Category: Nevin Manimala

JAMA Dermatol. 2023 May 3. doi: 10.1001/jamadermatol.2023.0846. Online ahead of print.

ABSTRACT

IMPORTANCE: Current topical treatment options for seborrheic dermatitis are limited by efficacy and/or safety.

OBJECTIVE: To assess safety and efficacy of roflumilast foam, 0.3%, in adult patients with seborrheic dermatitis affecting the scalp, face, and/or trunk.

DESIGN, SETTING, AND PARTICIPANTS: This multicenter (24 sites in the US and Canada) phase 2a, parallel group, double-blind, vehicle-controlled clinical trial was conducted between November 12, 2019, and August 21, 2020. Participants were adult (aged ≥18 years) patients with a clinical diagnosis of seborrheic dermatitis for a 3-month or longer duration and Investigator Global Assessment (IGA) score of 3 or greater (at least moderate), affecting 20% or less body surface area, including scalp, face, trunk, and/or intertriginous areas. Data analysis was performed from September to October 2020.

INTERVENTIONS: Once-daily roflumilast foam, 0.3% (n = 154), or vehicle foam (n = 72) for 8 weeks.

MAIN OUTCOMES AND MEASURES: The main outcome was IGA success, defined as achievement of IGA score of clear or almost clear plus 2-grade improvement from baseline, at week 8. Secondary outcomes included IGA success at weeks 2 and 4; achievement of erythema score of 0 or 1 plus 2-grade improvement from baseline at weeks 2, 4, and 8; achievement of scaling score of 0 or 1 plus 2-grade improvement from baseline at weeks 2, 4, and 8; change in Worst Itch Numeric Rating Scale (WI-NRS) score from baseline; and WI-NRS success, defined as achievement of 4-point or greater WI-NRS score improvement in patients with baseline WI-NRS score of 4 or greater. Safety and tolerability were also assessed.

RESULTS: A total of 226 patients (mean [SD] age, 44.9 [16.8] years; 116 men, 110 women) were randomized to roflumilast foam (n = 154) or vehicle foam (n = 72). At week 8, 104 (73.8%) roflumilast-treated patients achieved IGA success compared with 27 (40.9%) in the vehicle group (P < .001). Roflumilast-treated patients had statistically significantly higher rates of IGA success vs vehicle at week 2, the first time point assessed. Mean (SD) reductions (improvements) on the WI-NRS at week 8 were 59.3% (52.5%) vs 36.6% (42.2%) in the roflumilast and vehicle groups, respectively (P < .001). Roflumilast was well tolerated, with the rate of adverse events similar to that of the vehicle foam.

CONCLUSIONS AND RELEVANCE: The results from this phase 2a randomized clinical trial of once-daily roflumilast foam, 0.3%, demonstrated favorable efficacy, safety, and local tolerability in the treatment of erythema, scaling, and itch caused by seborrheic dermatitis, supporting further investigation as a nonsteroidal topical treatment.

TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT04091646.

PMID:37133856 | DOI:10.1001/jamadermatol.2023.0846

JAMA Cardiol. 2023 May 3. doi: 10.1001/jamacardio.2023.0857. Online ahead of print.

ABSTRACT

IMPORTANCE: Primary prevention of atherosclerotic cardiovascular disease (ASCVD) relies on risk stratification. Genome-wide polygenic risk scores (PRSs) are proposed to improve ASCVD risk estimation.

OBJECTIVE: To determine whether genome-wide PRSs for coronary artery disease (CAD) and acute ischemic stroke improve ASCVD risk estimation with traditional clinical risk factors in an ancestrally diverse midlife population.

DESIGN, SETTING, AND PARTICIPANTS: This was a prognostic analysis of incident events in a retrospectively defined longitudinal cohort conducted from January 1, 2011, to December 31, 2018. Included in the study were adults free of ASCVD and statin naive at baseline from the Million Veteran Program (MVP), a mega biobank with genetic, survey, and electronic health record data from a large US health care system. Data were analyzed from March 15, 2021, to January 5, 2023.

EXPOSURES: PRSs for CAD and ischemic stroke derived from cohorts of largely European descent and risk factors, including age, sex, systolic blood pressure, total cholesterol, high-density lipoprotein (HDL) cholesterol, smoking, and diabetes status.

MAIN OUTCOMES AND MEASURES: Incident nonfatal myocardial infarction (MI), ischemic stroke, ASCVD death, and composite ASCVD events.

RESULTS: A total of 79 151 participants (mean [SD] age, 57.8 [13.7] years; 68 503 male [86.5%]) were included in the study. The cohort included participants from the following harmonized genetic ancestry and race and ethnicity categories: 18 505 non-Hispanic Black (23.4%), 6785 Hispanic (8.6%), and 53 861 non-Hispanic White (68.0%) with a median (5th-95th percentile) follow-up of 4.3 (0.7-6.9) years. From 2011 to 2018, 3186 MIs (4.0%), 1933 ischemic strokes (2.4%), 867 ASCVD deaths (1.1%), and 5485 composite ASCVD events (6.9%) were observed. CAD PRS was associated with incident MI in non-Hispanic Black (hazard ratio [HR], 1.10; 95% CI, 1.02-1.19), Hispanic (HR, 1.26; 95% CI, 1.09-1.46), and non-Hispanic White (HR, 1.23; 95% CI, 1.18-1.29) participants. Stroke PRS was associated with incident stroke in non-Hispanic White participants (HR, 1.15; 95% CI, 1.08-1.21). A combined CAD plus stroke PRS was associated with ASCVD deaths among non-Hispanic Black (HR, 1.19; 95% CI, 1.03-1.17) and non-Hispanic (HR, 1.11; 95% CI, 1.03-1.21) participants. The combined PRS was also associated with composite ASCVD across all ancestry groups but greater among non-Hispanic White (HR, 1.20; 95% CI, 1.16-1.24) than non-Hispanic Black (HR, 1.11; 95% CI, 1.05-1.17) and Hispanic (HR, 1.12; 95% CI, 1.00-1.25) participants. Net reclassification improvement from adding PRS to a traditional risk model was modest for the intermediate risk group for composite CVD among men (5-year risk >3.75%, 0.38%; 95% CI, 0.07%-0.68%), among women, (6.79%; 95% CI, 3.01%-10.58%), for age older than 55 years (0.25%; 95% CI, 0.03%-0.47%), and for ages 40 to 55 years (1.61%; 95% CI, -0.07% to 3.30%).

CONCLUSIONS AND RELEVANCE: Study results suggest that PRSs derived predominantly in European samples were statistically significantly associated with ASCVD in the multiancestry midlife and older-age MVP cohort. Overall, modest improvement in discrimination metrics were observed with addition of PRSs to traditional risk factors with greater magnitude in women and younger age groups.

PMID:37133828 | DOI:10.1001/jamacardio.2023.0857

J Phys Chem B. 2023 May 3. doi: 10.1021/acs.jpcb.3c01202. Online ahead of print.

ABSTRACT

The role of entropy in mediating the dynamic outcomes of chemical reactions remains largely unknown. To evaluate the change of entropy along post-transition state paths, we have previously developed entropic path sampling that computes configurational entropy from an ensemble of reaction trajectories. However, one major caveat of this approach lies in its high computational demand: about 2000 trajectories are needed to converge the computation of an entropic profile. Here, by leveraging a deep generative model, we developed an accelerated entropic path sampling approach that evaluates entropic profiles using merely a few hundred reaction dynamic trajectories. The new method, called bidirectional generative adversarial network-entropic path sampling, can enhance the estimation of probability density functions of molecular configurations by generating pseudo-molecular configurations that are statistically indistinguishable from the true data. The method was established using cyclopentadiene dimerization, in which we reproduced the reference entropic profiles (derived from 2480 trajectories) using merely 124 trajectories. The method was further benchmarked using three reactions with symmetric post-transition-state bifurcation, including endo-butadiene dimerization, 5-fluoro-1,3-cyclopentadiene dimerization, and 5-methyl-1,3-cyclopentadiene dimerization. The results indicate the existence of a “hidden entropic intermediate”, which is a dynamic species that binds to a local entropic maximum where no free energy minimum is formed.

PMID:37133810 | DOI:10.1021/acs.jpcb.3c01202

Brain Behav. 2023 May 3:e3026. doi: 10.1002/brb3.3026. Online ahead of print.

ABSTRACT

OBJECTIVES: Since 1972, the U.S. Central Intelligence Agency (CIA) commissioned several research programs on remote viewing (RV) that were progressively declassified from 1995 to 2003. The main objectives of this research were to statistically replicate the original findings and address the question: What are the underlying cognitive mechanisms involved in RV? The research focused on emotional intelligence (EI) theory and intuitive information processing as possible hypothetical mechanisms.

METHODS: We used a quasi-experimental design with new statistical control techniques based on structural equation modeling, analysis of invariance, and forced-choice experiments to accurately objectify results. We measured emotional intelligence with the Mayer-Salovey-Caruso Emotional Intelligence Test. A total of 347 participants who were nonbelievers in psychic experiences completed an RV experiment using targets based on location coordinates. A total of 287 participants reported beliefs in psychic experiences and completed another RV experiment using targets based on images of places. Moreover, we divided the total sample into further subsamples for the purpose of replicating the findings and also used different thresholds on standard deviations to test for variation in effect sizes. The hit rates on the psi-RV task were contrasted with the estimated chance.

RESULTS: The results of our first group analysis were nonsignificant, but the analysis applied to the second group produced significant RV-related effects corresponding to the positive influence of EI (i.e., hits in the RV experiments were 19.5% predicted from EI) with small to moderate effect sizes (between 0. 457 and 0.853).

CONCLUSIONS: These findings have profound implications for a new hypothesis of anomalous cognitions relative to RV protocols. Emotions perceived during RV sessions may play an important role in the production of anomalous cognitions. We propose the Production-Identification-Comprehension (PIC) emotional model as a function of behavior that could enhance VR test success.

PMID:37133806 | DOI:10.1002/brb3.3026

Pediatr Nephrol. 2023 May 3. doi: 10.1007/s00467-023-05992-0. Online ahead of print.

ABSTRACT

BACKGROUND: Congenital anomalies of the kidney and urinary tract (CAKUT) are the most frequent causes of childhood chronic kidney disease (CKD). Using a large CAKUT cohort, we sought to identify the predictors of CKD and to develop a prediction model that informs a risk-stratified clinical pathway.

METHODS: This was a retrospective cohort study including cases with multicystic dysplastic kidneys (MCDK), unilateral kidney agenesis (UKA), kidney hypoplasia (KH), and posterior urethral valves (PUV). We identified risk factors for CKD (estimated glomerular filtration rate [eGFR] <60 ml/min/1.73 m²) and tested their performance in an adjusted multivariate binary regression model. Prediction probability scores for CKD were used to separate cases likely to develop complications from those not needing specialist follow-up.

RESULTS: We identified 452 eligible cases of CAKUT with 22% developing CKD. Strongest associations with CKD included primary diagnosis (OR 3.5, 95% CI 2.6-4.6), preterm delivery (OR 2.3, 95% CI 1.2-4.4), non-kidney anomalies (OR 1.8, 95% CI 1.1-3), first eGFR<90 (OR 8.9, 95% CI 4.4-18.1), small kidney size (OR 9, 95% CI 4.9-16.6), and additional kidney anomalies (OR 1.6, 95% CI 1.2-2.8). PUV (OR 4.7, 95% CI 1.5-15.3), first eGFR <90 (OR 4.4, 95% CI 2-9.7), and kidney length to body length ratio <7.9 (OR 4.2, 95% CI 1.9-9.2) were independent predictors of CKD. The regression model had a prediction accuracy of 80% and a prediction probability c-statistic of 0.81.

CONCLUSION: Using a large combined CAKUT cohort we identified risk factors for CKD. Our prediction model provides the first steps towards a risk-stratified clinical pathway. A higher resolution version of the Graphical abstract is available as Supplementary information.

PMID:37133803 | DOI:10.1007/s00467-023-05992-0

Neurosurg Rev. 2023 May 3;46(1):102. doi: 10.1007/s10143-023-01992-8.

ABSTRACT

Robotic assistance has improved electrode implantation precision in stereoelectroencephalography (SEEG) for refractory epilepsy patients. We sought to assess the relative safety of the robotic-assisted (RA) procedure compared to the traditional hand-guided one. A systematic search on PubMed, Web of Science, Embase, and Cochrane was performed for studies directly comparing robot-assisted vs. manually guided SEEG to treat refractory epilepsy. The primary outcomes included target point error (TPE), entry point error (EPE), time of implantation of each electrode, operative time, postoperative intracranial hemorrhage, infection, and neurologic deficit. We included 427 patients from 11 studies, of whom 232 (54.3%) underwent robot-assisted surgery and 196 (45.7%) underwent manually guided surgery. The primary endpoint, TPE, was not statistically significant (MD 0.04 mm; 95% CI – 0.21, – 0.29; p = 0.76). Nonetheless, EPE was significantly lower in the intervention group (MD – 0.57 mm; 95% CI – 1.08; – 0.06; p = 0.03). Total operative time was significantly lower in the RA group (MD – 23.66 min; 95% CI – 32.01, – 15.31; p < 0.00001), as well as the individual time of implantation of each electrode (MD – 3.35 min; 95% CI – 3.68, – 3.03; p < 0.00001). Postoperative intracranial hemorrhage did not differ between groups: robotic (9/145; 6.2%) vs. manual (8/139; 5.7%) (RR 0.97; 95% CI 0.40-2.34; p = 0.94). There was no statistically relevant difference in infection (p = 0.4) and postoperative neurological deficit (p = 0.47) incidence between the two groups. In this analysis, there is a potential relevance in the RA procedure when comparing the traditional one, since operative time, time of implantation of each electrode, and EPE were significantly lower in the robotic group. More research is needed to corroborate the superiority of this novel technique.

PMID:37133774 | DOI:10.1007/s10143-023-01992-8

Eur J Orthop Surg Traumatol. 2023 May 3. doi: 10.1007/s00590-023-03561-7. Online ahead of print.

ABSTRACT

BACKGROUND: This study aims to implement and assess the inter- and intra-reliability of a modernized radiolucency assessment system; the Radiolucency In cemented Stemmed Knee (RISK) arthroplasty classification. Furthermore, we assessed the distribution of regions affected by radiolucency in patients undergoing stemmed cemented total knee arthroplasty.

METHODS: Stemmed total knee arthroplasty cases over 7-year period at a single institution were retrospectively identified and reviewed. The RISK classification system identifies five zones in the femur and five zones in the tibia in both the anteroposterior (AP) and lateral planes. Post-operative and follow-up radiographs were scored for radiolucency by four blinded reviewers at two distinct time points four weeks apart. Reliability was assessed using the kappa statistic. A heat map was generated to demonstrate the reported regions of radiolucency.

RESULTS: 29 cases (63 radiographs) of stemmed total knee arthroplasty were examined radiographically using the RISK classification system. Intra-reliability (0.83) and Inter-reliability (0.80) scores were both consistent with a strong level of agreement using the kappa scoring system. Radiolucency was more commonly associated with the tibial component (76.6%) compared to the femoral component (23.3%), and the tibial anterior-posterior (AP) region 1 (medial plateau) was the most affected (14.9%).

CONCLUSION: The RISK classification system is a reliable assessment tool for evaluating radiolucency around stemmed total knee arthroplasty using defined zones on both AP and lateral radiographs. Zones of radiolucency identified in this study may be relevant to implant survival and corresponded well with zones of fixation, which may help inform future research.

PMID:37133754 | DOI:10.1007/s00590-023-03561-7

Eur J Orthop Surg Traumatol. 2023 May 3. doi: 10.1007/s00590-023-03557-3. Online ahead of print.

ABSTRACT

INTRODUCTION: Infection after total knee arthroplasty (TKA) impacts the patient, surgeon, and healthcare system significantly. Surgeons routinely use antibiotic-loaded bone cement (ALBC) in attempts to mitigate infection; however, little evidence supports the efficacy of ALBC in reducing infection rates compared to non-antibiotic-loaded bone cement (non-ALBC) in primary TKA. Our study compares infection rates of patients undergoing TKA with ALBC to those with non-ALBC to assess its efficacy in primary TKA.

METHODS: A retrospective review of all primary, elective, cemented TKA patients over the age of 18 between 2011 and 2020 was conducted at an orthopedic specialty hospital. Patients were stratified into two cohorts based on cement type: ALBC (loaded with gentamicin or tobramycin) or non-ALBC. Baseline characteristics and infection rates determined by MSIS criteria were collected. Multilinear and multivariate logistic regressions were performed to limit significant differences in demographics. Independent samples t test and chi-squared test were used to compare means and proportions, respectively, between the two cohorts.

RESULTS: In total, 9366 patients were included in this study, 7980 (85.2%) of whom received non-ALBC and 1386 (14.8%) of whom received ALBC. There were significant differences in five of the six demographic variables analyzed; patients with higher Body Mass Index (33.40 ± 6.27 vs. 32.09 ± 6.21; kg/m²) and Charlson Comorbidity Index values (4.51 ± 2.15 vs. 4.04 ± 1.92) were more likely to receive ALBC. The infection rate in the non-ALBC was 0.8% (63/7,980), while the rate in the ALBC was 0.5% (7/1,386). After adjusting for confounders, the difference in rates was not significant between the two groups (OR [95% CI]: 1.53 [0.69-3.38], p = 0.298). Furthermore, a sub-analysis comparing the infection rates within various demographic categories also showed no significant differences between the two groups.

CONCLUSION: Compared to non-ALBC, the overall infection rate in primary TKA was slightly lower when using ALBC; however, the difference was not statistically significant. When stratifying by comorbidity, use of ALBC still showed no statistical significance in reducing the risk of periprosthetic joint infection. Therefore, the advantage of antibiotics in bone cement to prevent infection in primary TKA is not yet elucidated. Further prospective, multicenter studies regarding the clinical benefits of antibiotic use in bone cement for primary TKA are warranted.

PMID:37133753 | DOI:10.1007/s00590-023-03557-3

J Racial Ethn Health Disparities. 2023 May 3. doi: 10.1007/s40615-023-01616-3. Online ahead of print.

ABSTRACT

Hemophilia-related distress (HRD) has been shown to be higher among those with lower educational attainment, but potential racial/ethnic differences have not been previously described. Thus, we examined HRD according to race/ethnicity. This cross-sectional study was a planned secondary analysis of the hemophilia-related distress questionnaire (HRDq) validation study data. Adults aged ≥ 18 years with Hemophilia A or B were recruited from one of two hemophilia treatment centers between July 2017-December 2019. HRDq scores can range from 0-120, and higher scores indicate higher distress. Self-reported race/ethnicity was grouped as Hispanic, non-Hispanic White (NHW) and non-Hispanic Black (NHB). Unadjusted and multivariable linear regression models were used to examine mediators of race/ethnicity and HRDq scores. Among 149 participants enrolled, 143 completed the HRDq and were included in analyses. Approximately 17.5% of participants were NHB, 9.1% were Hispanic and 72.0% were NHW. HRDq scores ranged from 2 to 83, with a mean of 35.1 [standard deviation (SD) = 16.5]. Average HRDq scores were significantly higher among NHB participants (mean = 42.6,SD = 20.6; p-value = .038) and similar in Hispanic participants (mean = 33.8,SD = 16.7, p-value = .89) compared to NHW (mean = 33.2,SD = 14.9) participants. In multivariable models, differences between NHB vs NHW participants persisted when adjusting for inhibitor status, severity, and target joint. However, after household income was adjusted for, differences in HRDq scores were no longer statistically significant (β = 6.0 SD = 3.7; p-value = .10). NHB participants reported higher HRD than NHW participants. Household income mediated higher distress scores in NHB compared to NHW participants, highlighting the urgent need to understand social determinants of health and financial hardship in persons with hemophilia.

PMID:37133726 | DOI:10.1007/s40615-023-01616-3

Genes Genomics. 2023 May 3. doi: 10.1007/s13258-023-01386-6. Online ahead of print.

ABSTRACT

BACKGROUND: The variable number of tandem repeat (VNTR) analyses are methods based on the detection of repeated sequences within the human genome. In order to perform DNA typing at the personal laboratory, it is necessary to improve the VNTR analysis.

OBJECTIVE: The VNTR markers were difficult to popularize because PCR amplification was difficult due to its GC-rich and long nucleotide sequence. The aim of this study was to select the multiple VNTR markers that could only be identified by PCR amplification and electrophoresis.

METHODS: We genotyped each of the 15 VNTR markers using genomic DNA from 260 unrelated individuals by PCR amplification. Differences in the fragment length of PCR products are visualized by agarose gel electrophoresis. To confirm their usefulness as a DNA fingerprint these 15 markers were simultaneously analyzed with the DNA of 213 individuals and verified the statistical significance. In addition, to investigate the usefulness of each of the 15 VNTR markers as paternity markers, Mendelian segregation by meiotic division within a family consisting of two or three generations was confirmed.

RESULTS: Fifteen VNTR loci selected in this study could be easily amplified by PCR and analyzed by electrophoresis, and were newly named DTM1 ~ 15. The number of total alleles in each VNTR showed from 4 to 16, and 100 to 1600 bp in length, and their heterozygosity ranged from 0.2341 to 0.7915. In simultaneous analysis of 15 markers from 213 DNAs, the probability of chance appearing the same genotype in different individuals was less than 4.09E-12, indicating its usefulness as a DNA fingerprint. These loci were transmitted through meiosis by Mendelian inheritance in families.

CONCLUSION: Fifteen VNTR markers have been found to be useful as DNA fingerprints for personal identification and kinship analysis that can be used at the personal laboratory level.

PMID:37133721 | DOI:10.1007/s13258-023-01386-6