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We recently reported the cross-neutralizing potential of two anti-CD4bs scFv monoclonals (D11 and 1F6) and one N332 V3-glycan directed scFv monoclonal (C11) identified from a human recombinant phage display library constructed from the PBMCs of HIV-1 sybtype C-infected adult cross-neutralizers. The CD4bs directed D11 scFv demonstrated 66% neutralization breadth and neutralized 33/50 viruses of different HIV-1 subtypes (43). In a recently conducted study, we observed the relative resistance of pediatric HIV-1 primary isolates to the existing bnAbs isolated from adults (33). HIV-1-infected children below the age of 2 if untreated, progress to AIDS, due to the immaturity of the immune system and limited exposure to diverse pathogens. Of late, however, cnAbs have been isolated from HIV-1 infected infants (31), providing us the impetus to generate a human recombinant scFv phage library and identify cross neutralizing CD4bs directed scFvs, using PBMCs from select pediatric cross-neutralizers. During the course of chronic infection, there is increase in breadth of the cnAbs induced by the diverse antigenicity of the circulating virus quasi-species (68–70). Our recent study on chronically infected children have also shown the presence of V1V2, V3, and CD4bs specific plasma antibodies in children, suggesting the development of bnAbs targeting multiple epitopes on HIV-1 envelope in these infected children (38).
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study
| 99.94 |
The advantage of pooling the PBMCs from these cross-neutralizers is to obtain a recombinant scFv library of diverse epitope specificities with high probability of having scFvs with broad and potent neutralizing activity (43). Such libraries can be probed in future using newer HIV-1 antigens to identify scFvs directed at different regions on the envelope. It is less probable to get such potent bnAbs of diverse specificities from a single infected donor. Moreover, by way of generating recombinant antibodies, it is possible to get distinct antibody gene usages favoring breadth and potency that may not be seen to evolve in naturally infected donors. The plasma antibodies binding with RSC3 core protein at high titers and not with the RSC3 mutant Δ371I/P363N suggested the presence of VRC01-like antibodies in these pediatric donors that further increased the probability of identifying anti-CD4bs VRC01-like scFvs from the pediatric scFv phage library constructed in this study.
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study
| 100.0 |
The scFv monoclonals 2B10 and 2E4 exhibited the same heavy chain gene usage of IGVH1-2, as is also shown by the anti-CD4bs VRC01 like bnAb lineage (13, 71). Also, unlike the anti-V1/V2 antibodies and V3-glycan antibodies, which have large CDRH3 lengths (8), the 2B10 and 2E4 scFv monoclonals have shorter CDRH3 lengths of 13 and 18 amino acid residues respectively, which is comparable with the CDRH3 lengths of VRC01-like antibodies (13). An interesting observation was the moderate frequency of VH nucleotide SHM, 10.1 and 11.1% in the scFv genes of 2B10 and 2E4, respectively, contributing to the neutralization breadth (77%) demonstrated by 2B10 scFv, suggesting the evolution of bnAbs in chronically infected children with higher SHM. Low levels of SHM (2–7%) have earlier been shown in infant derived antibodies with limited neutralization breadth (31).
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study
| 100.0 |
Genetic variations are documented between viruses of different subtypes (inter-clade) and also within a subtype (intra-clade) (21, 23–26). A salient finding of this study is the ability of the 2B10 scFv to effectively neutralizing subtype C viruses (77%); from India and across subtype C viruses from other geographical regions, identifying this monoclonal as a potential therapeutic reagent. It is important to generate similar antibodies that have neutralizing potential across viruses of each subtype that can serve as a pool of protective antibodies. Further, the 2B10 scFv specifically neutralized all the subtype C and subtype A viruses tested in this study, isolated from pediatric subjects which were previously reported to be resistant viruses when tested against a panel of first and second generation adult bnAbs (33). Some of the factors that may be responsible for this could be the differences in the immune responses that evolve in children than adults and the immune selection pressure on the circulating viruses in them. It could also be because the likelihood of intra-clade differences is less than inter-clade differences. Perhaps in the future, antibodies isolated from pediatric donors, such as the 2B10 scFv that neutralizes subtype C pediatric viruses of different origin, may have an important clinical role in preventing infection in children. This is all the more important because most of the known bnAbs have originated from non-subtype C infected adults, whereas the disease burden is more with subtype C viruses.
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study
| 99.94 |
To conclude, we have for the first time successfully generated a scFv phage library from HIV-1 subtype C chronically infected antiretroviral naïve children. From this library, we identified 2B10 as a cross-neutralizing CD4bs directed scFv monoclonal with reasonable breadth and potency, demonstrating neutralizing activity against tier 1, 2, and 3 viruses, including viruses of both adult and pediatric origin. Such anti-HIV-1 human scFvs, are potential candidates for conferring passive protection. Moreover, a combination of scFvs with antiretroviral drugs can be an effective strategy to suppress viremia at an early stage and thus block HIV-1 infection in children, mainly acquiring infection by vertical transmission.
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| 99.94 |
This study was approved by the Institute ethics committee, All India Institute of Medical Sciences (AIIMS), New Delhi, India (IEC/NP-536/04.11.2013), and all the experiments were carried out in accordance with relevant institutional and national guidelines and regulations. Written informed signed consent forms were obtained from the parents/guardians of all the study subjects.
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other
| 99.94 |
KL designed and planned the study, edited and finalized the manuscript. SS provided scientific inputs in phage library construction and in discussion section of the manuscript. RL and SKK provided the HIV-1 infected pediatric donors sample. SK performed the research, data analyses, and wrote the manuscript. RK helped SK in construction of phage library; MAM generated the pseudoviruses for neutralization assays; RT, MM, and MA helped SK for the purification of scFv protein, LK helped SK in competition ELISA and affinity determination of scFv monoclonals.
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other
| 99.94 |
Lymphocytic proliferation results from either monoclonal proliferation of neoplastic lymphoma cells or polyclonal proliferation as a normal immune response . A dysregulated or exaggerated response can destroy tissue and impair organ function. Triggers for the activation of cell-mediated immunity are usually microorganisms, such as Epstein-Barr virus (EBV), or possibly neoplastic cells, as seen in paraneoplastic syndromes . With the advancement of immunosuppressive therapy and molecular diagnostic techniques, iatrogenic lymphoproliferative disorder (LPD) in immunodysregulated patients are beginning to be recognized as an emerging medical problem today. We herein report a case of possibly iatrogenic LPD, which required more than two years from the initial presentation until confirmation of malignancy.
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clinical case
| 99.94 |
A 66-year-old woman with a history of rheumatoid arthritis was referred to our hospital after hospitalization at a nearby general care facility for altered mental status and weakness. She had developed a parotid tumor 18 months before while undergoing disease modifying anti-rheumatoid therapy with methotrexate. The tumor was surgically removed and diagnosed as benign T-cell proliferation. The methotrexate was replaced with a monoclonal antibody at that time, and the patient developed fever, fatigue, and hepatosplenomegaly shortly thereafter. A liver biopsy again demonstrated benign T-cell proliferation despite clinical suspicion of infectious mononucleosis. The monoclonal antibody (Tocilizumab) was discontinued, and dexamethasone was administered until clinical remission. Her physician had conducted tests for malignant lymphoma and infectious mononucleosis, all of which were negative. Systemic manifestations were not detected in the radiological findings or by repeated bone marrow analyses. After a disease-free period of eight months, she started to complain of fatigue and weakness and rapidly became bedridden.
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clinical case
| 100.0 |
When the patient was transferred to our hospital, she was weak and drowsy, and the neurological assessment was remarkable for spontaneous nystagmus and severe quadriparesis with positive pyramidal signs. She was normothermic without signs of meningeal irritation. Brain magnetic resonance imaging (MRI) demonstrated multiple lesions in the central nervous system (CNS). She was admitted for further evaluations and treatment as described below.
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clinical case
| 100.0 |
Hematological results were normal without any blast cells. A soluble IL-2 receptor was 473 U/mL in the serum (reference range: 122-496 U/mL) and 103 U/mL in the cerebrospinal fluid (CSF). Her CSF showed pleocytosis of the lymphocytes (18 × 106/L), elevated concentration of proteins (0.10 g/dL), immunoglobulins (IgG 21.8 mg/dL, IgM 1.4 mg/dL), and normal glucose concentration (64 mg/dL). Her serum was positive for rheumatoid factor (18 U/mL), anti-thyroperoxidase antibody (404 IU/mL), and anti-cardiolipin beta-2 glycoprotein I antibody (5.4 U/mL). Infectious workups were nonspecific for serum or CSF. Cytological analysis of the CSF revealed no atypical cells.
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clinical case
| 99.94 |
Brain MRI demonstrated an increased T2 signal at multiple sites in the brain parenchyma, such as the left cerebellar hemisphere, the brainstem, and the right thalamus, some of which were swollen and enhanced with gadolinium (Figures 1A-1F). No lesion was demonstrated in the cervical spinal cord MRI. Computed tomography (CT) scanning of the body did not reveal any massive lesions in the lung, the solid abdominal organs, or the lymph nodes. Malignant lymphoma, lymphomatoid granulomatosis (LYG), neurosarcoidosis, and neuroinflammatory response caused by an unidentified opportunistic infection were suspected.
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clinical case
| 99.94 |
A-B, T2-weighed imaging at initial presentation: (A) Hyperintense signal in the bilateral cerebellar hemispheres; (B) Hyperintensity noted in the bilateral thalamus and bioccipital subcortex; C-F, T2-weighted imaging and T1-weighted imaging with gadolinium enhancement immediately before brain biopsy; (C) Hyperintense lesions noted in the pons and the left side of the cerebellum; (D) Progression of the lesion of the thalamus on the right; (E) Ring-enhancing lesion of the cerebellum; (F) Ring-enhancing lesion of the thalamus.
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clinical case
| 99.9 |
Empirical treatment with methylprednisolone had only suboptimal effects. Repeated brain MRI revealed growth of the lesion in the right thalamus while the lesions in the limbic lobes subsided. Another course of methylprednisolone failed to improve her neurological deficit or radiological abnormality. Because the multiple lesions in the brain parenchyma were considered to be progressing as a whole, a brain biopsy was planned.
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clinical case
| 99.94 |
A stereotactic biopsy was performed under general anesthesia on the 98th day after admission. The tissue sections of the biopsy specimens were prepared for hematoxylin-eosin (HE) staining, periodic acid-Schiff staining, immunohistochemistry for antibodies (glial fibrillary acidic protein, cluster of differentiation 3 (CD3), CD4, CD8, CD10, CD20, CD68, CD79a, T-cell intracytoplasmic antigen-1 (TIA-1), granzyme B, latent membrane protein (LMP), Epstein-Barr virus nuclear antigen 2 (EBNA2), and Ki-67), and in situ hybridization for Epstein-Barr virus expressing mRNA (EBER). Cells in the tissue were extracted, and surface markers were analyzed by flow cytometry. The karyotype was assessed by G-banding.
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clinical case
| 100.0 |
Pathological examination revealed aggressive infiltration of lymphocytes destroying the parenchyma, which was surrounded by a sparsely infiltrated area (Figure 2A). Infiltrating small lymphocytes were positive for CD3. The pattern of infiltration was only partially perivascular, and vessel walls were basically intact (Figure 2B). Well-formed granulomas were not observed. There was a small population of B-cells positive for CD20 or CD79a. EBER and EBNA were both negative in all of the cellular components. Neutrophils and acidophils were rarely observed. Damaged tissue contained an abundance of histiocytes, along with reactive astrocytes. MIB-1 labeling index was less than one percent.
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clinical case
| 99.94 |
Based on these results and the radiological findings, the authors considered the disease to be a form of T-cell lymphoproliferative disorder, in spite of some clinical manifestations resembling lymphomatoid granulomatosis. Because the natural history of this disease condition was not obvious, and the general status of the patient was not deteriorating, we refrained from initiating immediate treatment. Meanwhile, another CT scan of the extracranial regions revealed cervical lymph node swelling.
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clinical case
| 99.94 |
Further, a needle biopsy of the cervical lymph node again revealed T-cell-dominant lymphatic pleocytosis. Flow cytometry demonstrated cellular components similar to those found in the other sites (Figure 3A). However, atypical large cells, which were positive for CD20, weakly positive for paired box 5 (PAX5), CD5, CD30, CD3, CD4, CD8, and TIA-1 and negative for granzyme B, were remarkably commingled with morphologically normal immune cells (Figure 3B). LMP and EBNA2 were negative, but some of the large cells were positive for EBER. The diagnosis of T-cell/histiocyte-rich large B-cell lymphoma (THRLBCL) was made based on the cellular composition and the molecular profile.
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clinical case
| 99.94 |
(A) Flow-cytometry data summarized on a radar chart. The specimens from the parotid gland, the brain, and the cervical lymph node each demonstrated proliferation of the T-cell lineage. (B) Large atypical cells are distributed sparsely against a background of lymph proliferation. (Cervical lymph node, hematoxylin-eosin stain, x 40). (C) magnetic resonance imaging after chemotherapy showed remarkable regression of the lesions.
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clinical case
| 99.9 |
Systemic chemotherapy with rituximab, high-dose methotrexate, and cytarabine was initiated immediately after the diagnosis. Although the imaging studies demonstrated remission of the CNS lesions after two sessions of chemotherapy, the patient remained bedridden (Figure 3C).
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clinical case
| 99.94 |
We described the first case on record of THRLBCL with phasic presentations of extranodal T-lymphoid hyperplasia. Although lymphoproliferative disorders and malignant lymphomas are well-recognized comorbidities in patients under immunosuppressive treatment , this case is remarkable for its presentation of contradictory benign and malignant characteristics. Whereas the metastatic features of the disease implied a malignancy, several facts such as the absence of neoplastic cells in the lesions, the blood, and the CSF, and the self-limiting invasiveness seemed to favor a benign interpretation, raising the issue of whether this disorder could correctly be classified as a single nosological entity.
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clinical case
| 99.94 |
It has been recognized recently that several B-cell neoplasms, such as diffuse large B-cell lymphoma (DLBCL), LYG, and some forms of Hodgkin lymphomas are EBV-related . According to Castillo, et al., DLBCL in the elderly has 100% EBER expression, and DLBCL associated with chronic inflammation, as well as 3-10% of DLBCL cases not otherwise specified, is related to EBV infection . LYG lesions at Stage II and III have 100% EBER expression by definition . Endemic type Burkitt’s lymphoma is also positive for EBV infection . Most of these disorders result from the relapse of dormant EBV secondary to acquired or congenital immunodeficiency status.
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review
| 99.75 |
Although it is difficult to determine how the disease progressed in this patient, two interpretations are possible. Firstly, the patient could have developed lymphoproliferative lesions like LYG, which were progressive. Dormant EBV in B-cells could have become active due to immunosuppression by low-dose methotrexate and/or the immunosenescence of the host, and the cell-mediated immune response could have been provoked by humoral factors from the EBV-positive-B-cells and/or products of EBV. The exaggerated neuroinflammatory response, not the clonal expansion of the neoplastic cells, was the primary pathology of the disease. However, pathological evidence of EBV infection in this patient was weak; EBER expression was absent in the parotid gland, liver, and brain specimens. Moreover, expression of EBER was not ubiquitous in the atypical B-cells observed in the cervical lymph node.
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clinical case
| 99.75 |
Secondly, the patient had developed THRLBCL with or without the influence of methotrexate, which caused multiple extranodal and nodal lesions. The location and the timing of the biopsy could have complicated the results of the CNS pathology. We selected a lesion in the right thalamus for biopsy, while the largest mass was located in the cerebellum. Furthermore, the brain biopsy was performed after two courses of high-dose corticosteroid administration because we expected that steroid therapy would prevent disease progression. Considering the fact that corticosteroids were not administered prior to the biopsies of the non-CNS lesion and that atypical B-cells were not detected in these specimens, this interpretation is less likely.
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clinical case
| 99.94 |
A case of non-CNS THRLBCL mimicking LYG was reported by Olivieri, et al. . The previously healthy patient presented with a large abdominal mass, left-sided inguinal adenopathy, and pulmonary nodular lesions. Pathological findings were remarkable due to the proliferation of EBV-negative large B-cells intermingled with non-neoplastic T-cells and perivascular hypercellularity. The lesion had a stronger malignant profile compared to our case, probably reflecting a different background in immunocompetency. The difficulty of managing these cases points to the need to understand better which signals provoke the infiltration of T-cells.
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clinical case
| 99.94 |
We experienced a case of secondary CNS THRLBCL whose clinical, radiological, and pathological interpretation was inconclusive until the final diagnosis. T-lymphocytic hyperplasia in the context of immunodysregulation may be responsible for occult neoplastic lymphocytes. Further understanding of the molecular pathomechanisms of these diseases will allow us to give the condition a better clinical entity, which would be the first step in order to manage them more effectively.
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clinical case
| 99.94 |
In the human genome, less than 2% of the transcripts encode proteins, and the remaining 98%–99% are non-coding RNAs (ncRNAs) .1 ncRNAs can be divided into two categories: short non-coding RNA (short/small ncRNA) and long non-coding RNA (long ncRNA). No particularly stringent boundary exists between these categories, except for the length of the ncRNA nucleotide sequence. An ncRNA of greater than 200 nt is defined as an lncRNA. In recent years, with the rapid development of RNA sequencing technology and computational methods, lncRNA has been gradually recognized by researchers. lncRNA is widely distributed among animals, plants, yeasts, and even viruses, and we now know that lncRNA can be involved in X chromosome silencing, genomic imprinting, chromatin modification, transcriptional activation, transcriptional interference, epigenetic regulation, and other important regulatory processes.2 These molecules are related to cell proliferation and differentiation, metabolism, and other physiological processes, as well as various pathological processes. The mutation and abnormal regulation of lncRNAs plays an important role in many human diseases, such as the occurrence and development of cancer and neurodegenerative diseases.3, 4, 5
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review
| 99.9 |
Neurodegenerative disease is characterized by the loss of neurons or myelin in the brain and spinal cord, deteriorating over time and leading to dysfunction.6, 7 The brain and spinal cord comprise neurons that have different functions, such as controlling motion, processing sensory information, and making decisions. The cells of the brain and spinal cord are generally not regenerated; thus, excessive damage can be devastating and irreversible. Neurodegenerative diseases are widespread worldwide. The long course and lack of effective treatment of these diseases impose a heavy burden on individuals, families, and society. In recent years, many studies have shown that lncRNA can participate in the regulation of neurodegenerative disease occurrence and development. Based on existing research results, this paper focuses on lncRNA in several common neurodegenerative diseases. We made a summary of lncRNAs involved in this review (Table 1).Table 1Dysregulated lncRNAs in Neurodegenerative DiseaseslncRNAsDescriptionAssociated DiseaseCulprit or BodyguardBiological FunctionBACE1-AStranscribe from the antisense protein-coding BACE 1 geneADculpritbind to BACE1 and increase the stability of its mRNA, thereby promoting the synthesis of BACE1 protein, and further increase the production of Aβ of cellsBC200homologous with rodent BC1 lncRNA; the earliest specific example showed lncRNAs conservationADculpritinduce APP mRNA translation via association with FMRP and then aggregate the accumulation of Aβ in the brain17Aembedded in the human G-protein-coupled receptor 51 geneADculpritimpair GABAB signaling pathway by decreasing GABAB R2 transcriptionNAT-Rad18transcribed from the antisense of protein coding gene Rad18ADculpritdown the expression of DNA repair protein Rad18 and enhance susceptibility to neuronal apoptosis51Aan antisense transcript of intron 1 of the SORL1 geneADculpritaltering the spliced form of SORL1 mRNA and resulting in Aβ42 accumulationGDNFOStranscribed from the opposite strand of GDNF geneADculpritnegatively regulate the expression of GDNFHttAS_v1antisense transcript of the Htt geneHDbodyguardreduce endogenous HTT transcript levelsBDNFOSantisense transcription product of BDNFHDbodyguardupregulates the transcription of BDNF and have a protective effect on neuronsNEAT1a nuclear-enriched ncRNA essential for the formation and maintenance of paraspecklesHDbodyguardessential for the integrity of the nuclear paraspeckle substructure; increase viability under oxidative stressHAR1F and HAR1Rantisense transcripts of the first HAR1 geneHDbodyguardinvolved in neurotransmission, memory structure, and synaptic plasticity in the mature brainDGCR5a transcript of DiGeorge critical region 5HDbodyguardinclude a genome binding site for REST and play an important transcriptional regulatory role in HDMEG3the human homolog of the mouse maternally expressed gene Gtl2, the first imprinted gene identified on the mouse distal chromosome 12HDculpritalter gene expression in response to neuronal activityABHD11-AS1homologous with rodent Abhd11os lncRNAHDbodyguardattenuate the toxicity of Htt mRNANaPINK1transcribed from the antisense of PINK1 locusPDbodyguardstabilize PINK1 expressionAS Uchl1antisense transcript of Uchl1PDbodyguardregulate the expression of UCHL1 at the post-transcriptional level, thus promoting the translation process and increasing protein synthesisHOTAIRantisense intergenic RNA transcribed from the HOXC locusPDculpritincrease the stability of LRRK2 mRNA and upregulated its expression, thus inducing DA neuronal apoptosisMALAT1also known as NEAT2 and is a highly conserved ncRNA highly expressed in neuronsPDculpritupregulate a-synuclein expression, thus driving the pathogenesis of PD
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review
| 99.9 |
lncRNAs were first found in rat full-length cDNA sequence libraries, usually overlapping or dispersed between transcripts. According to location and context, lncRNA can be divided into five categories, including inter-gene long-chain non-coding RNA (intergenic lncRNA, also known as long intergenic ncRNA or lincRNA, which is produced by the transcription of spacer sequences between genes encoded in the genome), intron long-chain non-coding RNA (intronic lncRNA, which is completely transcribed from introns within a protein-coding gene), sense long-chain non-coding RNA (sense lncRNA, transcribed from the coding strand of a protein-coding gene and partly or completely overlapping the gene exons), antisense long-chain non-coding RNA (antisense lncRNA, transcribed from the non-coding strand of a gene), and bidirectional long-chain non-coding RNA (bidirectional lncRNA, transcribed from the promoter region in two opposite directions) (Table 2).8, 9Table 2Classification of lncRNAsClassificationDescriptionExampleIntergenicproduced by the transcription of spacer sequences between genes encoded in the genomeXIST, TMEM161B-AS, HAR1, NEAT1, TUG1Intronictranscribed from introns within a protein-coding geneLnc-OR51B4-3, KCNIP4-IT1Sensetranscribed from the coding strand of a protein-coding gene and partly or completely overlapping the gene exonsSNHG4Antisensetranscribed from the non-coding strand of a geneBACE1-AS, MALAT1, lnc-LRR1, TUSC7Bidirectionaltranscribed from the promoter region in two opposite directionsHoxa11as, IGF2AS, HOTAIRM1
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study
| 99.94 |
At present, the source of lncRNA is not very clear. Ponting et al.10 thought that lncRNA may have arisen in the following ways: mutations in the open reading frames (ORFs) of protein-coding genes during early evolution, leading to structural disruption and then to lncRNA; chromatin recombination resulting in two originally distant non-transcript fragments coming together to produce lncRNA; duplication of non-coding genes formed by reverse transcription transposition; repetition of a certain sequence, resulting in lncRNA with adjacent repeat sequences; and DNA sequence insertion by a transposable element to produce functional lncRNA. Although many lncRNAs have no common origin, they play similar roles in the regulation of gene expression, and their most important function may be epigenetic regulation of the genome.10
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review
| 99.7 |
lncRNA is located in the nucleus or cytoplasm and lacks the ability to encode proteins. Initially, biologists thought that lncRNA had no biological function and was only the “noise” of genomic transcription, a byproduct of the activity of RNA polymerase II (RNA PII).11 However, with further research, people have gradually gained a deeper understanding of lncRNA, its presence in the subcellular structure, and its ability to regulate protein localization and activity. lncRNA can regulate gene expression by recruiting RNA PII or inducing chromatin recombination.12 Compared with small ncRNA, lncRNA has a relatively long chain of nucleotides, meaning that the internal folding of lncRNA molecules can form many specific and complex secondary spatial structures; these structures provide multiple sites, allowing interaction with a number of other molecules to perform biological functions involved in regulating growth and development,13 cell proliferation and differentiation,14 apoptosis,15 and other processes. Meanwhile, a variety of clinical diseases are closely related to lncRNA.16 Although the mechanisms of lncRNA involvement in various diseases are not fully understood, this study shows that lncRNA is widely involved in various regulatory mechanisms. lncRNA can be released after being activated by cellular stress and then form complexes with the ribosome to regulate gene expression. Molecular studies have suggested that lncRNA may work in the following modes. (1) Interacting with chromatin: lncRNA regulates the upstream promoter regions of coding genes by mediating chromatin remodeling and histone modification and then affects the expression of related genes. (2) Interacting with proteins: lncRNA can be used as a guiding molecule for a single protein or it can act as a scaffold molecule for two or more proteins to synthesize a protein complex and then recruit the complex to corresponding locations in coding genes to regulate the expression of downstream genes. In addition, lncRNA can also be used as a bait molecule for proteins. It can transfer proteins that are bound to the genome and change their intracellular localization, thereby inhibiting gene transcription and expression. (3) Interaction with other RNAs: many specific microRNA (miRNA) recognition sites are present in lncRNA. On the one hand, miRNAs can affect the stability of lncRNA in vivo, mediating the degradation of lncRNA and thus regulating its cell biological functions. On the other hand, lncRNA can act as a bait molecule for miRNA, targeting miRNA by target mimicry and inhibiting its further action, thus indirectly regulating the expression of miRNA target genes. In addition, lncRNA can act as an endogenous competitor of miRNA by binding miRNA-binding sites on mRNA.17, 18 Moreover, lncRNA can regulate mRNA at the post-transcriptional level by mRNA transcription inhibition, splicing, and degradation.19
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review
| 99.8 |
Aβ is a normal metabolite generated by the hydrolysis of β-amyloid precursor protein (APP). β-site APP cleaving enzyme 1 (BACE1), a membrane-bound aspartic protease, is involved in the processing of APP and cleaves it to Aβ. BACE1-AS (BACE1-antisense) is an antisense transcript of BACE1. The expression of BACE1-AS in the brain of AD patients is upregulated, suggesting that BACE1-AS may play a role in the pathogenesis of AD.21, 22 Studies have shown that BACE1-AS can bind to BACE1 mRNA, increase the stability of the latter, thereby promoting the synthesis of BACE1 protein,21 and further increase the production of Aβ of cells. Faghihi et al.23 found that the microRNA miR-485-5p, sharing the same binding sites with BACE1 to BACE1 mRNA, inhibited the expression of BACE1 through competition.
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study
| 100.0 |
Brain cytoplasmic (BC) RNA is another lncRNA that causes AD and brain aging. Mouse BC1 RNA and human BC200 RNA are lncRNA transcripts that are transported as ribonucleoprotein particles to the dendritic processes and bind to poly(A)-binding protein (PABP1), a regulator of translation initiation, thus regulating gene expression at the translational level.24 BC200 can interact with some RNA-binding proteins involved in aberrant transport of mRNA, leading to abnormal protein localization. Overexpression of BC200 in AD and the aging brain may cause synaptic/dendritic degeneration. Mus et al.25 found that the level of BC200 in the AD-affected brain region Brodmann area 9 was higher than that in the normal brain, and the relative level of BC200 RNA in the affected region increased in parallel with AD severity. Simultaneously, they found that in the advanced stage of AD, BC200 RNA often assumed a clustered perikaryal localization, indicating that dendritic loss is accompanied by somatic overexpression. Mus et al. concluded that this was a stress compensation mechanism initiated by dendritic sprouting and remodeling in AD degenerative lesions; they also thought that the abnormal localization and distribution of BC200 might be responsible for the cause and course of the disease. Whether BC200 overexpression in brain tissue is the cause of AD or an accompanying compensatory response will require further testing and confirmation.26 Recently, Zhang et al.27 showed that BC1 induces APP mRNA translation via association with a fragile X syndrome protein (FMRP). Inhibition of BC1 or BC1-FMRP association in AD mice blocks the aggregation of Aβ in the brain and improves spatial learning and memory. Expression of exogenous BC1 in mouse excitatory pyramidal neurons shows the opposite result. This study may provide a novel promising target for AD therapy.
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study
| 54.16 |
Under inflammatory stimulation, lncRNA-17A can direct G-protein-coupled receptor 51 (GPR51) splicing to produce isoform variant B of the B-type receptor for the neurotransmitter g-aminobutyric acid (GABA; GABAB receptor). Because only the canonical variant, isoform A, contains the complete C-terminal portion needed to interact with GABAB R1 to generate a functional heterodimeric receptor, this alternative splicing causes the synthesis of a non-functional GABAB receptor. In addition, the overexpression of 17A causes an overproduction of Aβ.28
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study
| 100.0 |
Some lncRNA polymorphisms are associated with AD pathogenesis. For example, rs7990916 (T > C) located in the lincRNA TCONS_00021856/linc-SLITRK5-11 gene showed significant differences between AD patients and a normal control group.29 Rad18 is involved in proliferating cell nuclear antigen (PCNA) ubiquitination and plays an important role in DNA repair following nerve injury. After Aβ-induced apoptosis, the Rad18 gene antisense transcription product lncRNA NAT-Rad18, which exerts post-transcriptional control over Rad18, is upregulated, suggesting that it may enhance susceptibility to neuronal apoptosis; excess cell loss may contribute to AD.30 lncRNA 51A is an antisense transcript of intron 1 of the sorting protein-related receptor 1 (SORL1) gene, resulting in Aβ42 accumulation by altering the spliced form of SORL1 mRNA.31 Zhou et al.32 have found 24 upregulated and 84 downregulated lncRNAs in AD patients compared with controls, most being intergenic. Gene set enrichment analysis identified a downregulated lncRNA, n341006, in association with the protein ubiquitination pathway, and a significantly upregulated lncRNA, n336934, linked to cholesterol homeostasis. The lncRNA GDNFOS is a transcriptional product transcribed from the opposite strand of glial-cell-line-derived neurotrophic factor (GDNF) that may negatively regulate the expression of GDNF to promote the course of AD.33 Neuroblastoma differentiation marker 29 (NDM29), which is an RNA polymerase (pol) III-transcribed ncRNA, can be promoted by inflammatory stimuli and induces APP synthesis, leading to the increase of Aβ secretion and the process may occur in AD (Figure 1).34Figure 1Role of lncRNAs in ADBACE1-AS can bind to BACE1 mRNA, increase the stability of the latter, and promote the synthesis of BACE1 protein, further increasing the production of cell Aβ. miRNA miR-485-5p has an inhibitory effect on BACE1 expression, whereas miRNA miR-485-5p and BACE1-AS have the same binding sites on BACE1 mRNA, so their regulation of BACE1 mRNA expression is antagonistic. BC1 induces APP mRNA translation via association with FMRP. Under inflammatory stimulation, lncRNA-17A can direct GPR51 splicing to produce GABAB receptor isoform variant B, thus causing the synthesis of a non-functional GABAB receptor. In addition, overexpression of 17A causes overproduction of Aβ.
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study
| 99.94 |
BACE1-AS can bind to BACE1 mRNA, increase the stability of the latter, and promote the synthesis of BACE1 protein, further increasing the production of cell Aβ. miRNA miR-485-5p has an inhibitory effect on BACE1 expression, whereas miRNA miR-485-5p and BACE1-AS have the same binding sites on BACE1 mRNA, so their regulation of BACE1 mRNA expression is antagonistic. BC1 induces APP mRNA translation via association with FMRP. Under inflammatory stimulation, lncRNA-17A can direct GPR51 splicing to produce GABAB receptor isoform variant B, thus causing the synthesis of a non-functional GABAB receptor. In addition, overexpression of 17A causes overproduction of Aβ.
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study
| 100.0 |
Given that aging is also one of the major risks of neurodegenerative diseases, the role of lncRNA in aging cannot be overlooked. Zhang et al.35 have identified 97 significantly upregulated and 114 significantly downregulated lncRNA transcripts from the senescence-accelerated mouse prone 8 (SAMP8) and senescence-accelerated mouse resistant 1 (SAMR1) models. These significantly dysregulated lncRNAs were involved in nerve growth factor term, the mitogen-activated protein kinase signaling pathway, and the AD pathway, thus regulating the development of AD.
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study
| 99.94 |
In HD, the Huntingtin (Htt) protein accumulates gradually in cells, forming large molecules that accumulate in the brain, affecting the function of nerve cells, and resulting in the progressive death of the striatum and cortical nerve cells. lncRNA HttAS_v1 is an antisense transcript of the Htt gene and is expressed at a low level in the frontal cortex of HD patients, leading to high expression of Htt mRNA, which in turn promotes HD pathogenesis.36 Htt modulates the nuclear translocation of the transcriptional repressor RE1 silencing transcription factor/neuron-restrictive silencer factor (REST/NRSF). Mutant Htt promotes abnormal nuclear-cytoplasmic transport of REST/NRSF and then leads to abnormal expression of REST target genes, including protein-coding and non-coding genes (Figure 2).37, 38Figure 2Role of the lncRNA HttAS-v1 in HDThe expression of HttAS-v1 is decreased in HD patients, resulting in high expression of Htt mRNA. Htt is involved in the translocation of REST/NRSF into the nucleus, retaining REST/NRSF in the cytosol and thereby preventing REST/NRSF target gene repression.
|
study
| 100.0 |
The expression of HttAS-v1 is decreased in HD patients, resulting in high expression of Htt mRNA. Htt is involved in the translocation of REST/NRSF into the nucleus, retaining REST/NRSF in the cytosol and thereby preventing REST/NRSF target gene repression.
|
study
| 100.0 |
BDNFOS is an antisense transcription product of brain-derived neurotrophic factor (BDNF), which upregulates the transcription of BDNF and the translation of BDNF-mRNA in HD. Small interfering RNA (siRNA) treatment with BDNFOS can induce Htt expression. BDNFOS has a protective effect on neurons and improves the HD phenotype,39 which is of some positive significance in the prevention and treatment of HD.
|
study
| 99.5 |
NEAT1 (nuclear paraspeckle assembly transcript 1) is a nuclear-enriched ncRNA essential for the formation and maintenance of paraspeckles, which are subnuclear bodies found in mammalian cells.40 Sunwoo et al.4 found that NEAT1 levels increased in R6/2 mice and HD patients. To determine the biological effects of NEAT1 on neuronal survival, they transfected neuro2A cells with NEAT1 short isoform vector and subjected them to H2O2-induced damage. The NEAT1-transfected cells showed increased viability under oxidative stress, confirming that NEAT1 upregulation contributes to neuroprotective mechanisms against neuronal damage, rather than to the pathology of neurodegenerative diseases.
|
study
| 100.0 |
To detect ncRNAs involved in the pathogenesis of HD, one study examined the ncRNA expression profile of human HD brain tissue and found that the expression of the lncRNAs HAR1F and HAR1R, which are antisense transcripts of the first human accelerated region 1 (HAR1) gene, was significantly reduced in the striatum. These lncRNAs are involved in neurotransmission, memory structure, and synaptic plasticity in the mature brain, and their aberrant expression is also associated with HD.41 The same study also demonstrated that abnormal REST nuclear-cytoplasmic exchange in the striatum of HD led to effective transcriptional repression of HAR1.42 The lncRNA DGCR5 is a transcript of DiGeorge critical region 5 (DGCR5) and includes a genome-binding site for REST, which plays an important transcriptional regulatory role in HD.43 The expression of the lncRNA MEG3, encoded by maternally expressed gene 3 (MEG3), was downregulated in HD brain tissue, and its downregulation was also inhibited by REST.44 There is much disparate research showing that MEG3 may be an important epigenetic regulator in the developing and adult human brain, which may stably alter gene expression in response to neuronal activity. If so, the downregulation of MEG3 in HD could plausibly have serious consequences. Overexpression of the lncRNA Abhd11os (ABHD11-AS1 in humans) attenuates the toxicity of Htt mRNA in murine models of HD. Studies have shown that knocking out the Abhd11os gene in the HD mouse model produces neurotoxicity, whereas overexpression of Abhd11os has a neuroprotective effect.45
|
study
| 97.06 |
Parkinson’s disease (PD) is a chronic progressive movement disorder caused by loss of brain dopaminergic neurons. PD is a common neurodegenerative disease in the elderly, with clinical symptoms such as resting tremor, muscle tension instability, and posture instability.
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other
| 99.9 |
Loss or overexpression of PTEN-induced kinase 1 (PINK1) results in abnormal dopamine release and impaired motor function.46 NaPINK1 is a human-specific ncRNA transcribed from the antisense orientation of the PINK1 locus that can stabilize PINK1 expression. NaPINK1 silencing results in decreased PINK1 expression in neurons.47
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study
| 99.94 |
The ubiquitin carboxy-terminal hydrolase L1 gene (Uchl1) has been shown to be closely related to brain function and neurodegenerative diseases. An antisense transcript of Uchl1, AS Uchl1, can regulate the expression of UCHL1 at the post-transcriptional level and enhance contact between post-transcriptional mRNA and polysaccharides, thus promoting the translation process and increasing protein synthesis. This activity has been disrupted in patients with familial PD, and studies have reported losses of UCHL1 activity in many other neurodegenerative diseases.48, 49 Regulation of Uchl1 expression can provide new ideas for PD treatment.
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study
| 99.8 |
Previous studies have showed that a-synuclein aggregation is the driving force in PD pathogenesis.50 Metastasis associated lung adenocarcinoma transcript 1 (MALAT1), also known as nuclear-enriched abundant transcript 2 (NEAT2), is a highly conserved ncRNA highly expressed in neurons.39, 51 Recently, research has shown MALAT1 overexpression upregulated a-synuclein expression, whereas inhibition of MALAT1 downregulated its expression only in the protein level rather than the mRNA level. Giving β-asarone, the major ingredient of Acorus tatarinowii Schott, can decrease the expression levels of MALAT1 and a-synuclein in the midbrain tissue of PD mice, suggesting β-asarone as a potential therapeutic agent for PD.52
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study
| 99.94 |
Leucine-rich repeat kinase 2 (LRRK-2) is thought to be involved in the initiation/development of PD.53 Recently, research has shown that HOTAIR (Hox transcript antisense intergenic RNA), an approximately 2.2-kb-long noncoding RNA transcribed from the HOXC locus, is upregulated in a mouse model of PD that is developed by intraperitoneal injection of MPTP. The upregulated HOTAIR can specifically increase the stability of LRRK2 mRNA and upregulated its expression, thus inducing DA neuronal apoptosis (Figure 3).54Figure 3Role of lncRNAs in PDNaPINK1 can stabilize PINK1 expression. AS Uchl1 can regulate the expression of UCHL1 at the post-transcriptional level and enhance contact between post-transcriptional mRNA and polysaccharides, thus promoting the translation process and increasing protein synthesis. HOTAIR can increase the stability of LRRK2 mRNA and upregulated its expression, thus inducing DA neuronal apoptosis. MALAT1 can upregulate a-synuclein expression, thus driving the pathogenesis of PD.
|
study
| 99.94 |
NaPINK1 can stabilize PINK1 expression. AS Uchl1 can regulate the expression of UCHL1 at the post-transcriptional level and enhance contact between post-transcriptional mRNA and polysaccharides, thus promoting the translation process and increasing protein synthesis. HOTAIR can increase the stability of LRRK2 mRNA and upregulated its expression, thus inducing DA neuronal apoptosis. MALAT1 can upregulate a-synuclein expression, thus driving the pathogenesis of PD.
|
study
| 100.0 |
Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease that has no effective therapeutic means at present. ALS is characterized by the progressive paralysis of the limbs and muscles involved in speech, swallowing, and respiration due to the progressive degeneration of spontaneous motor neurons. In 2011, the repeated amplification of a six-nucleotide motif (GGGGCC) in the protein-coding gene C9ORF72 (chromosome 9 ORF 72) became the first identified causative mutation in ALS and front temporal dementia (FTD).55, 56 Non-coding transcripts have now also been identified at the C9ORF72 locus. The transcription of the C9ORF72 repeats is bidirectional, producing both sense and antisense RNAs,57 both of which are elevated in the brains of ALS patients, and these transcripts are localized predominantly in the nucleus.58 C9ORF72 antisense lncRNA can inhibit C9ORF72 mRNA, thereby inhibiting gene expression. However, even if the expression of a disease-related gene is corrected in fibroblasts derived from a patient, the disease still cannot be treated.58
|
review
| 98.94 |
TDP43 (TAR DNA-binding domain protein 43) and FUS/TLS (fused in sarcoma/translated in liposarcoma) are RNA-binding proteins that are predominantly located in the nucleus and play a role in regulating RNA metabolism. Studies have shown that abnormal accumulation of FUS/TLS and TDP43 in the cytosol directly leads to the misfolding of wtSOD1 (wild-type Cu/Zn superoxide dismutase) in non-SOD1 FALS (familial ALS) and SALS (sporadic ALS), which means that they constitute common molecular pathogenesis mechanisms of ALS.59 A previous study found that lncRNA could recruit FUS/TLS to the genomic locus that encodes cyclin D1, where cyclin D1 transcription is repressed in response to DNA damage signals, resulting in increased tolerance to apoptosis signals and indicating that lncRNA may play a role in pathological changes in ALS (Figure 4).60, 61Figure 4Role of lncRNAs in ALSlncRNA could recruit FUS/TLS to the genomic locus that encodes cyclin D1, where cyclin D1 transcription is repressed in response to DNA damage signals, resulting in increased tolerance to apoptosis signals.
|
study
| 100.0 |
With the rapid development of RNA sequencing technology and computational methods, lncRNA has gradually been recognized by researchers, and the current research regarding lncRNA in neurological diseases has made some progress. The expression patterns of most lncRNAs are more tissue specific than those of their respective mRNAs, suggesting that lncRNAs can be used as molecular markers for disease diagnosis and drug design. In view of the specificity effects of certain lncRNAs, targeted therapeutic drugs can be designed to minimize the impact of other unrelated genes to achieve the purpose of personalized treatment. However, the evidence for the association of lncRNAs with neurological disease is mainly due to differences in expression, and only a few functions of lncRNAs have been clearly demonstrated. Dynamic analysis of changes in the body is constrained by available analytical techniques. Along with the specificity of lncRNA itself, such as its numerous species, the small amount of information contained in the original sequences and the limitation of research methods have contributed to the superficiality of our knowledge of the mechanism of lncRNA action and of other regulatory mechanisms. It remains necessary to continue to pursue in-depth research into the effects of lncRNA and other regulatory mechanisms affected by the microenvironment of the body.
|
review
| 99.9 |
Many elderly will experience a reduction in physical function, leading to more falls and injuries. This leads to a loss of independence, hospitalisation, long-term nursing home care as well as premature death [1, 2]. In 2013, 2.63 million people in Germany were in need of nursing care. Roughly two third of them received ambulatory nursing care and one third received care in a nursing home. From the years 2011 to 2013, people receiving nursing care increased by 5% . In 2014, 27% of the population aged 65–79 received either ambulatory or institutionalised nursing care . Given the projected demographic changes in Germany, the population in the age group ≥65 years will increase from 21% (17.3 million) in the year 2015 to 27% (21.8 million) in the year 2030 . Long term nursing care and institutionalisation in a nursing home can be associated with a significant reduction of quality of life, mainly due to loss of autonomy and social contacts . The increased need of long term nursing care poses a major economic challenge . Thus measures to prevent, minimise or delay long term nursing care for elderly are urgently needed.
|
review
| 99.4 |
Germany has mandatory nursing care insurance attached to statutory health insurance since 1995. Elderly with disabilities or dementia can apply for a nursing care level [Pflegestufe]. To identify elderly in need, a basic geriatric assessment performed in general practice was introduced in 2005 . Although elderly are entitled to rehabilitative services as codified in the Book V (SGB V) and XI (SGB XI) of the German social code general practitioners have only limited access to specialised rehabilitative services for geriatric patients. While the number of hospitals providing geriatric services is increasing, the demand for ambulatory services is not met . Elderly patients with a need for rehabilitation prefer to stay close to their home and relatives, maintaining their everyday life . Consequently, ambulatory rehabilitation is preferred. Rehabilitative services were and are still mainly available after hospitalisation e.g. for stroke or fracture after a fall.
|
other
| 99.9 |
Preventive ambulatory geriatric rehabilitation (AGR [Ambulante Geriatrische Komplexbehandlung]) was introduced in 2008 within the legal frame (§ 140 Book V of the social code) of selective contracts for integrated care. Therefore it is only available as a model intervention in some areas for holders of specific statutory health insurances (e.g. AOK Nordost). AGR is not part of regular health care.
|
other
| 99.94 |
It is intended as a community based outpatient intervention to improve patient’s physical function, increase patient’s safety and quality of life as well as to prevent falls and injuries, to avoid and delay hospitalisation, the progression of nursing care level and admission to nursing home.
|
other
| 99.94 |
A systematic review of controlled trials of ambulatory and hospital interventions to improve physical function and maintain independent living in elderly people concluded that they were effective to achieve the goal . This review comprised only one German trial which included geriatric patient post hospital discharge . However, AGR is primarily intended to prevent hospitalisation and not as a post-discharge rehabilitation. The effectiveness of German AGR programs has not been evaluated rigorously yet. Previous studies have relied on uncontrolled study designs .
|
review
| 99.9 |
The aim of our study is to evaluate the effectiveness of AGR regarding patient’s progression to higher nursing care levels, incident fractures, admission to nursing home, hospital admissions as well as health care costs. For this purpose we compare patients receiving AGR with patients receiving care as usual. We will estimate average treatment effects based on a cohort design using propensity score techniques to match cases and controls. The follow-up period will be up to 2 years.
|
study
| 100.0 |
Our secondary hypotheses are:AGR decreases and delays hospital admissions and reduces the days spent in hospital during follow-up time.AGR decreases and delays ambulatory care sensitive hospital admissions.AGR decreases total health care costs from the statutory health insurance perspective.
|
other
| 50.94 |
The conduct of a randomised controlled trial to assess the effectiveness of AGR is currently limited due to logistic and ethical reasons. Therefore we will conduct a matched cohort study using claims data. Anonymised data will be provided by the statutory health insurance AOK Nordost which comprises basic demographic data, data on nursing care level, admission to a nursing home, billing data for ambulatory services (EBM position numbers) and for hospital services (DRG-codes/OPS-codes), as well as diagnoses (ICD-10 codes), and all health care costs, including costs for hospitalisation, remedies and aids, ambulatory costs and costs for medication. To balance potential confounders, we will apply a propensity score matching. Controls will be matched patients insured by the AOK Nordost.
|
study
| 87.25 |
The observation period comprises 4 billing periods (each 3 months, corresponding to 1 year) prior to the intervention, the intervention (index) billing period, and up to 8 billing periods post intervention, resulting in a total observation period of up to 13 billing periods. The billing period covering the most days of the intervention will be considered as the index billing period. Participants in the intervention group received a 4 weeks AGR in between the years 2009 and 2013.
|
other
| 95.6 |
AGR is a multimodal intervention consisting of physiotherapy, ergotherapy, speech therapy, occupational therapy, social support by qualified social workers, psychological counselling and counselling regarding aids and care. Patients who are deemed suitable for AGR by their general practitioners can be referred to special rehabilitation centre for a geriatric assessment. If they fulfil eligibility criteria for AGR and agree to participate they receive the intervention. The intervention is tailored to the patients’ needs and delivered in individual and group sessions. Patients are commonly treated for a total of 20 days with two to three 30 min therapy units per day. Included are meals and a pick up and return service for the elderly every day. During the intervention period AGR was available in three locations in Mecklenburg-Vorpommern (Trassenheide, Ueckermünde, Waren) (Fig. 1).Fig. 1Map of Mecklenburg-Vorpommern with the three locations which provided AGR
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other
| 99.44 |
Due to selective contracts only patients insured by the AOK Nordost are entitled to receive AGR. The geriatric assessment comprises the activity of daily living scale (Barthel-Index), instrumental activity of daily living, Timed “Up & Go”, Chair-Rising-Test, Tandem Stance, Berg-Balance-Scale, and handgrip strength. Eligibility criteria are:Aged 70 and olderat least two geriatric multimorbidity listed in Table 1 impairment or handicap with functional deficitsat least one of the health conditions listed in Table 2 Table 1Geriatric multimorbidityCriteriaICD-10 codesImmobilityM96.8, M62.3, M62.5cognitive impairmentG30, F00 – F07incontinenceR32, N39, R15decubitus ulcerL89, L97, I83, L98MalnutritionR64, E41, E43, E44Disturbances in fluid and electrolyte balanceE86, E87, R60Depression and AnxietyF30 – F33, F40, F41chronic painR52paraesthesiaR20, G50 – G59, G60 – G64frailtyR54severe visual or hearing impairmentH25, H28, H52-H54, H90, H91 Table 2Eligibility criteria for participation in AGREligibility criteriaICD-10 codesStroke and other cerebrovascular disordersI60-I69Status post fractureS72.-Arterial obstructive disease with amputation or other surgeryI70.-Cox and osteoarthritis with Implantation of an endoprosthesisM16.-, M17.-Heart failureI50.-Exacerbated chronic obstructive pulmonary diseaseJ44.0, J44.1Pneumonia and other respiratory tract infectionsJ10-J22Other fractures and injuriesS00-T98Other arthropathiesM00-M25Spondylopathies and Discopathies, possibly with laminectomyM45-M51Coronary heart disease and other heart diseases with cardiac surgeryI05-I09; I20-I25Delirium and other organic brain psychosisF00-F05OsteoporosisM80-M81Secondary ParkinsonsyndromG20.9Symptoms, effecting the nervous system and musculoskeletal systemR29.5, R29.6, R29.8
|
other
| 99.0 |
We aim to quantify treatment effects for typical AGR patients. Therefore, we will exclude participants with rare conditions which are likely to affect the health course beyond the effects which can be reasonably assumed from AGR (e.g. organ transplantation, dialysis, chemotherapy) or participants with extremely high health care costs indicating severe conditions. Prespecified criteria used to exclude AGR participants from our analyses are shown in Table 3. Exclusion criteria for AGR participants also apply to potential controls.Table 3Criteria for the exclusion of AGR participants for study analysisExclusion criteria- Age <70 or >95 years in the intervention billing periodPrior to the intervention billing period:- nursing care >2- <360 insured days in the four previous billing periods- living in a nursing home- hospital costs without out of pocket spending at the last billing period >33.000 €- hospital costs without out of pocket spending during the four last billing periods ≥44.000 €- ambulatory costs during the last billing period ≥2.200 €- ambulatory costs during the four last billing periods ∑ ≥5.500€- remedy costs without out of pocket spending during the four previous billing periods ≥2.200 €- costs of aid without out of pocket spending during the four previous billing periods ≥4.000 €- drug costs without out of pocket spending during the four previous billing periods AGR ≥11.000 €- total health care costs without out of pocket spending during the four previous billing periods ≥44.000 €- diagnosed AIDS/HIV in the four previous billing periods- chemotherapy in the four previous billing periods- organ transplantation during the four previous billing periods- dialysis during the four previous billing periods
|
study
| 100.0 |
The intervention group consists of all AGR participants, receiving the AGR in Mecklenburg-Vorpommern during the years 2009–2013. This will comprise approximately 700 patients. Controls will be chosen from a pool of around 250.000 members of the AOK Nordost aged 70 years and older. Approximately 2800 controls will be selected from the pool.
|
other
| 98.94 |
Claims data will comprise the billing periods from 01.01.2008 until 31.12.2014, thus ensuring a minimal observation period of 12 months prior and after the index billing period. All variables are provided for each billing period during the observation period.
|
other
| 99.9 |
Four nursing care levels (0–3) are defined by the German social code XI (SGB XI). The nursing care level needs to be approved by the Medical Review Board of the statutory health insurances (MDK) in a standardised procedure. The definition for nursing care level is described in Table 4 . Elderly who do not reach the requirements for nursing care level I, but need help for daily living (SGB XI § 45a) receive care for their needs. This is referred to as nursing care level 0 .Table 4Definitions of the nursing care levels RequirementsNursing care leveltotal daily help(including help in household)personal help (included in total daily help) 1minimum 1,5 h>45 min 2minimum 3 h≥2 h, 3 times a day 3minimum 5 h≥4 h permanent help
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other
| 99.9 |
Secondary outcome variables are ‘any hospital admission’ (yes/no), ‘days spent in the hospital’, ‘ambulatory care sensitive hospital admissions’ (yes/no) and ‘total health care costs from the statutory health insurance perspective’ during the entire follow-up period and during each billing period in the follow-up period. Ambulatory care sensitive hospital admissions are defined as potentially preventable hospital admissions by interventions in primary care and are displayed in Table 5. Conditions were chosen from two studies [14, 15].Table 5Ambulatory care sensitive conditions used to define hospital admissions to be prevented by AGR (according to [14, 15])Ambulatory care sensitive conditionsICD-10 codeIschaemic heart diseasesI25.0, I25.1, I25.5, I25.6, I25.8, I25.9Heart failureI50Other diseases of the circulatory systemI05, I06, I08.0, I49.8, I49.9, I67.2, I67.4, I70, I73, I78, I80.0, I80.80, I83, I86, I87, I95, R00.0, R00.2Bronchitis & COPDJ20, J21, J40-J44, J47Mental and behavioural disorders due to use of alcohol or opioidsF10, F11Back pain [dorsopathies]M42, M47, M53, M54HypertensionI10 - I15Gastroenteritis and other diseases of intestinesK52.2, K52.8, K52.9, K57, K58, K59.0Intestinal infectious diseasesA01, A02, A04, A05, A07-A09Influenza and pneumoniaJ10, J11, J13, J14, J15.3, J15.4, J15.7, J15.8, J15.9, J16.8, J18.0, J18.1, J18.8, J18.9Ear nose throat infectionsH66, H67, J01-J04, J06, J31, J32, J35Depressive disordersF32, F33Diabetes mellitusE10.2-E10.6, E10.8, E10.9, E11, E13.6, E13.7, E13.9, E14, E16.2Gonarthrosis [arthrosis of knee]M17.0, M17.1, M17.4, M17.5, M17.9Soft tissue disordersG56.0, M67.4, M71.3, M75-M77, M79Other avoidable mental and behavioural disordersF40, F41, F43, F45, F50.0, F50.2, F60Diseases of the eyeH25, H40Diseases of urinary systemN30, N34, N39.0Sleep disordersG47Diseases of the skin and subcutaneous tissueA46, L01, L02, L04, L08.0, L08.8, L08.9, L60.0, L72.1, L98.0Thyroid disorderE03 - E05, E89.0Metabolic disordersE86, E87.6Melanoma and other malignant neoplasms of skinC43, C44Gastritis and duodenitisK21, K29.7, K29.9, K30, K31Migraine and headache syndromesG43, G44.0, G44.1, G44.3, G44.4, G44.8, R51Malnutrition & nutritional deficienciesE40 - 64, R63.6, D50, D51-D52, D53.1, D56Alcoholic liver diseaseK70Dental diseasesK02, K04-K06, K08, K12, K13Inflammatory diseases of female pelvic organs and disorders of female genital tractN70-N72, N75, N76, N84.1, N86, N87DementiaF01, F03Diseases of male genital organsN41, N45, N48.4AsthmaJ45Other polyneuropathiesG62Avoidable infectious and parasitic diseasesA15.3, A15.4, A15.9, A16.2, A16.3, A16.5, A16.8, A16.9, A34 - A37, A50-A58, A63, A64, A80, B05 - B07, B15, B16.1, B16.9, B17, B18.0, B18.1, B20 - B24, B26, B34.9, B51 - B54, B77, B86Convulsions, not elsewhere classifiedR56Decubitus ulcer and pressure areaL89ObesityE66Rare diseases with <5000 cases eachF80, R63.0, R63.3, R63.8, Z73CellulitisL03, L04, L08.0, L08.8, L08.9, L88, L98.0, I891, L010, L011, L020 - L024, L028, L029AnginaI20, I24.0, I24.8, I24.9, I25, R072, R073, R074, Z034, Z035Convulsions and epilepsyG25.3, G40, G41, O15, R56, R568Dehydration and infectionsA02, A04, A09, A05.9, A07.2, A08.0, A08.1, A08.3, A08.4, A08.5, E86, K52.0, K52.1, K52.2, K52.8, K52.9GangreneR02Iron-deficiency anaemiaD46.0, D46.1, D46.3, D46.4, D50.1, D50.8, D50.9, D51.0–D51.3, D51.8, D52.0, D52.1, D52.8, D52.9, D53.1, D57.1, D58.0, D58.1, D59.0 – D59.2, D59.9, D60.1, D60.8, D60.9, D61.0, D61.1, D64.0 - D64.4, D64.8Pelvic inflammatory diseaseN70, N73, N74Perforated/bleeding ulcerK20, K21.0, K21.9, K22.1, K22.6, K25.0 – K25.2, K25.4 – K25.6, K25.9, K26.0 – K26.2, K26.4 – K26.6, K27,K28.0 – 28.2, K28.4 – K28.6, K92.0, K92.1, K92.2, L97PyelonephritisN10, N11, N12, N13.6, N15.9, N30.0, N30.8, N30.9, N39.0,Atrial fibrillation and flutterI47.1, I47.9, I49.5, I49.8, I49.9, R00.0, R00.2, R00.8ConstipationK59.0Deliberate self-harmS16Dyspepsia and other stomach function disordersK21, K30HypokalaemiaE87.6NeurosesE10, E13.6 – E13.9, E14.9TuberculosisA15, A16, A17, A18, A19SchizophreniaF20, F21, F23.2, F25StrokeI61, I62, I63, I64, I66, I67.2, I69.8, R47.0
|
study
| 99.94 |
‘Total health care costs’ comprises expenditures for hospitalisation, remedies and medical aids, ambulatory costs, and medication. The variables concerning costs refer to costs excluding out-of-pocket spending except for remedies and medical aids where the available data does not allow for any separate analysis of out-of-pocket spending.
|
other
| 99.9 |
To balance the distribution of potential confounders among cases and controls we will conduct a propensity score matching using a many-to-one matching . Variables for the estimation of the propensity score will be selected based on their expected importance to predict AGR participation as well as the outcomes of interest.
|
study
| 99.94 |
We will perform a two-step matching process. In the first step, for all patients who received AGR in a determined billing period, we plan to match controls with similar morbidity and cost characteristics during a.) the four billing periods prior to the index period in which the intervention took place, and b.) by additionally including the index period in the matching. This first step allows for the definition of an index period in controls. Using variables during the index billing period is complicated by the fact that no information on the temporal sequence of events within a billing period is available due to legally obliged data protection agreements. However, ignoring the index period may lead to a systematic ignorance of events leading to AGR which might have taken place in the index period. Therefore results from both analysis scenarios (a., b.) will be systematically compared. The first-step will be conducted as an exact match (pre matching) on selected variables listed in Table 6. These variables were selected due to their high expected conceptual importance for the estimation of treatment effects. Should no adequate numbers of controls be found, a more lenient matching may be employed. Controls will be drawn with repetition across billing periods. We plan to match up to 100 controls per case at this stage.Table 6Matching criteriaMatching CriterionPre MatchingPropensity ScoreAgex ± 2 yearsxSexxxArea of residencexDays being insuredxLevel of nursing carexxHospital admission yes/noxxCharlson Comorbidity index (CCI)xDays spent in the hospitalxHospital costs without out-of-pocket spendingxxAmbulatory costsxCosts of remedyxCosts of medical aidxDrug costs without out-of-pocket spendingxxTotal costs with out-of-pocket spendingxMain diagnoses before AGR Musculo-skeletal x a Status post fracture or joint replacement Cox- or gonarthrosis with endoprothesisx Other fractures and injuriesx Other arthropatiesx Osteoporosisx Spondylopathies and Discopathies, possibly with laminectomyx Infection Pneumonia and other lung inflammationsx a x Cardio-vascular system Heart failure Chronic obstructive pulmonary disease (COPD)x Arterial obstructive disease with amputation or other surgeryx a x Coronary heart diseases with surgeryx Stroke and other cerebrovascular diseasesx Neuro-psychiatric Delirium and other organic brain psychosisx Secondary Parkinsonsyndromx a x Symptoms, effecting the nervous system and musculoskeletal systemxCharlson Comorbidity Index Any Malignancyxx Cerebrovascular diseasex Chronic pulmonary diseasex Congestive heart failurex Metastatic solid tumorx Dementiaxx Hemiplegia or paraplegiax Mild liver diseasex Myocardial infarctionx Renal diseasex Peripheral vascular diseasexGeriatric Multimorbidity Cognitive deficitx Chronic painx Depression, Anxietyx Incontinencex Severe visual/hearing impairmentx Paraesthesiax Immobilityxx Chemotherapyxx aAt least one diagnosis from each main diagnosis group will be used to match controls. Diagnoses are allowed to differ between cases and controls within the main diagnoses group
|
study
| 100.0 |
Subsequently, propensity scores will be calculated using a logistic regression model using coded morbidity and costs under the scenarios a.) and b.), based on all variables listed in Table 6, taking statistical interactions and nonlinear associations into account. Up to four controls may be assigned to one case without repetition.
|
study
| 99.94 |
Appropriate regression models (e.g. time-event models, mixed models, two-part models) will be applied to study effects on our primary and secondary outcomes. Because treatment might also affect censoring due to mortality, competing risks models (using the Fine-Gray approach) will be applied . Patients dying during the follow-up period will not be excluded from the analyses.
|
other
| 99.56 |
AGR is currently only available in few areas for elderly people from selected statutory health insurances which opted to offer AGR to their beneficiaries. Evaluation of this intervention was previously limited to uncontrolled study designs . To the best of our knowledge, this will be the first study to evaluate AGR using a quasi-experimental design. This study may provide an estimation of the effectiveness of AGR on progression to higher nursing care levels and hospitalisation and other endpoints of clinical relevance. Our results will be important for providers of AGR, policy makers and stakeholders to make informed decisions on whether to continue, modify or even expand AGR to other areas in Germany. Additionally, our results might help to optimise AGR by identifying subgroups of patients who are more likely to benefit from AGR.
|
study
| 99.94 |
A limitation will be the restriction to claims data. Clinical measurements from instruments used for the geriatric assessment are not available for the control group. This might impair the quality of the matching as potential imbalance between clinical data and individual motivation to participate in AGR cannot be ruled out even if a high balance on claims data is achieved. Therefore, residual confounding may still be an issue after our matching. Final decisions on the applied methods need to account for the precise properties of the data.
|
study
| 99.8 |
Nicotinamide (NA) is one form of niacin. A deficiency of this vitamin leads to loss of copper from the body, known as pellagra disease. Victims of pellagra show unusually high serum and urinary copper levels (Krishnamachari, 1974 ▸). The NA ring is the reactive part of nicotinamide adenine dinucleotide (NAD) and its phosphate (NADP), which are the major electron carriers in many biological oxidation-reduction reactions (You et al., 1978 ▸). The nicotinic acid derivative N,N-diethylnicotinamide (DENA) is an important respiratory stimulant (Bigoli et al., 1972 ▸).
|
study
| 66.3 |
Transition metal complexes with ligands of biochemical interest such as imidazole and some N-protected amino acids show interesting physical and/or chemical properties, through which they may find applications in biological systems (Antolini et al., 1982 ▸). The crystal structures of metal complexes with benzoic acid derivatives have been reported extensively because of the varieties of the coordination modes, for example, Co and Cd complexes with 4-aminobenzoic acid (Chen & Chen, 2002 ▸). The structures of some mononuclear complexes obtained from the reactions of transition metal(II) ions with nicotinamide (NA) and some benzoic acid derivatives as ligands have been determined previously, e.g. [Zn(C7H5O3)2(C6H6N2O)2] [(II); Necefoğlu et al., 2002 ▸], [Mn(C7H4ClO2)2(C10H14N2O)2(H2O)2] [(III); Hökelek et al., 2008 ▸] and [Zn(C7H4BrO2)2(C6H6N2O)2(H2O)2] [(IV); Hökelek et al., 2009 ▸].
|
study
| 99.44 |
The structure determination of the title compound, (I), a copper complex with two 4-sulfamoylbenzoate (SB) anions and two nicotinamide (NA) ligands and one coordinated water molecule, was undertaken in order to compare the results obtained with those reported previously. In this context, we synthesized the CuII-containing title compound, aquabis(nicotinamide-κN)bis(4-sulfamoylbenzoato-κO1)copper(II), [Cu(C7H6NO4S)2(C6H6N2O)2(H2O)], and report herein its crystal and molecular structures along with the Hirshfeld surface analysis.
|
study
| 100.0 |
The asymmetric unit of the crystal structure of the mononuclear title complex, (I), contains one half of the CuII ion, one 4-sulfamoylbenzoate (SB) anion and one nicotinamide (NA) molecule together with one half water molecule, all ligands coordinating in a monodentate manner (Fig. 1 ▸).
|
study
| 99.94 |
The CuII ion, located on a twofold rotation axis, is penta-coordinated via two nitrogen atoms of NA and two oxygen atoms of SB anions and one oxygen atom of the water molecule. The two carboxylate O atoms [O2 and O2i; symmetry code: (i) 1 − x, y, − z] of two symmetry-related monodentate SB anions and the two pyridine N atoms (N1 and N1i) of two symmetry-related monodentate NA ligands are at distances of 1.978 (2) and 2.025 (3) Å, respectively, from the Cu1 atom and form a slightly distorted square-planar arrangement. The sum of the bond angles N1—Cu1—O2i [87.79 (10)°], N1i—Cu1—O2i [92.08 (10)°], O2—Cu1—N1 [92.08 (10)°] and O2—Cu1—N1i [87.79 (10)°] in the basal plane around CuII ion is 359.74°. This confirms the presence of CuII ion with very slight deviation from the basal plane. The slightly distorted square-pyramidal coordination environment is completed by the water O atom (O6) at a distance of 2.147 (4) Å in the axial position.
|
study
| 100.0 |
The near equalities of the C1—O1 [1.237 (4) Å] and C1—O2 [1.273 (4) Å] bonds in the carboxylate groups indicate delocalized bonding arrangements, rather than localized single and double bonds. The O2—C1—O1 bond angle [125.2 (3)°] seems to be increased compared to that present in a free acid [122.2°]. The corresponding values for this angle in the closely related structures mentioned above are 123.5 (2) and 120.4 (2)° in (II), 125.2 (5)° in (III), and 124.3 (2)° in (IV); the benzoate ions are coordinated to the metal atoms only monodentately in (III) and (IV), and both monodentately and bidentately in (II). In the SB anion, the carboxylate group is twisted away from the attached C2–C7 benzene ring by 20.92 (17)°, while the benzene and N1/C8–C12 pyridine rings are oriented at a dihedral angle of 81.86 (12)°.
|
study
| 100.0 |
In the crystal, O—HW⋯OC, N—HNA⋯ONA, N—HSB⋯OC and N—HSB⋯OSB (W = water, C = carboxylate, NA = nicotinamide and SB = 4-sulfamoylbenzoate) hydrogen bonds (Table 1 ▸) link the molecules, enclosing (8) and (18) ring motifs (Fig. 2 ▸) into a three-dimensional architecture. Hydrogen bonding and van der Waals contacts are the dominant interactions in the crystal packing. No significant π–π, C—H⋯π or C—H⋯O interactions are observed.
|
study
| 99.94 |
In order to visualize the intermolecular interactions in the crystal of the title complex, a Hirshfeld surface (HS) analysis (Hirshfeld, 1977 ▸; Spackman & Jayatilaka, 2009 ▸) was carried out by using Crystal Explorer 17.5 (Turner et al., 2017 ▸). In the HS plotted over d norm (Fig. 3 ▸), the white surfaces indicate contacts with distances equal to the sum of van der Waals radii, and the red and blue colours indicate distances shorter (in close contact) or longer (distinct contact) than the van der Waals radii, respectively (Venkatesan et al., 2016 ▸). The bright-red spots appearing near SB-O1, SB-O4, NA-O5 and hydrogen atoms H21, H31, H32 and H61 indicate their role as the respective donors and acceptors in the dominant O—H⋯O and N—H⋯O hydrogen bonds; they also appear as blue and red regions, respectively, corresponding to positive and negative potentials on the HS mapped over electrostatic potential (Spackman et al., 2008 ▸; Jayatilaka et al., 2005 ▸) as shown in Fig. 4 ▸. The blue regions indicate the positive electrostatic potential (hydrogen-bond donors), while the red regions indicate the negative electrostatic potential (hydrogen-bond acceptors). The overall two-dimensional fingerprint plot and those delineated into H⋯O/O⋯H, H⋯H, H⋯C/C⋯H, H⋯N/N⋯H, O⋯C/C⋯O, O⋯O and N⋯C/C⋯N contacts (McKinnon et al., 2007 ▸) are illustrated in Fig. 5 ▸ a–h, respectively, together with their relative contributions to the Hirshfeld surface. The most important interaction is H⋯O/O⋯H contributing 42.2% to the overall crystal packing, which is reflected in Fig. 5 ▸ b as a pair of spikes with the tip at d e + d i ∼1.63 Å. The short H⋯O/O⋯H contacts are masked by strong O—H⋯O hydrogen bonding in this plot. In the fingerprint plot delineated into H⋯H contacts (Fig. 5 ▸ c), the 25.7% contribution to the overall crystal packing is reflected as widely scattered points of high density due to the large hydrogen content of the molecule. In the absence of C—H⋯π interactions in the crystal, the pair of characteristic wings resulting in the fingerprint plot delineated into H⋯C/C⋯H contacts with a 20.0% contribution to the HS, Fig. 5 ▸ d, and the pair of edges at d e + d i ∼2.58 Å result from short interatomic H⋯C/C⋯H contacts. The H⋯N/N⋯H (Fig. 5 ▸ e) and O⋯C/C⋯O (Fig. 5 ▸ f) contacts in the structure with 3.1% and 2.9% contributions to the HS have symmetrical distributions of points with the tips at d e + d i ∼2.8 Å and d e + d i ∼2.4 Å, arising from short interatomic H⋯N/N⋯H and O⋯C/C⋯O contacts, respectively. The O⋯O contacts assigned to short interatomic O⋯O contacts with a 1.6% contribution to the HS appear as an arrow-shaped distribution of points in Fig. 5 ▸ g, with the vertex at d e = d i ∼3.5 Å. Finally, the N⋯C/C⋯N contacts in the structure with a 1.6% contribution to the HS has a nearly symmetrical distribution of points, Fig. 5 ▸ h, with the scattered points of low density. The Hirshfeld surface representations with the function d norm plotted onto the surface are shown for the H⋯O/O⋯H, H⋯H, H⋯C/C⋯H, H⋯N/N⋯H and O⋯C/C⋯O interactions in Fig. 6 ▸ a–e, respectively.
|
study
| 100.0 |
The Hirshfeld surface analysis confirms the importance of H-atom contacts in establishing the packing. The large number of H⋯O/O⋯H, H⋯H and H⋯C/C⋯H interactions suggest that van der Waals interactions and hydrogen bonding play the major roles in the crystal packing (Hathwar et al., 2015 ▸).
|
study
| 99.94 |
The title compound was prepared by the reaction of CuSO4·5H2O (1.25 g, 5 mmol) in H2O (100 ml) and nicotinamide (1.22 g, 10 mmol) in water (25 ml) with sodium 4-sulfamoylbenzoate (2.23 g, 10 mmol) in water (150 ml) at room temperature. The mixture was filtered and set aside for several days at ambient temperature to crystallize, giving blue single crystals (yield: 2.11 g, 29%). Combustion analysis: found; C, 42.85; H, 3.70; N, 11.68; S, 8.70%. Calculated: C26H26CuN6O11S2 C, 42.96; H, 3.58; N, 11.57; S, 8.81%. FT–IR: 3363, 3163, 1692, 1677, 1602, 1519, 1432, 1380, 1340, 1301, 1162, 1138, 1093, 1058, 778, 730, 688, 615, 532, 479, 427 cm−1.
|
study
| 100.0 |
Crystal data, data collection and structure refinement details are summarized in Table 2 ▸. H atoms of the water molecule and the NH2 group of the nicotinamide (NA) molecule were located in a difference-Fourier map and refined freely. H atoms of the NH2 group of the 4-sulfomylbenzoate (SB) group were also located in a difference-Fourier map and the positions were refined with U iso(H) = 1.5U eq(N). The aromatic C-bound H atoms were positioned geometrically with C—H = 0.93 Å, and refined as riding with U iso(H) = 1.2U eq(C).
|
study
| 100.0 |
Chest pain is a common and often non-specific symptom that can be caused by a number of underlying conditions, one of the most serious being acute myocardial infarction. Whilst only around a third of these presentations are cardiac in origin , the potential severity of myocardial ischaemia necessitates rapid assessment and management.
|
other
| 99.94 |
In New Zealand, cardiovascular disease is the leading cause of mortality, with coronary artery disease responsible for 23% of all deaths in 1999. Over 52% of these deaths were due to myocardial infarction . Whilst rates of coronary artery disease are thought to be in decline, research has shown that Maori individuals are more likely to die from a myocardial infarction than age stratified European counterparts, with men and women at a 1.6 and 4.2 times increased risk, respectively [3, 4].
|
study
| 99.7 |
Furthermore, mortality associated with coronary artery disease in Maori’s under the age of 65 is almost three times that found in Europeans of a similar age . Cardiovascular disease is therefore a major public health concern in New Zealand, and campaigns to reduce the impact of modifiable risk factors such as smoking are widespread.
|
other
| 99.9 |
The National Institute for Health and Clinical Excellence (NICE) is an independent UK organisation which provides national guidance on promoting health and preventing and treating poor health. They published updated guidelines for the management of recent onset chest pain in March 2010 . This document is intended to streamline the management of new presentations with chest pain, and ensure that clinicians are up to date with current literature. The key points of this new guideline are summarised in Table 1.
|
other
| 99.8 |
The College of Emergency Medicine (UK) established standards for the treatment of suspected acute coronary syndrome . In their most recent publication, they present time-frames for assessment or intervention which emergency departments should strive to achieve. They suggest that 90% of all patients with chest pain should have aspirin and an ECG within 10 minutes of arrival at an emergency department, 75% of patients in pain should receive analgesia within 30 minutes, and 90% within an hour.
|
review
| 98.44 |
In recent years, cost reduction strategies have led to emergency departments worldwide admitting only those patients deemed essential for monitoring, and reducing a patient’s length of stay in hospital where possible, whilst maintaining a high standard of care. The focus of emergency medicine has now shifted to the development and implementation of high quality protocol based care, to ensure that all patients are screened in a systematic manner, and management is optimal.
|
other
| 99.8 |
Despite this, it is estimated that between 2 - 5% of acute myocardial infarction patients are discharged inappropriately . These individuals often have a very poor outcome, and in addition, the discharge of patients later found to have suffered a heart attack is a leading cause of malpractice lawsuits each year . It is essential to ensure that the highest standards of care are maintained, as such, audit is an important asset which may be used to implement quality evidence based medicine.
|
other
| 99.9 |
Whilst there are New Zealand based guidelines for the management of established acute coronary syndrome, there was no available comparable guideline for the initial management of recent onset chest pain. The aims of this clinical review were to assess baseline clinical standards in a regional emergency department in New Zealand, and to ascertain whether current practice had adapted to incorporate recent published developments in chest pain management.
|
review
| 99.9 |
All admissions to the emergency department of Tauranga Hospital between 01/09/10 and 31/10/10 were screened for the presenting complaint of ‘chest pain’ using the medical records database. Patients were included if they had either ongoing chest pain, or recent chest pain (< 12 hours) which was now resolved. Those under the age of 18 were excluded, as were presentations which were known to be non-cardiac at an early stage and therefore not managed on an appropriate pathway for audit.
|
study
| 99.75 |
This search generated records of 599 patients that fitted the inclusion criteria. After the population was identified, a sample size calculation was performed. As this audit is based on standards of 100%, the likelihood of a positive response for measured criteria is high, therefore a response distribution of 90% was chosen. To detect a statistical effect with a confidence level of 95%, and 5% margin of error, the minimum sample size required is 113. Using the statistical package for social sciences (SPSS) version 18.1, a simple randomisation scheme was employed, and 120 patients were identified.
|
study
| 99.8 |
Data was obtained from patient notes by the principal researcher and collected using an audit proforma consisting of 32 different variables (Appendix 1). Results were then compiled in a spread sheet. Data was handled using SPSS, and assessed for normality. Appropriate statistical tests were employed as detailed in the results section. The level of statistical significance was deemed (P < 0.05) for all calculations.
|
study
| 97.94 |
All patients were allocated a number, and data was recorded anonymously to ensure confidentiality was maintained. This research was exempt from formal ethical committee procedure, however, it was approved by the Research Manager of the Bay of Plenty District Health Board.
|
other
| 99.94 |
From the original population of 599, 120 patients were identified at random. Two cases identified by the randomisation scheme were not eligible for inclusion as their presentations were not considered to be cardiac in origin at time of admission, leaving a total number of 118 eligible cases (53 females and 65 males).
|
study
| 99.94 |
Ages of those in the sample were found to be normally distributed. Women were older than men (64.9 ± 18.5 vs 61.6 ± 17.2, P = 0.24). Time of admission was also found to be normally distributed within the sample. Results highlighting the performance of the department compared to NICE standards are shown in Table 2.
|
study
| 100.0 |
This bar graph depicts time to administration of pain relief after admission, versus the total percentage of patients requiring pain relief. The College of Emergency medicine targets of 75% pain relief within 30 minutes, and 90% within an hour, are shown in black.
|
other
| 99.9 |
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