Complexmodels positioned for impact to drug testing in pharma: a review.

Recent years have seen the creation and popularization of various complexmodels (CIVMs), such as organoids and organs-on-chip, as a technology with the potential to reduce animal usage in pharma while also enhancing our ability to create safe and efficacious drugs for patients. Public awareness of CIVMs has increased, in part, due to the recent passage of the FDA Modernization Act 2.0.

Effects of Tongue Strength Training on Quality of Life in Head and Neck Cancer Patients: Results From a Pilot Interventional Clinical Trial.

Background: Head and neck cancer (HNC) patients often have dysphagia following surgical and/or chemoradiation treatment, which can lead to reduced quality of life. Some patients suffer from decreased tongue strength and mobility that may cause discomfort and difficulty with swallowing. Our group has developed a patented genioglossus muscle strength trainer (GMST) to increase tongue protrusive force that has been used in patients with sleep apnea.

Pregnancy and stomas: a 9-year retrospective series at a major metropolitan hospital in Brisbane Queensland.

Background: Over 42 000 Australians live with a stoma, and this number increases annually. Pregnancy in stoma patients is a rare but complex condition and there is limited published literature regarding surgical and obstetric complications in pregnant stoma patients. The aim of this paper was to review stoma outcomes, perinatal morbidity and mortality, and early postpartum period in pregnant stoma patients.

Discovery of TRPA1 Antagonist : Derisking Preclinical Toxicity and Aldehyde Oxidase Metabolism with a Potential First-in-Class Therapy for Respiratory Disease.

Transient receptor potential ankyrin 1 (TRPA1) is a nonselective calcium ion channel highly expressed in the primary sensory neurons, functioning as a polymodal sensor for exogenous and endogenous stimuli, and has been implicated in neuropathic pain and respiratory disease. Herein, we describe the optimization of potent, selective, and orally bioavailable TRPA1 small molecule antagonists with strong target engagement in rodent models. Several lead molecules in preclinical single- and short-term repeat-dose toxicity studies exhibited profound prolongation of coagulation parameters.

Closing the gap between science and management of cold-water refuges in rivers and streams.

Human activities and climate change threaten coldwater organisms in freshwater ecosystems by causing rivers and streams to warm, increasing the intensity and frequency of warm temperature events, and reducing thermal heterogeneity. Cold-water refuges are discrete patches of relatively cool water that are used by coldwater organisms for thermal relief and short-term survival. Globally, cohesive management approaches are needed that consider interlinked physical, biological, and social factors of cold-water refuges.

Cross-modal functional connectivity supports speech understanding in cochlear implant users.

Sensory deprivation can lead to cross-modal cortical changes, whereby sensory brain regions deprived of input may be recruited to perform atypical function. Enhanced cross-modal responses to visual stimuli observed in auditory cortex of postlingually deaf cochlear implant (CI) users are hypothesized to reflect increased activation of cortical language regions, but it is unclear if this cross-modal activity is "adaptive" or "mal-adaptive" for speech understanding. To determine if increased activation of language regions is correlated with better speech understanding in CI users, we assessed task-related activation and functional connectivity of auditory and visual cortices to auditory and visual speech and non-speech stimuli in CI users (n = 14) and normal-hearing listeners (n = 17) and used functional near-infrared spectroscopy to measure hemodynamic responses.

Global burden of ototoxic hearing loss associated with platinum-based cancer treatment: A systematic review and meta-analysis.

Platinum-based chemotherapeutic agents cisplatin and carboplatin are widely used in cancer treatment worldwide and may result in ototoxic hearing loss. The high incidence of cancer and salient ototoxic effects of platinum-based compounds pose a global public health threat. The purpose of this study was twofold.

The importance of warm habitat to the growth regime of cold-water fishes.

A common goal of biological adaptation planning is to identify and prioritize locations that remain suitably cool during summer. This implicitly devalues areas that are ephemerally warm, even if they are suitable most of the year for mobile animals. Here we develop an alternative conceptual framework, the growth regime, which considers seasonal and landscape variation in physiological performance, focusing on riverine fish.

Perspectives on the evaluation and adoption of complex in vitro models in drug development: Workshop with the FDA and the pharmaceutical industry (IQ MPS Affiliate).

Complex in vitro models (CIVM) offer the potential to improve pharmaceutical clinical drug attrition due to safety and/ or efficacy concerns. For this technology to have an impact, the establishment of robust characterization and qualifi­cation plans constructed around specific contexts of use (COU) is required. This article covers the output from a workshop between the Food and Drug Administration (FDA) and Innovation and Quality Microphysiological Systems (IQ MPS) Affiliate.

A BCMA/CD16A bispecific innate cell engager for the treatment of multiple myeloma.

Despite the recent progress, multiple myeloma (MM) is still essentially incurable and there is a need for additional effective treatments with good tolerability. RO7297089 is a novel bispecific BCMA/CD16A-directed innate cell engager (ICE) designed to induce BCMA+ MM cell lysis through high affinity binding of CD16A and retargeting of NK cell cytotoxicity and macrophage phagocytosis. Unlike conventional antibodies approved in MM, RO7297089 selectively targets CD16A with no binding of other Fcγ receptors, including CD16B on neutrophils, and irrespective of 158V/F polymorphism, and its activity is less affected by competing IgG suggesting activity in the presence of M-protein.

Ordered Regression Models: a Tutorial.

Ordinal outcomes are common in the social, behavioral, and health sciences, but there is no commonly accepted approach to analyzing them. Researchers make a number of different seemingly arbitrary recoding decisions implying different levels of measurement and theoretical assumptions. As a result, a wide array of models are used to analyze ordinal outcomes, including the linear regression model, binary response model, ordered models, and count models.

Riverscape approaches in practice: perspectives and applications.

Landscape perspectives in riverine ecology have been undertaken increasingly in the last 30 years, leading aquatic ecologists to develop a diverse set of approaches for conceptualizing, mapping and understanding 'riverscapes'. Spatiotemporally explicit perspectives of rivers and their biota nested within the socio-ecological landscape now provide guiding principles and approaches in inland fisheries and watershed management. During the last two decades, scientific literature on riverscapes has increased rapidly, indicating that the term and associated approaches are serving an important purpose in freshwater science and management.

Methodological approach for determining the Minimal Important Difference and Minimal Important Change scores for the European Organisation for Research and Treatment of Cancer Head and Neck Cancer Module (EORTC QLQ-HN43) exemplified by the Swallowing scale.

Purpose: The aim of this study was to explore what methods should be used to determine the minimal important difference (MID) and minimal important change (MIC) in scores for the European Organisation for Research and Treatment of Cancer Head and Neck Cancer Module, the EORTC QLQ-HN43.

Methods: In an international multi-centre study, patients with head and neck cancer completed the EORTC QLQ-HN43 before the onset of treatment (t1), three months after baseline (t2), and six months after baseline (t3). The methods explored for determining the MID were: (1) group comparisons based on performance status; (2) 0.

Reflex vs. volitional cough differences amongst head and neck cancer survivors characterized by time since treatment and aspiration status.

Background: The aim of this study was to investigate differences in reflexive and volitional cough airflows in advanced stage head and neck cancer survivors as it relates to aspiration status and time since treatment. The hypothesis is that those who aspirate several years after treatment completion would demonstrate reduced airflows for all cough parameters compared to those recently status post treatment completion given the known progressive deterioration associated with radiotherapy.

Methods: Demographic and airflow data during both reflexive and volitional cough tasks and aspiration status as determined during fiberoptic endoscopic evaluation of swallow function were collected from 33 Head and Neck Cancer (HNC) survivors.

Prevalence of aminoglycoside-induced hearing loss in drug-resistant tuberculosis patients: A systematic review.

Objectives estimate the prevalence of ototoxic hearing loss in drug-resistant tuberculosis (DR-TB) patients treated with aminoglycoside antibiotics via a systematic review and meta-analysis. Estimate the annual preventable cases of hearing loss in DR-TB patients and leverage findings to discuss primary, secondary and tertiary prevention. Methods studies published between 2005 and 2018 that reported prevalence of post-treatment hearing loss in DR-TB patients were included.

Elevation and spatial structure explain most surface-water isotopic variation across five Pacific Coast basins.

The stable isotope ratios of stream water can be used to trace water sources within river basins; however, drivers of variation in water isotopic spatial patterns across basins must be understood before ecologically relevant and isotopically distinct water sources can be identified and this tool efficiently applied. We measured the isotope ratios of surface-water samples collected during summer low-flow across five basins in Washington and southeast Alaska (Snoqualmie, Green, Skagit, and Wenatchee Rivers, and Cowee Creek) and compared models (isoscapes) describing the spatial variation in surface-water isotope ratios across a range of hydraulic and climatic conditions. We found strong correlations between mean watershed (MWE) elevation and surface-water isotopic ratios on the windward west side of the Cascades and in Alaska, explaining 48-90% of variation in δO values.

Antibody-Mediated Delivery of Chimeric BRD4 Degraders. Part 2: Improvement of In Vitro Antiproliferation Activity and In Vivo Antitumor Efficacy.

Heterobifunctional compounds that direct the ubiquitination of intracellular proteins in a targeted manner via co-opted ubiquitin ligases have enormous potential to transform the field of medicinal chemistry. These chimeric molecules, often termed proteolysis-targeting chimeras (PROTACs) in the chemical literature, enable the controlled degradation of specific proteins via their direction to the cellular proteasome. In this report, we describe the second phase of our research focused on exploring antibody-drug conjugates (ADCs), which incorporate BRD4-targeting chimeric degrader entities.

Evaluation of a safe medication strategy intervention for people with dementia with an unplanned admission: Results from the Safe Medication Strategy Dementia Study.

Objective: To evaluate whether a safe medication strategy compared with usual care, provided to people with dementia during an unplanned admission, reduces readmissions to hospital and re-presentation to emergency departments within three months.

Methods: A prospective, controlled pre-/post-trial conducted at two regional hospitals in New South Wales, Australia.

Results: No treatment effect was seen for time to first re-presentation or readmission within three months (P = .

Evaluating the self-determination model for older youth in foster care: Establishing efficacy and exploring moderation of response to intervention.

Limited rigorous research has been conducted to evaluate the impact of interventions designed to promote the successful transitions of young people exiting foster care. The current study builds on previous experimental evaluations of the Model (MLM) for self-determination enhancement, which demonstrated effectiveness in improving educational and transition-to-adulthood outcomes for youth in foster care with disabilities, including those with mental health challenges. The model features one-on-one youth-directed coaching and near-peer mentoring to increase self-determination and goal achievement.

Longitudinal, lateral, vertical and temporal thermal heterogeneity in a large impounded river: implications for cold-water refuges.

Dam operations can affect mixing of the water column thereby influencing thermal heterogeneity spatially and temporally. This occurs by restricting or eliminating connectivity in longitudinal, lateral, vertical and temporal dimensions. We examined thermal heterogeneity across space and time and identified potential cold-water refuges for salmonids in a large impounded river in inland northwestern USA.

Evaluation of Carer Strain and Carer Coping with Medications for People with Dementia after Discharge: Results from the SMS Dementia Study.

This study reports carer strain and coping with medications for people with dementia with an unplanned admission to hospital, and it evaluates the impact of a safe medication intervention on carer coping and carer strain. This was a quasi-experimental pre/post-controlled trial that included a survey of carers about managing medications for people with dementia after discharge. For 88 carers who completed surveys, 33% were concerned about managing medications, and 40% reported difficulties with medication management, including resistive behaviours by people with dementia.