Category: Nevin Manimala

Ann Intern Med. 2022 Nov 8. doi: 10.7326/M22-1566. Online ahead of print.

ABSTRACT

BACKGROUND: Implantable cardioverter defibrillators (ICDs) improve survival in patients at risk for cardiac arrest, but are associated with intravascular lead-related complications. The subcutaneous ICD (S-ICD), with no intravascular components, was developed to minimize lead-related complications.

OBJECTIVE: To assess key ICD performance measures related to delivery of ICD therapy, including inappropriate ICD shocks (delivered in absence of life-threatening arrhythmia) and failed ICD shocks (which did not terminate ventricular arrhythmia).

DESIGN: Randomized, multicenter trial. (ClinicalTrials.gov: NCT02881255).

SETTING: The ATLAS trial.

PATIENTS: 544 eligible patients (141 female) with a primary or secondary prevention indication for an ICD who were younger than age 60 years, had a cardiogenetic phenotype, or had prespecified risk factors for lead complications were electrocardiographically screened and 503 randomly assigned to S-ICD (251 patients) or transvenous ICD (TV-ICD) (252 patients). Mean follow-up was 2.5 years (SD, 1.1). Mean age was 49.0 years (SD, 11.5).

MEASUREMENTS: The primary outcome was perioperative major lead-related complications.

RESULTS: There was a statistically significant reduction in perioperative, lead-related complications, which occurred in 1 patient (0.4%) with an S-ICD and in 12 patients (4.8%) with TV-ICD (-4.4%; 95% CI, -6.9 to -1.9; P = 0.001). There was a trend for more inappropriate shocks with the S-ICD (hazard ratio [HR], 2.37; 95% CI, 0.98 to 5.77), but no increase in failed appropriate ICD shocks (HR, 0.61 (0.15 to 2.57). Patients in the S-ICD group had more ICD site pain, measured on a 10-point numeric rating scale, on the day of implant (4.2 ± 2.8 vs. 2.9 ± 2.2; P < 0.001) and 1 month later (1.3 ± 1.8 vs. 0.9 ± 1.5; P = 0.035).

LIMITATION: At present, the ATLAS trial is underpowered to detect differences in clinical shock outcomes; however, extended follow-up is ongoing.

CONCLUSION: The S-ICD reduces perioperative, lead-related complications without significantly compromising the effectiveness of ICD shocks, but with more early postoperative pain and a trend for more inappropriate shocks.

PRIMARY FUNDING SOURCE: Boston Scientific.

PMID:36343346 | DOI:10.7326/M22-1566

Health Aff (Millwood). 2022 Nov;41(11):1635-1644. doi: 10.1377/hlthaff.2021.01955.

ABSTRACT

The relationship between immigrant entry and COVID-19 spread in the United States has driven much political discussion and policy, including the implementation of Title 42 by the Centers for Disease Control and Prevention. To examine the relationship between COVID-19 spread and immigrant entry, we compared 2020-21 immigrant flows with local COVID-19 rates, using estimates of border crossings from the Border Patrol and visas issued through the Department of Labor’s seasonal guest worker program. Our analysis capturing seasonal guest worker entry at the national level showed no statistically significant relationship with COVID-19 rates. Our analyses of Southwest border crossings showed a small, statistically significant relationship between immigrant flows and COVID-19 rates in border counties (0.14 percent increase in local cases per 100,000 residents for each additional 100 immigrants). However, this estimate is modest compared with the fact that half of all month-to-month changes in case rates were greater than 59 percent. Furthermore, the modest increase became nonsignificant with increasing local vaccination rates. Estimates also did not maintain their statistical significance when analyzed with some alternative approaches. Our findings support existing evidence that the short-term impacts of immigrant flow on local COVID-19 rates were minimal.

PMID:36343326 | DOI:10.1377/hlthaff.2021.01955

J Chin Med Assoc. 2022 Nov 1;85(11):1044-1050. doi: 10.1097/JCMA.0000000000000783. Epub 2022 Nov 2.

ABSTRACT

BACKGROUND: Overall survival of systemic lupus erythematosus (SLE) patients significantly increased in recent decades, however, the relative risk of mortality is still high. Long-term survival outcome of pediatric SLE remains unclear. This study aims to explore the long-term survival rate and its predictors in patients with systemic lupus erythematosus (SLE).

METHODS: A retrospective, hospital-based cohort study was performed between 2004 and 2018 in a tertiary referral medical center in Taiwan. Data on comorbidities, medications, and causes of admission were collected for risk factor analysis using time-dependent multivariate Cox proportional hazards models.

RESULTS: A total of 2392 adults and 115 pediatric SLE patients were enrolled (female, n = 2157 and 95, respectively). The 10-year survival rates were 93.2%, 90.2%, 98.9%, and 100% in adult women, adult men, girls, and boys with SLE, respectively. The overall mortality rate was 2.09 case/100 patient-years (PY) for male SLE and 1.39 case/100 PY for female SLE patients. Male SLE patients did not have a statistically significantly higher mortality rate than female SLE patients in each age stratification. Infectious disease (n = 119), heart failure (n = 21), and cerebrovascular accident (n = 14) were the leading causes of death in adult SLE patients. Advanced age (hazard ratio [HR]: 1.04, 95% confidence interval [CI]: 1.03-1.05), treatment with mean dosage of systemic glucocorticoid equivalent to >10 mg/d of prednisolone (HR: 1.71, 95% CI: 1.14-2.57), comorbidities with malignancy (HR: 1.94, 95% CI: 1.22-3.09), chronic kidney disease (HR: 1.86, 95% CI: 1.25-2.77), hypertension (HR: 1.42, 95% CI: 1.01-1.98), and admission due to bacterial pneumonia (HR: 1.92, 95% CI: 1.12-3.31) and sepsis (HR: 2.78, 95% CI: 1.51-5.13) were independent risk factors for mortality in SLE patients.

CONCLUSION: SLE patients with advanced age, malignancy, chronic kidney disease, hypertension, treated with a higher average dosage of glucocorticoids, and admission due to bacterial pneumonia and sepsis have an increased risk of mortality.

PMID:36343272 | DOI:10.1097/JCMA.0000000000000783

Proc Natl Acad Sci U S A. 2022 Nov 16;119(46):e2200822119. doi: 10.1073/pnas.2200822119. Epub 2022 Nov 7.

ABSTRACT

Epilepsy is a disorder characterized by paroxysmal transitions between multistable states. Dynamical systems have been useful for modeling the paroxysmal nature of seizures. At the same time, intracranial electroencephalography (EEG) recordings have recently discovered that an electrographic measure of epileptogenicity, interictal epileptiform activity, exhibits cycling patterns ranging from ultradian to multidien rhythmicity, with seizures phase-locked to specific phases of these latent cycles. However, many mechanistic questions about seizure cycles remain unanswered. Here, we provide a principled approach to recast the modeling of seizure chronotypes within a statistical dynamical systems framework by developing a Bayesian switching linear dynamical system (SLDS) with variable selection to estimate latent seizure cycles. We propose a Markov chain Monte Carlo algorithm that employs particle Gibbs with ancestral sampling to estimate latent cycles in epilepsy and apply unsupervised learning on spectral features of latent cycles to uncover clusters in cycling tendency. We analyze the largest database of patient-reported seizures in the world to comprehensively characterize multidien cycling patterns among 1,012 people with epilepsy, spanning from infancy to older adulthood. Our work advances knowledge of cycling in epilepsy by investigating how multidien seizure cycles vary in people with epilepsy, while demonstrating an application of an SLDS to frame seizure cycling within a nonlinear dynamical systems framework. It also lays the groundwork for future studies to pursue data-driven hypothesis generation regarding the mechanistic drivers of seizure cycles.

PMID:36343269 | DOI:10.1073/pnas.2200822119

Proc Natl Acad Sci U S A. 2022 Nov 16;119(46):e2210247119. doi: 10.1073/pnas.2210247119. Epub 2022 Nov 7.

ABSTRACT

Genetic variants in SLC22A5, encoding the membrane carnitine transporter OCTN2, cause the rare metabolic disorder Carnitine Transporter Deficiency (CTD). CTD is potentially lethal but actionable if detected early, with confirmatory diagnosis involving sequencing of SLC22A5. Interpretation of missense variants of uncertain significance (VUSs) is a major challenge. In this study, we sought to characterize the largest set to date (n = 150) of OCTN2 variants identified in diverse ancestral populations, with the goals of furthering our understanding of the mechanisms leading to OCTN2 loss-of-function (LOF) and creating a protein-specific variant effect prediction model for OCTN2 function. Uptake assays with ¹⁴C-carnitine revealed that 105 variants (70%) significantly reduced transport of carnitine compared to wild-type OCTN2, and 37 variants (25%) severely reduced function to less than 20%. All ancestral populations harbored LOF variants; 62% of green fluorescent protein (GFP)-tagged variants impaired OCTN2 localization to the plasma membrane of human embryonic kidney (HEK293T) cells, and subcellular localization significantly associated with function, revealing a major LOF mechanism of interest for CTD. With these data, we trained a model to classify variants as functional (>20% function) or LOF (<20% function). Our model outperformed existing state-of-the-art methods as evaluated by multiple performance metrics, with mean area under the receiver operating characteristic curve (AUROC) of 0.895 ± 0.025. In summary, in this study we generated a rich dataset of OCTN2 variant function and localization, revealed important disease-causing mechanisms, and improved upon machine learning-based prediction of OCTN2 variant function to aid in variant interpretation in the diagnosis and treatment of CTD.

PMID:36343260 | DOI:10.1073/pnas.2210247119

Proc Natl Acad Sci U S A. 2022 Nov 16;119(46):e2212205119. doi: 10.1073/pnas.2212205119. Epub 2022 Nov 7.

ABSTRACT

This paper presents estimates of the prevalence of dementia in the United States from 2000 to 2016 by age, sex, race and ethnicity, education, and a measure of lifetime earnings, using data on 21,442 individuals aged 65 y and older and 97,629 person-year observations from a nationally representative survey, the Health and Retirement Study (HRS). The survey includes a range of cognitive tests, and a subsample underwent clinical assessment for dementia. We developed a longitudinal, latent-variable model of cognitive status, which we estimated using the Markov Chain Monte Carlo method. This model provides more accurate estimates of dementia prevalence in population subgroups than do previously used methods on the HRS. The age-adjusted prevalence of dementia decreased from 12.2% in 2000 (95% CI, 11.7 to 12.7%) to 8.5% in 2016 (7.9 to 9.1%) in the 65+ population, a statistically significant decline of 3.7 percentage points or 30.1%. Females are more likely to live with dementia, but the sex difference has narrowed. In the male subsample, we found a reduction in inequalities across education, earnings, and racial and ethnic groups; among females, those inequalities also declined, but less strongly. We observed a substantial increase in the level of education between 2000 and 2016 in the sample. This compositional change can explain, in a statistical sense, about 40% of the reduction in dementia prevalence among men and 20% among women, whereas compositional changes in the older population by age, race and ethnicity, and cardiovascular risk factors mattered less.

PMID:36343247 | DOI:10.1073/pnas.2212205119

Proc Natl Acad Sci U S A. 2022 Nov 16;119(46):e2204346119. doi: 10.1073/pnas.2204346119. Epub 2022 Nov 7.

ABSTRACT

A grand challenge in materials science is to identify the impact of molecular composition and structure across a range of length scales on macroscopic properties. We demonstrate a unified experimental-theoretical framework that coordinates experimental measurements of mesoscale structure with molecular-level physical modeling to bridge multiple scales of physical behavior. Here we apply this framework to understand charge transport in a semiconducting polymer. Spatially-resolved nanodiffraction in a transmission electron microscope is combined with a self-consistent framework of the polymer chain statistics to yield a detailed picture of the polymer microstructure ranging from the molecular to device relevant scale. Using these data as inputs for charge transport calculations, the combined multiscale approach highlights the underrepresented role of defects in existing transport models. Short-range transport is shown to be more chaotic than is often pictured, with the drift velocity accounting for a small portion of overall charge motion. Local transport is sensitive to the alignment and geometry of polymer chains. At longer length scales, large domains and gradual grain boundaries funnel charges preferentially to certain regions, creating inhomogeneous charge distributions. While alignment generally improves mobility, these funneling effects negatively impact mobility. The microstructure is modified in silico to explore possible design rules, showing chain stiffness and alignment to be beneficial while local homogeneity has no positive effect. This combined approach creates a flexible and extensible pipeline for analyzing multiscale functional properties and a general strategy for extending the accesible length scales of experimental and theoretical probes by harnessing their combined strengths.

PMID:36343237 | DOI:10.1073/pnas.2204346119

J Nurs Educ. 2022 Nov;61(11):617-623. doi: 10.3928/01484834-20220912-03. Epub 2022 Nov 1.

ABSTRACT

BACKGROUND: Higher education wants a satisfied workforce to ensure the organization reaches their stated or evolving goals; however, if faculty are dissatisfied, there can be harmful and long-term consequences on productivity and organizational outcome. This study examined nursing faculty’s job satisfaction and intent to stay in universities in the United States and Canada.

METHOD: This study used a nonexperimental, survey research design with correlational analysis. The sample included 746 U.S. and Canadian nursing faculty. A secondary data source from the Collaborative on Academic Careers in Higher Education also was used; the data contained responses to an online survey.

RESULTS: Job satisfaction demonstrated statistically significant positive relationships with personal and family policies, collaboration, tenure clarity, institutional leadership, shared governance, and engagement.

CONCLUSION: Understanding the different factors influencing job satisfaction and intent to stay is one step toward meeting the challenge of a diversified academic nursing workforce. [J Nurs Educ. 2022;61(11):617-623.].

PMID:36343191 | DOI:10.3928/01484834-20220912-03

J Biopharm Stat. 2022 Nov 7:1-17. doi: 10.1080/10543406.2022.2141769. Online ahead of print.

ABSTRACT

Overall survival, progression-free survival, objective response/complete response, and duration of (complete) response are frequently used as the primary and secondary efficacy endpoints for designs and analyses of oncology clinical trials. However, these endpoints are typically analyzed separately. In this article, we introduce an evidence synthesis approach to prioritize the benefit outcomes by applying the generalized pairwise comparisons (GPC) method, and use win statistics (win ratio, win odds and net benefit) to quantify treatment benefit. Under the framework of GPC, the main advantage of this evidence synthesis approach is the ability to combine relevant outcomes of various types into a single summary statistic without relying on any parametric assumptions. It is particularly relevant since health authorities and the pharmaceutical industry are increasingly incorporating structured quantitative methodologies in their benefit-risk assessment. We apply this evidence synthesis approach to an oncology phase 3 study in first-line renal cell carcinoma to assess the overall effect of an investigational treatment by ranking the most clinically relevant endpoints in cancer drug development. This application and a simulation study demonstrate that the proposed approach can synthesize the evidence of treatment effect from multiple prioritized benefit outcomes, and has substantial advantage over conventional methods that analyze each individual endpoint separately. We also introduce a newly developed R package WINS for statistical inference based on win statistics.

PMID:36343174 | DOI:10.1080/10543406.2022.2141769

Cornea. 2022 Dec 1;41(12):1525-1529. doi: 10.1097/ICO.0000000000003033. Epub 2022 Mar 30.

ABSTRACT

PURPOSE: To assess the changes in the posterior corneal curvature after pre-Descemet’s endothelial keratoplasty (PDEK) and correlate with the visual outcomes.

METHODS: Eyes with pseudophakic bullous keratopathy, aphakic bullous keratopathy, and Fuchs dystrophy undergoing PDEK were included. The main outcome measures were the topography (OrbscanIIz, Bausch and Lomb) indices-total corneal power (TCP) in diopters (D), radius of the posterior curvature (mm), and best-fit sphere of the posterior corneal surface (BFS in D) at preoperative and postoperative 1 month, 3 months, and 6 months.

RESULTS: Overall, 43 eyes of 43 patients with a mean age of 68 ± 9.6 years were studied. The mean preoperative TCP 43.1 D ± 2.3 reduced to 42.4 D ± 2.6 at 3 months (P < 0.010). There was a statistically significant decrease in the mean posterior corneal curvature at 1 month and 3 months postoperatively (P = 0.002). There was no significant change in the TCP and posterior corneal curvature at 6 months (P > 0.05). The mean BFS showed an increase at 1 month (53.45 ± 5.2 D) and 3 months (52.95 ± 5.1 D) and decrease at 6 months (51.90 ± 5.3 D). The overall change in BFS (P > 0.05) was not significant. There was significant improvement in visual acuity (P < 0.05). The best-corrected visual acuity was ≥20/40 in 79.07% and ≥20/60 in 100% at 6 months. There was no statistically significant correlation between the change in the best-corrected visual acuity and TCP, posterior corneal curvature, or BFS.

CONCLUSIONS: Although there was immediate postoperative change in the posterior curvature, no significant change was induced by PDEK.

PMID:36343167 | DOI:10.1097/ICO.0000000000003033