Nevin Manimala

Hum Brain Mapp. 2022 Jul 16. doi: 10.1002/hbm.26009. Online ahead of print.

ABSTRACT

Extracting population-wise information from medical images, specifically in the neurological domain, is crucial to better understanding disease processes and progression. This is frequently done in a whole-brain voxel-wise manner, in which a population of patients and healthy controls are registered to a common co-ordinate space and a statistical test is performed on the distribution of image intensities for each location. Although this method has yielded a number of scientific insights, it is further from clinical applicability as the differences are often small and altogether do not permit for a high-performing classifier. In this article, we take the opposite approach of using a high-performing classifier, specifically a traditional convolutional neural network, and then extracting insights from it which can be applied in a population-wise manner, a method we call voxel-based diktiometry. We have applied this method to diffusion tensor imaging (DTI) analysis for Parkinson’s disease (PD), using the Parkinson’s Progression Markers Initiative database. By using the network sensitivity information, we can decompose what elements of the DTI contribute the most to the network’s performance, drawing conclusions about diffusion biomarkers for PD that are based on metrics which are not readily expressed in the voxel-wise approach.

PMID:35841274 | DOI:10.1002/hbm.26009

Am J Transplant. 2022 Jul 16. doi: 10.1111/ajt.17151. Online ahead of print.

ABSTRACT

Immunogenicity following an additional dose of Coronavirus disease 2019 (COVID-19) vaccine was investigated in an extended primary series among kidney transplant (KT) recipients. Eighty-five KT participants were randomized to receive either an mRNA (M group; n=43) or viral vector (V group; n=42) vaccine. Among them, 62% were male, with a median (IQR) age of 50(43-59) years and post-transplantation duration of 46(26-82) months. At 2 weeks post-additional dose, there was no difference in the seroconversion rate between the M and V groups (70%vs.65%, p=0.63). A median (IQR) of anti-RBD antibody level was not statistically different between the M group compared with the V group (51.8[5.1-591] vs. 28.5[2.9-119.3] BAU/ml, p=0.18). Furthermore, the percentage of participants with positive SARS-CoV-2 surrogate virus neutralization test results was not statistically different between groups (20%vs.15%, p=0.40). S1-specific T-cell and RBD-specific B-cell responses were also comparable between the M and V groups (230[41-420] vs. 268[118-510], p=0.65 and 2[0-10] vs. 2[0-13] spot-forming units/10⁶ peripheral blood mononuclear cells, p=0.60). In conclusion, compared with an additional dose of viral vector COVID-19 vaccine, a dose of mRNA COVID-19 vaccine did not elicit significantly different responses in KT recipients, regarding either humoral or cell-mediated immunity.

PMID:35841235 | DOI:10.1111/ajt.17151

Epilepsia. 2022 Jul 16. doi: 10.1111/epi.17367. Online ahead of print.

ABSTRACT

OBJECTIVE: Dravet syndrome (DS) and Lennox-Gastaut syndrome (LGS) are rare treatment-resistant childhood epilepsies classed as developmental and epileptic encephalopathies. ELEKTRA investigated the efficacy and safety of soticlestat (TAK-935) as adjunctive therapy in children with DS or LGS (NCT03650452).

METHODS: ELEKTRA was a phase 2, randomized, double-blind, placebo-controlled study of soticlestat (≤300 mg twice daily, weight-adjusted) in children (aged 2-17 years) with DS, demonstrating ≥3 convulsive seizures/month, or with LGS, demonstrating ≥4 drop seizures/month at baseline. The 20-week treatment period comprised an 8-week dose-optimization period and a 12-week maintenance period. Efficacy endpoints included change from baseline in seizure frequency vs placebo. Safety assessments included incidence of treatment-emergent adverse events (TEAEs).

RESULTS: ELEKTRA enrolled 141 participants; 126 (89%) completed the study. The modified intent-to-treat population included 139 participants who received ≥1 dose of study drug and had ≥1 efficacy assessment (DS, n=51; LGS, n=88). ELEKTRA achieved its primary endpoint: the combined soticlestat-treated population demonstrated a placebo-adjusted median reduction in seizure frequency of 30.21% during the maintenance period (P=.0008, n=139). During this period, placebo-adjusted median reductions in convulsive and drop seizure frequencies of 50.00% (P=.0002; patients with DS) and 17.08% (P=.1160; patients with LGS), respectively, were observed. TEAE incidences were similar between the soticlestat (80.3%) and placebo (74.3%) groups and were mostly mild or moderate in severity. Serious TEAEs were reported by 15.5% and 18.6% of participants receiving soticlestat and placebo, respectively. TEAEs reported in soticlestat-treated patients with ≥5% difference from placebo were lethargy and constipation. No deaths were reported.

SIGNIFICANCE: Soticlestat treatment resulted in statistically significant, clinically meaningful reductions from baseline in median seizure frequency (combined patient population) and in convulsive seizure frequency (DS cohort). Drop seizure frequency showed a nonstatistically significant numerical reduction in children with LGS. Soticlestat had a safety profile consistent with previous studies.

PMID:35841234 | DOI:10.1111/epi.17367

Biometrics. 2022 Jul 16. doi: 10.1111/biom.13721. Online ahead of print.

ABSTRACT

We consider analyses of case-control studies assembled from electronic health records (EHRs) where the pool of cases is contaminated by patients who are ineligible for the study. These ineligible patients, referred to as “false cases”, should be excluded from the analyses if known. However, the true outcome status of a patient in the case pool is unknown except in a subset whose size may be arbitrarily small compared to the entire pool. To effectively remove the influence of the false cases on estimating odds ratio parameters defined by a working association model of the logistic form, we propose a general strategy to adaptively impute the unknown case status without requiring a correct phenotyping model to help discern the true and false case statuses. Our method estimates the target parameters as the solution to a set of unbiased estimating equations constructed using all available data. It outperforms existing methods by achieving robustness to mismodeling the relationship between the outcome status and covariates of interest, as well as improved estimation efficiency. We further show that our estimator is root-n-consistent and asymptotically normal. Through extensive simulation studies and analysis of real EHR data, we demonstrate that our method has desirable robustness to possible misspecification of both the association and phenotyping models, along with statistical efficiency superior to the competitors. This article is protected by copyright. All rights reserved.

PMID:35841231 | DOI:10.1111/biom.13721

Cent Eur J Public Health. 2022 Jun;30(Supplement):S50-S56. doi: 10.21101/cejph.a7240.

ABSTRACT

OBJECTIVES: The study aimed to investigate the use of electronic cigarettes (EC) among medical students, their knowledge and beliefs (opinion about harmfulness and addiction potential) on ECs, perceptions of the risk, as well as to assess the type of education and cessation training they received during their study at Faculty of Medicine, Comenius University in Bratislava, Slovakia.

METHODS: This cross-sectional, anonymous online e-mailed survey was conducted among medical students via the Study Department by sending e-mails containing the survey link. Participants completed the online questionnaire adapted from the American Survey on Tobacco and Alternative Tobacco Products. It included questions about the personal use of EC, perceptions about the harms and their role in disease causation, education and cessation training, and practices related to conventional cigarettes (CC), EC, and alternative tobacco products (ATP). The e-mailed questionnaire filled in 577 medical students (71.9% women) from Comenius University in Bratislava, the average age was 23 ± 2 years. The sample comprised 486 (84.2%) Slovak and 91 (15.8%) foreign students. The data were analysed using the Statistical Package for Social Science (SPSS) version 25.

RESULTS: There were 385 (66.7%) non-smokers, 111 (19.3%) ex-smokers and 81 (14%) current smokers in the study sample. EC currently use 13.5% of medical students, with a statistically significant intersexual difference (22.2% males vs. 10.12% females; OR = 2.53, 95% CI: 1.55-4.13), more foreign students than Slovak students (24.2% vs. 11.52%; OR = 2.44, 95% CI: 1.41-4.26), more smokers of conventional cigarettes than non-smokers (46.9% vs. 8.06%; OR = 10.07, 95% CI: 5.85-17.34). EC seems to be less harmful to 59.97% of students, mostly in the age group ≤ 24 (61.76% vs. 51.49%; OR = 1.46, 95% CI: 1.03-2.07), 41.25% of students consider EC to be less addictive, 55.6% think they do not get enough education on EC during their medical study.

CONCLUSION: The results overall show the high consumption of tobacco products and the lack of knowledge and awareness among medical students, future health care providers. In health promotion and disease prevention, they should serve as a model for their patients and for the general public as well. Our study emphasizes the need for intervention in this field at medical faculties and for support of further monitoring in Slovakia and other countries and draws attention to the ongoing lack of EC regulation.

PMID:35841226 | DOI:10.21101/cejph.a7240

Cent Eur J Public Health. 2022 Jun;30(Supplement):S43-S49. doi: 10.21101/cejph.a6883.

ABSTRACT

OBJECTIVES: Low birth weight (LBW) is one of the major factors affecting child morbidity and mortality worldwide. Every day, approximately 800 women die from causes related to pregnancy and childbirth worldwide. Maternal ill health increases the risk of LBW. This study seeks to investigate determinants and incidence of LBW.

METHODS: This study was conducted based on the medical records of mothers and their 1,946 infants born in 2016-2019 at the Department of Gynaecology and Obstetrics of Louis Pasteur University Hospital in Košice. Data on mothers and newborn infants were obtained from the Reports on mothers at childbirth. The inclusion criteria were singleton births and birth weight > 500 g. The exclusion criteria were twins or multiple births, congenital anomalies and stillbirths, birth weight ≥ 4,000 g or ≤ 500 g, and Roma ethnicity. Roma children are more likely to be born prematurely, with low birth weight. Roma mothers have different lifestyle. Univariate analysis was employed to evaluate the association between the independent variables and LBW. Variables that were found to be statistically significant were then further analysed using multivariable logistic analysis for each dependent variable. The implementation of the research was approved by the Ethics Committee.

RESULTS: Of 1,946 newborns, 271 (13.90%) have low birth weight. The mean of birth weight at delivery was 3,068.62 (SD 671.16) grams. Factors that were associated with LBW were primary maternal education (OR = 2.98, 95% CI: 1.08-8.21, p = 0.034), marital status single (OR = 2.88, 95% CI: 1.68-4.94, p < 0.001), number of prenatal care visits less than 8 (OR = 1.62, 95% CI: 1.01-2.61, p = 0.047), and preterm birth (OR = 74.94, 95% CI: 45.44-123.61, p < 0.001).

CONCLUSION: The reducing of LBW requires strategies to improve maternal lifestyle, maternal care before, during and after birth and to strengthen social support.

PMID:35841225 | DOI:10.21101/cejph.a6883

Cent Eur J Public Health. 2022 Jun;30(Supplement):S37-S42. doi: 10.21101/cejph.a6812.

ABSTRACT

OBJECTIVES: Eating habits, regular fluid intake, lifestyle and body composition are a primary point of research. The research focused on urolithiasis approaching potential danger, trying to interpret risk factors responsible for urolithiasis and disease recurrence.

METHODS: Research file contains 166 patients suffering from urolithiasis, 87 (52.4%) males and 79 (47.6%) females, and 172 healthy subjects from control group. All data was accessed using fully anonymous and confidential questionnaires, then evaluated in the statistical GNU PSPP 1.4 software.

RESULTS: More than 3/4 patients have a BMI higher than 24.9 and almost 40% of subjects have obesity class I, II, or III. Patients have higher BMI than subjects (d = 1.285; p < 0.001), and females have significantly higher BMI than males (d = 0.385; p = 0.007). Female patients have higher BMI than Slovak healthy females (p < 0.001; MD = 4.581; CI: 3.24-5.93). Patients have a lower daily water intake than subjects (φc = 0.157; p = 0.04) and more than ²/3 of patients have insufficient water intake. Sedentary employment prevails markedly in patients than in subjects. Patients are much less physically active than subjects (φc = 0.633; p < 0.001) and the difference is rising with increasing age of patients (ρ = – 0.232; p = 0.003). Low physical and working activity are characteristic for patients in this study. Patients smoke more often in comparison to subjects (φc = 0.261; p < 0.001). Patients consume more meats (red and white), cocoa and lentils. A lot of patients exceed recommended daily intake of pork and beef.

CONCLUSIONS: Many conditions are different for the healthy population and patients’ group. High BMI, low fluid intake, exceeded red meat consumption, and low physical activity are the strongest factors for developing urolithiasis. Patients should consume more fluids daily, exercise frequently and vigorously, and lower amount of red meat consumed.

PMID:35841224 | DOI:10.21101/cejph.a6812

Cent Eur J Public Health. 2022 Jun;30(Supplement):S32-S36. doi: 10.21101/cejph.a6811.

ABSTRACT

OBJECTIVES: Smoking during pregnancy is causally associated with reduced birth weight and is strongly related to preterm birth. This study analyses the differences in birth outcomes between non-smokers and women who continued to smoke during pregnancy.

METHODS: We conducted a study of 1,359 mothers who gave birth in 2017-2019 at the Department of Gynaecology and Obstetrics of Louis Pasteur University Hospital in Košice. Data on mothers and newborn infants have been reported from the birth book and from the reports on mothers at childbirth. For low birth weight we considered the weight of a newborn being less than 2,500 g and as for premature birth we referred to childbirth before pregnancy week 37. Two groups of mothers were classified according to the smoking habit during pregnancy and statistically processed in IBM SPSS Statistics 23.0.

RESULTS: Infants born by women who smoked during pregnancy had the lower birth weight (2,769.0 grams on average) compared to non-smokers (3,224.1 grams) (p < 0.001). The differences in prevalence of premature birth have not been confirmed as statistically significant. Women who continued smoking during pregnancy were significantly more likely to be very young (OR = 5.9; 95% CI: 3.9-8.9; p < 0.001), unmarried (OR = 9.3; 95% CI: 6.1-14.0; p < 0.001), of lower level of education (OR = 39.6; 95% CI: 22.6-69.5; p < 0.001), and more likely to consume alcohol (OR = 6.6; 95% CI: 5.8-7.5; p < 0.01), and drugs (OR = 6.6; 95% CI: 5.8-7.5; p < 0.01) during pregnancy. When pregnant, they were most likely to see a doctor for the first time after the first trimester (OR = 0.1; 95% CI: 0.1-0.2; p < 0.001) and were more likely to see a doctor less than 8 times (OR = 6.1; 95% CI: 4.2-8.8; p < 0.001) during pregnancy.

CONCLUSION: Tobacco prevention and cessation campaigns should focus on improving pregnancy outcomes in the future.

PMID:35841223 | DOI:10.21101/cejph.a6811

Am J Med Genet B Neuropsychiatr Genet. 2022 Jul 15. doi: 10.1002/ajmg.b.32911. Online ahead of print.

ABSTRACT

Testing the association between genetic scores for Attention Deficit Hyperactivity Disorder (ADHD) and health conditions, can help us better understand its complex etiology. Electronic health records linked to genetic data provide an opportunity to test whether genetic scores for ADHD correlate with ADHD and additional health outcomes in a health care context across different age groups. We generated polygenic scores (ADHD-PGS) trained on summary statistics from the latest genome-wide association study of ADHD (N = 55,374) and applied them to genome-wide data from 12,383 unrelated individuals of African-American ancestry and 66,378 unrelated individuals of European ancestry from the Vanderbilt Biobank. Overall, only Tobacco use disorder (TUD) was associated with ADHD-PGS in the African-American ancestry group (Odds ratio [95% confidence intervals] = 1.23[1.16-1.31], p = 9.3 × 10^-09 ). Eighty-six phenotypes were associated with ADHD-PGS in the European ancestry individuals, including ADHD (OR[95%CIs] = 1.22[1.16-1.29], p = 3.6 × 10^-10 ), and TUD (OR[95%CIs] = 1.22[1.19-1.25], p = 2.8 × 10^-46 ). We then stratified outcomes by age (ages 0-11, 12-18, 19-25, 26-40, 41-60, and 61-100). Our results suggest that ADHD polygenic scores are associated with ADHD diagnoses early in life and with an increasing number of health conditions throughout the lifespan (even in the absence of ADHD diagnosis). This study reinforces the utility of applying trait-specific PGSs to biobank data, and performing exploratory sensitivity analyses, to probe relationships among clinical conditions.

PMID:35841203 | DOI:10.1002/ajmg.b.32911

Clin Pharmacol Ther. 2022 Jul 15. doi: 10.1002/cpt.2712. Online ahead of print.

ABSTRACT

Vericiguat, a novel stimulator of soluble guanylate cyclase (sGC), is indicated for the treatment of patients following a hospitalization for heart failure or need for outpatient IV diuretics, with symptomatic chronic heart failure and ejection fraction less than 45%. Pharmacokinetic (PK) data from the phase II trial SOCRATES-REDUCED (SOluble guanylate Cyclase stimulatoR in heArT failurE Study) and the phase III trial VICTORIA (Vericiguat Global Study in Patients with Heart Failure with Reduced Ejection Fraction) were used to characterize vericiguat PK. A total of 8,092 concentration records from 2,321 participants (362 from SOCRATES-REDUCED and 1,959 from VICTORIA) were utilized for the development of the population PK (PPK) model. The final PK model was a one-compartment model with first-order absorption and linear elimination. Baseline body weight and time-varying body weight were identified as statistically significant covariates affecting apparent clearance (CL/F) and volume of distribution (V_c ), respectively. Age, sex, race, bilirubin, estimated glomerular filtration rate (eGFR), and albumin did not affect vericiguat PK. Baseline disease-related factors, such as left ventricular ejection fraction, New York Heart Association (NYHA) class, and N-terminal pro B-type natriuretic peptide (NT-proBNP), also did not influence vericiguat PK. Since vericiguat is a titrated drug, the impact of vericiguat PK on the titration to and maintenance of the target dose in VICTORIA was assessed. The distribution of steady-state doses in VICTORIA was similar across CL/F quartiles, suggesting that the ability to reach and maintain dosing at the target 10 mg dose was not related to vericiguat exposure.

PMID:35841202 | DOI:10.1002/cpt.2712