Category: Nevin Manimala

JAMA Ophthalmol. 2023 Aug 17. doi: 10.1001/jamaophthalmol.2023.3315. Online ahead of print.

ABSTRACT

IMPORTANCE: The 3-dimensional (3-D) structural phenotype of glaucoma as a function of severity was thoroughly described and analyzed, enhancing understanding of its intricate pathology beyond current clinical knowledge.

OBJECTIVE: To describe the 3-D structural differences in both connective and neural tissues of the optic nerve head (ONH) between different glaucoma stages using traditional and artificial intelligence-driven approaches.

DESIGN, SETTING, AND PARTICIPANTS: This cross-sectional, clinic-based study recruited 541 Chinese individuals receiving standard clinical care at Singapore National Eye Centre, Singapore, and 112 White participants of a prospective observational study at Vilnius University Hospital Santaros Klinikos, Vilnius, Lithuania. The study was conducted from May 2022 to January 2023. All participants had their ONH imaged using spectral-domain optical coherence tomography and had their visual field assessed by standard automated perimetry.

MAIN OUTCOMES AND MEASURES: (1) Clinician-defined 3-D structural parameters of the ONH and (2) 3-D structural landmarks identified by geometric deep learning that differentiated ONHs among 4 groups: no glaucoma, mild glaucoma (mean deviation [MD], ≥-6.00 dB), moderate glaucoma (MD, -6.01 to -12.00 dB), and advanced glaucoma (MD, <-12.00 dB).

RESULTS: Study participants included 213 individuals without glaucoma (mean age, 63.4 years; 95% CI, 62.5-64.3 years; 126 females [59.2%]; 213 Chinese [100%] and 0 White individuals), 204 with mild glaucoma (mean age, 66.9 years; 95% CI, 66.0-67.8 years; 91 females [44.6%]; 178 Chinese [87.3%] and 26 White [12.7%] individuals), 118 with moderate glaucoma (mean age, 68.1 years; 95% CI, 66.8-69.4 years; 49 females [41.5%]; 97 Chinese [82.2%] and 21 White [17.8%] individuals), and 118 with advanced glaucoma (mean age, 68.5 years; 95% CI, 67.1-69.9 years; 43 females [36.4%]; 53 Chinese [44.9%] and 65 White [55.1%] individuals). The majority of ONH structural differences occurred in the early glaucoma stage, followed by a plateau effect in the later stages. Using a deep neural network, 3-D ONH structural differences were found to be present in both neural and connective tissues. Specifically, a mean of 57.4% (95% CI, 54.9%-59.9%, for no to mild glaucoma), 38.7% (95% CI, 36.9%-40.5%, for mild to moderate glaucoma), and 53.1 (95% CI, 50.8%-55.4%, for moderate to advanced glaucoma) of ONH landmarks that showed major structural differences were located in neural tissues with the remaining located in connective tissues.

CONCLUSIONS AND RELEVANCE: This study uncovered complex 3-D structural differences of the ONH in both neural and connective tissues as a function of glaucoma severity. Future longitudinal studies should seek to establish a connection between specific 3-D ONH structural changes and fast visual field deterioration and aim to improve the early detection of patients with rapid visual field loss in routine clinical care.

PMID:37589980 | DOI:10.1001/jamaophthalmol.2023.3315

JAMA Netw Open. 2023 Aug 1;6(8):e2329147. doi: 10.1001/jamanetworkopen.2023.29147.

ABSTRACT

IMPORTANCE: US firefighters are a working population at risk of chronic diseases, including obesity, cardiovascular disease, and cancer. This risk may be mitigated by a healthy diet.

OBJECTIVE: To evaluate the effect of a Mediterranean nutrition intervention using a behavioral/environmental approach (firefighter/fire station/home) at the individual participant level.

DESIGN, SETTING, AND PARTICIPANTS: This 12-month cluster randomized clinical trial included US career firefighters from fire stations and homes within 2 Indiana fire departments. Participants were randomized by fire station to either Mediterranean diet or control (usual care). The study was conducted from October 2016 to December 2019, and data were analyzed in November 2022.

INTERVENTION: For the first 12 months of the study, firefighters located at fire stations randomized to the intervention group were provided with access to supermarket discounts and free samples of Mediterranean diet foods, online nutrition education platforms, email announcements and reminders, family and peer education and support, and chef demonstrations. Firefighters in fire stations allocated to the control group received no intervention and were instructed to follow their usual diet.

MAIN OUTCOMES AND MEASURES: Change in dietary habits at 12 months as measured by a modified Mediterranean diet score (range, 0 to 51 points) at baseline and 6-month and 12-month follow-up. Cardiometabolic parameters were secondary outcomes.

RESULTS: Of 485 included firefighters, 458 (94.4%) were male, and the mean (SD) age was 47 (7.5) years. A total of 241 firefighters (27 fire stations) were randomized to the Mediterranean nutrition intervention, and 244 (25 fire stations) were randomized to usual diet. Outcomes were analyzed using generalized linear mixed models for modified Mediterranean diet score at 6 months (n = 336) and 12 months (n = 260), adjusting for baseline age, sex, race and ethnicity, fire department, physical activity, and waist circumference. In the intervention group compared with the control group, the modified Mediterranean diet score significantly increased by 2.01 points (95% CI, 0.62-3.40; P = .005) at 6 months and by 2.67 points (95% CI, 1.14-4.20; P = .001) at 12 months. Among secondary outcomes, changes in cardiometabolic risk factors were not statistically significant at 1 year. Results from analyses with multilevel multiple imputation for missingness were similar.

CONCLUSIONS AND RELEVANCE: In this Mediterranean nutrition intervention of multicomponent behavioral/environmental changes, career firefighters had increased adherence to a Mediterranean diet.

TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT02941757.

PMID:37589978 | DOI:10.1001/jamanetworkopen.2023.29147

JAMA Netw Open. 2023 Aug 1;6(8):e2329253. doi: 10.1001/jamanetworkopen.2023.29253.

ABSTRACT

IMPORTANCE: FRAX is the most widely used and validated fracture risk prediction tool worldwide. Vertebral fractures, which are an indicator of subsequent osteoporotic fractures, can be identified using dual-energy x-ray absorptiometry (DXA) vertebral fracture assessment (VFA).

OBJECTIVE: To assess the calibration of FRAX and develop a simple method for improving FRAX-predicted fracture probability in the presence of VFA-identified fracture.

DESIGN, SETTING, AND PARTICIPANTS: This prognostic study analyzed the DXA and VFA results of all individuals who underwent a VFA between March 31, 2010, and March 31, 2018, who were included in the Manitoba Bone Mineral Density Registry. These individuals were randomly assigned to either the development cohort or validation cohort. A modified algorithm-based qualitative approach was used by expert readers to code VFAs as positive (≥1 vertebral fractures detected) or negative (0 vertebral fracture detected). Statistical analysis was conducted from August 7, 2022, to May 22, 2023.

EXPOSURES: FRAX scores for major osteoporotic fracture (MOF) and hip fracture were calculated with or without VFA results.

MAIN OUTCOMES AND MEASURES: Incident fractures and death were ascertained using linked population-based health care provincial data. Cumulative incidence curves for MOF and hip fracture were constructed, including competing mortality, to predict the 10-year observed risk of fracture. The observed probability was compared with FRAX-predicted fracture probability with and without VFA results and recalibrated FRAX from derived multipliers.

RESULTS: The full cohort of 11 766 individuals was randomly allocated to the development cohort (n = 7854; 7349 females [93.6%]; mean [SD] age, 75.7 [6.8] years) or the validation cohort (n = 3912; 3713 females [94.9%]; mean [SD] age, 75.5 [6.9] years). Over a mean (SD) observation time of 3.8 (2.3) years, with the longest observation at 7.5 years, FRAX was well calibrated in subgroups with negative VFA results. For individuals without a prior clinical fracture but with a positive VFA result, the 10-year FRAX-predicted MOF probability was 16.3% (95% CI, 15.7%-16.8%) without VFA information and 23.4% (95% CI, 22.7%-24.1%) with VFA information. The observed 10-year probabilities were 26.9% (95% CI, 26.0%-27.8%) and 11.2% (95% CI, 10.3%-12.1%), respectively, resulting in recalibration multipliers of 1.15 (95% CI, 0.87-1.43) for MOF and 1.31 (95% CI, 0.75-1.87) for hip fracture. For individuals with a prior clinical fracture and a positive VFA result, the 10-year FRAX-predicted probabilities were 25.0% (95% CI, 24.2%-25.7%) for MOF and 9.3% (95% CI, 8.7%-10.0%) for hip fracture. The observed 10-year probabilities were 38.1% (95% CI, 37.0%-39.1%) for MOF and 16.4% (95% CI, 15.4%-17.4%) for hip fracture, resulting in a recalibration multiplier of 1.53 (95% CI, 1.10-1.96) for MOF and 1.76 (95% CI, 1.17-2.35) for hip fracture. Good calibration (>0.90) was confirmed using the derived multipliers in the validation cohort.

CONCLUSIONS AND RELEVANCE: Results of this prognostic study suggest that FRAX underestimated fracture risk in patients with VFA-identified fractures. Simple multipliers could recover FRAX calibration in individuals with VFA-identified fractures.

PMID:37589976 | DOI:10.1001/jamanetworkopen.2023.29253

JAMA Netw Open. 2023 Aug 1;6(8):e2329559. doi: 10.1001/jamanetworkopen.2023.29559.

ABSTRACT

IMPORTANCE: To our knowledge, there are no complete population-based studies of the risks of developing second malignant tumors after papillary thyroid carcinoma (PTC) in patients following the Chernobyl nuclear accident.

OBJECTIVE: To study the risk of second primary cancers in patients with PTC after the Chernobyl disaster.

DESIGN, SETTING, AND PARTICIPANTS: This was a retrospective cohort study conducted in the Republic of Belarus over a 31-year time frame evaluating patients with primary PTC and second malignant tumors. Personal data from the Belarussian Cancer Registry were used in the investigation, and only second primary cancers were included in the analysis. Patients were observed from January 1, 1990, to December 31, 2021, for the establishment of second primary malignant tumors.

MAIN OUTCOMES AND MEASURES: For analysis, synchronous and metachronous tumors were grouped into 1 group (second primary cancer group). If the patient had more than 2 cancers, they were observed until development of a second tumor and, subsequently, the development of a third tumor. The starting point for calculating the number of person-years was the date of thyroid cancer diagnosis. The end point for calculating the number of person-years was the date of diagnosis of the second primary malignant tumor, the date of death, the date of the last visit of the patient, or December 31, 2021 (the end the of study period). The incidence of a second primary malignant tumor with PTC was calculated for the study groups using standardized incidence ratios.

RESULTS: Of the 30 568 patients with a primary PTC included in this study, 2820 (9.2%) developed a second malignant tumor (2204 women and 616 men); the mean (SD) age of all patients at time of the primary cancer was 53.9 (12.6) years and at time of the secondary cancer was 61.5 (11.8) years. Overall, the standardized incidence ratio was statistically significant for all types of cancer (1.25; 95% CI, 1.21-1.30), including solid malignant tumors (1.20; 95% CI, 1.15-1.25) and all leukemias (1.61; 95% CI, 2.17-2.13). Cancers of the digestive system (466 cases [21.1%]), genital organs (376 cases [17.1%]), and breasts (603 cases [27.4%]) were the most prevalent second primary tumors in women following PTC. Second primary tumors of the gastrointestinal tract (146 cases [27.7%]), genitourinary system (139 cases [22.6%]), and urinary tract (139 cases [22.6%]) were the most prevalent in men. Urinary tract cancers (307 cases [10.9%]) and gastrointestinal tumors (612 cases [21.4%]) were the most prevalent second primary tumors overall.

CONCLUSIONS AND RELEVANCE: This cohort study reports the increased incidence of solid secondary tumors in men and women over a 31-year time frame after the Chernobyl disaster. Moreover, there was a statistically significant increased risk of second tumors of the breast, colon, rectum, mesothelium, eye, adnexa, meninges, and adrenal glands as well as Kaposi sarcoma. These data might have an effect on the follow-up of this cohort of patients to detect secondary malignant tumors at an early stage.

PMID:37589974 | DOI:10.1001/jamanetworkopen.2023.29559

JAMA Netw Open. 2023 Aug 1;6(8):e2329568. doi: 10.1001/jamanetworkopen.2023.29568.

ABSTRACT

IMPORTANCE: The diagnostic performance of the fibrosis-4 index (FIB-4) and nonalcoholic fatty liver disease (NAFLD) fibrosis score (NFS) for advanced fibrosis in lean patients with NAFLD is limited.

OBJECTIVE: To evaluate the diagnostic performance of the FIB-4 and NFS in lean individuals with NAFLD.

DESIGN, SETTING, AND PARTICIPANTS: This diagnostic study included adults with biopsy-proven NAFLD from 6 referral centers in Asia from 1995 to 2019. Cohorts were matched by age and sex between the lean and nonlean groups. All statistical analyses were executed from October 2022 to March 2023.

MAIN OUTCOMES AND MEASURES: The diagnostic performance of the FIB-4 and NFS at the current cutoff for advanced hepatic fibrosis in lean (body mass index [BMI] below 23 [calculated as weight in kilograms divided by height in meters squared]) and nonlean (BMI above 23) patients were evaluated.

RESULTS: A total of 1501 patients were included in analysis (mean [SD] age, 46.1 [16.4] years); 788 male (52.5%), 115 lean (7.7%), 472 (30.2%) Korean, 821 (48.7%) Japanese, and 341 (21.3%) Taiwanese. Among the age- and sex-matched cohort, the mean (SD) age was 52.3 (15.1) years and 41.2% (47 of 114) were male. The diagnostic performance and areas under the operating characteristic curve of the FIB-4 (lean, 0.807 vs nonlean, 0.743; P = .28) and NFS (lean, 0.790 vs nonlean, 0.755; P = .54) between the 2 groups were comparable in the age- and sex-matched cohort. The sensitivity and specificity of the NFS showed increasing and decreasing tendency according to the BMI quartiles (P for trend < .001), while those of the FIB-4 did not (P for trend = .05 and P = .20, respectively). Additionally, although the areas under the operating characteristic curve of the FIB-4 and NFS were not significantly different in the lean group (0.807 vs 0.790; P = .09), the sensitivity of the current NFS cutoff values was lower in the lean group than in that of FIB-4 (54.4% vs 81.8%; P = .03).

CONCLUSIONS AND RELEVANCE: In this cohort study, the performance of the FIB-4 and NFS in diagnosing advanced fibrosis did not differ significantly between the 2 groups overall. However, in lean NAFLD, while the sensitivity for diagnosing advanced hepatic fibrosis remained reasonable at the current cutoff level, the sensitivity of NFS at the current cutoff was too low to be an adequate screening tool.

PMID:37589973 | DOI:10.1001/jamanetworkopen.2023.29568

JAMA Netw Open. 2023 Aug 1;6(8):e2329577. doi: 10.1001/jamanetworkopen.2023.29577.

ABSTRACT

IMPORTANCE: To encourage the appropriate utilization of emergency care, cost-sharing for emergency care was increased from HK$100 (US $12.8) to HK$180 (US $23.1) per visit in June 2017 in all public hospitals in Hong Kong. However, there are concerns that this increase could deter appropriate emergency department (ED) visits and be associated with income-related disparities.

OBJECTIVE: To examine changes in ED visits after the fee increase.

DESIGN, SETTING, AND PARTICIPANTS: This retrospective cohort study used administrative data from June 2015 to May 2019 from all public hospitals in Hong Kong. Participants included all Hong Kong residents aged 64 years and younger, categorized into low-income, middle-income, and high-income groups according to the median household income in their district of residence. Data analysis was performed from May to June 2023.

MAIN OUTCOMES AND MEASURES: The primary outcome was the ED visit rate per 100 000 people per month, categorized into 3 severity levels (emergency, urgent, and nonurgent). Secondary outcomes include general outpatient (GOP) visit rate, emergency admission rate, and in-hospital mortality rate per month at public hospitals. Segmented regression analyses were used to estimate changes in the level and slope of outcome variables before and after the fee increase.

RESULTS: This study included a total of 5 441 679 ED patients (2 606 332 male patients [47.9%]; 2 108 933 patients [38.5%] aged 45-64 years), with 2 930 662 patients (1 407 885 male patients [48.0%]; 1 111 804 patients [37.9%] aged 45-64 years) from the period before the fee increase. The fee increase was associated with an 8.0% (95% CI, 7.1%-9.0%) immediate reduction in ED visits after June 2017, including a 5.9% (95% CI, 3.3%-8.5%) reduction in urgent visits and an 8.9% (95% CI, 8.0%-9.8%) reduction in nonurgent visits. In addition, a 5.7% (95% CI, 4.7%-6.8%) reduction of emergency admissions was found, whereas no significant changes were observed in in-hospital mortality. Specifically, a statistically significant increase in GOP visits (4.1%; 95% CI, 0.9%-7.2%) was found within the low-income group, but this association became insignificant after controlling for the social security group, who were exempted from payment, as a control.

CONCLUSIONS AND RELEVANCE: In this cohort study, the fee increase was not associated with changes in ED visits for emergency conditions, but there was a negative and significant association with both urgent and nonurgent conditions across all income groups. Considering the marginal increase in public GOP services, further study is warranted to examine strategies to protect low-income people from avoiding necessary care.

PMID:37589972 | DOI:10.1001/jamanetworkopen.2023.29577

J Clin Endocrinol Metab. 2023 Aug 17:dgad473. doi: 10.1210/clinem/dgad473. Online ahead of print.

ABSTRACT

BACKGROUND: Large extracellular vesicles (lEV) enriched for endothelial and blood cell markers are increased in metabolic conditions such as obesity or type 2 diabetes (T2D), actively contribute to the atherosclerosis process, and have been identified as diagnostic and prognostic biomarkers for cardiovascular disease (CVD). Although bariatric surgery (BS) in individuals with obesity is related to decreased cardiovascular (CV) risk and increased life expectancy, post-BS these subjects are still at higher CV risk compared to the general population. We aimed to compare the lEV profiles between individuals with obesity, with or without T2D, before and 1-year after BS, and normal-weight controls.

METHODS: Prospective longitudinal study with individuals eligible for BS, with or without T2D (T2D and OB groups, respectively) and healthy controls (HC-group) matched by age and sex. The concentration and phenotype of lEV were assessed by flow cytometry.

RESULTS: The study cohort included 108 individuals (age 48.0 ± 10.5 years; 84.3% females). Before BS, the OB-group presented higher concentrations of lEV enriched for endothelial and blood cell biomarkers than the HC, but lower concentrations than those observed in the T2D-group (p < 0.05). BS resulted in a significant reduction in most of the lEV enriched for cell-specific markers in both subgroups. lEV differences between OB and T2D groups were no longer observed post-BS (p > 0.05). However, compared with HC, OB and T2D groups still showed increased concentrations of lEV enriched for platelet and endothelial cell markers (p < 0.05).

CONCLUSION: At one year after BS, lEV concentrations remain above the physiological range. These abnormalities might contribute to explaining the increased CV risk after BS and underscore the importance of long-term CV risk factor control in post-BS individuals.

PMID:37589958 | DOI:10.1210/clinem/dgad473

J Clin Endocrinol Metab. 2023 Aug 17:dgad484. doi: 10.1210/clinem/dgad484. Online ahead of print.

ABSTRACT

BACKGROUND: Few long-term randomized trials have evaluated the efficacy of testosterone replacement therapy (TRT) in improving sexual function and hypogonadal symptoms in men with hypogonadism and whether effects are sustained beyond 12 months.

OBJECTIVE: Testosterone Replacement therapy for Assessment of long-term Vascular Events and efficacy ResponSE in hypogonadal men (TRAVERSE) study evaluated the effect of TRT on major adverse cardiovascular events in middle-aged and older men with hypogonadism. The Sexual Function Study, nested within the parent trial, determined testosterone’s efficacy in improving sexual activity, hypogonadal symptoms, libido, and erectile function among men reporting low libido.

METHODS: Among 5204 men, 45 to 80 years, with two testosterone concentrations <300 ng/dL, hypogonadal symptoms, and cardiovascular disease (CVD) or increased CVD risk enrolled in TRAVERSE trial, 1161 with low libido were enrolled in the Sexual Function Study (587 randomized to receive 1.62% testosterone gel and 574 to placebo gel for the duration of their participation in the study). Primary outcome was change from baseline in sexual activity score. Secondary outcomes included hypogonadal symptoms, erectile function, and sexual desire.

RESULTS: TRT was associated with significantly greater improvement in sexual activity than placebo [estimated mean (95% confidence interval) between-group difference 0.49 (0.19,0.79) and 0.47 (0.11,0.83) acts per day] at 6 and 12 months, respectively, omnibus test p = 0.011]; treatment effect was maintained at 24 months. TRT improved hypogonadal symptoms and sexual desire, but not erectile function, compared to placebo.

CONCLUSIONS: In middle-aged and older men with hypogonadism and low libido, TRT for two years improved sexual activity, hypogonadal symptoms, and sexual desire, but not erectile function.

PMID:37589949 | DOI:10.1210/clinem/dgad484

Clin Transplant. 2023 Aug 17:e15104. doi: 10.1111/ctr.15104. Online ahead of print.

ABSTRACT

BACKGROUND AND AIMS: The relationship between the Follicular Cytotoxic T cell subgroup and expression levels of PD1/PD-L1 genes and the development of donor specific antibody (DSA) is unknown. In this study, we aimed to examine CD8+CXCR5+PD-1+ follicular cytotoxic T cell levels and expression levels of PD1/PD-L1 genes in peripheral blood lymphocytes in de-novo DSA positive and negative kidney transplant recipients (KTR).

METHODS: In our study, expression of PD-1/ PD-L1 genes by Real-Time Quantitative PCR method and CD8+CXCR5+PD-1+ T cell expression levels by flow cytometric method were obtained from peripheral blood samples. 63 participants were included in the study (de-novo DSA positive recipients (n = 22, group 1), de-novo DSA negative recipients (n = 20, group 2) and healthy control (n = 21, group 3). All patients had negative PRA before kidney transplantation. Expression (%) levels of target cells were evaluated by flow cytometry method. IBM SPSS Statistics for Windows Version 22 and R.3.3.2 software were used to evaluate the data.

RESULTS: The demographic data of the groups were similar. PD-1 mRNA expression was higher in de-novo DSA positive KTR than negative (respectively, 1.03 ± .29/.82 ± .15, p: .001). CD8+CXCR5+PD-1+ T cell expression levels were found to be higher in the de-novo DSA positive group than in the negative group and similar to the healthy group (respectively, 3.06 ± 1.98/.52 ± .40, p:.001, 3.06 ± 1.98/2.78 ± .59, p:.62). The percentage of CD8+CXCR5+PD-1+ expressing T cells was significantly lower in the HLA-Class II+ group than other groups (HLA CI/II/ I+II, respectively, 3.63 ± 2.72/1.65 ± .50/3.68 ± 1.67, p: .04).

CONCLUSIONS: In our study, a significant relationship was found between DSA formation and PD-1 mRNA level and CD8+CXCR5+PD-1+ follicular cytotoxic T cell in KTR.

PMID:37589946 | DOI:10.1111/ctr.15104

Exp Brain Res. 2023 Aug 17. doi: 10.1007/s00221-023-06684-9. Online ahead of print.

ABSTRACT

Predicting the time course of motion sickness symptoms enables the evaluation of provocative stimuli and the development of countermeasures for reducing symptom severity. In pursuit of this goal, we present an observer-driven model of motion sickness for passive motions in the dark. Constructed in two stages, this model predicts motion sickness symptoms by bridging sensory conflict (i.e., differences between actual and expected sensory signals) arising from the observer model of spatial orientation perception (stage 1) to Oman’s model of motion sickness symptom dynamics (stage 2; presented in 1982 and 1990) through a proposed “Normalized innovation squared” statistic. The model outputs the expected temporal development of human motion sickness symptom magnitudes (mapped to the Misery Scale) at a population level, due to arbitrary, 6-degree-of-freedom, self-motion stimuli. We trained model parameters using individual subject responses collected during fore-aft translations and off-vertical axis of rotation motions. Improving on prior efforts, we only used datasets with experimental conditions congruent with the perceptual stage (i.e., adequately provided passive motions without visual cues) to inform the model. We assessed model performance by predicting an unseen validation dataset, producing a Q² value of 0.86. Demonstrating this model’s broad applicability, we formulate predictions for a host of stimuli, including translations, earth-vertical rotations, and altered gravity, and we provide our implementation for other users. Finally, to guide future research efforts, we suggest how to rigorously advance this model (e.g., incorporating visual cues, active motion, responses to motion of different frequency, etc.).

PMID:37589937 | DOI:10.1007/s00221-023-06684-9