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To aid in the positioning of dosimeters, organ locations were transferred onto the phantom using a permanent marker from full‐scale printouts of the hybrid dataset. Thin slits were cut into the axial slices of the phantom to allow placement of both the FOC dosimeters and passage of the optical fiber that connects the scintillator to the readout PMT (see Fig. 4). For small organs, absorbed dose values obtained near the centroid of the organ were adopted as the organ dose. For larger organs where dose gradients are a concern, the organ was equally subdivided and dosimeters were placed near the centroid of each of these subdivisions. The average reading from all dosimeters placed in the organ was then adopted as the average organ dose. Table 2 lists all of the organs investigated, as well as the number of measurement locations used to evaluate the dose to each organ.
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other
| 31.55 |
In order to calculate the average dose to the red bone marrow, weighting factors were applied to individual red bone marrow sites (a total of 19 points in 12 sites) based on their percent weight contribution to the total red bone marrow, as shown in Eq. 2: (2)DRBM=∑iDabs,i∗Ai where Dabs,i is the absorbed dose to soft tissue at location i, and Ai is the weight fraction of red bone marrow located at location i. The absorbed dose to soft tissue was used to approximate the dose to the red bone marrow because the mass energy‐absorption coefficient for red bone marrow is within 5% of the mass energy‐absorption coefficient for soft tissue at X‐rays energies greater than 30 keV. (26) Dose to the bone surface was calculated in a similar fashion using Eq. 2, except Ai was replaced with Ei – the weight fraction of endosteum at location i. Table 3 shows weight fractions of red bone marrow and endosteum used for the bone sites investigated in this study, taken from the development of the hybrid computational phantom series. (27)
|
other
| 30.3 |
The absorbed dose to lung tissue was calculated using Eq. 3: (3)Dlung=Dabsμˉenρsoft tissuelung where (μ¯enρ)soft tissuelung is the ratio of average mass energy absorption coefficients of lung tissue to soft tissue at the measured HVL. (25) The absorbed dose to skin (for the whole body) was calculated similarly using Eq. 4: (4)Dskin=Dabs∗AirradiatedAtotal∗μˉenρsoft tissueskin where (μ¯enρ)soft tissueskin is the ratio of average mass energy absorption coefficients of skin to soft tissue at the measured HVL (25) and AirradiatedAtotal is the ratio of irradiated skin area to the gross surface area of the entire phantom. The gross surface area of the phantom used in this study was estimated to be 1.83 m2, using the computational model as a reference. The irradiated area was also estimated using the computational model as a reference and values of 0.12 m2, 0.32 m2, and 0.20 m2 were used for the head, chest, and pelvis scans, respectively. The absorbed dose at the surface of the phantom was evaluated by placing two dosimeters in the primary field at the anterior and left lateral sides of the phantom and averaging the readings from these two dosimeters.
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other
| 37.34 |
It should be emphasized that the doses reported in this study result from using technical imaging settings provided by the manufacturer as their installed default protocols. No attempt was made to compare doses at the same image quality, but rather at clinically relevant scan settings. Consequently, there may be differences between the image quality achieved by the different systems, which was also evaluated. A Catphan 440 (The Phantom Laboratory, Salem, NY) image quality phantom was used to assess the image quality of each CBCT system as it is used clinically. Image quality was assessed using the following Catphan modules: CTP401 slice geometry and sensitometry module, and CTP592 low‐ and high‐contrast resolution module. The CTP592 module has a series of high‐resolution test patterns, ranging from 5 through 15 lp/cm, which were used for visual evaluation of spatial resolution. This module also includes a series of 0.5% low‐contrast targets for evaluating low‐contrast detectability. Unfortunately, the 0.5% low‐contrast targets were designed to evaluate fan‐beam CT systems and are too demanding for CBCT image quality tests. As a result, they cannot be seen in the reconstructed CBCT images. For this reason, the CTP401 module was used as a substitute to compare the low‐contrast detectability of each CBCT system. This module includes five acrylic spheres of varying diameters (2, 4, 6, 8, and 10 mm diameter) that have approximately 3% contrast (29) and can be seen in the reconstructed images. By visually evaluating the smallest sphere that could be seen in the reconstructed images, the CTP401 module was effectively used to illustrate the differences in low‐contrast detectability between the two systems. The Catphan phantom was scanned using the same clinical protocols used during organ dose measurements. All images were reconstructed at a 5 mm slice width, with a matrix size of 512×512 pixels.
|
other
| 32.25 |
The measured organ and effective doses from the XVI and OBI are shown in Tables 4 and 5, respectively. The “whole body” bone marrow and bone surface doses were calculated as previously discussed, while the “irradiated site” bone marrow and bone surface doses are an average of only the bone sites in the primary field. For head scans, this includes the cranium and cervical vertebrae; for chest scans, the proximal humerus, clavicles, scapula, ribs, sternum, and thoracic vertebrae; and for pelvis scans, the os coxae, sacrum, and proximal femur. The “irradiated site” skin dose is an average of the dose measured from the two dosimeters placed in the primary field on the anterior and left lateral surfaces of the phantom.
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other
| 31 |
The head scan covered the brain, salivary glands, extrathoracic region, oral mucosa, and parts of the esophagus. Of all the organs, the lens of the eye received the maximum dose of 1.07 mGy for the XVI, while the brain received the maximum dose of 3.01 mGy for the OBI. Image quality was assessed through visual evaluation of the reconstructed images of the Catphan phantom. The CTP592 resolution module was used to evaluate the spatial resolution. The 8 lp/cm pattern could be visually resolved in the OBI images, while none of the test patterns could be resolved in the XVI images, the largest of which was 5 lp/cm. The CTP401 module was used to evaluate low‐contrast detectability, with only the largest of the acrylic spheres (10 mm diameter) being visible on the OBI images; none of the spheres were visible on the XVI images. The images from the OBI were also noticeably sharper than those from the XVI. This can be seen in Fig. 5, which shows an example of the reconstructed images of the CTP592 resolution phantom using the head protocol for each system.
|
other
| 33.75 |
The chest scan covered the lungs, breast, heart, thymus, thyroid, and parts of the esophagus, liver, stomach and spleen. The thyroid received the maximum dose of 19.24 mGy for the XVI, while the breast received the maximum dose of 5.34 mGy for the OBI. Again, the OBI showed superior spatial resolution, with the 5 lp/cm pattern visible in the reconstructed images, while none of the resolution test patterns were visible on the XVI images. The OBI also showed better low‐contrast detectability with the 4 mm diameter acrylic sphere being visible on the OBI images; the 6 mm diameter acrylic sphere was the smallest that could be seen on the XVI images. The reconstructed OBI images again appeared sharper overall than the XVI images.
|
other
| 31.78 |
The pelvis scan covered the prostate, bladder, testes, and parts of the small intestine and colon. The testes received the maximum dose for both systems at 29 and 34.61 mGy for the XVI and OBI, respectively. The images for the pelvis protocol appeared very similar to those seen for the chest protocol, yielding similar results for resolution and low‐contrast detectability. The 5 lp/cm pattern could be resolved on the OBI images, while none of the test patterns could be resolved on the XVI images. For low‐contrast detectability, the 4 mm diameter acrylic sphere was visible on the OBI images, while the 6 mm diameter acrylic sphere was the smallest that could be seen on the XVI images. The reconstructed OBI images again appeared sharper overall than the XVI images.
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other
| 32.12 |
It is important to differentiate the data presented in the current study with that which can be found in current literature. Kan et al. (13) published an organ and effective dose study performed on the OBI using a female anthropomorphic phantom and TLDs. While the study provides useful dose information for the OBI, the recent release of OBI software version 1.4.13.0 includes new protocols which have not yet been investigated in the literature. Previous protocols for the OBI were all at a fixed tube voltage (125 kVp) and consisted of full rotation scans. The updated OBI protocols utilize body region specific tube voltages, with lower energies for less attenuating body regions. Tube voltages include 100 kV, 110 kV, and 125 kV for the head, chest, and pelvis, respectively. Additionally, the new head protocol for the OBI utilizes only a partial rotation rather than a full rotation for image acquisition. Lastly, the tube current time product for all OBI protocols has been reduced substantially. All of these changes result in lower patient doses, with the dose to many organs being reduced by 50% or more from previously published works utilizing earlier versions of the manufacturer installed protocols. (13) For the XVI system, there have been very few organ dose studies published in the literature. (4) , (11) Additionally, these studies report the dose to only a limited number of organs, and they were performed before the release of software version 4.0, which included the introduction of new protocols and the use of bowtie filters. While the tube current time product has been increased with the use of the new protocols to account for the added filtration, results indicate that individual organ doses for the XVI have remained comparable to the limited studies in the literature..
|
study
| 28.6 |
The results of the image quality tests are shown in Table 6. Resolution was evaluated by the smallest resolution test pattern that could be visualized, and low‐contrast detectability was evaluated by the smallest acrylic sphere that could be visualized in the image quality phantom.
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other
| 32.88 |
Results of image quality tests for manufacturer installed protocols. Resolution was evaluated by the smallest pattern that could be visually resolved in the CTP592 module, and detectability was evaluated by the smallest acrylic sphere that could be visually resolved in the CTP401 module.
|
clinical case
| 30.25 |
An interesting similarity between the XVI and OBI is the fact that they both use partial rotation scans for their head protocols (200° and 204°, respectively). On the XVI, image acquisition begins at the anterior surface of the patient and rotates around the left lateral side of the head, finishing posteriorly (when the patient is placed in a supine position). On the OBI, image acquisition moves from left to right lateral (or vice versa) while rotating around the posterior surface of the patient. Due to the choice of acquisition angles, superficial organs located on the anterior surface of the head are directly irradiated during image acquisition with the XVI but not with the OBI, resulting in comparatively higher doses to some organs for the XVI. For example, the dose to the lens of the eye on the XVI system was 52% higher than the dose to a centrally‐located organ such as the brain, while on the OBI system the dose to the lens of the eye was approximately a factor of 5 less than the dose to the brain. This result suggests modifying the manufacturer installed head protocol on the XVI such that the X‐ray tube rotates around the posterior side of the head where there are no critical organs rather than the anterior side of the head which has several superficial organs of interest.
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other
| 31.03 |
The chest protocol for each system utilized a full rotation scan. However, the beam width for the XVI was larger than the OBI (26 cm compared to 16 cm) resulting in higher doses to organs outside of the treatment volume. The thyroid was one such organ, which is included in the larger field of view and subsequently received the highest dose of any organ during a chest scan from the XVI, but was outside of the primary field on the OBI. Contributing to the thyroid dose on the XVI was also the fact that the outer body contour was smaller in this region, resulting in less attenuation of the primary beam as the tube rotated around the body. This finding suggests reducing the beam width of the XVI in future versions if the necessary information can be gained from a narrower beam width such as is used on the OBI to avoid unnecessarily irradiating organs outside of the treatment volume. As expected, the breast received the highest dose on the OBI due to its anatomical location at the periphery of the body.
|
other
| 29.2 |
The pelvis scans for each system also utilized a full rotation. Interestingly, the OBI had organ doses similar to those measured using the XVI, even though the tube current time product was approximately a factor of 2.4 smaller. This can be attributed to the fact that the OBI has a larger beam width (16 cm compared to 12.5), resulting in additional scattered radiation, as well as a lower HVL (see HVLs in Table 1). As reported by Song et al., (7) the lower HVL of the OBI results in more dose being deposited per unit mAs than the XVI. Additionally, the testes were completely in the primary beam of the OBI, but were only partially covered by the XVI beam because of its smaller beam width, resulting in a higher gonad dose for the OBI than XVI. Similar to the chest scan, the larger beam width resulted in more organs outside of the treatment volume being irradiated and an increased scatter dose inside of the scan volume.
|
study
| 30.03 |
The effective dose for each scan is also shown at the bottom of Tables 4 and 5. The head scans for both the XVI and OBI had very low effective doses (0.04 and 0.12 mSv, respectively) due to the fact that the most of the organs in the primary field for a head scan have low weighting factors. The chest scan yielded effective doses of 7.15 and 1.82 mSv for the XVI and OBI, respectively. The higher effective dose for the XVI chest scan was due to its larger beam width, which covered more organs, and higher tube current time product, which resulted in higher overall organ doses. The pelvis scan for each system had similar effective doses at 3.73 and 4.34 mSv for the XVI and OBI, respectively. As is evident from the data presented in this study, the effective dose for each protocol was small due to the limited number of organs involved in each scan. This is especially true for the pelvis scans, where both the gonads and prostate received doses greater than 25 mGy, but most other organs received little if any dose. The effective dose was on the order of only 3–4 mSv. Therefore, organ doses are likely more meaningful for predicting future risk, such as organ specific disease, but the effective dose offers a single number to compare the different protocols and equipment quickly and easily.
|
other
| 31.78 |
The image analysis performed in this study quantified the observed image quality for each system and imaging protocol – supplementing the extensive dosimetry measurements performed. Again, it is important to remember that the protocols selected for this study were those recommended by the manufacturer for clinical use. When first comparing the reconstructed OBI images to the XVI images, it was readily apparent that the XVI images were not as sharp and had more artifacts (streaking and rings). As mentioned in the results, the OBI outperformed the XVI in both observed resolution and low‐contrast detectability for all three protocols investigated, but also delivered higher doses for two of the three protocols. However, this increased image quality did not always come at the cost of higher dose, with the chest protocol for the OBI actually yielding lower dose and better image quality.
|
other
| 30.38 |
Data presented in this study shows that daily use of CBCT for patient positioning will deliver a substantial imaging dose to organs in the primary imaging field. It should be noted that when used for daily position verification, the organ doses listed in Tables 4 and 5 must be multiplied by the total number of fractions, which can be as high as 30–40. This results in organ doses exceeding 1 Gy in some cases, such as the testes, indicating that the dose from daily CBCT imaging in a high fraction therapy regimen should be taken into consideration during the treatment planning process.
|
other
| 31.86 |
A comprehensive set of organ dose measurements were performed using an anthropomorphic phantom and fiber‐optic coupled dosimetry system for the two commercially available kilovoltage CBCT systems (Elekta XVI and Varian OBI). The systems were evaluated by performing organ dose and image quality measurements for three clinically relevant scan sites (head, chest, and pelvis) using the latest manufacturer installed clinical protocols. Organ dose measurements demonstrated that the XVI yielded higher doses for a chest scan, while the OBI yielded higher doses for both head and pelvis scans. The dosimetric differences between these two CBCT systems are magnified over the course of a fractionated treatment with daily imaging. Specifically, the XVI chest scan delivers a dose 30 cGy higher to the lung than the OBI chest scan during a 30‐fraction regimen. For head and pelvis scans, the OBI delivers a dose 6.9 cGy higher to the brain and 16.8 cGy higher to the gonads, respectively, over the course of a 30‐fraction regimen. Image quality measurements demonstrated that the OBI provided superior image quality, with both better spatial resolution and low‐contrast detectability when using default clinical protocols. Results also showed a decrease in organ dose for the OBI when compared to previous studies which used an earlier version of the manufacturer installed clinical protocols. The new XVI protocols yielded doses similar to previously published work, despite an increase in tube current time product and the use of bow‐tie filters. In summary, the organ doses reported in this study provide practitioners a useful measure of absorbed dose from the latest manufacturer‐installed CBCT imaging protocols to weigh the added benefit of improved patient positioning against the additional radiation dose of using CBCT imaging.
|
other
| 27.1 |
Advanced glycation endproducts (AGEs) are thought to be involved in the pathogenesis of many age-related diseases, such as diabetes mellitus, atherosclerosis, cataract and Alzheimer’s disease. AGEs are formed by glycation and oxidation of free amino groups of proteins, lipids and nucleic acids. This metabolic process is complex and heterogeneous, yielding numerous different AGE adducts, such as pentosidine, Nε-(carboxymethyl)lysine (CML), Nε-(carboxyethyl)lysine (CEL) and 5-hydro-5-methylimidazolone (MG-H1).
|
study
| 29.22 |
In diabetes, prolonged hyperglycemia and oxidative stress accelerate the accumulation of some AGEs. Besides via the classical Maillard reaction, AGEs are formed through the reaction of α-dicarbonyls, such as 3-deoxyglucosone (3-DG), methylglyoxal (MGO), and glyoxal (GO), with protein amino groups. Accumulation of AGEs also strongly depends on tissue turnover because AGEs are mainly irreversibly linked to tissue proteins. Therefore, tissues with slow turnover (such as the skin, lens, and cartilage) capture decades-long glycaemia. In tissues with fast turnover (such as plasma, epidermis and mucosa), AGEs accumulate to a lesser extent since they are rapidly broken down to AGE peptides or free AGEs, which are excreted through the kidney.
|
other
| 29.9 |
AGEs promote tissue dysfunction in vitro and in vivo by altering protein structure, by cross-linking of long lived molecules and through binding to the receptor for advanced glycation endproducts (RAGE). Both α-dicarbonyls and AGEs have been linked to diabetic complications and have been postulated to play a pathological role in the development of these complications[5–7].
|
study
| 28.16 |
Several studies have shown elevated serum and vitreous AGE levels in diabetic retinopathy (DR). Furthermore, AGEs have been suggested to influence the transition of retinopathy from the non-proliferative to the proliferative state. However, vitreous AGE levels have mainly been measured in DR patients with proliferative diabetic retinopathy (PDR) or diabetic macular edema (DME) and have always been compared to non-diabetic controls undergoing vitrectomy for several eye conditions. Currently, it is unclear whether vitreous AGE levels are already elevated in diabetes before the development of PDR or DME.
|
other
| 29.94 |
The aim of the present study was to investigate several AGEs (pentosidine, CML, CEL and MG-H1) and α-dicarbonyls (3-DG, MGO, and GO) in the vitreous of type 2 diabetes patients (T2DM) without PDR in relation to non-diabetic controls. We examined vitreous samples obtained during vitrectomy from T2DM patients with a rhegmatogenous retinal detachment (RRD) and compared these to non-diabetic controls with comparable retinal detachment severity. Pentosidine is a cross-linking AGE which is thought to serve as an adequate marker for overall AGE levels. In addition, DR could be influenced by AGEs through RAGE activation and, therefore, we also analysed several AGEs which have been shown to interact with RAGE.
|
other
| 33.28 |
Participants were initially recruited in a prospective cohort study in which 410 RRD patients were included between November 2013 and August 2015 in our tertiary referral center (NTR4289). All patients gave written informed consent, and the study was approved by the Medical Ethics Committee of the University Medical Center Groningen and adhered to the Declaration of Helsinki. The present cross-sectional analysis is a sub-study hereof that addresses the secondary explicated research aim mentioned above. In this sub-study, 31 T2DM patients were 1:2 matched on age, estimated glomerular filtration rate (eGFR), smoking, intra-ocular lens implantation, and proliferative vitreoretinopathy (PVR) to 62 non-diabetic patients. Diabetes mellitus was defined by criteria from the American Diabetes Association or twice measured values of HbA1c ≥48 mmol/mol. Absence of diabetes and prediabetes in the non-diabetic patients was ascertained by absence of a history of diabetes, absence of anti-diabetic medication usage, and by presence of a normal HbA1c level (<42mmol/mol) and a normal non-fasting glucose level (≤ 7.8 mmol/l).
|
other
| 36.44 |
Clinical data and general characteristics were obtained by chart review and questionnaires. The following exclusion criteria applied to all subjects: known renal disease with impairment of renal function (eGFR <60 ml/min), dialysis treatment, history of renal transplantation, current infection or active inflammatory disease. Presence of DR was established by fundus photography or by ophthalmic examination by an ophthalmologist. Both pre- and postoperatively, patients were examined accurately by fundoscopy. When DR was not specifically mentioned in latest notes of the ophthalmologist or retinal surgeon, it was assumed that DR could be classified as absent or minimal background DR.
|
other
| 37.62 |
Non-fasting venous blood was collected by venipuncture. Plasma glucose, HbA1c, serum creatinine and C-reactive protein (CRP) were measured using standard procedures. Renal function was evaluated by eGFR calculated by the Modification of Diet in Renal Disease (MDRD) formula: eGFR = 186 × [serum creatinine (μmol/L) × 0.0113]−1.154 × age-0.203 (× 0.742 for women). CRP was measured to ensure that no active infection or inflammatory disease was present.
|
other
| 36.84 |
At the start of the vitrectomy procedure, undiluted vitreous samples were collected from the midvitreous by aspirating the vitreous manually through a syringe connected to the vitrectome. The samples were frozen within 15–30 minutes and stored at -80°C until further use. Measurement methods of AGEs and α-dicarbonyls have been described in detail elsewhere: pentosidine was measured using high performance liquid chromatography (HPLC) with a fluorescence detector; lysine and protein-bound and free CML, CEL, and MG-H1 were measured using ultra performance liquid chromatography tandem mass spectrometry (UPLC MS/MS); derivatized 3-DG, MGO, and GO were analyzed by UPLC MS/MS.
|
other
| 37.5 |
Skin autofluorescence (SAF) was measured on the left forearm using the AGE Reader (DiagnOptics Technologies BV, Groningen, The Netherlands), a non-invasive desk-top device using the characteristic fluorescent properties of certain AGEs to estimate the level of AGE accumulation in the skin. Technical details concerning the optical technique have been extensively described elsewhere.
|
other
| 39.9 |
Characteristics of retinal detachment were determined during surgery. Surface area of detached retina in relation to total retinal surface was scored in quartiles. Proliferative vitreoretinopathy (PVR) was graded A to C, according to the Retina Society PVR classification. When PVR grade A was present, patients were classified as ‘non-PVR’; when PVR grades B or C were present, patients were classified as ‘PVR’.
|
other
| 35.7 |
Sample size was based on previously reported pentosidine concentrations in diabetes and control patients in which the effect size was 1.1. Based on α = 0.05 and power = 80%, the minimum number of subjects needed in this study was 25 T2DM patients and 50 control patients. Data obtained from each sample group were presented as mean and standard deviation (SD) or as median and interquartile range (IQR). Differences between T2DM patients and controls were tested using χ2 tests for categorical variables, t-tests for normally distributed continuous variables and Mann-Whitney U tests for remaining variables. Spearman correlation coefficients were used for a correlation analysis. Statistical significance was accepted at p < 0.05. Statistical analyses were performed using SPSS version 22 (IBM Corp., Armonk, NY, USA).
|
other
| 34.1 |
Clinical characteristics of the study population stratified for T2DM patients and controls are shown in Table 1. There was no significant difference in clinical characteristics between the two subgroups, except for body mass index, non-fasting glucose, and HbA1cFurthermore, there was no significant difference in intra-operatively present characteristics of retinal detachment (i.e. surface area of detachment, PVR grade and detachment duration), indicating comparable disease severity between the subgroups.
|
other
| 31.39 |
Sixty-two non-diabetic patients (age range: 44–83 years) formed the control subgroup. In this group, 27% of the patients used anti-hypertensives and 15% of the patients used statins. Furthermore, 4 patients had a history of myocardial infarction or cerebrovascular accident. Medication use of both anti-hypertensives (p = 0.002) and statins (p < 0.001), but not history of macrovascular events (p = 0.058), was significantly lower in the control group compared to T2DM.
|
other
| 32.78 |
Biochemical characteristics of the vitreous stratified for T2DM patients and controls are shown in Table 2. Correlation analysis between AGEs and α-dicarbonyls on the one hand and general characteristics (like age, gender, HbA1c, and eGFR) on the other hand revealed some weak to moderate correlations. In the T2DM subgroup, 3-DG (r = 0.592, p = 0.001) was associated with HbA1c, while pentosidine (r = –0.022, p = 0.908) and the other AGEs and α-dicarbonyls were not. Additionally, SAF was not associated with any of the vitreous AGEs and α-dicarbonyls in the T2DM subgroup. Further results of the correlation analysis are not shown.
|
other
| 34.72 |
For normally distributed continuous variables, data are given as mean ± SD and p-values are based on t-tests. For other variables, data are shown as median (interquartile range) and p-values are based on Mann-Whitney U tests. T2DM, type 2 diabetes mellitus; CML, Nε-(carboxymethyl)lysine; CEL, Nε-(carboxyethyl)lysine; MG-H1, 5-hydro-5-methylimidazolone; 3-DG, 3-deoxyglucosone; MGO, methylglyoxal; GO, glyoxal.
|
clinical case
| 30.47 |
This study addressed the accumulation of several AGEs and their potential precursors (α-dicarbonyls) in a unique body compartment: the vitreous body. Our results show that both protein-bound pentosidine and 3-DG were significantly elevated in T2DM patients as compared to non-diabetic controls matched for age, eGFR, smoking, intra-ocular lens implantation and PVR. However, the levels of other protein-bound AGEs (CML, CEL, and MG-H1), free AGEs (CML, CEL, and MG-H1), and other α-dicarbonyls (MGO and GO) did not differ between the two groups.
|
other
| 33.44 |
For categorical variables, data are displayed as percentages and p-values are based on χ2 tests. For normally distributed continuous variables, data are given as mean ± SD and p-values are based on t-tests. For remaining variables, data are shown as median (interquartile range) and p-values are based on Mann-Whitney U tests. Note: no statistical tests were performed on the parameters on which both groups were matched. T2DM, type 2 diabetes mellitus; NA, not applicable; BMI, body mass index; PVR, proliferative vitreoretinopathy; eGFR, estimated glomerular filtration rate.
|
clinical case
| 32.4 |
Thirty-one T2DM patients (age range: 43–84 years) participated in the study, including 6 who were newly diagnosed with diabetes at inclusion. Median diabetes duration, as recorded by the general practitioner, was 2.2 (0.3–7.4) years. Maximum diabetes duration was 26.3 years. Two patients were treated with insulin only, 3 patients with a combination of insulin and metformin, 10 patients with metformin and 6 patients with a combination of 2 oral anti-diabetics. The remaining 10 patients were not treated medically or had only received lifestyle advice before inclusion. In the T2DM subgroup, 61% of the patients used anti-hypertensives and 48% of the patients used statins. Microvascular complications were present in 2 patients: 1 patient had diabetic neuropathy and 1 patient had non proliferative DR. In the remaining 30 patients, DR was classified as absent or minimal background retinopathy. Six patients had a history of myocardial infarction or cerebrovascular accident.
|
review
| 29.66 |
It has been proposed that AGEs and α-dicarbonyls may be considered as major initiators of retinal microvascular complications in T2DM. Enhanced reactive oxygen species (ROS) generation induced by AGE-RAGE interaction appears to be a likely cause of pericyte loss, the earliest histopathological hallmark of DR. Furthermore, AGEs are considered to stimulate vascular endothelial growth factor (VEGF) expression in pericytes, which is considered to promote neovascularization in DR. Moreover, it has been suggested that AGEs might contribute to persistent central vitreo-retinal adhesions, which leads to vitreoretinal traction that can exacerbate the course of DR.
|
study
| 30.28 |
Several reports have shown elevated levels of pentosidine (measured by HPLC or enzyme-linked immunosorbent assay (ELISA)) in the vitreous of patients with PDR compared to non-diabetic controls. However, one study reported that the significantly higher levels in the T2DM group disappeared when levels of pentosidine (measured by HPLC) were corrected for vitreous protein concentration. This is important because this may suggest that the increase in pentosidine concentration might simply reflect alterations in the blood-retinal barrier in DR. Furthermore, the aging vitreous consists of areas of synchisis and syneresis, which could lead to sampling errors while taking a vitreous biopsy.
|
other
| 31.16 |
In the current study, pentosidine concentrations expressed per mmol of lysine residues were significantly elevated in T2DM patients. Since lysine is used as a proxy for the total amount of protein available for AGE modification expression of AGEs per mmol of lysine provides an adjustment for differences in protein amount in the vitreous biopsy. The current study is also of value because it shows that pentosidine levels are already elevated in T2DM patients without extensive microvascular damage to the retina.
|
other
| 32.4 |
Concerning 3-DG in diabetes, no previous reports have addressed its level in other tissues than plasma. In plasma, several studies have reported elevated levels of 3-DG in both T1DM and T2DM[37–39], and 3-DG has been suggested to play a role in the development of vascular complications. In agreement with these previous reports, the current study shows elevated 3-DG levels in the vitreous of T2DM patients.
|
other
| 37.47 |
Our observation that other protein-bound AGEs (CML, CEL, and MG-H1) and α-dicarbonyls (MGO and GO) were not elevated in the vitreous of T2DM patients compared to controls was unexpected. Of these AGEs and α-dicarbonyls, only protein-bound CML has been previously investigated in the vitreous of patients with diabetes. In that study, CML was found to be increased in PDR patients compared to controls. In addition, increased levels of several protein-bound AGEs and α-dicarbonyls have been found in the plasma of patients with diabetes. Furthermore, in most studies, accumulation of AGEs in skin and serum are strongly associated with the severity of diabetic complications.
|
other
| 33.03 |
Since free AGEs are breakdown products of protein-bound AGEs, the absence of elevated levels of free AGEs indicates that the lack of differences in protein-bound CML, CEL, and MG-H1 in the current study is not a result of differences in degradation of these products. To illustrate, when degradation of proteins in the vitreous would be present to a greater extent in T2DM patients, one would expect that free AGEs would be elevated in these patients.
|
other
| 34.66 |
Skin autofluorescence, as an extensively validated marker of skin accumulation of AGEs, tended to be greater in T2DM patients compared to controls. This is in line with previous publications in which skin autofluorescence was increased in patients with diabetes, particularly in case of complications. The difference in skin fluorescence in our study was just not significant, which is probably due to the short diabetes duration and limited numbers of patients and complications.
|
other
| 30.47 |
Several factors should be considered in interpreting the noted dissimilarities of our results with previous research. First, our study group consisted of T2DM patients with a relatively short duration of diabetes and without PDR. Second, it is important to distinguish between the results of measurements in different body compartments. It is not correct to directly compare results of plasma values to vitreous values because of differences in tissue turnover. Moreover, the vitreous is unique in its supply of nutrients and exposure to plasma components because of the blood-retinal barrier. Third, methodological differences in AGE measurements may contribute to discrepancies in results, especially when AGE levels are not expressed per protein content of the samples. Further, limited blood contamination in the vitreous samples of 4 diabetes and 5 control patients could have influenced our results. However, previous research indicated that limited blood contamination did not confound AGE measurements in the vitreous of RRD patients. Additionally, several frequently used drugs (such as anti-hypertensives and statins) have been shown to inhibit AGE formation in vitro and in vivo. Although the influence of these drugs on AGE accumulation in human tissues with slow turnover has to be further elucidated, the more frequent use of anti-hypertensives and statins in T2DM patients may have masked our results by lowering AGE levels in these patients. Finally, our current study size may be too small to detect differences in other AGEs than pentosidine, since our sample size calculation was based on previously reported pentosidine values only.
|
other
| 31.64 |
Overall, it is difficult to provide a concise explanation as to why most of the measured AGEs and α-dicarbonyls in the current study were similar in the vitreous of the two patient groups while only pentosidine and 3-DG were elevated in the diabetes group. Correlation analysis showed a moderate correlation of 3-DG with HbA1c in the diabetes subgroup, indicating a relation with glycaemic control. This observation suggests an influence of mechanisms outside the eye on vitreous AGE content. Whether this association is causal, or merely a reflection of the underlying disease process cannot be determined by the current study. The generally weak relations between AGE levels in tissues with slow turnover and plasma stress the need for differentiating the behaviour of different AGEs and α-dicarbonyls within and between different tissue compartments. Another recent illustration of this need for differentiating AGE behaviour is given in a study which showed a close correlation of SAF and plasma pentosidine, but not of plasma CML and CEL, with arterial pulse wave velocity.
|
other
| 30.86 |
Because of its cross-sectional design, the current study could not address the causal role of AGEs in DR. Prospective studies are needed to investigate the role of AGEs in the development of DR and their potential to influence the transition of retinopathy from the non-proliferative to the proliferative state.
|
other
| 32.2 |
The major strength of the current study is that several AGEs and α-dicarbonyls were measured with state-of-the-art techniques based on UPLC MS/MS. Furthermore, only patients with RRD (with and without T2DM) were investigated in this study. This is an advantage to investigate the influence of diabetes on AGE accumulation in the vitreous per se. Moreover, it is usually hard to find a homogeneous diabetes group without PDR and a homogeneous control group for which vitreous samples are available since vitrectomy procedures are only performed in limited patient groups. On the other hand, the inclusion of only RRD patients is a limitation of this study. Care must be taken in extrapolating the results to T2DM patients and controls without RRD since the blood-retinal barrier may be disrupted to varying degrees in RRD. Furthermore, our results concerning free AGEs and α-dicarbonyls should be interpreted with caution. Since the exact behaviour of free AGEs and α-dicarbonyls in the vitreous is unknown, the results concerning these products could be subject to sampling errors.
|
other
| 31.94 |
In summary, this study shows that levels of protein-bound pentosidine and 3-DG were increased in the vitreous of T2DM patients with a relatively short duration of diabetes. Since AGEs have been suggested to be involved in the development of DR, this study provides a basis for future studies in DR by showing an overview of several specific AGEs and α-dicarbonyls in the vitreous of early diabetes and non-diabetic subjects. Prospective studies with standardized AGE measurements in diabetes patients are needed to further elucidate the exact role of different AGEs and α-dicarbonyls in the development of DR.
|
other
| 31.55 |
Despite the rapid increasing number of patients treated with ESD for EGC, there is no definite consensus on the optimal follow-up strategy. Some studies have shown that the incidence rate of MGT after ESD was not constant over time, and half of events occurred in the first 2–3 years [17, 18]. Considering these findings, investigation of clinical factors associated with interval to development of MGT might affect the follow-up strategy especially in some high-risk patient group. The aim of this study was to evaluate the clinical characteristics and long-term outcomes of patients with EGC according to the time interval to MGT, and associated clinical factors.
|
other
| 37.03 |
A total of 1,780 consecutive patients who had undergone ESD for EGC at Seoul National University Hospital between January 2005 and June 2014 were retrospectively reviewed. ESD was performed according to the following criteria: well or moderately differentiated adenocarcinoma less than 2 cm in diameter which is confined to mucosa, without evidence of lymph node (LN) or distant metastasis on endoscopic ultrasonography and abdominal computerized tomography. The resection was considered curative if following expanded criteria were fulfilled on the pathologic evaluation of ESD specimens. Expanded criteria were defined as en bloc resection, negative horizontal and vertical resection margin, no evidence of lymphovascular invasion, and including any of the followings: (a) differentiated mucosal cancer without ulceration, regardless of size, (b) differentiated mucosal cancer ≤ 3 cm with ulceration, (c) undifferentiated mucosal cancer ≤ 2 cm, (d) differentiated SM1 (tumor invasion < 500 μm from the muscularis mucosa) cancer ≤ 3 cm. For patients with gastric lesions fulfilling all the other criteria but negative horizontal resection margin, close follow-up strategy with endoscopic biopsy was applied, as the resection margin could be free of tumor because of the electrocauterization effect. In this patient population, if repeated follow-up endoscopy with biopsy revealed no evidence of residual tumor on the previously resected site, the lesion was also regarded as curatively resected.
|
other
| 34.22 |
Gastric cancer is the fifth most common cancer in the world, half of which occurs in eastern Asia. Although the incidence and mortality rates are steadily decreasing worldwide, more than 0.7 million people died of gastric cancer in 2012, making it the third leading cause of death from malignancy . The importance of early detection of gastric cancer cannot be overemphasized, as tumor stage is one of the most powerful prognostic factors . In Korea, more than half of newly detected gastric cancers are in their early stages due to the biennial upper endoscopic examination included in the National Cancer Screening Program [3–5]. Prognosis of early gastric cancer (EGC) is generally excellent after surgical resection, with a 5-year overall survival rate (OS) over 90 percent [6, 7]. Recently, endoscopic resection is widely accepted as a reasonable treatment option in some cases with EGC when the probability of lymph node metastasis is negligible. Data from previous studies show that clinical outcomes such as 5-year OS and recurrence rate after endoscopic submucosal dissection (ESD) are comparable to those after gastrectomy in patients with EGC [8–10]. In addition, ESD is by far a less invasive technique compared to gastrectomy and enables preservation of the whole stomach, which improves quality of life after the procedure [11, 12].
|
other
| 31.12 |
Development of metachronous gastric tumor (MGT) arising from the remnant stomach has always been a major concern after subtotal gastrectomy or endoscopic resection. According to literature, the overall incidence of MGT over a long-term period after endoscopic resection range from 4.3 to 8.5%, while that after partial gastrectomy is about 2.4% [13–16].
|
study
| 29.69 |
Patients were excluded if they had previous history of gastric cancer, gastrectomy or endoscopic resection, or underwent subsequent gastrectomy due to non-curative ESD. Tumors containing poorly differentiated, signet ring cell, poorly cohesive, or mucinous carcinoma portion in more than 50% of area were categorized as undifferentiated group. The Institutional Review Board of the Seoul National University Hospital approved this study (IRB number: H-1606-007-765). Patient consent was waived, given the retrospective nature of this study.
|
other
| 37.78 |
All ESD procedures were performed using a standard single-channel endoscope (Olympus H260; Olympus Optical), as previously described [19, 20]. In brief, after marking the perimeter 5 mm outside the lesion with several spots using a needle knife (KD- 1L; Olympus) with a forced 20 W coagulation current (VIO 300D; Erbe, Tübingen, Germany), normal saline mixed with indigo carmine and diluted epinephrine (1:100,000) was injected to lift the submucosal layer. Then a small initial incision was made with a needle knife. Subsequent circumferential mucosal incision, followed by dissection of submucosal layer, was made using an insulation-tipped knife (Kachu Technology Co. Ltd., Seoul, Korea).
|
other
| 33.44 |
Location and macroscopic type of EGC lesions were assessed according to the Japanese Classification of Gastric Carcinoma (JCGC) . We grouped type 0-I (protruding) and type 0-IIa (superficial elevated) together as elevated type, while grouping type 0-IIb (superficial flat), 0-IIc (superficial depressed), 0-III (excavated), 0-IIa+IIc, and 0-IIb+IIc together as non-elevated type. After ESD, endoscopically resected specimens were immediately stretched and pinned on a flat polystyrene board to prevent folding, and then fixed in 10% formalin. Fixed specimens were then sectioned serially at 2-mm intervals for histologic evaluation. Histologic type, size of tumor, depth of invasion, tumor involvement and lymphovascular invasion were evaluated in accordance with JCGC.
|
other
| 39.47 |
During the ESD procedure, four pieces of non-cancerous gastric mucosal tissue (two from the lesser curvature of antrum and the other two from the lesser curvature of mid body) were obtained by endoscopic biopsy. The tissue samples were examined for histologic evaluation of atrophic change, intestinal metaplasia (IM), and Helicobacter pylori status according to the updated Sydney System . The H. pylori status was evaluated using the rapid urease test (CLO® test; Kimberly-Clark, UT, USA) and histologic examination. If any of these two test results was positive, H. pylori infection was considered to be present.
|
other
| 40.12 |
The initial endoscopic follow-up was routinely performed 3 months after ESD. Subsequent follow-up examinations comprising endoscopy, abdominal computed tomography (CT) and chest radiography were scheduled at 6-month intervals for 12 months after ESD, and annually thereafter. Endoscopic biopsy was done on the post-ESD scar or other suspicious mucosal lesions as needed during the follow-up period.
|
other
| 35.72 |
Synchronous and metachronous gastric tumor were defined as second gastric adenocarcinoma or dysplasia detected ≤ 1 year and > 1 year after ESD, respectively. Simultaneous gastric tumors at the time of initial ESD were also interpreted as synchronous lesions.
|
other
| 35.66 |
Patients with MGT were divided into two groups according to the time interval to occurrence of MGT. As the median time interval to MGT was 37 months, patients diagnosed with MGT within 36 months after the initial ESD were categorized as early occurrence group (n = 52), and the rest were grouped as late occurrence group (n = 63), for the sake of convenience in analysis. The patients with MGT were predominantly male (87.8%), but there was no significant difference in sex, age, body mass index (BMI), and H. pylori status between the two groups (Table 1). Regarding the initial tumor characteristics, patients of the early occurrence group were more likely to have non-elevated type (p = 0.002), absent or mild IM of antral mucosa (p = 0.002), and less likely to have synchronous gastric tumor (p = 0.042) than those of the late occurrence group. Otherwise, there were no significant differences in curative resection rate, histologic type, location, size, depth of invasion, and presence of coexisting underlying dysplastic lesion between the two groups of patients. Metachronous tumor developed from the previous ESD sites in 13 patients, and from a distant area of the stomach in 102 patients. There were no significant differences in the recurrence site between the early occurrence group and the late occurrence group (6/52 vs 7/63, p = 0.943). Mean follow-up duration was 65.5 ± 26.1 months in the early occurrence group and 86.3 ± 23.3 months in the late occurrence group, respectively (p < 0.001).
|
other
| 32.53 |
The univariate analysis using the Kaplan-Meier method and log-rank test showed that non-elevated type at the time of initial ESD was associated with early occurrence of MGT (p = 0.011) (Fig 3A). Absence of synchronous primary lesions also showed almost significant tendency toward early occurrence of MGT (p = 0.050) (Fig 3B). Unlike these factors, age, sex, BMI, curative resection, histologic type by Lauren classification, location, size, depth of invasion, coexisting underlying dysplastic lesion, and severity of atrophic change or IM of mid body and antrum were not significantly associated with early occurrence of MGT (Table 2). In addition to gross type and synchronicity of primary lesion, factors like age, sex, H. pylori status, and IM of antrum were also analysed in the multivariate Cox proportional hazard model, as they were previously suggested as possible risk factors for MGT.[23–27] In multivariate analysis, non-elevated type (HR 1.966; 95% CI: 1.141–3.386; p = 0.015), absence of synchronous gastric lesion (HR 1.911; 95% CI: 1.163–3.141; p = 0.011) were still independent risk factors for early occurrence of MGT (Table 3).
|
other
| 29.69 |
Pearson’s chi square test or Fisher’s exact test was used to compare categorical variables, and Student’s t-test or Mann-Whitney U test was used to compare continuous variables. The cumulative incidences of MGT by various clinicopathologic factors were evaluated using the Kaplan–Meier method, while the differences between groups were compared with the log-rank test for univariate analysis. Significant univariate factors (P < 0.05) and other relevant variables based on previous studies were examined in multivariate Cox proportional hazards regression model to identify independent factors associated with early development of MGT. Results of the analyses were presented as hazard ratios (HRs) with 95% confidence intervals (CIs). P value < 0.05 was considered statistically significant. All statistical analyses were performed using SPSS version 23 (SPSS Inc., Chicago, IL, USA).
|
other
| 35.28 |
Among the 1,780 patients who received ESD for EGC, 115 patients who underwent subsequent gastrectomy due to non-curative ESD and 10 patients with prior history of gastric cancer, gastrectomy or endoscopic resection were excluded. Consequently, 1,655 patients were retrospectively reviewed and MGT was confirmed in 115 patients (6.9%, 92 cancers and 23 dysplasias) (Fig 1), while synchronous gastric tumor was found in 31 patients (1.9%, 20 cancers and 11 dysplasias). Among these patients with MGT, trend of tumor development over time was analysed with Kaplan-Meier method (Fig 2). The median time interval to the first MGT was 37 months (interquartile range [IQR], 24–54 months). The mean follow-up duration was 76.9 ± 26.6 months (range: 18–123). Eighty percent of MGTs developed within 60 months from ESD and the longest interval to MGT was 111 month.
|
other
| 31 |
(A) Kaplan-Meier survival curve for overall survival in the whole patient group. (B) Kaplan-Meier survival curves for overall survival in early occurrence group and late occurrence group. (C) Kaplan-Meier survival curve for overall survival after diagnosis of MGT in the whole patient group. (D) Kaplan-Meier survival curves for overall survival after diagnosis of MGT in early occurrence group and late occurrence group.
|
other
| 32.7 |
As ESD is frequently performed for treatment of differentiated mucosal EGC especially in East Asia nowadays, the patients with EGC can maintain better quality of life after ESD than after gastrectomy via reservation of the whole stomach. At the same time, MGT arising from the remnant stomach is undoubtedly one of the most concerning issues after ESD because this may be directly related to poor prognosis. While accumulated experiences with endoscopic resection over nearly two decades has led to the consensus of indication for the procedure, when to discontinue endoscopic follow-up is still a debatable issue. Focusing on this specific subject, we investigated the clinicopathologic factors associated with the time interval to between the development of MGT and the initial ESD.
|
other
| 35.2 |
H. pylori status was evaluated in 104/115 (90.4%) patients. Among 42/104 cases (36.5%) with H. pylori infection, eradication therapy was performed in 15/42 patients (35.7%). Among 15 cases with H. pylori eradication, successful eradication was confirmed in 11 patients (73.3%). Among those with initial H. pylori infection, the time interval to MGT was not different between the group with successful H. pylori eradication (n = 11) and the group with persistent H. pylori infection (n = 31) (38.2 vs 44.2 months, p = 0.245). Excluding 2 patients who lacked clinical information of atrophic change or IM of stomach, 38 out of 40 patients (95.0%) had either atrophic gastritis or IM in antrum or mid body. Kaplan-Meier analysis of the cumulative incidence of MGT in time-dependent manner and log-rank test revealed no statistical difference between the two groups (p = 0.502).
|
other
| 33.28 |
Among 115 patients with MGT, metachronous lesion was cancer in 92 patients (80.0%), and dysplasia in 23 patients (20.0%). Gastric cancer was advanced lesion in 4/92 patients (4.8%) and EGC in 80/92 patients (87.0%). The other 8 patients could not be assessed, as they had only extragastric lesions or did not undergo resection of the lesion due to severe comorbidities, or refused further evaluation. Characteristics of MGT lesions were compared between the early occurrence group and the late occurrence group. Among 52 patients with early MGT and 63 patients with late MGT, metachronous lesion was cancer in 40 patients and 52 patients, respectively, and the proportions were not different between the two groups (p = 0.454). Regarding the patients with only intragastric metachronous cancer, differentiated type histology was present in 32/39 patients with early MGC, and in 39/50 patients with late MGC (p = 0.637). Proportion of elevated type (4/35 vs 6/44, p = 1.000) was also not different between the two groups of patients.
|
other
| 32.44 |
Among 115 patients with MGT, metachronous lesions were treated with repeated ESD in 87 patients (75.7%), surgical resection in 22 patients (19.1%), and chemotherapy in 1 patient (0.87%). Regarding the remaining 5 patients, one patient was carefully observed without definitive treatment for MGT because of underlying metastatic hepatocellular carcinoma, and the other 4 patients did not show up after the diagnosis of MGT.
|
other
| 33.2 |
Among 115 patients, 11 patients (9.6%) died during a median follow-up period of 7.3 years (IQR, 5.1–8.9 years). In Kaplan-Meier curve for overall survival, the 5-year, 7-year, and 10-year OSs for the whole group of patients were 93.4%, 90.3%, and 81.3%, respectively (Fig 4A). Subsequent log-rank test showed that there was no significant difference in overall survival between the early occurrence group and the late occurrence group (Fig 4B). In addition, the 5-year OS after diagnosis of MGT was 87.2% (Fig 4C), and there was no significant difference in overall survival after diagnosis of MGT between the two groups (Fig 4D). Cause of death was gastric cancer in 3 patients (2.6%), and the 10-year disease-specific survival rate was 97.3%. The time intervals to MGT were 17, 35, and 40 months in these 3 patients, respectively.
|
other
| 31.78 |
In this study, the 5-year cumulative incidence of MGT was 5.6% and overall cumulative incidence was 6.9% over the mean follow-up duration of 76.9 month. These incidence rates are lower compared to those observed in previous studies [13–15]. This difference may be attributable to H. pylori eradication therapy applied after ESD to some of the patients with H. pylori infection, considering the protective effect of eradication therapy against development of MGT . The incidence rate of MGT was not constant over time after ESD. Considering half of MGT occurred in the 2nd or 3rd year after the procedure, meticulous endoscopic inspection is required after ESD especially in the early follow-up period. In addition, as one fifth of MGT occurred later than 5 years after ESD, long-term follow-up might be beneficial to some patients with adequate life expectancy without severe comorbidities.
|
other
| 29.98 |
There have been some studies suggesting the association between endoscopic gross appearances and clinical behaviour of EGC [28, 29]. A total of 546 (35%) patients had elevated lesion among 1,780 cases undergoing ESD for EGC in our study, compared to 15.9–19.8% in previous studies with surgically treated EGC patients [28, 30, 31]. This might be attributable to the difference of target patient groups, as overt ulceration or undifferentiated histology was contraindication for ESD. Additionally, considering that elevated gross type is directly associated with differentiated type histology, this association may explain why elevated type was taking relatively large proportion than expected . Meanwhile, 21/115 (18.3%) patients with MGT had elevated initial lesion, and only 3 out of 21 patients with elevated type EGC (14.3%) had occurrence of MGT in 3 years. As epigenetic change with microsatellite instability seems to have a role in growth pattern of EGC, methylation induced suppression of DNA mismatch repair genes might be a factor affecting the time interval to development of MGT.
|
study
| 33.56 |
Absence of synchronous gastric tumor was another independent risk factor for early occurrence of MGT. Detection of synchronous gastric tumor is largely dependent on the skill and experience of the endoscopist as well as the location or size of the lesion, and also reflects how meticulous the examination was done. To be detectable on the endoscopic examination, neoplastic lesion should grow large enough over time. This means there is still some chance of missed small EGCs or precancerous lesions after an endoscopic examination. Although we have categorized gastric tumor detected simultaneously with the index EGC or in the first year after ESD as synchronous tumor due to the possibility of overlooked lesion, some of the early MGTs might still be the consequences of initially missed neoplastic lesions. If coexisting precancerous lesions or small EGC lesions were detected initially and resected together with the index EGC, it can be inferred that new gastric neoplastic lesion would rarely be found in the next few years. Therefore, presence of synchronous gastric tumor would be a factor partially reflecting how precisely the endoscopic evaluation was performed and whether precancerous lesions were removed initially.
|
study
| 31.73 |
As the study population encompassed post-ESD patients over 10 years, H. pylori eradication therapy was individually applied to each of the patient considering several factors like age, comorbidities or patient’s preference. Among 42 H. pylori-infected patients, successful eradication was achieved in 11 patients and the time interval to the first MGT was not different between the two groups with and without persistent H. pylori infection. We also observed that almost every patient with initial H. pylori infection had atrophic change or IM in some part of the stomach. Although the number of patients who achieved successful eradication was rather small, H. pylori infection or eradication did not affect the time interval to occurrence of MGT after ESD. This finding, which is similar to the result from the previous study by Lim et al., implies that H. pylori eradication therapy may not delay or prevent the progression of malignant change, especially when the neoplastic change has reached a certain degree. In addition to H. pylori status, sex and IM were not associated with early occurrence of MGT. We also compared various characteristics of MGT such as histology, differentiation, and gross type between the early occurrence group and the late occurrence group, which showed no significant differences between the two groups. Although statistically insignificant, the mean age was lower in the late occurrence group than in the early occurrence group. This is closely associated with the fact that elderly patients are more likely to die from various causes other than gastric cancer. In young patients, late MGTs are more common than in old patients because of relatively long survival time and long follow-up duration.
|
other
| 32.06 |
Both the 5-year OS after initial ESD and the 5-year OS after diagnosis of MGT were over 85% in this study, which are comparable to the same figure of patients with EGC, showing that patients who once underwent ESD for EGC have excellent prognosis even after the diagnosis of MGT if adequately treated. In addition, there was no statistical difference in overall survival between the early occurrence group and the late occurrence group, implying that long-term prognoses of the two groups of patients were not significantly different.
|
other
| 34.44 |
As high grade dysplasia is widely considered as premalignant lesion, it is reasonable to count this lesion as MGT. Although low grade dysplasia has relatively low risk of progression to malignant lesion, pathologic discrepancies commonly exist between the specimens obtained with single endoscopic biopsy and resected specimens as a whole. Due to this histologic heterogeneity of tumor, endoscopic resection of low grade dysplasia is generally recommended. Considering these issues in clinical practice, dysplasia of any degree was included in MGT in our study. To the best of our knowledge, this is the first study to investigate the association between the time interval to MGT and the prognosis of patients with EGC treated by ESD, as well as risk factors for early occurrence of MGT. An additional strength of this study was the availability of long term follow-up data. The mean follow-up duration was over 6 years, and every patient included in the analysis had follow-up duration longer than 18 months.
|
other
| 33.1 |
This study has some limitations. As a restrospective, single-center study, the result should be cautiously interpreted and adapted in general population. Possibility of some degree of bias could not be ruled out due to its retrospective nature. For this reason, we tried to minimalize possible biases through multivariate analysis. Although atrophic gastritis and IM was not evaluated in every patient, the histologic change of gastric mucosa was examined and graded by pathological review, which is more reliable method than mere macroscopic inspection. Regarding H. pylori status, we reviewed two different tests including histologic examination to avoid false negative results, but individual history of previous H. pylori eradication before the ESD procedure was not available.
|
other
| 31.84 |
In conclusion, non-elevated type and absence of synchronous gastric tumor were independent risk factors for early development of MGT. These factors can be interpreted as being related with missed gastric tumors at initial endoscopic examination. Meticulous endoscopic inspection is required after ESD for EGC, especially in early follow-up periods. Long-term follow-up is also recommended regardless of H. pylori status in patients with adequate life expectancy without severe comorbidities.
|
study
| 29.27 |
Traumatic brain injury (TBI) is the leading cause of disability in young people . A recent review of paediatric TBI estimated that each year TBI affects over 3 million children worldwide, and that over 80% of these are mild . The definition of what constitutes a mild TBI varies between studies; however, the Centre for Disease Control suggests the following: “Mild TBI is an injury to the head (arising from blunt trauma or acceleration or deceleration forces) that results in one or more of the following: any period of confusion, disorientation, or impaired consciousness; any dysfunction of memory around the time of injury; loss of consciousness lasting less than 30 min; or the onset of observed signs or symptoms of neurological or neuropsychological dysfunction” . Previous cross-sectional research has shown increased substance use , disruptive behaviour disorders , school violence and conduct problems [7, 8] in participants with a history of mild TBI.
|
study
| 27.7 |
Evidence for a prospective association between mild TBI and negative behavioural outcomes comes from three cohort studies. In a sample of over one million Swedish people, having a TBI registered with hospital before age 25 years was associated with increased risk of adverse outcomes, including drawing a disability pension, psychiatric visit or hospitalisation, low educational attainment, and welfare recipiency. For those with a mild TBI, the risk ratios for these outcomes ranged from 1.18 to 1.52 . Findings from the Northern Finland 1966 Birth Cohort Study indicate that a mild TBI before age 14 years was associated with drinking to intoxication at age 14 years . In the same cohort, male participants with a TBI before age 15 years were at higher risk of committing a crime registered with the Ministry of Justice from ages 16 to 31 years, and those with a TBI had a twofold increased risk of developing a psychiatric disorder, which increased to fourfold for criminality combined with a psychiatric disorder . In the Christchurch Health and Development Study (CHDS), participants who had experienced a mild TBI requiring an inpatient hospital stay between birth and age five years had higher self- and parent-ratings of conduct disorder/oppositional defiant disorder and substance abuse at age 14–16 years , and a higher likelihood of alcohol and drug dependence at age 16–25 years, which mediated a relationship between the same injury and an increased number of arrests, property offences and violent offences . Any mild TBI at age 6–15 years was linked with increased arrests and property offences at age 16–25 years, hospitalisation for the injury was additionally associated with violent offences .
|
study
| 32.72 |
Confounders Models were adjusted for confounders that preceded the TBI measurements and were previously shown to have associations with TBI. Confounders considered included: (1) pre-birth confounders (mother’s age and education at birth , social class (based on either the paternal or maternal self-reported highest occupation level related to the Registrar General’s classification of occupations) and gender), and (2) childhood confounders (early life events , parenting style (based on self-report questionnaires assessing parental bonding, positive and negative parenting experiences) , maternal alcohol use and maternal tobacco smoking). Tobacco, alcohol and cannabis were mutually adjusted for by including these variables as covariates in the final adjustment model.
|
other
| 28.52 |
Ordinal regression was used to explore the association between childhood injuries from birth to age 16 years, and the three-level variables relating to substance use (tobacco and cannabis) and criminal behaviour (offences, trouble with the police) at age 17 years. The gologit2 command was used to permit testing for the more parsimonious proportional odds model (PO). We first, for the univariable model consisting of outcome and exposure, compared constrained (PO) and unconstrained (non-PO) models using a likelihood ratio test, accepting the simpler model if the p value was greater than 0.01. Next, confounders were included without the PO restriction for these additional covariates. Finally, support for PO for the exposure was re-examined within these multivariable models.
|
other
| 31.22 |
Injury groups In the ALSPAC questionnaires, parents were asked if their child had incurred any injuries across a range of ages up to 11 years. Similar self-report questionnaires were completed by the offspring; at age 15 years participants reported on fractures incurred since their 12th birthday, including skull fractures, and at age 16 years participants reported on a head injury since their 14th birthday or fractures in the last 6 months. Information was gathered from a series of postal questionnaires. A positive response to the item “head injury resulting in a loss of consciousness” or the item “cracked or broke skull” was used to identify participants in the mild TBI group. A positive response to any of the items “broke arm or hand”, “broke leg or foot” or “broken other bone” was used to identify participants in the orthopaedic injury (OI) control group. Participants who incurred both a head injury and a broken bone were included in the TBI group only. Participants for whom there were no positive responses to the above items were included in the no injury control group. For the secondary analyses, participants were assigned to either a childhood or an adolescent injury group based on the age at which their first injury occurred.
|
other
| 33.47 |
Substance use Data on tobacco, alcohol and cannabis use was gathered by a self-report questionnaire at age 17 years. Problematic use was assessed at age 17 years using the Fagerström Test for Nicotine Dependence (FTND) , Alcohol Use Disorders Identification Test (AUDIT) , and the Cannabis Abuse Screening Test (CAST) . Responses were used to create category variables for each substance. The FTND is a six-item scale with total scores ranging from 0 to 10; the tobacco variable contained the levels: “not regular smoker”, “weekly smoker” and “FTND score of over 4”. The AUDIT consists of ten items with total score ranging from 0 to 40, we used a cut-off score of 8 to identify hazardous drinkers. The alcohol use variable contained the levels “non-hazardous use” and “hazardous use”. The CAST is a four item scale with a total score range from 0 to 6; cannabis use was categorised as “not used in the last 12 months”, “used in the last 12 months” and “CAST score of one or more”. Conservative cut-off scores were used to define problematic use to reflect the young age of the participants.
|
other
| 32.66 |
In this study, we investigated the association between mild TBI and risk behaviour in a United Kingdom birth cohort. TBI was based on incidences of skull fracture and loss of consciousness due to a head injury reported by parents and children at multiple time points up to age 16 years. Risk behaviour was defined as psychiatric symptoms, substance use, and criminal behaviours. To strengthen causal inference we incorporated a negative control exposure group, where confounding structures are likely to be similar but there is no pathway between the exposure and the outcome . If the observed association is larger for exposure of interest than for the negative control exposure this increases confidence that the association may be causal . Previously, in the Swedish population study, individuals who sustained non-TBI fall-related injuries were less likely to have poor adult outcomes than those with a TBI before age 25 years . Additionally, Fazel and colleagues found that participants with a history of epilepsy were less likely to commit violent crime than those who sustained a TBI . In our study, participants with a history of fracture or broken bone formed the negative control exposure group as this type of injury has a similar confounding structure to TBI but lacks the plausible biological mechanism (i.e., brain injury) for an association with risk behaviour. The effect of age at injury was investigated in secondary analyses separating the cohort into those with childhood injuries and those with adolescent injuries.
|
other
| 29.38 |
Participants were drawn from a longitudinal birth cohort study, the Avon Longitudinal Study of Parents and Children (ALSPAC). Initially 14,541 pregnant women who were expected to give birth between 1 April 1991 and 31 December 1992 were recruited into the study in the South West region of England . The study website contains details of all data available through a fully searchable data dictionary (http://www.bris.ac.uk/alspac/researchers/data-access/data-dictionary/). Ethics approval for the study was obtained from the ALSPAC Ethics and Law Committee and the Local Research Ethics Committees.
|
other
| 34.53 |
Criminal behaviour A self-report questionnaire at age 17 years was used to assess criminal behaviour in terms of offences committed and trouble with the police . Participants were classified as either having committed “no offences”, “at least one non-violent offence” or “at least one violent offence” based on questions relating to behaviours such as theft, assault and property damage. There was a single item asking if the participant had “sold illegal drugs to someone” within this questionnaire. A second variable related to whether or not a participant had ever been in trouble with the police was included with the levels “never”, “in trouble with the police with no conviction” and “one or more criminal record offence”.
|
other
| 30.66 |
Psychiatric symptoms Parents completed one measure of psychiatric symptoms, the Strengths and Difficulties Questionnaire (SDQ), while the offspring completed the Development and Well-Being Assessment (DAWBA). The SDQ is a 25-item parent-rated scale; each item can be rated as ‘not true’, ‘somewhat true’ or ‘certainly true’. There are ten strengths, fourteen difficulties and one neutral item within five subscales. Parents completed the entire SDQ; however, only two of the subscales assessing conduct problems and peer problems at age 16 years were included in the current analysis. The DAWBA is a semi-structured interview administered to the offspring at age 15 years. The interview contains sections measuring symptoms of various emotional, behavioural and hyperactivity disorders with skip-rules. The questions are designed to closely follow the diagnostic criteria for psychiatric disorders as defined by the Diagnostic and Statistical Manual of Mental Disorders, 4th Edition (DSM-IV) or the International Classification of Diseases (ICD-10). A composite variable of externalising disorder symptoms, as well as individual variables relating to diagnoses of oppositional defiant disorder (ODD), conduct disorder (CD) and attention deficit hyperactivity disorder (ADHD) at age 15 years were included as variables in the secondary analysis on childhood injuries.
|
other
| 30.56 |
Logistic regression was used to explore the association between childhood injuries and the two-level variables relating to substance use (alcohol) and psychiatric symptoms. Separate secondary analyses were conducted using childhood injuries, sustained between birth and age 11 years, and adolescent injuries, sustained between age 12 and age 16, to explore the impact of age at injury.
|
other
| 30.94 |
The impact of confounders on the relationship between TBI and risk behaviours was explored by comparing unadjusted estimates with those adjusted for pre-birth variables (model 1) and those further adjusted for childhood variables (model 2). Substance use and crime frequently co-occur. To explore the impact this relationship may have on the main association of interest, an additional model adjusted for other substance use variables (model 3) was conducted for analyses of each of the substance use and crime variables. This model included adjustment for crime variables in the analyses on substance use. As each level of adjustment increases, the sample size decreases as those with missing data are excluded from the analysis. As a sensitivity analysis, all analyses were conducted on the full sample and then conducted on only those participants with complete data (i.e., complete cases). Comparisons were made between the no injury controls and each injury group, and also directly between the TBI group and the OI group. For the comparison between the TBI and OI groups, additional sensitivity analyses were conducted excluding participants who had incurred both a TBI and OI. Analyses were conducted using Stata version 13 (StataCorp LP, Texas).
|
review
| 29.9 |
TBI traumatic brain injury, OI orthopaedic injury, Unadjusted Injuries from birth to age 16 years with main substance use variable in each analysis, Model 1 As unadjusted with additional adjustment for pre-birth confounders (mother’s age at birth, mother’s education at birth, social class and gender), Model 2 As Model 1 with additional adjustment for childhood confounders (early life events, parental bonding, positive and negative parenting experiences, maternal alcohol use and maternal tobacco smoking), Model 3 As Model 2 with additional adjustment for substance use and crime variables
|
clinical case
| 28.05 |
Individuals with TBI were more likely to have committed at least one offence (unadjusted OR = 1.72, 95% CI 1.32–2.23) and to have been in trouble with the police (unadjusted OR 1.62, 95% CI 1.21–2.17). The association with committing at least one offence was robust to adjustment for pre-birth and childhood confounders, while the association with being in trouble with the police was attenuated. Further adjustment for substance use variables substantially weakened the associations between TBI and offences and TBI and trouble with the police. In the negative control analyses, OI was associated with criminal behaviours (offences: unadjusted OR = 1.48, 95% CI 1.23–1.77; trouble with the police: unadjusted OR = 1.42, 95% CI 1.15–1.74), but while the association with offences was robust to adjustment for pre-birth and childhood confounders and substance use, the association with trouble with the police was attenuated substantially following adjustment. There was no clear evidence for increased odds of either offending or being in trouble with the police in the direct comparison between TBI and OI. These results are shown in Table 3. The findings from the complete case and additional sensitivity analyses did not differ substantially and can be seen in Supplementary Tables S6, S7 and S8.Table 3Associations between traumatic brain injury and orthopaedic injuries from birth to age 16 years and criminal behaviours at age 17 yearsCriminal behaviourOR (95% CI)UnadjustedModel 1Model 2Model 3Offencesa,b n 3846339629902115TBI vs no injury1.72 (1.32–2.23)1.56 (1.17–2.07)1.67 (1.24–2.24)1.29 (0.09–1.88)OI vs no injury1.48 (1.23–1.77)1.35 (1.11–1.65)1.41 (1.14–1.74)1.67 (1.27–2.19)TBI vs OI1.16 (0.87–1.54)1.15 (0.85–1.56)1.18 (0.86–1.63)0.77 (0.52–1.16)Omnibus p <0.0010.0010.001<0.001Trouble with the policea,c n 3782334029472077TBI vs no injury1.62 (1.21–2.17)1.33 (0.96–1.84)1.44 (1.03–2.01)1.17 (0.77–1.77)OI vs no injury1.42 (1.15–1.74)1.21 (0.97–1.52)1.23 (0.96–1.56)1.03 (0.75–1.42)TBI vs OI1.14 (0.83–1.57)1.09 (0.77–1.55)1.17 (0.81–1.69)1.14 (0.71–1.81)Omnibus p <0.0010.0640.0620.765Sample size reduces per adjustment as the participants who are missing covariate data get excluded TBI traumatic brain injury, OI orthopaedic injury, Unadjusted Injuries from birth to age 16 years with main crime variable in each analysis, Model 1 As unadjusted with additional adjustment for pre-birth confounders (mother’s age at birth, mother’s education at birth, social class and gender), Model 2 As Model 1 with additional adjustment for childhood confounders (early life events, parental bonding, positive and negative parenting experiences, maternal alcohol use and maternal tobacco smoking), Model 3 As Model 2 with additional adjustment for substance use variables aGeneralised ordinal regression bOffences measured by self-report questionnaire at age 17 years cTrouble with the police measured by self-report questionnaire at age 17 years
|
clinical case
| 31.6 |
Descriptive statistics for the sample are shown in Table 1 and a flow chart of the final sample in Fig. 1. Between birth and age 16 years, there were 800 participants with a reported TBI (57% male), 2305 participants with a reported OI (56% male) and 8307 participants with neither injury reported (50% male). There were 289 participants included in the TBI groups who had incurred both a TBI and an OI. There were 56 participants who experienced more than one TBI. Participants with a TBI were more likely to be male and to have more adverse early life events. Unexpectedly, individuals with no reported injury were more likely to come from a low income family and to live in rented subsidised housing; their mothers had a lower level of education and were on average six months younger than mothers of children with TBI.Table 1Descriptive statistics for covariates; injuries from birth to age 16 yearsNo injuryTBIOI p value*(n = 8307)(n = 800)(n = 2305) N (%) N (%) N (%)Male4109 (49.5)457 (57.1)1283 (55.7)<0.001Social class IV–Va 3052 (42.9)273 (37.7)786 (39.5)0.001Rented subsidised housing967 (12.5)60 (8.0)181 (8.5)<0.001Mother completed secondary school4826 (63.4)434 (57.7)1236 (58.9)<0.001Maternal daily smoking2246 (28.6)212 (27.6)576 (26.7)0.186Maternal daily alcohol use989 (12.6)110 (14.3)309 (14.3)0.067Three or more early life eventsb 4107 (52.9)470 (61.6)1220 (57.1)<0.001M (SD)M (SD)M (SD)Maternal age at birth (years)28.42 (4.76)28.92 (4.76)28.72 (4.74)0.001Bonding at 8 monthsc 28.25 (3.68)28.08 (3.55)28.20 (3.59)0.512Positive parenting experience at 21 monthsd 5.99 (1.51)6.01 (1.53)6.00 (1.55)0.934Negative parenting experience at 21 monthsd 20.80 (2.74)20.63 (2.84)20.77 (2.73)0.281 TBI traumatic brain injury, OI orthopaedic injury * p values calculated using Chi square or analysis of variance aHighest social class of either parent is skilled non-manual or lower occupation based on the Registrar General’s classification of occupations bParent-reported questionnaire relating to upsetting events in the child’s life completed when offspring was 6, 30, 42 and 81 months old cParent-report questionnaire completed when offspring was 8 months old dPositive and negative parenting experiences based on parent-completed questionnaire when offspring was 21 months old Fig. 1Flow chart of final sample
|
review
| 29 |
Individuals with TBI were at increased odds of hazardous use of alcohol (unadjusted OR = 1.51, 95% CI 1.21–1.90), problematic use of tobacco (unadjusted OR = 1.47, 95% CI 1.12–1.94) and problematic use of cannabis (unadjusted OR = 1.54, 95% CI 1.22–1.94). These associations were robust to adjustment for pre-birth and childhood confounders. Mutual adjustment for the other substance use variables weakened the associations of TBI with alcohol and cannabis use, and fully attenuated the association with tobacco use. In the negative control analyses, OI was associated with cannabis use (unadjusted OR = 1.22, 95% CI 1.04–1.43), but this was attenuated following adjustment for pre-birth and childhood confounders. There was no evidence for any associations between OI and alcohol or tobacco use, implying that the associations observed are specific to TBI. In the direct comparison to those with OI, participants with TBI were at increased odds of hazardous alcohol use only (unadjusted OR 1.34, 95% CI 1.05–1.72). These results are shown in Table 2. Excluding participants with both TBI and OI strengthened the association between TBI and alcohol use (unadjusted OR 1.48, 95% CI 1.10–1.99; adjusted OR 1.57, 95% CI 1.13–2.18); findings from this analysis can be seen in Supplementary Table S4 and S5. The findings from the complete case analyses did not differ substantially and can be seen in Supplementary Table S3.Table 2Associations between traumatic brain injury and orthopaedic injuries from birth to age 16 years and substance use at age 17 yearsSubstance useOR (95% CI)UnadjustedModel 1Model 2Model 3Alcohola,c n 3694326328842074TBI vs no injury1.51 (1.21–1.90)1.46 (1.15–1.85)1.56 (1.21–2.01)1.31 (0.94–1.82)OI vs no injury1.13 (0.97–1.31)1.06 (0.90–1.25)1.06 (0.89–1.27)0.77 (0.61–0.98)TBI vs OI1.34 (1.05–1.72)1.37 (1.06–1.79)1.47 (1.11–1.94)1.69 (1.17–2.45)Omnibus p 0.0450.2650.2510.080Tobaccob,d n 3099274124202074TBI vs no injury1.47 (1.12–1.94)1.51 (1.12–2.03)1.46 (1.06–2.01)1.09 (0.74–1.62)OI vs no injury1.16 (0.96–1.42)1.20 (0.97–1.49)1.22 (0.97–1.54)1.15 (0.86–1.55)TBI vs OI1.26 (0.93–1.72)1.26 (0.91–1.74)1.19 (0.84–1.70)0.95 (0.61–1.47)Omnibus p 0.0600.0440.0500.331Cannabisb,e n 3979350530902074TBI vs no injury1.54 (1.22–1.94)1.36 (1.06–1.75)1.39 (1.07–1.80)1.23 (0.87–1.74)OI vs no injury1.22 (1.04–1.43)1.15 (0.97–1.37)1.15 (0.96–1.39)1.02 (0.79–1.33)TBI vs OI1.26 (0.98–1.62)1.18 (0.90–1.55)1.20 (0.90–1.60)1.20 (0.82–1.77)Omnibus p 0.0040.0540.0710.718Sample size reduces per adjustment as the participants who are missing covariate data get excluded TBI traumatic brain injury, OI orthopaedic injury, Unadjusted Injuries from birth to age 16 years with main substance use variable in each analysis, Model 1 As unadjusted with additional adjustment for pre-birth confounders (mother’s age at birth, mother’s education at birth, social class and gender), Model 2 As Model 1 with additional adjustment for childhood confounders (early life events, parental bonding, positive and negative parenting experiences, maternal alcohol use and maternal tobacco smoking), Model 3 As Model 2 with additional adjustment for substance use and crime variables aLogistic regression bGeneralised ordinal regression cAlcohol measured using the Alcohol Use Disorder Identification Test (AUDIT) dTobacco measured using the Fagerström Test for Nicotine Dependence eCannabis measured using the Cannabis Abuse Screening Test
|
clinical case
| 28.9 |
TBI traumatic brain injury, OI orthopaedic injury, Unadjusted Injuries from birth to age 16 years with main crime variable in each analysis, Model 1 As unadjusted with additional adjustment for pre-birth confounders (mother’s age at birth, mother’s education at birth, social class and gender), Model 2 As Model 1 with additional adjustment for childhood confounders (early life events, parental bonding, positive and negative parenting experiences, maternal alcohol use and maternal tobacco smoking), Model 3 As Model 2 with additional adjustment for substance use variables
|
clinical case
| 27.9 |
Participants with TBI were at increased risk of having conduct problems (unadjusted OR = 1.58, 95% CI 1.11–2.25), and this association was slightly strengthened following adjustment for pre-birth and childhood confounders. There was no evidence for an association between TBI status and peer problems. In the negative control analyses, there was no evidence for an association between OI status and conduct or peer problems. There was no clear evidence for increased odds of either conduct or peer problems in the direct comparison between TBI and OI. These results are shown in Table 4. The findings from the complete case and additional sensitivity analyses did not differ substantially and can be seen in Supplementary Tables S9, S10 and S11.Table 4Associations between traumatic brain injury and orthopaedic injuries from birth to age 16 years and psychiatric symptoms based on the Strengths and Difficulties Questionnaire (SDQ) at age 17 yearsSDQOR (95% CI)UnadjustedModel 1Model 2Conduct problemsa,b n 563449974493TBI vs no injury1.58 (1.11–2.25)1.78 (1.22–2.59)1.62 (1.08–2.41)OI vs no injury1.15 (0.87–1.50)1.12 (0.83–1.52)1.07 (0.78–1.47)TBI vs OI1.38 (0.93–2.05)1.58 (1.03–2.42)1.51 (0.96–2.37)Omnibus p 0.1810.2420.445Peer problemsa,c n 562649874483TBI vs no injury1.11 (0.79–1.55)0.99 (0.68–1.42)0.85 (0.57–1.26)OI vs no injury0.96 (0.76–1.22)0.81 (0.62–1.06)0.79 (0.60–1.05)TBI vs OI1.15 (0.79–1.67)1.21 (0.80–1.83)1.07 (0.68–1.67)Omnibus p 0.8520.1380.090Sample size reduces per adjustment as the participants who are missing covariate data get excluded TBI traumatic brain injury, OI orthopaedic injury, Unadjusted Injuries from birth to age 16 years with main SDQ variable in each analysis, Model 1 As unadjusted with additional adjustment for pre-birth confounders (mother’s age at birth, mother’s education at birth, social class and gender), Model 2 As Model 1 with additional adjustment for childhood confounders (early life events, parental bonding, positive and negative parenting experiences, maternal alcohol use and maternal tobacco smoking) aLogistic regression bConduct problems based on parent-completed Strengths and Difficulties Questionnaire at age 17 years cPeer problems based on parent-completed Strengths and Difficulties Questionnaire at age 17 years
|
clinical case
| 29.33 |
TBI traumatic brain injury, OI orthopaedic injury, Unadjusted Injuries from birth to age 16 years with main SDQ variable in each analysis, Model 1 As unadjusted with additional adjustment for pre-birth confounders (mother’s age at birth, mother’s education at birth, social class and gender), Model 2 As Model 1 with additional adjustment for childhood confounders (early life events, parental bonding, positive and negative parenting experiences, maternal alcohol use and maternal tobacco smoking)
|
study
| 26.39 |
Both childhood (between birth and age 11 years) and adolescent (between age 12 and 16 years) TBI were associated with problematic cannabis use at age 17 years in the unadjusted models (childhood: unadjusted OR = 1.61, 95% CI 1.14–2.28; adjusted OR = 1.45, 95% CI 0.98–2.15; adolescent: unadjusted OR = 1.49, 95% CI 1.11 to 1.99; adjusted OR 1.36, 95% CI 0.98–1.88). Adolescent TBI was also associated with increased hazardous use of alcohol at age 17 years (unadjusted OR = 1.71, 95% CI 1.28–2.27; adjusted OR 1.72, 95% CI 1.25–2.37) and problematic use of tobacco at age 17 years (unadjusted OR = 1.56, 95% CI 1.11–2.19; adjusted OR = 1.71, 95% CI 1.15–2.52). In the negative control analyses, adolescent OI was associated with problematic use of tobacco (unadjusted OR 1.50, 95% CI 1.13–2.00; adjusted OR 1.76, 95% CI 1.25–2.48). There was no evidence of an association between OI status and any of the other substance use measures. Relative to adolescent OI, adolescent TBI was associated with increased odds of alcohol use only (unadjusted OR = 1.61, 95% CI 1.13–2.31; adjusted OR 1.76, 95% CI 1.17–2.63).
|
review
| 28.88 |
The adolescent TBI group were more likely to have committed at least one offence at age 17 years (unadjusted OR = 2.05, 95% CI 1.50–2.80; adjusted OR 1.99, 95% CI 1.40–2.82) and to have been in trouble with the police at age 17 years (unadjusted OR = 1.74, 95% CI 1.22–2.48; adjusted OR = 1.51, 95% CI 1.00–2.29). In negative control analyses, adolescent OI was associated with having committed at least one offence (adolescent: unadjusted OR = 1.89, 95% CI 1.44–2.45; adjusted OR 1.53, 95% CI 1.11–2.11).
|
review
| 27.95 |
Childhood TBI was associated with increased conduct problems on the SDQ at age 17 years (unadjusted OR = 2.20, 95% CI 1.37–3.53; adjusted OR = 1.90, 95% CI 1.11–3.26). As DAWBA information was available at age 15 years, odds ratios were also calculated for the association between childhood TBI and externalising disorders from this scale. DAWBA externalising symptoms are a combination of ODD, CD and ADHD symptoms. The results of the DAWBA analysis can be seen in Supplementary Table S18. Participants with childhood TBI were more likely to have externalising symptoms (unadjusted OR = 2.25, 95% CI 1.32–3.81; adjusted OR = 1.83, 95% CI 0.98–3.41). Analyses of the three separate disorders revealed a strong effect size of TBI on ADHD (adjusted OR = 3.15, 95% CI 1.07–9.28). Relative to childhood OI, childhood TBI was associated with increased odds of conduct problems (unadjusted OR 2.10, 95% CI 1.23–3.57; adjusted OR 1.98, 95% CI 1.08–3.65) and externalising symptoms (unadjusted OR 2.65, 95% CI 1.43–4.91; adjusted 2.11, 95% CI 1.03–4.32). The full sample and complete case analyses for childhood and adolescent injuries are provided in Supplementary Tables S12–S39.
|
review
| 28.9 |
We used data from a longitudinal birth cohort to explore the association between sustaining a mild TBI before age 16 years and subsequent substance use, criminal behaviour and psychiatric symptoms. There are three main findings. First, relative to having no injury, sustaining a mild TBI between birth and age 16 was associated with problematic alcohol, tobacco and cannabis use, a higher likelihood of committing an offence and a higher likelihood of having conduct problems at age 17 years. Second, in negative control analyses, there was evidence that sustaining a mild TBI was associated with hazardous alcohol use relative to sustaining an OI–adding evidence for a possible causal association between TBI and later alcohol misuse—while both mild TBI and OI were associated with committing offences. Third, additional analyses suggest that age at injury may be important for certain outcomes; participants with a mild TBI between birth and age 11 years had higher odds of psychiatric symptoms at age 17 years, while participants who incurred a mild TBI between age 12 and 16 years had higher odds of problematic substance use and criminal behaviours at age 17 years.
|
study
| 26.53 |
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