The Utilization of the Accelerated Approval Pathway in Oncology: A Case Study of Pembrolizumab.

The accelerated approval (AA) pathway was established by the United States Food and Drug Administration (FDA) to provide earlier access to therapies for patients with serious medical conditions and unmet medical needs. Since its inception, the AA pathway has been used for novel treatments across different therapeutic areas, but most prominently in oncology, including the immune checkpoint inhibitor class. This review article describes the history of regulatory approvals for pembrolizumab, an immunotherapy agent targeting programmed death receptor-1 (PD-1), and use of the AA pathway and the corresponding regulatory decisions made by the FDA.

Heat Tolerance Testing and the Return to Duty Decision: A Two-Year Case Cohort Analysis.

Background: Among individuals with prior exertional heat illness (EHI), heat tolerance testing (HTT) may inform risk and return to duty/activity. However, little is known about HTT's predictive validity, particularly for EHI recurrence. Our project sought to demonstrate the predictive validity of HTT in EHI recurrence and HTT's utility as a diagnostic tool in exertional heat stroke (EHS).

Challenges of Agitation in Dementia: A Plea for Early Discussion.

Behavioral and psychological symptoms of dementia (BPSD) occur frequently among people with dementia and are known precipitants for placement in care facilities. Despite the social, financial, and psychological impact on dementia care, education and discussions on BPSD have not been routinely included in advance care planning (ACP). As a result, families can face great challenges in making complex medical decisions when their loved ones are admitted to the geriatric psychiatric inpatient unit with refractory BPSD.

Clinical Trial Diversity in Oncology: FDA Takes Action with Post-Marketing Requirements or Commitments.

In recent years, there has been a renewed focus on promoting the inclusion of patients from racial and ethnic minority groups in oncology clinical trials. FDA Oncology has long pointed to the underrepresentation of racial minorities in registration trials leading to approval. US FDA's Guidance on diversity discusses how diversity could be handled within clinical trials, giving recommendations on broadening eligibility criteria, inclusive trial practices, and alternative trial designs.

Point-of-care Ultrasound to Distinguish Retinal Detachment and Ruptured Arterial Microaneurysm.

Case Presentation: We present the case of an older male with point-of-care-ultrasound (POCUS) imaging consistent with retinal detachment who was instead found by ophthalmology to have a ruptured arterial microaneurysm with vitreous and preretinal hemorrhage. The patient later had complete resolution of his symptoms. We discuss this retinal detachment "mimic.

Oncology Products in the European Union: An Analysis of Regulatory Approvals with a CHMP Oral Explanation.

Background: The oral explanation (OE) is a critical event during new marketing authorisation procedures in the European Union (EU). The primary objective of the present study was to investigate how many procedures, having an OE in front of the Committee for Medicinal Products for Human Use (CHMP), resulted in a regulatory approval for oncology products.

Methods: Procedures for new marketing authorisation applications (MAAs) and Type II variations (new indication) for oncology products with at least one OE (with or without a Scientific Advisory Group (SAG) meeting) and for which the outcome took place between 31 January 2016 to 31 January 2020 were included in the analysis.

The Evolving Practice of Psychiatry in the Era of Integrated Care.

Background: Integrating behavioral health care into the primary care setting is increasingly recognized as an effective way to manage mental illness and substance use disorders on a population level in the United States. The term "integrated care," however, is used in many ways and encompasses several different models.

Objectives: The aim of this article is to provide a conceptual framework to understand the landscape of models of integrated care and to use this framework to contrast the roles of behavioral health providers in integrated settings with those in traditional behavioral health delivery models.

Collaborative Care for Women With Depression: A Systematic Review.

Background: The collaborative care model has been found to be effective for depression management in various primary care populations; however, no review has synthesized trials tailored to treat women.

Objective: The purpose of this systematic review is to evaluate the current evidence for collaborative depression care for women.

Methodology: We searched for English language articles via MEDLINE, CINAHL, PsycINFO, EMBASE, Cochrane Library, and reference lists of key articles.

Antipsychotic prescribing patterns in a Medicare Advantage population of older individuals with dementia.

Background: Antipsychotic medications are widely used to treat behavioral symptoms of dementia. However, studies have shown that antipsychotic use in patients with dementia is associated with risk of side effects.

Aims: The aim of this study is to examine antipsychotic prescribing patterns for beneficiaries with dementia enrolled in a Medicare Advantage program and identify opportunities to improve prescribing practices.

Public Stigma towards Older Adults with Depression: Findings from the São Paulo-Manaus Elderly in Primary Care Study.

This study investigates three domains of public stigma (perceived negative reactions, perceived discrimination, and dangerousness) against older adults with depression. The sample comprised of older adults registered with primary care clinics (n = 1,291) and primary health care professionals (n = 469) from São Paulo and Manaus, Brazil. Participants read a vignette describing a 70-year-old individual (Mary or John) with a depressive disorder and answered questions measuring stigma.

Identification and treatment of depression of older adults in primary care: findings from the São Paulo Ageing and Health Study.

Background: Depression, diabetes and hypertension are major contributors to the global burden of disease; however, the majority of research on depression and co-morbid conditions originates in high-income countries.

Objective: This study examines the depression identification rate and compares treatment rates of depression with those of diabetes and hypertension among elderly individuals served in primary care through the Family Health Program (FHP) in São Paulo, Brazil.

Method: A total of 1558 São Paulo Ageing and Health Study participants (low-income adults ≥65 years old living in São Paulo) registered in the FHP were included for analysis.

Perinatal depression screening in a Women, Infants, and Children (WIC) program: perception of feasibility and acceptability among a multidisciplinary staff.

Objective: Best practices for addressing women's mental health and screening for depression in public health clinics are not available. Clinic staff are often responsible for screening for depression; however, few studies examine staff perceptions on feasibility and acceptability of using perinatal screening for mood disorders in ethnically diverse public health clinics.

Methods: During December 2012, we conducted four focus groups using a semistructured interview guide with public health clinic staff of varying disciplines (n=25) in a Special Supplemental Nutrition Program for Women, Infants, and Children.

Access improvement to aircraft passengers' hand luggage.

Background: Efficient use of space and passenger comfort in aircraft interiors are major issues. There is not much research available about the flying experience regarding passengers' personal belongings.

Objective: The objective of this study is to explore concepts within the current aircraft seats which improve the passenger experience related to their personal belongings like wallets, mobile phones and laptops.

Optimization of benzodiazepinones as selective inhibitors of the X-linked inhibitor of apoptosis protein (XIAP) second baculovirus IAP repeat (BIR2) domain.

The IAPs are key regulators of the apoptotic pathways and are commonly overexpressed in many cancer cells. IAPs contain one to three BIR domains that are crucial for their inhibitory function. The pro-survival properties of XIAP come from binding of the BIR domains to the pro-apoptotic caspases.

Benzazepinones and benzoxazepinones as antagonists of inhibitor of apoptosis proteins (IAPs) selective for the second baculovirus IAP repeat (BIR2) domain.

XIAP is a key regulator of apoptosis, and its overexpression in cancer cells may contribute to their survival. The antiapoptotic function of XIAP derives from its BIR domains, which bind to and inhibit pro-apoptotic caspases. Most known IAP inhibitors are selective for the BIR3 domain and bind to cIAP1 and cIAP2 as well as XIAP.

Identification of RO4597014, a Glucokinase Activator Studied in the Clinic for the Treatment of Type 2 Diabetes.

To resolve the metabolite redox cycling associated with our earlier clinical compound 2, we carried out lead optimization of lead molecule 1. Compound 4 showed improved lipophilic ligand efficiency and demonstrated robust glucose lowering in diet-induced obese mice without a liability in predictive preclinical drug safety studies. Thus, it was selected as a clinical candidate and further studied in type 2 diabetic patients.

Real-time hyperspectral fluorescence imaging of pancreatic β-cell dynamics with the image mapping spectrometer.

The development of multi-colored fluorescent proteins, nanocrystals and organic fluorophores, along with the resulting engineered biosensors, has revolutionized the study of protein localization and dynamics in living cells. Hyperspectral imaging has proven to be a useful approach for such studies, but this technique is often limited by low signal and insufficient temporal resolution. Here, we present an implementation of a snapshot hyperspectral imaging device, the image mapping spectrometer (IMS), which acquires full spectral information simultaneously from each pixel in the field without scanning.

Discovery of piragliatin--first glucokinase activator studied in type 2 diabetic patients.

Glucokinase (GK) activation as a potential strategy to treat type 2 diabetes (T2D) is well recognized. Compound 1, a glucokinase activator (GKA) lead that we have previously disclosed, caused reversible hepatic lipidosis in repeat-dose toxicology studies. We hypothesized that the hepatic lipidosis was due to the structure-based toxicity and later established that it was due to the formation of a thiourea metabolite, 2.

Snapshot advantage: a review of the light collection improvement for parallel high-dimensional measurement systems.

The snapshot advantage is a large increase in light collection efficiency available to high-dimensional measurement systems that avoid filtering and scanning. After discussing this advantage in the context of imaging spectrometry, where the greatest effort towards developing snapshot systems has been made, we describe the types of measurements where it is applicable. We then generalize it to the larger context of high-dimensional measurements, where the advantage increases geometrically with measurement dimensionality.

Depth-resolved image mapping spectrometer (IMS) with structured illumination.

We present a depth-resolved Image Mapping Spectrometer (IMS) which is capable of acquiring 4D (x, y, z, λ) datacubes. Optical sectioning is implemented by structured illumination. The device's spectral imaging performance is demonstrated in a multispectral microsphere and mouse kidney tissue fluorescence imaging experiment.

Real-time snapshot hyperspectral imaging endoscope.

Hyperspectral imaging has tremendous potential to detect important molecular biomarkers of early cancer based on their unique spectral signatures. Several drawbacks have limited its use for in vivo screening applications: most notably the poor temporal and spatial resolution, high expense, and low optical throughput of existing hyperspectral imagers. We present the development of a new real-time hyperspectral endoscope (called the image mapping spectroscopy endoscope) based on an image mapping technique capable of addressing these challenges.

Targeted expression of p35 reveals a role for caspases in formation of the adult abdominal cuticle in Drosophila.

Programmed cell death is a fundamental aspect of metazoan development associated with the elaboration of disparate tissues and structures. Specialized cysteine proteases, the caspases, are mediators of cell death; once activated they cleave substrate proteins to dismantle doomed cells. Caspase activity is regulated by several cellular and viral inhibitors.

Novel glucokinase activators: a patent review (2008 - 2010).

Importance Of The Field: Small molecule glucokinase activators (GKAs) continue to represent a potential strategy to treat type 2 diabetes (T2D). Glucokinase (GK) primarily exerts its effect through modulatory actions in pancreatic β-cells and hepatocytes. It couples insulin secretion in the pancreas with plasma glucose concentration and improves glucose utilization in the liver, thus, affecting two key aspects of glucose homeostasis.

2,3-Disubstituted acrylamides as potent glucokinase activators.

The phenylacetamide 1 represents the archtypical glucokinase activator (GKA) in which only the R-isomer is active. In order to probe whether the chiral center could be replaced, we prepared a series of olefins 2 and show in the present work that these compounds represent a new class of GKAs. Surprisingly, the SAR of the new series paralleled that of the saturated derivatives with the exception that there was greater tolerance for larger alkyl and cycloalkyl groups at R(2) region in comparison to the phenylacetamides.

Improving spatial resolution of a fiber bundle optical biopsy system.

To reduce the number of invasive tissue biopsies and needle aspirations performed during cancer screenings, endo-microscopes can be used to image tissue in vivo. However, when optical fiber bundles are used to transmit the image, the resolution of such systems is limited by undersampling due to the spacing of the bundle's individual fibers for a given field of view. We propose a method to increase the sampling of an optical biopsy system and thereby improve the system's resolution.