Category: Statistics

Pharmacogenomics. 2022 Jun 8. doi: 10.2217/pgs-2022-0037. Online ahead of print.

ABSTRACT

Antidepressant medications are frequently used as the first line of treatment for depression. However, their effectiveness is highly variable and influenced by genetic factors. Recently, pharmacogenetic studies, including candidate-gene, genome-wide association studies or polygenic risk scores, have attempted to uncover the genetic architecture of antidepressant response. Genetic variants in at least 27 genes are linked to antidepressant treatment response in both coding and non-coding genomic regions, but evidence is largely inconclusive due to the high polygenicity of the trait and limited cohort sizes in published studies. Future studies should increase the number and diversity of participants to yield sufficient statistical power to characterize the genetic underpinnings and biological mechanisms of treatment response, improve results generalizability and reduce racial health-related inequities.

PMID:35673953 | DOI:10.2217/pgs-2022-0037

Curr Opin Neurol. 2022 Jun 1;35(3):271-277. doi: 10.1097/WCO.0000000000001057.

ABSTRACT

PURPOSE OF REVIEW: Although substantial progress has been made in understanding the natural history of multiple sclerosis (MS) and the development of new therapies, many questions concerning disease behavior and therapeutics remain to be answered. Data generated from real-world observational studies, based on large MS registries and databases and analyzed with advanced statistical methods, are offering the scientific community answers to some of these questions that are otherwise difficult or impossible to address. This review focuses on observational studies published in the last 2 years designed to compare the effectiveness of escalation vs. induction treatment strategies, to assess the effectiveness of treatment in pediatric-onset and late-onset MS, and to identify the clinical phenotype of secondary progressive (SP)MS.

RECENT FINDINGS: The main findings originating from real-world studies suggest that MS patients who will qualify for high-efficacy disease-modifying therapies (DMTs) should be offered these as early as possible to prevent irreversible accumulation of neurological disability. Especially pediatric patients derive substantial benefits from early treatment. In patients with late-onset MS, sustained exposure to DMTs may result in more favorable outcomes. Data-driven definitions are more accurate in defining transition to SPMS than diagnosis based solely on neurologists’ judgment.

SUMMARY: Patients, physicians, industry, and policy-makers have all benefited from real-world evidence based on registry data, in answering questions of diagnostics, choice of treatment, and timing of treatment decisions.

PMID:35674068 | DOI:10.1097/WCO.0000000000001057

Vasa. 2022 Jun 8. doi: 10.1024/0301-1526/a001012. Online ahead of print.

ABSTRACT

Background: Peripheral artery disease (PAD) affects more than 202 million people worldwide. Several studies have shown that patients with PAD are often undertreated, and that statin utilization is suboptimal. European and American guidelines highlight statins as the first-line lipid-lowering therapy to treat patients with PAD. Our objective with this meta-analysis was to further explore the impact of statins on lower extremities PAD endpoints and examine whether statin dose (high vs. low intensity) impacts outcomes. Patients and methods: We performed a systematic review and meta-analysis according to the PRISMA guidelines. Any study that presented a comparison of use of statins vs. no statins for PAD patients or studies comparing high vs. low intensity statins were considered to be potentially eligible. We excluded studies with only critical limb threatening ischemia (CLTI) patients. The Medline (PubMed) database was searched up to January 31, 2021. A random effects meta-analysis was performed. Results: In total, 39 studies and 275,670 patients were included in this meta-analysis. In total, 136,025 (49.34%) patients were on statins vs. 139,645 (50.66%) who were not on statins. Statin use was associated with a reduction in all cause-mortality by 42% (HR: 0.58, 95% CI: 0.49-0.67, p<0.01) and cardiovascular death by 43% (HR: 0.57, 95% CI: 0.40-0.74, p<0.01). Statin use was associated with an increase in amputation-free survival by 56% (HR: 0.44, 95% CI: 0.30-0.58, p<0.01). The risk of amputation and loss of patency were reduced by 35% (HR: 0.65, 95% CI: 0.41-0.89, p<0.01) and 46% (HR: 0.54, 95% CI: 0.34-0.74, p<0.01), respectively. Statin use was also associated with a reduction in the risk of major adverse cardiovascular events (MACE) by 35% (HR: 0.65, 95% CI: 0.51-0.80, p<0.01) and myocardial infarction rates by 41% (HR: 0.59, 95% CI: 0.33-0.86, p<0.01). Among patients treated with statins, the high-intensity treatment group was associated with a reduction in all cause-mortality by 36% (HR: 0.64, 95% CI: 0.54-0.74, p<0.01) compared to patients treated with low intensity statins. Conclusions: Statin treatment among patients with PAD was associated with a statistically significant reduction in all-cause mortality, cardiovascular mortality, MACE, risk for amputation, or loss of patency. Higher statin dose seems to be associated with improved outcomes.

PMID:35673949 | DOI:10.1024/0301-1526/a001012

Eur J Phys Rehabil Med. 2022 Jun 8. doi: 10.23736/S1973-9087.22.07361-0. Online ahead of print.

ABSTRACT

BACKGROUND: One of the most overspread postural abnormalities is forward head posture (FHP) and it is described as head projection anteriorly in relation to the trunk which appears mainly in sagittal plane. Scapular stabilization exercise (SSE) is capable of restoring each of thoracic cage and head neutral optimum position by neck and shoulder muscles interactions and through controlling scapular position and movement.

AIM: This study was conducted to investigate the impact of adding scapular stabilization (SSE) to postural correctional exercises (PCE) on symptomatic forward head posture.

DESIGN: The pre-post single-masking (assessor) randomized experimental trial.

SETTING: Participants with postural dysfunction in form of forward head posture admitted to outer clinic of the Faculty of Physical Therapy.

POPULATION: Sixty participants (20 to 35 years) with symptomatic FHP and recruited from outer clinic at faculty of physical therapy.

METHODS: participants were allocated randomly by opaque sealed envelope to two groups who are referred from an orthopedist: Group “A” received Scapular stabilization exercises and postural correction exercises, whereas Group “B” received only postural correctional exercises; treatments were performed three times / week for 10 weeks. The craniovertebral angle, pressure pain threshold, cervical flexor and extensor muscles endurance, Arabic neck disability index, upper trapezius and sternocleidomastoid muscle root mean square during rest and activity were used to evaluate the patients’ pre-treatment and post-treatment.

RESULTS: within group analysis for sixty participants reported statistical significant difference between baseline and post-treatment as p-value <0.05 with more refinement in stabilization exercise group.

CONCLUSIONS: Adding Scapular Stabilization exercises to postural correctional exercises is more effective method than postural correctional exercises seldom for the management of forward head posture patients.

CLINICAL REHABILITATION IMPACT: Both scapular stabilization and postural correction exercise increase craniovertebral angle and pressure pain threshold and decrease muscle activity and disability. Scapular stabilization alone increase craniovertebral angle and pressure pain threshold and decrease muscle activity and disability more than postural correction exercise. In addition of statistical significant difference in all variables but there were clinical change in disability only.

PMID:35673945 | DOI:10.23736/S1973-9087.22.07361-0

J Ultrasound Med. 2022 Jun 8. doi: 10.1002/jum.16032. Online ahead of print.

ABSTRACT

OBJECTIVES: To investigate ultrasound appearance and the survival outcomes for patients with primary thyroid lymphoma (PTL).

METHODS: Ultrasonic images and clinical characteristics from pathologically confirmed 69 PTL patients (2008-2019) were retrospectively analyzed. The clinical characteristics, ultrasonic characters, and prognostic factors were analyzed. Survival curves were plotted using the Kaplan-Meier method. Univariate and multivariate analyses were performed.

RESULTS: Of the 69 study patients, 23 were indolent PTL and 46 were aggressive PTL. Age (>70 years old) and elevated lactate dehydrogenase levels were statistically different clinical features between aggressive and indolent PTL. From ultrasonic images, 34 cases were nodular, 11 diffuse, and 24 mixed pattern. Mixed types displayed high invasiveness (45.7%) while diffuse types displayed higher inertness (39.1%), with statistically significant differences (P = .000). Invaded thyroid capsule and increased chaotic vascularity also showed significant differences between aggressive and indolent PTL. We also observed statistical difference in overall survival rates between aggressive and indolent PTL (P = .032). Single factor K-M analyses showed that age >70 years, aggressive pathology, and Ki67 >30% were positively correlated with the risk of poor PTL survival (P < .05).

CONCLUSIONS: Multimodal ultrasound provides accurate ultrasonographic information and facilitates PTL invasiveness diagnostics for improved clinical treatment. In addition, PTL patients aged >70 years, with aggressive pathology, and Ki67 >30% were more likely to have a poor survival outcome.

PMID:35673932 | DOI:10.1002/jum.16032

Clin Pediatr (Phila). 2022 Jun 8:99228221102827. doi: 10.1177/00099228221102827. Online ahead of print.

ABSTRACT

We aimed to investigate the effectiveness of an antibiotic stewardship program (ASP) on antibiotic prescription in children with community-acquired pneumonia (CAP). Antibiotic purchasing data were collected for children aged 3 months to 18 years diagnosed with CAP from November 2016 to April 2017 (pre-intervention period) and from November 2017 to April 2018 (post-intervention period). The intervention was a 1-day seminar for primary care pediatricians on the diagnosis and treatment of CAP in children according to national guidelines. There was a substantial decrease in the use of azithromycin after the intervention. In younger children, there was a 42% decrease, alongside an increased use of amoxicillin (P < .001). In older children, there was a smaller, non-statistically significant decrease in the use of azithromycin (P = .45). Our data demonstrate that the implementation of an ASP was associated with a reduction in the use of broad-spectrum antibiotics and macrolides and increased guideline adherence for the safe treatment of CAP.

PMID:35673872 | DOI:10.1177/00099228221102827

J Am Chem Soc. 2022 Jun 8. doi: 10.1021/jacs.2c04459. Online ahead of print.

ABSTRACT

Sarco/endoplasmic reticulum Ca²⁺-ATPase (SERCA) is a membrane protein on the endoplasmic reticulum (ER) that transports Ca²⁺ from the cytosol into the ER. As its function is associated with various biological phenomena, SERCA has been recognized as a promising druggable target. Here, we report the second-strongest SERCA-inhibitory compound known to date, which we isolated from the marine cyanobacterium Leptochromothrix valpauliae and named iezoside (1). The structure of iezoside (1) is fundamentally different from that of any other SERCA inhibitor, and its potency is the strongest among marine natural products (K_i 7.1 nM). In this article, we report our comprehensive analysis of iezoside (1), which covers its isolation, structural characterization supported by density functional theory (DFT) calculations and statistical analysis, total synthesis, and clarification of the mode of action of its potent antiproliferative activity (IC₅₀ 6.7 ± 0.4 nM against HeLa cells).

PMID:35673891 | DOI:10.1021/jacs.2c04459

J R Soc Interface. 2022 Jun;19(191):20220094. doi: 10.1098/rsif.2022.0094. Epub 2022 Jun 8.

ABSTRACT

Gaussian processes (GPs), implemented through multivariate Gaussian distributions for a finite collection of data, are the most popular approach in small-area spatial statistical modelling. In this context, they are used to encode correlation structures over space and can generalize well in interpolation tasks. Despite their flexibility, off-the-shelf GPs present serious computational challenges which limit their scalability and practical usefulness in applied settings. Here, we propose a novel, deep generative modelling approach to tackle this challenge, termed PriorVAE: for a particular spatial setting, we approximate a class of GP priors through prior sampling and subsequent fitting of a variational autoencoder (VAE). Given a trained VAE, the resultant decoder allows spatial inference to become incredibly efficient due to the low dimensional, independently distributed latent Gaussian space representation of the VAE. Once trained, inference using the VAE decoder replaces the GP within a Bayesian sampling framework. This approach provides tractable and easy-to-implement means of approximately encoding spatial priors and facilitates efficient statistical inference. We demonstrate the utility of our VAE two-stage approach on Bayesian, small-area estimation tasks.

PMID:35673858 | DOI:10.1098/rsif.2022.0094

Open Biol. 2022 Jun;12(6):210337. doi: 10.1098/rsob.210337. Epub 2022 Jun 8.

ABSTRACT

The circulating low-density lipoprotein concentration in blood can be reduced by the administration of statins. Frequently simvastatin (SV) is prescribed. Due to the reported pleiotropic effects of SV the aim of this study was to evaluate mineralization effects on human adipose tissue-derived stromal cells upon administration of SV. After informed consent human adipose tissue-derived stromal cells were obtained from tissue surplus of regular treatments of 14 individuals. According to established protocols after adding various SV concentrations (0.01 µM, 0.1 µM, 1.0 µM, 2.0 µM), alkaline phosphate (osteoblastic marker), mineralization capability and viability were determined at day 18, 21 and 28. The Kruskal-Wallis test was performed for statistical analysis. After adding SV a dose-dependent significant decreased viability and levels of alkaline phosphatase (p < 0.01) and a significantly increased mineralization (p < 0.01) of the primary cultures was recognized during the late mineralization stage. Mineralization of the human adipose tissue-derived stromal cells was induced by SV, possibly originated from alternative pathways than the alkaline phosphatase pathway. Further investigations should be performed regarding switching into the osteoblastic differentiation and as a possible source of cells that can be used as the basis for a potential bone graft substitute, which may allow an extension of the field of application.

PMID:35673853 | DOI:10.1098/rsob.210337

Stat Med. 2022 Jun 8. doi: 10.1002/sim.9427. Online ahead of print.

ABSTRACT

Routinely-collected health data can be employed to emulate a target trial when randomized trial data are not available. Patients within provider-based clusters likely exert and share influence on each other’s treatment preferences and subsequent health outcomes and this is known as dissemination or spillover. Extending a framework to replicate an idealized two-stage randomized trial using routinely-collected health data, an evaluation of disseminated effects within provider-based clusters is possible. In this article, we propose a novel application of causal inference methods for dissemination to retrospective cohort studies in administrative claims data and evaluate the impact of the normality of the random effects distribution for the cluster-level propensity score on estimation of the causal parameters. An extensive simulation study was conducted to study the robustness of the methods under different distributions of the random effects. We applied these methods to evaluate baseline prescription for medications for opioid use disorder among a cohort of patients diagnosed with opioid use disorder and adjust for baseline confounders using information obtained from an administrative claims database. We discuss future research directions in this setting to better address unmeasured confounding in the presence of disseminated effects.

PMID:35673849 | DOI:10.1002/sim.9427