among the different mammalian CA isoforms is present, and where other inhibitors classes were not seen bound earlier. This explains why coumarins are among the most isoform-selective CA inhibitors known to date among the many chemotypes endowed with such biological activity. As coumarins are widespread secondary metabolites in some bacteria, plants, fungi, and ascidians, many such compounds from various natural sources have been investigated for their CA inhibitory properties and for possible biomedical applications, mainly as anticancer agents targeting hypoxic tumours.
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3,055 |
Ezrin is essential for the entry of Japanese encephalitis virus into the human brain microvascular endothelial cells
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Japanese encephalitis virus (JEV) remains the predominant cause of viral encephalitis worldwide. It reaches the central nervous system upon crossing the blood–brain barrier through pathogenic mechanisms that are not completely understood. Here, using a high-throughput siRNA screening assay combined with verification experiments, we found that JEV enters the primary human brain microvascular endothelial cells (HBMEC) through a caveolae-mediated endocytic pathway. The role of ezrin, an essential host factor for JEV entry based on our screening, in caveolae-mediated JEV internalization was investigated. We observed that JEV internalization in HBMEC is largely dependent on ezrin-mediated actin cytoskeleton polymerization. Moreover, Src, a protein predicted by a STRING database search, was found to be required in JEV entry. By a variety of pharmacological inhibition and immunoprecipitation assays, we found that Src, ezrin, and caveolin-1 were sequentially activated and formed a complex during JEV infection. A combination of in vitro kinase assay and subcellular analysis demonstrated that ezrin is essential for Src-caveolin-1 interactions. In vivo, both Src and ezrin inhibitors protected ICR suckling mice against JEV-induced mortality and diminished mouse brain viral load. Therefore, JEV entry into HBMEC requires the activation of the Src-ezrin-caveolin-1 signalling axis, which provides potential targets for restricting JEV infection.
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3,056 |
Platelet and Vascular Biomarkers Associate With Thrombosis and Death in Coronavirus Disease
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3,057 |
Impact of COVID-19 on Public Mental Health and the Buffering Effect of a Sense of Coherence
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INTRODUCTION: It is claimed that the coronavirus disease 2019 (COVID-19) pandemic has had a negative impact on mental health. However, to date, prospective studies are lacking. Moreover, it is important to identify which factors modulate the stress response to the pandemic. Previously, sense of coherence (SOC) has emerged as a particularly important resistance factor. OBJECTIVE: This prospective study aimed to assess the impact of the COVID-19 outbreak on mental health and to investigate the ability of pre-outbreak SOC levels to predict changes in psychopathological symptoms. METHODS: This study assessed psychopathological symptoms and SOC before and after the COVID-19 outbreak as well as post-outbreak COVID-19-related traumatic distress in a German-speaking sample (n =1,591). Bivariate latent change score (BLCS) modeling was used to analyze pre- to post-outbreak changes in psychopathological symptoms and the ability of SOC to predict symptom changes. RESULTS: Overall, there was no change in psychopathological symptoms. However, on an individual-respondent level, 10% experienced a clinically significant increase in psychopathological symptoms and 15% met cut-off criteria for COVID-19-related traumatic distress. Using BLCS modeling, we identified a high-stress group experiencing an increase in psychopathological symptoms and a decrease in SOC and a low-stress group showing the reversed pattern. Changes in SOC and psychopathological symptoms were predicted by pre-outbreak SOC and psychopathological symptom levels. CONCLUSIONS: Although mental health was stable in most respondents, a small group of respondents characterized by low levels of SOC experienced increased psychopathological symptoms from pre- to post-outbreak. Thus, SOC training might be a promising approach to enhance the resistance to stressors.
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3,058 |
Histopathology of Parasellar Neoplasms
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The anatomical and histological complexity of the parasellar region as well as the presence of embryonic remnants determine the huge diversity of parasellar neoplasms. Some of them are only located in the parasellar region, whereas others can occur elsewhere, within or outside the central nervous system. Their spectrum ranges from histologically benign and low-grade malignant to high-grade malignant tumours. Although rare, metastases can pose differential diagnostic dilemmas. The severity of the clinical picture, the challenges of surgery and the risk of adverse sequelae related to surgery or radiotherapy make parasellar tumours interesting entities for the clinicians irrespective of their histological malignancy grade. Due to the different cell origins of parasellar tumours, the World Health Organization classification system does not categorise them as a distinct group. Detailed criteria for classification and malignancy grading are presented in the classification systems covering central nervous system tumours, haematological malignancies and tumours of the soft tissue and bone. In the last few years, molecular genetic features have been integrated into the diagnosis of several types of the parasellar tumours enhancing diagnostic accuracy and providing information of the value for targeting therapies. In this review, we will present histopathological and molecular genetic features, updated classification criteria and recent advances in the diagnostics and rationale for novel pharmacological therapies of selected types of parasellar neoplasms.
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3,059 |
Differences in Lung and Lobe Volumes between Supine and Standing Positions Scanned with Conventional and Newly Developed 320-Detector-Row Upright CT: Intra-Individual Comparison
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BACKGROUND: No clinical studies to date have compared unilateral lung or lobe volumes between the supine and standing positions. OBJECTIVES: To compare lung/lobe volumes on computed tomography (CT) between these two positions and evaluate the correlation between the total lung volume and total lung capacity (TLC) on pulmonary function tests (PFTs). METHODS: Thirty-two asymptomatic volunteers underwent both conventional CT (supine position) and upright CT (standing position), during deep inspiration breath-hold, and PFTs on the same day. We measured lung/lobe volumes on CT in each position. Paired t tests were used for statistical analysis. RESULTS: The volumes of the total lung (10.9% increase), right lung (10.3% increase), right upper lobe (8.6% increase), right lower lobe (14.6% increase), left lung (11.6% increase), left upper lobe (7.1% increase), and left lower lobe (16.0% increase) were significantly greater in the standing position than in the supine position (all p < 0.0001). The right middle lobe volume was similar between the two positions (p = 0.16). Intraclass correlation coefficients for agreement between total lung volumes on CT in the supine/standing positions and the TLC on PFT were 0.891/0.938, respectively. CONCLUSIONS: While the volumes of the bilateral upper and lower lobes and bilateral lungs were significantly greater in the standing than in the supine position, with lower lobes showing larger changes, the right middle lobe volume did not change significantly between positions. The total lung volume on upright CT in the standing position was more similar to TLC on PFT than that in the supine position.
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3,060 |
Diagnosis, Background, and Treatment of Hypothalamic Damage in Craniopharyngioma
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Craniopharyngiomas (CP) are rare brain tumors managed primarily with surgery and radiotherapy. There are 2 phenotypes of CP, i.e., one with a rather good outcome without hypothalamic damage and another with hypothalamic damage. With hypothalamic damage, progressive disease with recurrent operations and additional cranial radiotherapy often result in hypothalamic obesity, an affected psychosocial life, and cognitive dysfunction. The morbidity and mortality are increased for particularly cerebrovascular diseases. Preoperative hypothalamic involvement to predict hypothalamic damage is important for decision making for hypothalamus-sparing surgery. Also a postoperative hypothalamic damage evaluation with the use of hypothalamus volume measurement can predict hypothalamic obesity, which is important for early treatment options. The morbidity of CP includes cognitive dysfunction with attention deficits and impaired episodic memory and processing speed. Again patients with hypothalamic damage are more affected. Treatment options of hypothalamic obesity in the chronic phase are scarce and not convincingly successful. The most optimal situation is to try to hinder or stop the evolution of hypothalamic obesity. Prevention of hypothalamic damage is recommended, with special regard to hypothalamus-sparing therapeutic approaches that respect the integrity of essential nuclei located in both the medial and the posterior hypothalamic areas.
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3,061 |
Abstracts from the 2020 Annual Scientific Meeting of the British and Irish Hypertension Society (BIHS)
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3,062 |
Trends in acute myocardial infarction admissions during the COVID-19 pandemic in Ankara, Turkey
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3,063 |
Serotype specific epitopes identified by neutralizing antibodies underpin immunogenic differences in Enterovirus B
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Echovirus 30 (E30), a serotype of Enterovirus B (EV-B), recently emerged as a major causative agent of aseptic meningitis worldwide. E30 is particularly devastating in the neonatal population and currently no vaccine or antiviral therapy is available. Here we characterize two highly potent E30-specific monoclonal antibodies, 6C5 and 4B10, which efficiently block binding of the virus to its attachment receptor CD55 and uncoating receptor FcRn. Combinations of 6C5 and 4B10 augment the sum of their individual anti-viral activities. High-resolution structures of E30-6C5-Fab and E30-4B10-Fab define the location and nature of epitopes targeted by the antibodies. 6C5 and 4B10 engage the capsid loci at the north rim of the canyon and in-canyon, respectively. Notably, these regions exhibit antigenic variability across EV-Bs, highlighting challenges in development of broad-spectrum antibodies. Our structures of these neutralizing antibodies of E30 are instructive for development of vaccines and therapeutics against EV-B infections.
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3,064 |
BBIQ, a pure TLR7 agonist, is an effective influenza vaccine adjuvant
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Better adjuvants are needed for vaccines against seasonal influenza. TLR7 agonists are potent activators of innate immune responses and thereby may be promising adjuvants. Among the imidazoquinoline compounds, 1-benzyl-2-butyl-1H-imidazo[4,5-c]quinolin-4-amine (BBIQ) was reported to be a highly active TLR7 agonist but has remained relatively unexplored because of its commercial unavailability. Indeed, in silico molecular modeling studies predicted that BBIQ had a higher TLR7 docking score and binding free energy than imiquimod, the gold standard TLR7 agonist. To circumvent the availability issue, we developed an improved and higher yield method to synthesize BBIQ. Testing BBIQ on human and mouse TLR7 reporter cell lines confirmed it to be TLR7 specific with significantly higher potency than imiquimod. To test its adjuvant potential, BBIQ or imiquimod were admixed with recombinant influenza hemagglutinin protein and administered to mice as two intramuscular immunizations 2 weeks apart. Serum anti-influenza IgG responses assessed by ELISA 2 weeks after the second immunization confirmed that the mice that received vaccine admixed with BBIQ had significantly higher anti-influenza IgG1 and IgG2c responses than mice immunized with antigen alone or admixed with imiquimod. This confirmed BBIQ to be a TLR7-specific adjuvant able to enhance humoral immune responses.
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3,065 |
Puromycin reactivity does not accurately localize translation at the subcellular level
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Puromycin is a tyrosyl-tRNA mimic that blocks translation by labeling and releasing elongating polypeptide chains from translating ribosomes. Puromycin has been used in molecular biology research for decades as a translation inhibitor. The development of puromycin antibodies and derivatized puromycin analogs has enabled the quantification of active translation in bulk and single-cell assays. More recently, in vivo puromycylation assays have become popular tools for localizing translating ribosomes in cells. These assays often use elongation inhibitors to purportedly inhibit the release of puromycin-labeled nascent peptides from ribosomes. Using in vitro and in vivo experiments in various eukaryotic systems, we demonstrate that, even in the presence of elongation inhibitors, puromycylated peptides are released and diffuse away from ribosomes. Puromycylation assays reveal subcellular sites, such as nuclei, where puromycylated peptides accumulate post-release and which do not necessarily coincide with sites of active translation. Our findings urge caution when interpreting puromycylation assays in vivo.
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3,066 |
Update Alert 2: Masks for Prevention of Respiratory Virus Infections, Including SARS-CoV-2, in Health Care and Community Settings
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3,067 |
Beliefs and Information Seeking in Patients With Cancer in Southwest China: Survey Study
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BACKGROUND: Although previous studies have reported the cancer information-seeking behaviors among patients in high-income countries, the cancer information-seeking practices of patients living in low- and middle-income areas are less known. OBJECTIVE: This study investigated the beliefs and information-seeking patterns of cancer patients in southwest China. METHODS: A questionnaire was designed, and data were collected in two hospitals (N=285) in southwest China. Statistical analyses included bivariate analyses and regressions. RESULTS: Patients’ attitudes towards cancer fatalism were significantly influenced by marital status (P<.001), education (P<.001), and household income (P<.001). Moreover, endorsing fatalistic belief was positively associated with age (r=0.35, P<.001). The regression model showed that younger patients (odds ratio [OR] 0.96, 95% CI 0.93-0.99) and those with higher education (OR 1.75, 95% CI 1.09-2.81) were more likely to seek information. Additionally, patients who were less confident in getting information were more likely to find information (OR 1.70, 95% CI 1.15-2.52), while fatalism belief was not significant in the regression (OR 0.65, 95% CI 0.22-1.95). CONCLUSIONS: This study explored the information-seeking patterns of cancer patients in southwest China. It was found that many Chinese people endorsed cancer fatalism. These pessimistic beliefs about the potential to prevent and to cure cancer correlate with rather than cause cancer-related information seeking. However, self-efficacy about the confidence in finding needed cancer information was a significant predictor of information-seeking.
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3,068 |
Host Transcriptional Response to Persistent Infection with a Live-Attenuated Porcine Reproductive and Respiratory Syndrome Virus Strain
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Both virulent and live-attenuated porcine reproductive and respiratory syndrome virus (PRRSV) strains can establish persistent infection in lymphoid tissues of pigs. To investigate the mechanisms of PRRSV persistence, we performed a transcriptional analysis of inguinal lymphoid tissue collected from pigs experimentally infected with an attenuated PRRSV strain at 46 days post infection. A total of 6404 differentially expressed genes (DEGs) were detected of which 3960 DEGs were upregulated and 2444 DEGs were downregulated. Specifically, genes involved in innate immune responses and chemokines and receptors associated with T-cell homing to lymphoid tissues were down regulated. As a result, homing of virus-specific T-cells to lymphoid tissues seems to be ineffective, evidenced by the lower frequencies of virus-specific T-cell in lymphoid tissue than in peripheral blood. Genes associated with T-cell exhaustion were upregulated. Likewise, genes involved in the anti-apoptotic pathway were upregulated. Collectively, the data suggested that the live-attenuated PRRSV strain establishes a pro-survival microenvironment in lymphoid tissue by suppressing innate immune responses, T-cell homing, and preventing cell apoptosis.
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3,069 |
Self-quarantined: becoming accustomed to being a semi-prisoner
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3,070 |
National reporting of deaths after enhanced Ebola surveillance in Sierra Leone
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BACKGROUND: Sierra Leone experienced the largest documented epidemic of Ebola Virus Disease in 2014–2015. The government implemented a national tollfree telephone line (1-1-7) for public reporting of illness and deaths to improve the detection of Ebola cases. Reporting of deaths declined substantially after the epidemic ended. To inform routine mortality surveillance, we aimed to describe the trends in deaths reported to the 1-1-7 system and to quantify people’s motivations to continue reporting deaths after the epidemic. METHODS: First, we described the monthly trends in the number of deaths reported to the 1-1-7 system between September 2014 and September 2019. Second, we conducted a telephone survey in April 2017 with a national sample of individuals who reported a death to the 1-1-7 system between December 2016 and April 2017. We described the reported deaths and used ordered logistic regression modeling to examine the potential drivers of reporting motivations. FINDINGS: Analysis of the number of deaths reported to the 1-1-7 system showed that 12% of the expected deaths were captured in 2017 compared to approximately 34% in 2016 and over 100% in 2015. We interviewed 1,291 death reporters in the survey. Family members reported 56% of the deaths. Nearly every respondent (94%) expressed that they wanted the 1-1-7 system to continue. The most common motivation to report was to obey the government’s mandate (82%). Respondents felt more motivated to report if the decedent exhibited Ebola-like symptoms (adjusted odds ratio 2.3; 95% confidence interval 1.8–2.9). CONCLUSIONS: Motivation to report deaths that resembled Ebola in the post-outbreak setting may have been influenced by knowledge and experiences from the prolonged epidemic. Transitioning the system to a routine mortality surveillance tool may require a robust social mobilization component to match the high reporting levels during the epidemic, which exceeded more than 100% of expected deaths in 2015.
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3,071 |
The Need to Develop Standard Measures of Patient Adherence for Big Data: Viewpoint
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Despite half a century of dedicated studies, medication adherence remains far from perfect, with many patients not taking their medications as prescribed. The magnitude of this problem is rising, jeopardizing the effectiveness of evidence-based therapies. An important reason for this is the unprecedented demographic change at the beginning of the 21st century. Aging leads to multimorbidity and complex therapeutic regimens that create a fertile ground for nonadherence. As this scenario is a global problem, it needs a worldwide answer. Could this answer be provided, given the new opportunities created by the digitization of health care? Daily, health-related information is being collected in electronic health records, pharmacy dispensing databases, health insurance systems, and national health system records. These big data repositories offer a unique chance to study adherence both retrospectively and prospectively at the population level, as well as its related factors. In order to make full use of this opportunity, there is a need to develop standardized measures of adherence, which can be applied globally to big data and will inform scientific research, clinical practice, and public health. These standardized measures may also enable a better understanding of the relationship between adherence and clinical outcomes, and allow for fair benchmarking of the effectiveness and cost-effectiveness of adherence-targeting interventions. Unfortunately, despite this obvious need, such standards are still lacking. Therefore, the aim of this paper is to call for a consensus on global standards for measuring adherence with big data. More specifically, sound standards of formatting and analyzing big data are needed in order to assess, uniformly present, and compare patterns of medication adherence across studies. Wide use of these standards may improve adherence and make health care systems more effective and sustainable.
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3,072 |
What You Need to Know Before Implementing a Clinical Research Data Warehouse: Comparative Review of Integrated Data Repositories in Health Care Institutions
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BACKGROUND: Integrated data repositories (IDRs), also referred to as clinical data warehouses, are platforms used for the integration of several data sources through specialized analytical tools that facilitate data processing and analysis. IDRs offer several opportunities for clinical data reuse, and the number of institutions implementing an IDR has grown steadily in the past decade. OBJECTIVE: The architectural choices of major IDRs are highly diverse and determining their differences can be overwhelming. This review aims to explore the underlying models and common features of IDRs, provide a high-level overview for those entering the field, and propose a set of guiding principles for small- to medium-sized health institutions embarking on IDR implementation. METHODS: We reviewed manuscripts published in peer-reviewed scientific literature between 2008 and 2020, and selected those that specifically describe IDR architectures. Of 255 shortlisted articles, we found 34 articles describing 29 different architectures. The different IDRs were analyzed for common features and classified according to their data processing and integration solution choices. RESULTS: Despite common trends in the selection of standard terminologies and data models, the IDRs examined showed heterogeneity in the underlying architecture design. We identified 4 common architecture models that use different approaches for data processing and integration. These different approaches were driven by a variety of features such as data sources, whether the IDR was for a single institution or a collaborative project, the intended primary data user, and purpose (research-only or including clinical or operational decision making). CONCLUSIONS: IDR implementations are diverse and complex undertakings, which benefit from being preceded by an evaluation of requirements and definition of scope in the early planning stage. Factors such as data source diversity and intended users of the IDR influence data flow and synchronization, both of which are crucial factors in IDR architecture planning.
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3,073 |
The peroxisome counteracts oxidative stresses by suppressing catalase import via Pex14 phosphorylation
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Most of peroxisomal matrix proteins including a hydrogen peroxide (H(2)O(2))-decomposing enzyme, catalase, are imported in a peroxisome-targeting signal type-1 (PTS1)-dependent manner. However, little is known about regulation of the membrane-bound protein import machinery. Here, we report that Pex14, a central component of the protein translocation complex in peroxisomal membrane, is phosphorylated in response to oxidative stresses such as H(2)O(2) in mammalian cells. The H(2)O(2)-induced phosphorylation of Pex14 at Ser232 suppresses peroxisomal import of catalase in vivo and selectively impairs in vitro the interaction of catalase with the Pex14-Pex5 complex. A phosphomimetic mutant Pex14-S232D elevates the level of cytosolic catalase, but not canonical PTS1-proteins, conferring higher cell resistance to H(2)O(2). We thus suggest that the H(2)O(2)-induced phosphorylation of Pex14 spatiotemporally regulates peroxisomal import of catalase, functioning in counteracting action against oxidative stress by the increase of cytosolic catalase.
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3,074 |
A missense in HSF2BP causing primary ovarian insufficiency affects meiotic recombination by its novel interactor C19ORF57/BRME1
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Primary Ovarian Insufficiency (POI) is a major cause of infertility, but its etiology remains poorly understood. Using whole-exome sequencing in a family with three cases of POI, we identified the candidate missense variant S167L in HSF2BP, an essential meiotic gene. Functional analysis of the HSF2BP-S167L variant in mouse showed that it behaves as a hypomorphic allele compared to a new loss-of-function (knock-out) mouse model. Hsf2bp(S167L/S167L) females show reduced fertility with smaller litter sizes. To obtain mechanistic insights, we identified C19ORF57/BRME1 as a strong interactor and stabilizer of HSF2BP and showed that the BRME1/HSF2BP protein complex co-immunoprecipitates with BRCA2, RAD51, RPA and PALB2. Meiocytes bearing the HSF2BP-S167L variant showed a strongly decreased staining of both HSF2BP and BRME1 at the recombination nodules and a reduced number of the foci formed by the recombinases RAD51/DMC1, thus leading to a lower frequency of crossovers. Our results provide insights into the molecular mechanism of HSF2BP-S167L in human ovarian insufficiency and sub(in)fertility.
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3,075 |
Using social media to analyze public psychological status during the recovery period of COVID-19 in China
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BACKGROUND: During the outbreak, billions of people were eager to get information about COVID-19 through social media. Social media can not only deliver reliable information to the public but can in turn reflect changes in the public’s psychological status. Insight into the public’s hotspots of concern and mental status through media background tools contributes to the formulation of public health policies and the clarification of epidemic development mode. METHODS: WeChat is the largest social media in China. Taking the recovery period of COVID-19 in China, for example, we collected WeChat Index data and analyzed the public’s concern about the course of COVID-19 and the restoration of emotional tendency through keywords search. RESULTS: With the gradual control of the COVID-19 in China, the public psychological status changes from negative to neutral, accompanied by a weakening of negative emotions and an increase in positive emotions. Every obvious inflection point of improvement in social operation is reflected in the increase of public attention and the relaxation of lifestyle. CONCLUSIONS: Social media can be used to monitor the public psychological status and the development mode and trend of infection in one country during a pandemic.
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3,076 |
Religions in action: the role of interreligious dialogue in the COVID-19 pandemic
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Recent correspondence letters to the editor of this journal pointed on the praxis of faith in the context of COVID-19 pandemic. The #ChurchinAction presents the role of religious interventions in times of COVID-19. However, a question is raised: how to promote interreligious dialogue in the context of COVID-19 pandemic? To address this question, people of different faiths/religions should come together in promoting the life and dignity of the human person, a sense of community, and participation, respecting the rights and responsibilities of each person, helping the poor and vulnerable sectors of the society, respecting the dignity of work and the rights of the workers, solidarity and caring for the whole creation. In this perspective, interreligious dialogue highlighted the importance of world religions in order to provide a spiritual intervention. The dialogue of life, dialogue of action, dialogue of theological exchange, and dialogue of religious experiences promote interreligious dialogue in the context of COVID-19 pandemic.
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3,077 |
COVID-19: The need to heed distress calls of healthcare workers
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3,078 |
Corrigendum to: Descriptive analysis of social determinant factors in urban communities affected by COVID-19
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3,079 |
Recommendations for the assessment and monitoring of skeletal manifestations in children with Gaucher disease
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3,080 |
A Decade of Genetic Counseling in Frontotemporal Dementia Affected Families: Few Counseling Requests and much Familial Opposition to Testing
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A decade of genetic counseling of frontotemporal dementia (FTD) affected families has generated two important observations. First, the uptake rate for presymptomatic testing for FTD is low in our department of Clinical Genetics at the Erasmus Medical Center in the Netherlands. Second, FTD at-risk counselees reported substantial familial opposition to genetic testing, which is distinct from the attitude in Huntington Disease affected families. We hypothesize that the low acceptance for FTD genetic counseling is consequential to the familial opposition and explain this within the theoretical framework of separation-individuation. Furthermore, we hypothesize that separation-individuation problems do not similarly influence the acceptance of HD genetic counseling, due to the educative role of the well-organised patient organization for HD in the Netherlands. We offer counseling recommendations that serve to facilitate the individuation of the counselee with respect to the FTD genetic test.
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3,081 |
Examining the Relationship Between Genetic Counselors’ Attitudes Toward Deaf People and the Genetic Counseling Session
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Given the medical and cultural perspectives on deafness it is important to determine if genetic counselors’ attitudes toward deaf people can affect counseling sessions for deafness genes. One hundred fifty-eight genetic counselors recruited through the National Society of Genetic Counselors Listserv completed an online survey assessing attitudes toward deaf people and scenario-specific comfort levels discussing and offering genetic testing for deafness. Respondents with deaf/Deaf friends or who work in prenatal or pediatric settings had more positive attitudes toward deaf people than those without deaf/Deaf friends or those working in ‘other’ settings. More positive attitudes toward deaf people correlated with higher comfort level talking about genetic testing for the two scenarios involving culturally Deaf clients; and correlated with higher comfort level offering genetic testing to culturally Deaf clients wishing to have a deaf child. Attitudes and comfort level were not correlated in the scenarios involving hearing or non-culturally deaf clients. These results suggest that genetic counselors’ attitudes could affect information provision and the decision making process of culturally Deaf clients. Cultural sensitivity workshops in genetic counseling training programs that incorporate personal interactions with culturally Deaf individuals are recommended. Additional suggestions for fostering personal interactions are provided.
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3,082 |
Publishing a Master’s Thesis: A Guide for Novice Authors
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Publication of original research, clinical experiences, and critical reviews of literature are vital to the growth of the genetic counseling field, delivery of genetic counseling services, and professional development of genetic counselors. Busy clinical schedules, lack of time and funding, and training that emphasizes clinical skills over research skills may make it difficult for new genetic counselors to turn their thesis projects into publications. This paper summarizes and elaborates upon a presentation aimed at de-mystifying the publishing process given at the 2008 National Society of Genetic Counselors Annual Education Conference. Specific topics include familiarizing prospective authors, particularly genetic counseling students, with the basics of the publication process and related ethical considerations. Former students’ experiences with publishing master’s theses also are described in hopes of encouraging new genetic counselors to submit for publication papers based on their thesis projects.
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3,083 |
Pre-counseling Education for Low Literacy Women at Risk of Hereditary Breast and Ovarian Cancer (HBOC): Patient Experiences Using the Cancer Risk Education Intervention Tool (CREdIT)
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The Cancer Risk Education Intervention Tool (CREdIT) is a computer-based (non-interactive) slide presentation designed to educate low-literacy, and ethnically and racially diverse public hospital patients at risk of Hereditary Breast and Ovarian Cancer (HBOC) about genetics. To qualitatively evaluate participants’ experience with and perceptions of a genetic education program as an adjunct to genetic counseling, we conducted direct observations of the intervention, semi-structured in person interviews with 11 women who viewed CREdIT, and post-counseling questionnaires with the two participating genetic counselors. Five themes emerged from the analysis of interviews: (1) genetic counseling and testing for breast/ovarian cancer was a new concept; (2) CREdIT’s story format was particularly appealing; (3) changes in participants’ perceived risk for breast cancer varied; (4) some misunderstandings about individual risk and heredity persisted after CREdIT and counseling; (5) the context for viewing CREdIT shaped responses to the presentation. Observations demonstrated ways to make the information provided in CREdIT and by genetic counselors more consistent. In a post-session counselor questionnaire, counselors’ rating of the patient’s preparedness before the session was significantly higher for patients who viewed CREdIT prior to their appointments than for other patients. This novel educational tool fills a gap in HBOC education by tailoring information to women of lower literacy and diverse ethnic/racial backgrounds. The tool was well received by interview participants and counselors alike. Further study is needed to examine the varied effects of CREdIT on risk perception. In addition, the implementation of CREdIT in diverse clinical settings and the cultural adaptation of CREdIT to specific populations reflect important areas for future work.
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3,084 |
Effect of Pre-test Genetic Counseling for Deaf Adults on Knowledge of Genetic Testing
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Empirical data on genetic counseling outcomes in the deaf population are needed to better serve this population. This study was an examination of genetics knowledge before and after culturally and linguistically appropriate pre-test genetic counseling in a diverse deaf adult sample. Individuals ≥18 years old with early-onset sensorineural deafness were offered connexin-26/30 testing and genetic counseling. Participants completed questionnaires containing 10 genetics knowledge items at baseline and following pre-test genetic counseling. The effects of genetic counseling, prior beliefs about etiology, and participant’s preferred language on genetics knowledge scores were assessed (n = 244). Pre-test genetic counseling (p = .0007), language (p < .0001), prior beliefs (p < .0001), and the interaction between counseling and beliefs (p = .035) were predictors of genetics knowledge. American Sign Language (ASL)-users and participants with “non-genetic/unknown” prior beliefs had lower knowledge scores than English-users and participants with “genetic” prior beliefs, respectively. Genetics knowledge improved after genetic counseling regardless of participants’ language; knowledge change was greater for the “non-genetic/unknown” beliefs group than the “genetic” beliefs group. ASL-users’ lower knowledge scores are consistent with evidence that ethnic and cultural minority groups have less genetics knowledge, perhaps from exposure and access disparities. Culturally and linguistically appropriate pre-test genetic counseling significantly improved deaf individuals’ genetics knowledge. Assessing deaf individuals’ prior beliefs is important for enhancing genetics knowledge.
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3,085 |
Focusing on Patient Needs and Preferences May Improve Genetic Counseling for Colorectal Cancer
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During cancer genetic counseling, different items which counselors consider important are discussed. However, relatively little empirical evidence exists regarding the needs and preferences of counselees. In this study needs and preferences were assessed from counselees with a personal and/or family history of colorectal cancer (CRC), who were referred for genetic counseling regarding CRC. They received a slightly modified version of the QUOTE-GENE(ca) questionnaire prior to their first visit to the Hereditary Cancer Clinic. Response rate was 60 % (48/80 participants). Counselees rated the importance of 45 items assessing their needs and preferences regarding the content and process of genetic counseling. Participants rated the items regarding discussion of information about their familial CRC risk (100 %) and preventive options (98 %) as important or very important. Fewer participants rated items concerning general information on genetics as important. Sensitive communication during counseling was considered very important by a large percentage of counselees. Generally, no major differences were seen between participants in relation to individual characteristics. Our data suggest that focusing on familial CRC risk and surveillance options, in combination with sensitive communication may lead to better satisfaction with genetic counseling.
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3,086 |
Counseling Customers: Emerging Roles for Genetic Counselors in the Direct-to-Consumer Genetic Testing Market
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Individuals now have access to an increasing number of internet resources offering personal genomics services. As the direct-to-consumer genetic testing (DTC GT) industry expands, critics have called for pre- and post-test genetic counseling to be included with the product. Several genetic testing companies offer genetic counseling. There has been no examination to date of this service provision, whether it meets critics’ concerns and implications it may have for the genetic counseling profession. Considering the increasing relevance of genetics in healthcare, the complexity of genetic information provided by DTC GT, the mediating role of the internet in counseling, and potential conflicts of interest, this is a topic which deserves further attention. In this paper we offer a discourse analysis of ways in which genetic counseling is represented on DTC GT websites, blogs and other online material. This analysis identified four types of genetic counseling represented on the websites: the integrated counseling product; discretionary counseling; independent counseling; and product advice. Genetic counselors are represented as having the following roles: genetics educator; mediator; lifestyle advisor; risk interpreter; and entrepreneur. We conclude that genetic counseling as represented on DTC GT websites demonstrates shifting professional roles and forms of expertise in genetic counseling. Genetic counselors are also playing an important part in how the genetic testing market is taking shape. Our analysis offers important and timely insights into recent developments in the genetic counseling profession, which have relevance for practitioners, researchers and policy makers concerned with the evolving field of personal genomics.
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3,087 |
Glioma infiltration of the corpus callosum: early signs detected by DTI
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The most frequent primary brain tumors, anaplastic astrocytomas (AA) and glioblastomas (GBM): tend to invasion of the surrounding brain. Histopathological studies found malignant cells in macroscopically unsuspicious brain parenchyma remote from the primary tumor, even affecting the contralateral hemisphere. In early stages, diffuse interneural infiltration with changes of the apparent diffusion coefficient (ADC) and fractional anisotropy (FA) is suspected. The purpose of this study was to investigate the value of DTI as a possible instrument of depicting evidence of tumor invasion into the corpus callosum (CC). Preoperatively, 31 patients with high-grade brain tumors (8 AA and 23 GBM) were examined by MRI at 3 T, applying a high-resolution diffusion tensor imaging (DTI) sequence. ADC- and FA-values were analyzed in the tumor-associated area of the CC as identified by fiber tracking, and were compared to matched healthy controls. In (MR-)morphologically normal appearing CC the ADC values were elevated in the tumor patients (n = 22; 0.978 × 10(−3) mm²/s) compared to matched controls (0.917 × 10(−3) mm²/s, p < 0.05), and the corresponding relative FA was reduced (rFA: 88 %, p < 0.01). The effect was pronounced in case of affection of the CC visible on MRI (n = 9; 0.978 × 10(−3) mm²/s, p < 0.05; rFA: 72 %, p < 0.01). Changes in diffusivity and anisotropy in the CC can be interpreted as an indicator of tumor spread into the contralateral hemisphere not visible on conventional MRI.
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3,088 |
An Assessment of Time Involved in Pre-test Case Review and Counseling for a Whole Genome Sequencing Clinical Research Program
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Whole genome sequencing (WGS) is being used for evaluation of individuals with undiagnosed disease of suspected genetic origin. Implementing WGS into clinical practice will place an increased burden upon care teams with regard to pre-test patient education and counseling about results. To quantitate the time needed for appropriate pre-test evaluation of participants in WGS testing, we documented the time spent by our clinical research group on various activities related to program preparation, participant screening, and consent prior to WGS. Participants were children or young adults with autism, intellectual or developmental disability, and/or congenital anomalies, who have remained undiagnosed despite previous evaluation, and their biologic parents. Results showed that significant time was spent in securing allocation of clinical research space to counsel participants and families, and in acquisition and review of participant’s medical records. Pre-enrollment chart review identified two individuals with existing diagnoses resulting in savings of $30,000 for the genome sequencing alone, as well as saving hours of personnel time for genome interpretation and communication of WGS results. New WGS programs should plan for costs associated with additional pre-test administrative planning and patient evaluation time that will be required to provide high quality care. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1007/s10897-014-9697-4) contains supplementary material, which is available to authorized users.
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3,089 |
Counselees’ Expressed Level of Understanding of the Risk Estimate and Surveillance Recommendation are Not Associated with Breast Cancer Surveillance Adherence
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We studied counselees’ expressed understanding of the risk estimate and surveillance recommendation in the final consultation for breast cancer genetic counseling in relation with their risk perception, worry and cancer surveillance adherence 1 year post-counseling. Consecutive counselees were included from 2008 to 2010. Counselees with an indication for diagnostic DNA-testing for themselves or a breast cancer affected relative were requested to complete online questionnaires before and after counseling and one year after counseling (N = 152–124). Self-reported surveillance was compared to surveillance recommendations. Consultations were videotaped. Counselees’ reactions to the risks and recommendations were coded. Statements about the risk perception and surveillance intentions of breast cancer unaffected counselees were transcribed. Associations with outcomes were explored. Almost all breast cancer unaffected counselees (>90 %) reacted to their risk estimate with an utterance indicating understanding and this reaction was not significantly associated with their post-visit risk perception alignment. Over one-third (38.6 %) overestimated their risk post-counseling. Few counselees (5.8 %) expressed surveillance intentions. One year after counseling, about three-quarters (74.0 %) of the breast cancer unaffected counselees had adhered to the surveillance recommendation. Almost one-quarter (23.3 %) had performed more mammograms/MRI scans than recommended, which was associated with prior mammography uptake (n = 47; X(2) = 5.2; p = .02). Counselees’ post-counseling overestimation of their risk, high levels of worry and high surveillance uptake were not reflected in their reactions to the counselor’s information during the final visit. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1007/s10897-015-9869-x) contains supplementary material, which is available to authorized users.
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3,090 |
Genetic Counselors’ Perspectives and Practices Regarding Expanded Carrier Screening after Initial Clinical Availability
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Expanded carrier screening (ECS), introduced in 2009, identifies carriers for dozens or hundreds of recessive diseases. At the time of its introduction into clinical use, perspectives of the genetic counseling community regarding ECS were unknown. We conducted a survey in early 2012 of GCs and report the results here. They represent a snapshot of opinions and usage at that time, providing a baseline for comparison as the technology continues to evolve and as usage increases. The survey assessed personal perspectives, opinions on clinical implementation and clinical utilization of ECS. The sample included 337 GCs of varying clinical fields, of whom 150 reported practicing in reproductive settings. Our findings demonstrate that, at the time, GCs indicated general agreement with ECS as a concept – for example, most GCs agreed that carrier screening should address diseases outside of current guidelines and also indicated personal interest in electing ECS. There were also disagreements or concerns expressed regarding appropriate pre- and post-test counseling (e.g., the content and delivery mode of adequate informed consent) and practical implementation (e.g., the amount of time available for follow-up care). This was the first quantitative study of a large number of GCs and it revealed initial overall support for ECS among the GC profession. The authors plan to re-administer a similar survey, which may reveal changes in opinions and/or utilization over time. A follow up survey would also allow further exploration of questions uncovered by these data.
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3,091 |
A Systematic Review of the Impact of Genetic Counseling on Risk Perception Accuracy
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This review presents an overview of the impact of genetic counseling on risk perception accuracy in papers published between January 2000 and February 2007. The results suggest that genetic counseling may have a positive impact on risk perception accuracy, though some studies observed no impact at all, or only for low-risk participants. Several implications for future research can be deduced. First, future researchers should link risk perception changes to objective risk estimates, define risk perception accuracy as the correct counseled risk estimate, and report both the proportion of individuals who correctly estimate their risk and the average overestimation of the risk. Second, as the descriptions of the counseling sessions were generally poor, future research should include more detailed description of these sessions and link their content to risk perception outcomes to allow interpretation of the results. Finally, the effect of genetic counseling should be examined for a wider variety of hereditary conditions. Genetic counselors should provide the necessary context in which counselees can understand risk information, use both verbal and numerical risk estimates to communicate personal risk information, and use visual aids when communicating numerical risk information.
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3,092 |
Reactions to and Desire for Prognostic Testing in Choroidal Melanoma Patients
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To determine if choroidal melanoma patients want cytogenetic prognostic information. Ninety-nine choroidal melanoma patients completed a questionnaire regarding their opinions about receiving prognostic information. The perceived usefulness of prognostic information was evaluated in patients who had undergone cytogenetic testing. Depressive symptoms, quality of life, and interest in supportive counseling during test receipt were assessed. Ninety-seven percent of respondents reported that they would have wanted prognostic information at the time of their treatment and 98% of respondents reported that supportive counseling should be offered when prognostic information is given. Patients who had received a more favorable prognostic result were more likely to endorse the usefulness of cytogenetic testing than were patients who had received a less favorable prognostic result. Psychological status did not vary significantly as a function of cytogenetic test result. Prognostic information was important to patients with choroidal melanoma, even in the absence of prophylactic measures which might improve prognosis.
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3,093 |
Vestibular prognosis in idiopathic sudden sensorineural hearing loss with vestibular dysfunction treated with oral or intratympanic glucocorticoids: a protocol for randomized controlled trial
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BACKGROUND: Idiopathic sudden sensorineural hearing loss (ISSNHL) is a rapid-onset sensorineural hearing impairment with unclear etiology and unsatisfying treatment effects. Vestibular dysfunction has been considered as a poor indicator in the clinical manifestations and prognosis of ISSNHL, which occurred in approximately 28–57% cases. Glucocorticoids, administered through oral or intratympanic way, are currently regularly and standardly applied for ISSNHL to improve the hearing outcome. However, the vestibular prognosis of ISSNHL after routine treatments remains seldom explored. This study aims to compare the effectiveness of oral and intratympanic glucocorticoids in ISSNHL with vestibular dysfunction in terms of the pattern and trajectory of possible process of vestibular function recovery. METHODS/DESIGN: A randomized, outcome-assessor- and analyst-blinded, controlled, clinical trial (RCT) will be carried out. Seventy-two patients with ISSNHL complaining of vestibular dysfunction appearing as vertigo or imbalance will be recruited and randomized into either oral or intratympanic glucocorticoid therapy group with a 1:1 allocation ratio. The primary outcomes will be vestibular function outcomes assessed by sensory organization test, caloric test, video head impulse test, cervical vestibular evoked myogenic potential, and ocular vestibular evoked myogenic potential; the secondary outcomes include self-reported vestibular dysfunction symptoms; dizziness-related handicap, visual analogue scale for vertigo and tinnitus; and pure tone audiometry. Assessments of primary outcomes will be performed at baseline and at 4 and 8 weeks post-randomization, while assessments of secondary outcomes will be performed at baseline and 1, 2, 4, and 8 weeks post-randomization. DISCUSSION: Previous intervention studies of ISSNHL included only hearing outcomes, with little attention paid on the prognosis of vestibular dysfunction. This trial will be the first RCT study focusing on the progress and prognosis of vestibular dysfunction in ISSNHL. The efficacy of two commonly used therapies of glucocorticoids will be compared in both auditory and vestibular function fields, rather than in the hearing outcome alone. TRIAL REGISTRATION: ClinicalTrials.gov NCT03974867. Registered on 23 July 2019
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3,094 |
Is the allocation of medical and health resources effective? Characteristic facts from regional heterogeneity in China
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BACKGROUND: Over the last decade, the expenditure on public medical and health has increased greatly in China, however, problems as low efficiency and unfairness still exist. How to accurately describe the effectiveness of existing medical and health resources in combination with regional heterogeneity is of great significance to China’s medical and health reform. METHODS: Based on provincial panel data for the period of 2005 to 2017, combining expected output and unexpected output, this paper constructs a super-efficiency three-stage SBM-DEA model, to measure and analyze the spatial-temporal heterogeneity characteristics and influencing factors of public medical and health efficiency (PMHE). RESULTS: (1) After the impacts of random error and external environmental factors are removed, the mean value of overall PMHE is 0.9274, failing to reach DEA efficiency, and PMHE shows a fluctuated downward trend. (2) The adjusted PMHE level shows a prominent spatial imbalance at the stage 3. The average efficiency level is ranked by the East > the West > the Central > the Northeast. (3) The increases of GDP per capita and population density are beneficial to the improvement of PMHE, while income level and education level are disadvantageous to PMHE, and last, the urbanization level, an uncertain effect. (4) There is no σ convergence of the PMHE in the East, the Central and the West, that is, the internal differences may gradually expand in the future, while the Northeast shows a significant σ convergence trending of PMHE. (5) The state’s allocation of medical and health resources has undergone major changes during “The Twelfth Five-Year Plan”. CONCLUSION: This study innovatively incorporates undesired outputs of health care into the efficiency evaluation framework by constructing the main efficiency evaluation indicators. The results of the robust evaluation conclude that China’s existing investment in medical and health resources is generally not effective. Therefore, although China’s health care reform has made certain achievement, it is still necessary to expand the investment in health care resources.
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3,095 |
The clinical, immunological and genetic features of 12 Chinese patients with STAT3 mutations
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BACKGROUND: Loss-of-function (LOF) mutations in signal transducer and activator of transcription 3 (STAT3) is one of the causes of STAT3 hyperimmunoglobulin E (IgE) syndrome (STAT3-HIES), while gain-of-function (GOF) mutations in STAT3 lead to immune dysregulation diseases. We retrospectively analyzed the age, common clinical symptoms, immunologic and molecular manifestations in 11 patients with LOF STAT3 mutations and 1 patient with a GOF STAT3 mutation. METHODS: Twelve patients were enrolled in our study. Serum immunoglobulin measurements, lymphocyte subset detection and whole-exome sequencing were performed. RESULTS: The median age at diagnosis of STAT3-HIES patients was 4.74 years. Eczema, recurrent respiratory infections, fevers, abscesses and Staphylococcus aureus infections were the classic manifestations. Elevated serum IgE levels are not always observed in conjunction with high eosinophil counts. A moderate viral DNA load was also measured in peripheral blood mononuclear cells. We noticed that c. 1144C>T was the most common mutation site, followed by c.1311C>A. Additionally, c.1311C>A and c. 1826G>C are two novel mutations. Eight patients achieved notable improvement after receiving intravenous immunoglobulin. CONCLUSION: We updated the current knowledge of this topic. We found an earlier median age at diagnosis, a higher survival rate, and a general lack of nonimmunological abnormalities; we also described the treatment details and novel mutations involve in STAT3-HIES and compared STAT3 LOF and GOF mutations.
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3,096 |
Gene expression and regulatory factors of the mechanistic target of rapamycin (mTOR) complex 1 predict mammalian longevity
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Species longevity varies significantly across animal species, but the underlying molecular mechanisms remain poorly understood. Recent studies and omics approaches suggest that phenotypic traits of longevity could converge in the mammalian target of rapamycin (mTOR) signalling pathway. The present study focuses on the comparative approach in heart tissue from 8 mammalian species with a ML ranging from 3.5 to 46 years. Gene expression, protein content, and concentration of regulatory metabolites of the mTOR complex 1 (mTORC1) were measured using droplet digital PCR, western blot, and mass spectrometry, respectively. Our results demonstrate (1) the existence of differences in species-specific gene expression and protein content of mTORC1, (2) that the achievement of a high longevity phenotype correlates with decreased and inhibited mTORC1, (3) a decreased content of mTORC1 activators in long-lived animals, and (4) that these differences are independent of phylogeny. Our findings, taken together, support an important role for mTORC1 downregulation in the evolution of long-lived mammals. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (10.1007/s11357-020-00210-3) contains supplementary material, which is available to authorized users.
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3,097 |
Modified Asano-Ohya-Khrennikov quantum-like model for decision-making process in a two-player game with nonlinear self- and cross-interaction terms of brain’s amygdala and prefrontal-cortex
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In this report, we propose a modification on the Asano-Ohya-Khrennikov quantum-like decision-making process model of a two-player game by adding additional nonlinear terms to the related comparison step dynamical equation. The additions are in the form of a self-interaction and cross-interaction of the brain’s amygdala and prefrontal cortex. We show that the cross-interaction significantly determines the final decision of a player, whether it becomes a rational or an irrational choice. In contrast, the nonlinear self-interaction term provides a feedback mechanism that speeds up the corresponding decision-making process. We also suggest the form of expectation values of the overall reaction rate coefficients of those nonlinear terms by making an analogy with the original model formulation.
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3,098 |
Useful parameters for the motion analysis of facial skin care in Japanese women
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BACKGROUND: Facial skin care (FSC) is an important routine for Japanese women. Hand motions during FSC physically affect psychological state. However, it is very difficult to evaluate hand motions during personal and complex FSC. The objective of this study was to find out objective and quantitative parameters for hand motions during facial skin care (FSC). Women who enjoy and soothe during FSC (Enjoyment group (E group), n = 20) or not (non-enjoyment group (NE group), n = 19) were recruited by an advance questionnaire. The same lotion, emulsion, and cream were provided to all subjects, and they used sequentially in the same way as the women’s daily FSC. The motion of the marker on the back side of the right middle finger during FSC was tracked by a motion capture system. The heart rate variability (HRV) was also measured before and after FSC for evaluating psychological effect. RESULTS: The averaged acceleration (Avg. ACC), approximate entropy (ApEn), and power law scaling exponent (Rest γ) of the cumulative duration of slow motion from the sequential data of acceleration were evaluated. Compared to the NE group, the E group showed a lower Avg. ACC when using emulsion (p = 0.005) and cream (p = 0.007), a lower ApEn when using emulsion (p = 0.003), and a lower Rest γ (p = 0.024) when using all items, suggesting that compared to the NE group, the E group had more tender and regular motion, and sustainable slow motions, especially in the use of emulsion. In the E group, the low/high-frequency component of HRV decreased significantly after FSC, suggesting suppression of sympathetic activity (p = 0.045). NE group did not. For all subjects, ApEn and Rest γ showed significantly positive correlation with the increase in the low/high-frequency component of HRV after FSC (p < 0.01). ApEn showed significantly negative correlation with the increase in the high-frequency component of HRV after FSC (p < 0.05). Avg. ACC did not show significant correlation with them. These results suggested that the behavior of FSC influences the autonomic nerve system. CONCLUSIONS: ApEn and Rest γ are useful parameters for evaluating quality of hand motions during FSC.
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3,099 |
Assessment of a biofluid mechanics-based model for calculating portal pressure in canines
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BACKGROUND: Portal hypertension is a severe complication caused by various chronic liver diseases. The standard methods for detecting portal hypertension (hepatic venous pressure gradient and free portal pressure) are available in only a few hospitals due to their technical difficulty and invasiveness; thus, non-invasive measuring methods are needed. This study aimed to establish and assess a novel model to calculate free portal pressure based on biofluid mechanics. RESULT: Comparison of each dog’s virtual and actual free portal pressure showed that a biofluid mechanics-based model could accurately predict free portal pressure (mean difference: -0.220, 95% CI: − 0.738 to 0.298; upper limit of agreement: 2.24, 95% CI: 1.34 to 3.14; lower limit of agreement: -2.68, 95% CI: − 3.58 to − 1.78; intraclass correlation coefficient: 0.98, 95% CI: 0.96 to 0.99; concordance correlation coefficient: 0.97, 95% CI: 0.93 to 0.99) and had a high AUC (0.984, 95% CI: 0.834 to 1.000), sensitivity (92.3, 95% CI: 64.0 to 99.8), specificity (91.7, 95% CI: 61.5 to 99.8), positive likelihood ratio (11.1, 95% CI: 1.7 to 72.8), and low negative likelihood ratio (0.08, 95% CI: 0.01 to 0.6) for detecting portal hypertension. CONCLUSIONS: Our study suggests that the biofluid mechanics-based model was able to accurately predict free portal pressure and detect portal hypertension in canines. With further research and validation, this model might be applicable for calculating human portal pressure, detecting portal hypertensive patients, and evaluating disease progression and treatment efficacy.
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