Rapid biphasic decay of intact and defective HIV DNA reservoir during acute treated HIV disease.

Despite antiretroviral therapy (ART), HIV persists in latently-infected cells (the HIV reservoir) which decay slowly over time. Here, leveraging >500 longitudinal samples from 67 people living with HIV (PLWH) treated during acute infection, we developed a mathematical model to predict reservoir decay from peripheral CD4 + T cells. Nonlinear generalized additive models demonstrated rapid biphasic decay of intact DNA (week 0-5: t ~ 2.

Prevention of adverse HIV treatment outcomes: machine learning to enable proactive support of people at risk of HIV care disengagement in Tanzania.

Objectives: This study aimed to develop a machine learning (ML) model to predict disengagement from HIV care, high viral load or death among people living with HIV (PLHIV) with the goal of enabling proactive support interventions in Tanzania. The algorithm addressed common challenges when applying ML to electronic medical record (EMR) data: (1) imbalanced outcome distribution; (2) heterogeneity across multisite EMR data and (3) evolving virological suppression thresholds.

Design: Observational study using a national EMR database.

Variable and interactive effects of Sex, APOE and TREM2 on the deposition of tau in entorhinal and neocortical regions.

The canonical AD pathological cascade posits that the accumulation of amyloid beta ( ) is the initiating event, accelerating the accumulation of tau in the entorhinal cortex (EC), which subsequently spreads into the neocortex. Here in a sample of over 1300 participants with multimodal imaging and genetic information we queried how genetic variation affects these stages of the AD cascade. We observed that females and homozygotes are more susceptible to the effects of on the primary accumulation of tau, with greater EC tau for a given level of .

Imaging of adeno-associated viral capsids for purposes of gene editing using CEST NMR/MRI.

Purpose: Gene therapy using adeno-associated virus (AAV) vector-mediated gene delivery has undergone substantial growth in recent years with promising results in both preclinical and clinical studies, as well as emerging regulatory approval. However, the inability to quantify the efficacy of gene therapy from cellular delivery of gene-editing technology to specific functional outcomes is an obstacle for efficient development of gene therapy treatments. Building on prior works that used the CEST reporter gene lysine rich protein, we hypothesized that AAV viral capsids may generate endogenous CEST contrast from an abundance of surface lysine residues.

Rapid Biphasic Decay of Intact and Defective HIV DNA Reservoir During Acute Treated HIV Disease.

Despite antiretroviral therapy (ART), HIV persists in latently-infected cells ("the reservoir") which decay slowly over time. Here, leveraging >500 longitudinal samples from 67 people with HIV (PWH) treated during acute infection, we developed a novel mathematical model to predict reservoir decay from peripheral CD4+ T cells. Nonlinear generalized additive models demonstrated rapid biphasic decay of intact DNA (week 0-5: t~2.

Rudi Kundini, Pamoja Kundini (RKPK): study protocol for a hybrid type 1 randomized effectiveness-implementation trial using data science and economic incentive strategies to strengthen the continuity of care among people living with HIV in Tanzania.

Background: Economic incentives can improve clinical outcomes among in-care people living with HIV (PLHIV), but evidence is limited for their effectiveness among out-of-care PLHIV or those at risk of disengagement. We propose a type 1 hybrid effectiveness-implementation study to advance global knowledge about the use of economic incentives to strengthen the continuity of HIV care and accelerate global goals for HIV epidemic control.

Methods: The Rudi Kundini, Pamoja Kundini study will evaluate two implementation models of an economic incentive strategy for supporting two groups of PLHIV in Tanzania.

Sensitivity analysis with iterative outlier detection for systematic reviews and meta-analyses.

Meta-analysis is a widely used tool for synthesizing results from multiple studies. The collected studies are deemed heterogeneous when they do not share a common underlying effect size; thus, the factors attributable to the heterogeneity need to be carefully considered. A critical problem in meta-analyses and systematic reviews is that outlying studies are frequently included, which can lead to invalid conclusions and affect the robustness of decision-making.

Assessing the Most Vulnerable Subgroup to Type II Diabetes Associated with Statin Usage: Evidence from Electronic Health Record Data.

There have been increased concerns that the use of statins, one of the most commonly prescribed drugs for treating coronary artery disease, is potentially associated with the increased risk of new-onset Type II diabetes (T2D). Nevertheless, to date, there is no robust evidence supporting as to whether and what kind of populations are indeed vulnerable for developing T2D after taking statins. In this case study, leveraging the biobank and electronic health record data in the Partner Health System, we introduce a new data analysis pipeline and a novel statistical methodology that address existing limitations by (i) designing a rigorous causal framework that systematically examines the causal effects of statin usage on T2D risk in observational data, (ii) uncovering which patient subgroup is most vulnerable for developing T2D after taking statins, and (iii) assessing the replicability and statistical significance of the most vulnerable subgroup via a bootstrap calibration procedure.

Rudi Kundini, Pamoja Kundini (RKPK): study protocol for a hybrid type 1 randomized effectiveness-implementation trial using data science and economic incentive strategies to strengthen the continuity of care among people living with HIV in Tanzania.

Background: Economic incentives can improve clinical outcomes among in-care people living with HIV (PLHIV), but evidence is limited for their effectiveness among out-of-care PLHIV or those at-risk of disengagement. We propose a type 1 hybrid effectiveness-implementation study to advance global knowledge about the use of economic incentives to strengthen the continuity of HIV care and accelerate global goals for HIV epidemic control.

Methods: The Rudi Kundini, Pamoja Kundini study will evaluate two implementation models of an economic incentive strategy for supporting two groups of PLHIV in Tanzania.

A robust harmonization approach for cognitive data from multiple aging and dementia cohorts.

Introduction: Although many cognitive measures have been developed to assess cognitive decline due to Alzheimer's disease (AD), there is little consensus on optimal measures, leading to varied assessments across research cohorts and clinical trials making it difficult to pool cognitive measures across studies.

Methods: We used a two-stage approach to harmonize cognitive data across cohorts and derive a cross-cohort score of cognitive impairment due to AD. First, we pool and harmonize cognitive data from international cohorts of varying size and ethnic diversity.

Machine learning with routine electronic medical record data to identify people at high risk of disengagement from HIV care in Tanzania.

Machine learning methods for health care delivery optimization have the potential to improve retention in HIV care, a critical target of global efforts to end the epidemic. However, these methods have not been widely applied to medical record data in low- and middle-income countries. We used an ensemble decision tree approach to predict risk of disengagement from HIV care (missing an appointment by ≥28 days) in Tanzania.

Single-cell transcriptomics highlights immunological dysregulations of monocytes in the pathobiology of COPD.

Background: Chronic obstructive pulmonary disease (COPD) is a common respiratory disease, whose pathogenetic complexity was strongly associated with aging/smoking and poorly understood.

Methods: Here we performed single-cell RNA sequencing (scRNA-seq) analysis of 66,610 cells from COPD and age-stratified control lung tissues of donors with different smoking histories to prioritize cell types most perturbed in COPD lungs in aging/smoking dependent or independent manner. By performing an array of advanced bioinformatic analyses, such as gene set enrichment analysis, trajectory analysis, cell-cell interactions analysis, regulatory potential analysis, weighted correlation network analysis, functional interaction analysis, and gene set variation analysis, we integrated cell-type-level alterations into a system-level malfunction and provided a more clarified COPD pathological model containing specific mechanisms by which aging and smoking facilitate COPD development.

Efficient targeted learning of heterogeneous treatment effects for multiple subgroups.

In biomedical science, analyzing treatment effect heterogeneity plays an essential role in assisting personalized medicine. The main goals of analyzing treatment effect heterogeneity include estimating treatment effects in clinically relevant subgroups and predicting whether a patient subpopulation might benefit from a particular treatment. Conventional approaches often evaluate the subgroup treatment effects via parametric modeling and can thus be susceptible to model mis-specifications.

Noninvasively differentiating acute and chronic nephropathies via multiparametric urea-CEST, nuclear Overhauser enhancement-CEST, and quantitative magnetization transfer MRI.

Purpose: Standardized blood tests often lack adequate sensitivity and specificity to capture the gradual progression of renal injuries. We suggest a multiparametric molecular MRI approach as a noninvasive tool for monitoring renal function loss and distinguishing different types of renal injuries.

Methods: CEST and quantitative magnetization transfer (qMT) imaging were performed on cisplatin (n = 16) and aristolochic acid (AA)-induced nephropathy (n = 22) mouse models at 7T with an infusion of either saline or urea.

Calcium sensitive receptor and claudin-14 expression in kidney tissues of two kidney stone models.

Intoduction: The differences in protein expression of calcium sensitive receptor (CaSR) and claudin-14 in a kidney stone model established by nanobacteria (NB) and ethylene glycol (EG) were compared.

Material And Methods: Ninety Wistar male rats were randomly divided into the NB group, the EG group, and the blank control group (NC group), with 30 rats in each group. Three rats of each group were sacrificed every week after injection.

Inhibition of gap junction communication between cells can induce apoptosis of corpus cavernosum smooth muscle in guinea pigs.

In this study, we aimed to investigate the effect of gap junction (GJ) on apoptosis of smooth muscle. Forty adult male guinea pigs were randomly divided into four groups with 10 guinea pigs in each group. Adeno-associated virus (AAV) and Gap27 were injected at the root of the corpus cavernosum.

Hemodialysis exacerbates proteolytic imbalance and pro-fibrotic platelet dysfunction.

Multi-organ fibrosis among end stage renal disease (ESRD) patients cannot be explained by uremia alone. Despite mitigation of thrombosis during hemodialysis (HD), subsequent platelet dysfunction and tissue dysregulation are less understood. We comprehensively profiled plasma and platelets from ESRD patients before and after HD to examine HD-modulation of platelets beyond thrombotic activation.

DSCAM/PAK1 pathway suppression reverses neurogenesis deficits in iPSC-derived cerebral organoids from patients with Down syndrome.

Down syndrome (DS), caused by trisomy of chromosome 21, occurs in 1 of every 800 live births. Early defects in cortical development likely account for the cognitive impairments in DS, although the underlying molecular mechanism remains elusive. Here, we performed histological assays and unbiased single-cell RNA-Seq (scRNA-Seq) analysis on cerebral organoids derived from 4 euploid cell lines and from induced pluripotent stem cells (iPSCs) from 3 individuals with trisomy 21 to explore cell-type-specific abnormalities associated with DS during early brain development.

Systematic identification of risk factors and drug repurposing options for Alzheimer's disease.

Introduction: Several Mendelian randomization studies have been conducted that identified multiple risk factors for Alzheimer's disease (AD). However, they typically focus on a few pre-selected risk factors.

Methods: A two-sample Mendelian randomization (MR) study was used to systematically examine the potential causal associations of 1037 risk factors/medical conditions and 31 drugs with the risk of late-onset AD.

CAR (CARSKNKDC) Peptide Modified ReNcell-Derived Extracellular Vesicles as a Novel Therapeutic Agent for Targeted Pulmonary Hypertension Therapy.

In recent years, mesenchymal stem cells (MSCs)-derived extracellular vesicles (EVs) are emerging as a potential therapeutic agent for pulmonary hypertension (PH). However, the full realization of MSCs-derived EVs therapy has been hampered by the absence of standardization in MSCs culture and the challenges of industrial scale-up. The study was to exploit an alternative replacement for MSCs using currently commercialized stem cell lines for effective targeted PH therapy.

Effect of Routine Sport Participation on Short-Term Clinical Neurological Outcomes: A Comparison of Non-Contact, Contact, and Collision Sport Athletes.

Objectives: To compare pre-season to post-season changes on a battery of clinical neurological outcome measures between non-contact, contact, and collision sport athletes over multiple seasons of play.

Methods: 244 high school and collegiate athletes participating in multiple non-contact, contact, and collision sports completed standardized annual pre-season and post-season assessments over 1-4 years. Pre/post-season changes in 10 outcome measures assessing concussion symptoms, neurocognitive performance, and balance were compared between the groups using linear mixed models.

Biological significance of long non-coding RNA FTX expression in human colorectal cancer.

The purpose of this study was to determine the expression of long non-coding RNA (lncRNA) FTX and analyze its prognostic and biological significance in colorectal cancer (CRC). A quantitative reverse transcription PCR was performed to detect the expression of long non-coding RNA FTX in 35 pairs of colorectal cancer and corresponding noncancerous tissues. The expression of long non-coding RNA FTX was detected in 187 colorectal cancer tissues and its correlations with clinicopathological factors of patients were examined.