A Benchmark, Expand, and Calibration (BenchExCal) Trial Emulation Approach for Using Real-World Evidence to Support Indication Expansions: Design and Process for a Planned Empirical Evaluation.

Real-world evidence involving healthcare database studies is well established for making causal inferences in post-market drug safety studies and methods, data, and research infrastructure for evaluating effectiveness have advanced in recent years. The rapidly expanding field of etiologic research using insurance claims and electronic health records databases is being evaluated for supporting effectiveness claims. One such use case to support regulatory decision-making on effectiveness is for expanding indications beyond existing effectiveness claims.

[Evaluation of antibiotics resistance and transmission risk of in rice-frog coculture system].

In order to assess the antibiotic resistance of and its transmission risk in a rice-frog coculture system in Zhejiang Province, this study collected . from isolated soil, field water, and frog feces from the rice-frog coculture systems in four different areas of Zhejiang Province. The collected isolates were identified by 16S rRNA sequencing, while their antibiotic-resistant phenotypes were determined by Kirby-Bauer (K-B) method.

Use of proton pump inhibitors and risk of severe COVID-19: A case-control study in United States Medicare beneficiaries.

Background: Concerns have been raised regarding proton pump inhibitor (PPI) use and risk of severe coronavirus disease 2019 (COVID-19). Observational studies have yielded heterogeneous results and were subject to important methodological limitations.

Aims: To examine the association between the receipt of PPIs and risk of COVID-19 hospitalizations and severe in-hospital outcomes or death.

[Biological and genome characteristics of a novel broad host-range phage ΦEP1 infecting enteroinvasive ].

We analyzed the biological and genome characteristics of a phage infecting enteroinvasive (EIEC), aiming to provide resources and a reference for the prevention and treatment of EIEC. With the EIEC preserved in our laboratory as the host bacterium, one strain of phage was isolated from the effluent sample from a chicken farm in Huzhou, Zhejiang and named ΦEP1. The titer, optimal multiplicity of infection, one-step growth curve, temperature, pH value, chloroform and bile salt sensitivity of ΦEP1 were determined by the double-layer agar plate method.

Triple challenges-small sample size in both exposure and control groups to scan rare maternal outcomes in a signal identification approach: a simulation study.

There is a dearth of safety data on maternal outcomes after perinatal medication exposure. Data-mining for unexpected adverse event occurrence in existing datasets is a potentially useful approach. One method, the Poisson tree-based scan statistic (TBSS), assumes that the expected outcome counts, based on incidence of outcomes in the control group, are estimated without error.

Statistical methods to control for confounders in rare disease settings that use external control.

In the drug development for rare disease, the number of treated subjects in the clinical trial is often very small, whereas the number of external controls can be relatively large. There is no clear guidance on choosing an appropriate statistical method to control baseline confounding in this situation. To fill this gap, we conduct extensive simulations to evaluate the performance of commonly used matching and weighting methods as well as the more recently developed targeted maximum likelihood estimation (TMLE) and cardinality matching in small sample settings, mimicking the motivating data from a pediatric rare disease.

Statistical methods for handling missing data to align with treatment policy strategy.

The International Council for Harmonization (ICH) E9(R1) addendum recommends choosing an appropriate estimand based on the study objectives in advance of trial design. One defining attribute of an estimand is the intercurrent event, specifically what is considered an intercurrent event and how it should be handled. The primary objective of a clinical study is usually to assess a product's effectiveness and safety based on the planned treatment regimen instead of the actual treatment received.

Retrieved-Dropout-Based multiple imputation for time-to-event data in cardiovascular outcome trials.

Recently, retrieved-dropout-based multiple imputation has been used in some therapeutic areas to address the treatment policy estimand, mostly for continuous endpoints. In this approach, data from subjects who discontinued study treatment but remained in study were used to construct a model for multiple imputation for the missing data of subjects in the same treatment arm who discontinued study. We extend this approach to time-to-event endpoints and provide a practical guide for its implementation.

Local field potentials identify features of cortico-hippocampal communication impacted by stroke and environmental enrichment therapy.

. Cognitive and memory impairments are common sequelae after stroke, yet how middle cerebral artery (MCA) stroke chronically affects the neural activity of the hippocampus, a brain region critical for memory but remote from the stroke epicenter, is poorly understood. Environmental enrichment (EE) improves cognition following stroke; however, the electrophysiology that underlies this behavioral intervention is still elusive.

Resampling-based stepwise multiple testing procedures with applications to clinical trial data.

Endpoints in clinical trials are often highly correlated. However, the commonly used multiple testing procedures in clinical trials either do not take into consideration the correlations among test statistics or can only exploit known correlations. Westfall and Young constructed a resampling-based stepdown method that implicitly utilizes the correlation structure of test statistics in situations with unknown correlations.

Regression calibration to correct correlated errors in outcome and exposure.

Measurement error arises through a variety of mechanisms. A rich literature exists on the bias introduced by covariate measurement error and on methods of analysis to address this bias. By comparison, less attention has been given to errors in outcome assessment and nonclassical covariate measurement error.

Experimental cortical stroke induces aberrant increase of sharp-wave-associated ripples in the hippocampus and disrupts cortico-hippocampal communication.

The functional consequences of ischemic stroke in the remote brain regions are not well characterized. The current study sought to determine changes in hippocampal oscillatory activity that may underlie the cognitive impairment observed following distal middle cerebral artery occlusion (dMCAO) without causing hippocampal structural damage. Local field potentials were recorded from the dorsal hippocampus and cortex in urethane-anesthetized rats with multichannel silicon probes during dMCAO and reperfusion, or mild ischemia induced by bilateral common carotid artery occlusion (CCAO).

Widespread optogenetic expression in macaque cortex obtained with MR-guided, convection enhanced delivery (CED) of AAV vector to the thalamus.

Background: In non-human primate (NHP) optogenetics, infecting large cortical areas with viral vectors is often a difficult and time-consuming task. Previous work has shown that parenchymal delivery of adeno-associated virus (AAV) in the thalamus by convection-enhanced delivery (CED) can lead to large-scale transduction via axonal transport in distal areas including cortex. We used this approach to obtain widespread cortical expression of light-sensitive ion channels.

Marginal structural models to estimate the effects of time-varying treatments on clustered outcomes in the presence of interference.

Marginal structural models are a class of causal models useful for characterizing the effect of treatment in the presence of time-varying confounding. They are more widely used than structural nested models, partly because these models are easier to understand and to implement. We extend marginal structural models to situations with clustered observations with unit- and cluster-level treatment and introduce an appropriate inferential method.

Validating a Local Failure Risk Stratification for Use in Prospective Studies of Adjuvant Radiation Therapy for Bladder Cancer.

Purpose: To inform prospective trials of adjuvant radiation therapy (adj-RT) for bladder cancer after radical cystectomy, a locoregional failure (LF) risk stratification was proposed. This stratification was developed and validated using surgical databases that may not reflect the outcomes expected in prospective trials. Our purpose was to assess sources of bias that may affect the stratification model's validity or alter the LF risk estimates for each subgroup: time bias due to evolving surgical techniques; trial accrual bias due to inclusion of patients who would be ineligible for adj-RT trials because of early disease progression, death, or loss to follow-up shortly after cystectomy; bias due to different statistical methods to estimate LF; and subgrouping bias due to different definitions of the LF subgroups.

Perturbation of Brain Oscillations after Ischemic Stroke: A Potential Biomarker for Post-Stroke Function and Therapy.

Brain waves resonate from the generators of electrical current and propagate across brain regions with oscillation frequencies ranging from 0.05 to 500 Hz. The commonly observed oscillatory waves recorded by an electroencephalogram (EEG) in normal adult humans can be grouped into five main categories according to the frequency and amplitude, namely δ (1-4 Hz, 20-200 μV), θ (4-8 Hz, 10 μV), α (8-12 Hz, 20-200 μV), β (12-30 Hz, 5-10 μV), and γ (30-80 Hz, low amplitude).

Hemodynamic and Light-Scattering Changes of Rat Spinal Cord and Primary Somatosensory Cortex in Response to Innocuous and Noxious Stimuli.

Neuroimaging technologies with an exceptional spatial resolution and noninvasiveness have become a powerful tool for assessing neural activity in both animals and humans. However, the effectiveness of neuroimaging for pain remains unclear partly because the neurovascular coupling during pain processing is not completely characterized. Our current work aims to unravel patterns of neurovascular parameters in pain processing.

The Scalp Confounds Near-Infrared Signal from Rat Brain Following Innocuous and Noxious Stimulation.

Functional near-infrared imaging (fNIRI) is a non-invasive, low-cost and highly portable technique for assessing brain activity and functions. Both clinical and experimental evidence suggest that fNIRI is able to assess brain activity at associated regions during pain processing, indicating a strong possibility of using fNIRI-derived brain activity pattern as a biomarker for pain. However, it remains unclear how, especially in small animals, the scalp influences fNIRI signal in pain processing.

An Olfactory Cilia Pattern in the Mammalian Nose Ensures High Sensitivity to Odors.

In many sensory organs, specialized receptors are strategically arranged to enhance detection sensitivity and acuity. It is unclear whether the olfactory system utilizes a similar organizational scheme to facilitate odor detection. Curiously, olfactory sensory neurons (OSNs) in the mouse nose are differentially stimulated depending on the cell location.

Structural Nested Mean Models to Estimate the Effects of Time-Varying Treatments on Clustered Outcomes.

In assessing the efficacy of a time-varying treatment structural nested models (SNMs) are useful in dealing with confounding by variables affected by earlier treatments. These models often consider treatment allocation and repeated measures at the individual level. We extend SNMMs to clustered observations with time-varying confounding and treatments.

A mixture model using likelihood-based and Bayesian approaches for identifying responders and non-responders in longitudinal clinical trials.

A longitudinal mixture model for classifying patients into responders and non-responders is established using both likelihood-based and Bayesian approaches. The model takes into consideration responders in the control group. Therefore, it is especially useful in situations where the placebo response is strong, or in equivalence trials where the drug in development is compared with a standard treatment.

Occult pelvic lymph node involvement in bladder cancer: implications for definitive radiation.

Purpose: To inform radiation treatment planning for clinically staged, node-negative bladder cancer patients by identifying clinical factors associated with the presence and location of occult pathologic pelvic lymph nodes.

Methods And Materials: The records of patients with clinically staged T1-T4N0 urothelial carcinoma of the bladder undergoing radical cystectomy and pelvic lymphadenectomy at a single institution were reviewed. Logistic regression was used to evaluate associations between preoperative clinical variables and occult pathologic pelvic or common iliac lymph nodes.

Optimizing bladder cancer locoregional failure risk stratification after radical cystectomy using SWOG 8710.

Background: Clinical trials of radiation after radical cystectomy (RC) and chemotherapy for bladder cancer are in development, but inclusion and stratification factors have not been clearly established. In this study, the authors evaluated and refined a published risk stratification for locoregional failure (LF) by applying it to a multicenter patient cohort.

Methods: The original stratification, which was developed using a single-institution series, produced 3 subgroups with significantly different LF risk based on pathologic tumor (pT) classification and the number of lymph nodes identified.

Relationship between body fat distribution and upper airway dynamic function during sleep in adolescents.

Introduction: The obstructive sleep apnea syndrome (OSAS) is associated with increased visceral adipose tissue (VAT) in adults; however, few studies have evaluated VAT in relation to upper airway function in adolescents. We hypothesized that increased neck circumference (NC) and VAT would be associated with increased upper airway collapsibility.

Methods: Adolescents (24 obese patients with OSAS, 22 obese control patients, and 29 lean control patients) underwent abdominal magnetic resonance imaging, and measurement of upper airway pressure-flow relationships in the activated and hypotonic upper airway states.

Longitudinal strain in Friedreich Ataxia: a potential marker for early left ventricular dysfunction.

Background: Friedreich's ataxia (FRDA) is a neurodegenerative disorder resulting from deficiency of frataxin, characterized by cardiac hypertrophy associated with heart failure and sudden cardiac death. However, the relationship between remodeling and novel measures of cardiac function such as strain, and the time-dependent changes in these measures are poorly defined.

Methods And Results: We compared echocardiographic parameters of cardiac size, hypertrophy, and function in 50 FRDA patients with 50 normal controls and quantified the following measures of cardiac remodeling and function: left ventricular (LV) volumes, mass, relative wall thickness (RWT), ejection fraction (EF), and myocardial strain.