Seven Practical Recommendations for Designing and Conducting Qualitative Research in Medical Education.

Qualitative research seeks to provide context, nuance, and depth of understanding in regard to systems, behaviors, and/or lived experiences. As such, it plays a key role in many areas of medical education. Composed of myriad methods and methodologies, each of which may be valuable for some areas of inquiry but less so for others, qualitative research can be challenging to design, conduct, and report. This challenge can be conceptualized as ensuring that the study design, conduct, and reporting are "fit for purpose," following directly from a well-formulated research question. In this Perspective, we share seven important and practical recommendations to enhance the design and conduct of high-quality qualitative research in medical education: 1) craft a strong research question, 2) link the study design to this question, 3) assemble a team with diverse expertise, 4) prioritize information power when selecting recruitment and sampling strategies, 5) collect data carefully, 6) rigorously analyze data, and 7) disseminate results that tell a complete story.

The Florida Geriatric Head Trauma CT Clinical Decision Rule.

BACKGROUND: Several clinical decision rules have been devised to guide head computed tomography (CT) use in patients with minor head injuries, but none have been validated in patients 65 years or older. We aimed to derive and validate a head injury clinical decision rule for older adults. METHODS: We conducted a secondary analysis of an existing dataset of consecutive emergency department (ED) patients >65 years old with blunt head trauma. The main predictive outcomes were significant intracranial injury and Need for Neurosurgical Intervention on CT. The secondary outcomes also considered in the model development and validation were All Injuries and All Intracranial Injuries. Predictor variables were identified using multiple variable logistic regression, and clinical decision rule models were developed in a split-sample derivation cohort and then tested in an independent validation cohort. RESULTS: Of 5776 patients, 233 (4.0%) had significant intracranial injury and an additional 104 (1.8%) met CT criteria for Need for Neurosurgical Intervention. The best performing model, the Florida Geriatric Head Trauma CT Clinical Decision Rule, assigns points based on several clinical variables. If the points totaled 25 or more, a CT scan is indicated. The included predictors were arrival via Emergency Medical Services (+30 points), Glasgow Coma Scale (GCS) <15 (+20 points), GCS <14 (+50 points), antiplatelet medications (+17 points), loss of consciousness (+16 points), signs of basilar skull fracture (+50 points), and headache (+20 points). Utilizing this clinical decision rule in the validation cohort, a point total ≥25 had a sensitivity and specificity of 100.0% (95% CI: 96.0-100) and 12.3% (95% CI: 10.9-13.8), respectively, for significant intracranial injury and Need for Neurosurgical Intervention. CONCLUSIONS: The Florida Geriatric Head Trauma CT Clinical Decision Rule has the potential to reduce unnecessary CT scans in older adults, without compromising safe emergency medicine practice.

An efficient and high-throughput method for the evaluation of mitochondrial dysfunction in frozen brain samples after traumatic brain injury.

Mitochondrial function analysis is a well-established method used in preclinical and clinical investigations to assess pathophysiological changes in various disease states, including traumatic brain injury (TBI). Although there are multiple approaches to assess mitochondrial function, one common method involves respirometric assays utilizing either Clark-type oxygen electrodes or fluorescent-based Seahorse analysis (Agilent). However, these functional analysis methods are typically limited to the availability of freshly isolated tissue samples due to the compromise of the electron transport chain (ETC) upon storage, caused by freeze-thaw-mediated breakdown of mitochondrial membranes. In this study, we propose and refine a method for evaluating electron flux through the ETC, encompassing complexes I, II, and IV, in frozen homogenates or mitochondrial samples within a single well of a Seahorse plate. Initially, we demonstrate the impact of TBI on freshly isolated mitochondria using the conventional oxidative phosphorylation protocol (OxPP), followed by a comparison with ETC analysis conducted on frozen tissue samples within the context of a controlled cortical impact (CCI) model of TBI. Additionally, we explore the effects of mitochondrial isolation from fresh versus snap-frozen brain tissues and their storage at -80°C, assessing its impact on electron transport chain protocol (ETCP) activity. Our findings indicate that while both sets of samples were frozen at a single time point, mitochondria from snap-frozen tissues exhibited reduced injury effects compared to preparations from fresh tissues, which were either homogenized or isolated into mitochondria and subsequently frozen for later use. Thus, we demonstrate that the preparation of homogenates or isolated mitochondria can serve as an appropriate method for storing brain samples, allowing for later analysis of mitochondrial function, following TBI using ETCP.

Study protocol of a randomized controlled trial comparing backward walking to forward walking training on balance in multiple sclerosis: The TRAIN-MS trial.

Balance impairment and accidental falls are a pervasive challenge faced by persons with multiple sclerosis (PwMS), significantly impacting their quality of life. While exercise has proven to be an effective intervention for improving mobility and functioning in PwMS, current exercise approaches predominantly emphasize forward walking (FW) and balance training, with variable improvements in balance and fall rates. Backward walking (BW) has emerged as a promising intervention modality for enhancing mobility and strength outcomes; however, significant gaps remain. Specifically, there is limited knowledge about the efficacy of BW interventions on outcomes such as static, anticipatory, and reactive balance, balance confidence, falls, and cognition. This randomized controlled trial aims to determine the feasibility, acceptability, and impact of 8-weeks of backward walking training (TRAIN-BW) as compared to forward walking training (TRAIN-FW). Ninety individuals with MS with self-reported walking dysfunction or ≥ 2 falls in the past 6 months will be randomized in blocks, stratified by sex and disease severity to either the TRAIN-BW or TRAIN-FW intervention groups. Adherence and retention rates will be used to determine feasibility and the Client Satisfaction Questionnaire will be used to assess acceptability. The primary outcomes will be static, anticipatory, and reactive balance. Secondary outcomes include walking velocity, balance confidence, concern about falling, cognition, physical activity, and fall rates measured prospectively for 6 months after post-testing. Additionally, the extent to which cognitive functioning influences response to intervention will be examined. Backward walking training may be an innovative intervention to address balance impairments and falls in persons with MS.

Deconstructing Intratumoral Heterogeneity through Multiomic and Multiscale Analysis of Serial Sections.

Tumors may contain billions of cells, including distinct malignant clones and nonmalignant cell types. Clarifying the evolutionary histories, prevalence, and defining molecular features of these cells is essential for improving clinical outcomes, since intratumoral heterogeneity provides fuel for acquired resistance to targeted therapies. Here we present a statistically motivated strategy for deconstructing intratumoral heterogeneity through multiomic and multiscale analysis of serial tumor sections (MOMA). By combining deep sampling of IDH-mutant astrocytomas with integrative analysis of single-nucleotide variants, copy-number variants, and gene expression, we reconstruct and validate the phylogenies, spatial distributions, and transcriptional profiles of distinct malignant clones. By genotyping nuclei analyzed by single-nucleus RNA-seq for truncal mutations, we further show that commonly used algorithms for identifying cancer cells from single-cell transcriptomes may be inaccurate. We also demonstrate that correlating gene expression with tumor purity in bulk samples can reveal optimal markers of malignant cells and use this approach to identify a core set of genes that are consistently expressed by astrocytoma truncal clones, including AKR1C3, whose expression is associated with poor outcomes in several types of cancer. In summary, MOMA provides a robust and flexible strategy for precisely deconstructing intratumoral heterogeneity and clarifying the core molecular properties of distinct cellular populations in solid tumors.

Treatment of moderate acute malnutrition through community health volunteers is a cost-effective intervention: Evidence from a resource-limited setting.

Treatment outcomes for acute malnutrition can be improved by integrating treatment into community case management (iCCM). However, little is known about the cost-effectiveness of this integrated nutrition intervention. The present study investigates the cost-effectiveness of treating moderate acute malnutrition (MAM) through community health volunteer (CHV) and integrating it with routine iCCM. A cost-effectiveness model compared the costs and effects of CHV sites plus health facility-based treatment (intervention) with the routine health facility-based treatment strategy alone (control). The costing assessments combined both provider and patient costs. The cost per DALY averted was the primary metric for the comparison, on which sensitivity analysis was performed. Additionally, the integrated strategy's relative value for money was evaluated using the most recent country-specific gross domestic product threshold metrics. The intervention dominated the health facility-based strategy alone on all computed cost-effectiveness outcomes. MAM treatment by CHVs plus health facilities was estimated to yield a cost per death and DALY averted of US$ 8743 and US$ 397, respectively, as opposed to US$ 13,846 and US$ 637 in the control group. The findings also showed that the intervention group spent less per child treated and recovered than the control group: US$ 214 versus US$ 270 and US$ 306 versus US$ 485, respectively. Compared with facility-based treatment, treating MAM by CHVs and health facilities was a cost-effective intervention. Additional gains could be achieved if more children with MAM are enrolled and treated.

MLIP and Its Potential Influence on Key Oncogenic Pathways.

Muscle-enriched A-type lamin-interacting protein (MLIP) is an emerging protein involved in cellular homeostasis and stress adaptation. Eukaryotic cells regulate various cellular processes, including metabolism, DNA repair, and cell cycle progression, to maintain cellular homeostasis. Disruptions in this homeostasis can lead to diseases such as cancer, characterized by uncontrolled cell growth and division. This review aims to explore for the first time the unique role MLIP may play in cancer development and progression, given its interactions with the PI3K/Akt/mTOR pathway, p53, MAPK9, and FOXO transcription factors, all critical regulators of cellular homeostasis and tumor suppression. We discuss the current understanding of MLIP's involvement in pro-survival pathways and its potential implications in cancer cells' metabolic remodeling and dysregulated homeostasis. Additionally, we examine the potential of MLIP as a novel therapeutic target for cancer treatment. This review aims to shed light on MLIP's potential impact on cancer biology and contribute to developing innovative therapeutic strategies.

Body composition as a determinant of the therapeutic index with androgen signaling inhibition.

BACKGROUND: Androgen signaling is central to prostate cancer and men's health. Prior data indicates that increasing body fat is unfavorable in the localized setting yet associated with favorable outcomes in men with metastatic disease. Understanding the biological links between adiposity and prostate cancer may optimize the therapeutic index with ASI. We hypothesized that host adiposity and androgen synthesis are linked to the efficacy and toxicity of ASI for men with metastatic castration-resistant prostate cancer (mCRPC). METHODS: A post-hoc analysis was done of NCT02703623 where men with mCRPC (n = 186) were treated for 8 weeks with abiraterone acetate, prednisone, and apalutamide (AAPA), and a satisfactory response was defined as a PSA decline >50%. Body composition was measured on baseline CT scans. Germline DNA WES was performed with a focus on variants in steroidogenic genes. Adipokine levels were measured in pre-treatment plasma. RESULTS: Germline polymorphisms in 3 genes involved in androgen synthesis (AKR1C3 rs12529, CYP17A1 rs6162, SRD5A2 rs523349) were associated with differences in body composition at baseline on ADT alone (prior to receipt of AAPA). Elevated subcutaneous adipose tissue index (SATi, p = 0.02), visceral adipose tissue index (VATi, p = 0.03), and BMI (p = 0.04) were associated with satisfactory response to AAPA. Leptin had positive correlation with VATi (r = 0.47) and SATi (r = 0.48). CONCLUSION: Inherited polymorphisms in androgen synthesis correlated with differences in body composition after exposure to ADT and warrant further investigation as candidate markers for body composition toxicity. Elevated subcutaneous and visceral adiposity were associated with improved response to ASI.

Globospiramine Exhibits Inhibitory and Fungicidal Effects against Candida albicans via Apoptotic Mechanisms.

Candidiasis is considered an emerging public health concern because of the occurrence of drug-resistant Candida strains and the lack of an available structurally diverse antifungal drug armamentarium. The indole alkaloid globospiramine from the anticandidal Philippine medicinal plant Voacanga globosa exhibits a variety of biological activities; however, its antifungal properties remain to be explored. In this study, we report the in vitro anticandidal activities of globospiramine against two clinically relevant Candida species (C. albicans and C. tropicalis) and the exploration of its possible target proteins using in silico methods. Thus, the colony-forming unit (CFU) viability assay revealed time- and concentration-dependent anticandidal effects of the alkaloid along with a decrease in the number of viable CFUs by almost 50% at 60 min after treatment. The results of the MIC and MFC assays indicated inhibitory and fungicidal effects of globospiramine against C. albicans (MIC = 8 µg/mL; MFC = 8 µg/mL) and potential fungistatic effects against C. tropicalis at lower concentrations (MIC = 4 µg/mL; MFC > 64 µg/mL). The FAM-FLICA poly-caspase assay showed metacaspase activation in C. albicans cells at concentrations of 16 and 8 µg/mL, which agreed well with the MIC and MFC values. Molecular docking and molecular dynamics simulation experiments suggested globospiramine to bind strongly with 1,3-ß-glucan synthase and Als3 adhesin-enzymes indirectly involved in apoptosis-driven candidal inhibition.

Decentralized clinical trials for medications to reduce the risk of dementia: Consensus report and guidance.

INTRODUCTION: Recent growth in the functionality and use of technology has prompted an increased interest in the potential for remote or decentralized clinical trials in dementia. There are many potential benefits associated with decentralized medication trials, but we currently lack specific recommendations for their delivery in the dementia field. METHODS: A modified Delphi method engaged an expert panel to develop recommendations for the conduct of decentralized medication trials in dementia prevention. A working group of researchers and clinicians with expertise in dementia trials further refined the recommendations. RESULTS: Overall, the recommendations support the delivery of decentralized trials in dementia prevention provided adequate safety checks and balances are included. A total of 40 recommendations are presented, spanning aspects of decentralized clinical trials, including safety, dispensing, outcome assessment, and data collection. DISCUSSION: These recommendations provide an accessible, pragmatic guide for the design and conduct of remote medication trials for dementia prevention. HIGHLIGHTS: Clinical trials of medication have begun adopting decentralized approaches. Researchers in the field lack guidance on what would be appropriate circumstances and frameworks for what would be appropriate circumstances and frameworks for the use of decentralized trial methods in dementia prevention. The present report provides consensus-based expert recommendations for decentralized clinical trials for dementia prevention.

Effects of burning and photochemical degradation of Macondo surrogate oil on its composition and toxicity.

Petroleum products in the environment can produce significant toxicity through photochemically driven processes. Burning surface oil and photochemical degradation were two mechanisms for oil removal after the Deepwater Horizon (DWH) oil spill in the Gulf of Mexico. After burning, residual oil remains in the environment and may undergo further weathering, a poorly understood fate. Although photochemistry was a major degradation pathway of the DWH oil, its effect on burned oil residue in the environment is under studied. Here, we ignited Macondo surrogate crude oil and allowed it to burn to exhaustion. Water-accommodated fractions (WAFs) of the burn residue were created in full sunlight to determine the effects of photochemical weathering on the burned oil residue. Our findings show that increased dissolved organic carbon concentrations (DOC) for the light unburned and light burned after sunlight exposure positively correlated to decreased microbial growth and production inhibition (i.e. more toxic) when compared to the dark controls. Optical and molecular analytical techniques were used to identify the classes of compounds contributing to the toxicity in the dark and light burned and dark and light unburned WAFs. After light exposure, the optical composition between the light unburned and light burned differed significantly (p < 0.05), revealing key fluorescence signatures commonly identified as crude oil degradation products. Fourier transform ion cyclotron resonance mass spectrometry (FT-ICR MS) analysis showed more condensed aromatic, reduced oxygenated compounds present in the light burned than in the light unburned. FT-ICR MS also showed an increase in the percent relative abundance of carboxyl-rich alicyclic molecules (CRAM) like compounds in the light burned compared to light unburned. The increase in CRAM suggests that the composition of the light burned is more photorefractory, i.e., reduced, explaining the residual toxicity observed in microbial activity. Overall, these data indicate burning removes some but not all toxic compounds, leaving behind compounds which retain considerable toxicity. This study shows that burn oil residues are photolabile breaking down further into complex reduced compounds.

Malingering in Adolescent Psychiatry: A Case Report of Fabricated Symptoms to Avoid Legal Consequences.

Malingering is characterized by the deliberate fabrication and/or exaggeration of symptoms for secondary gain, posing a diagnostic challenge in healthcare settings. In this report, we present a 15-year-old male with a history of psychiatric disorders who attempted suicide to avoid legal sentencing, subsequently developing a stutter following an altercation with another patient. Despite initial concern for a concussion, further evaluation revealed malingering as the underlying motive. This case highlights the importance of identifying malingering in adolescents, which calls for a careful approach and thorough assessment for it to be distinguished from an authentic illness. Early identification of malingering optimizes resource allocation and ensures appropriate care for patients who have genuine medical needs.

Functional lower extremity strength influences stepping strategy in community-dwelling older adults during single and dual-task walking.

As age increases, a decline in lower extremity strength leads to reduced mobility and increased fall risks. This decline outpaces the age-related reduction in muscle mass, resulting in mobility limitations. Older adults with varying degrees of mobility-disability use different stepping strategies. However, the link between functional lower extremity strength and stepping strategy is unknown. Therefore, understanding how age-related reductions in functional lower extremity strength influence stepping strategy is vital to unraveling mobility limitations. Twenty participants (17F, 72 ± 6 years) were recruited and tested at a local community event. Participants were outfitted with inertial measurement units (IMU) and walked across a pressurized walkway under single and dual motor task conditions (walking with and without carrying a tray with water) at their usual and fast speeds. Participants were dichotomized into normal (11) or low functional strength groups (9) based on age-specific normative cutoffs using the instrumented 5-repetition Sit-to-Stand test duration. Our study reveals that older adults with normal strength prefer adjusting their step time during walking tasks, while those with reduced strength do not exhibit a preferred stepping strategy. This study provides valuable insights into the influence of functional lower extremity strength on stepping strategy in community-dwelling older adults during simple and complex walking tasks. These findings could aid in diagnosing gait deviations and developing appropriate treatment or management plans for mobility disability in older adults.

Polypharmacology-Driven Discovery and Design of Highly Selective, Dual and Multitargeting Inhibitors of Mycobacterium tuberculosis - A Review.

The increasing demand for novel antitubercular agents has been the main 'force' of many TB research efforts due to the uncontrolled growing number of drug-resistant strains of M. tuberculosis in the clinical setting. Many strategies have been employed to address the drug-resistant issue, including a trend that is gaining attention, which is the design and discovery of Mtb inhibitors that are either dual- or multitargeting. The multiple-target design concept is not new in medicinal chemistry. With a growing number of newly discovered Mtb proteins, numerous targets are now available for developing new biochemical/cell-based assays and computer-aided drug design (CADD) protocols. To describe the achievements and overarching picture of this field in anti- infective drug discovery, we provide in this review small molecules that exhibit profound inhibitory activity against the tubercle bacilli and are identified to trace two or more Mtb targets. This review also presents emerging design methodologies for developing new anti-TB agents, particularly tailored to structure-based CADD. Dedicated on the special occasion of the 70th birthday of Prof. Dr. Ma. Alicia Aguinaldo, whose scientific efforts elevated antituberculosis drug discovery in the Philippines.

Measurement Properties of Backward Walking and Its Sensitivity and Feasibility in Predicting Falls in People With Multiple Sclerosis.

BACKGROUND: People with multiple sclerosis (MS) experience mobility impairments that elevate fall risk, increasing the need to identify clinical measures that accurately predict falls. Backward walking (BW) better differentiates fallers from nonfallers in MS. However, no studies have reported the measurement properties of the backward walking Timed 25-Foot Walk (B-T25-FW) and BW metrics, like BW velocity. Additionally, it is unknown whether BW can predict future falls in MS or its link to activity levels. This study assessed the reliability and responsiveness of B-T25-FW and BW metrics, including BW velocity. It also examined whether BW could predict falls at 3 and 6 months and its association with activity levels. METHODS: During 2 separate visits, 23 people with MS completed the forward walking Timed 25-Foot Walk (F-T25-FW) and B-T25-FW, as well as forward walking and BW assessments in which spatiotemporal measures were recorded. Test-retest reliability was determined with intraclass correlation coefficients, and minimum detectable changes were calculated. Correlation analyses explored the relationship between BW velocity, B-T25-FW, prospective falls, and activity levels. RESULTS: B-T25-FW and BW velocity exhibited excellent test-retest reliability. Large effect sizes to interpret clinically meaningful change in the B-T25-FW and BW velocity were also found. Both metrics demonstrated modest negative correlations with falls at 3 and 6 months and correlated strongly with very active minutes at 3- and 6-months post study. CONCLUSIONS: The B-T25-FW and BW velocity are effective and reliable in clinical use for evaluating functional mobility in people with MS, are sensitive enough to detect subtle changes, and may be a meaningful marker for tracking disease progression and treatment efficacy.

Immunogenicity, reactogenicity, and IgE-mediated immune responses of a mixed whole-cell and acellular pertussis vaccine schedule in Australian infants: A randomised, double-blind, noninferiority trial.

BACKGROUND: In many countries, infant vaccination with acellular pertussis (aP) vaccines has replaced use of more reactogenic whole-cell pertussis (wP) vaccines. Based on immunological and epidemiological evidence, we hypothesised that substituting the first aP dose in the routine vaccination schedule with wP vaccine might protect against IgE-mediated food allergy. We aimed to compare reactogenicity, immunogenicity, and IgE-mediated responses of a mixed wP/aP primary schedule versus the standard aP-only schedule. METHODS AND FINDINGS: OPTIMUM is a Bayesian, 2-stage, double-blind, randomised trial. In stage one, infants were assigned (1:1) to either a first dose of a pentavalent wP combination vaccine (DTwP-Hib-HepB, Pentabio PT Bio Farma, Indonesia) or a hexavalent aP vaccine (DTaP-Hib-HepB-IPV, Infanrix hexa, GlaxoSmithKline, Australia) at approximately 6 weeks old. Subsequently, all infants received the hexavalent aP vaccine at 4 and 6 months old as well as an aP vaccine at 18 months old (DTaP-IPV, Infanrix-IPV, GlaxoSmithKline, Australia). Stage two is ongoing and follows the above randomisation strategy and vaccination schedule. Ahead of ascertainment of the primary clinical outcome of allergist-confirmed IgE-mediated food allergy by 12 months old, here we present the results of secondary immunogenicity, reactogenicity, tetanus toxoid IgE-mediated immune responses, and parental acceptability endpoints. Serum IgG responses to diphtheria, tetanus, and pertussis antigens were measured using a multiplex fluorescent bead-based immunoassay; total and specific IgE were measured in plasma by means of the ImmunoCAP assay (Thermo Fisher Scientific). The immunogenicity of the mixed schedule was defined as being noninferior to that of the aP-only schedule using a noninferiority margin of 2/3 on the ratio of the geometric mean concentrations (GMR) of pertussis toxin (PT)-IgG 1 month after the 6-month aP. Solicited adverse reactions were summarised by study arm and included all children who received the first dose of either wP or aP. Parental acceptance was assessed using a 5-point Likert scale. The primary analyses were based on intention-to-treat (ITT); secondary per-protocol (PP) analyses were also performed. The trial is registered with ANZCTR (ACTRN12617000065392p). Between March 7, 2018 and January 13, 2020, 150 infants were randomised (75 per arm). PT-IgG responses of the mixed schedule were noninferior to the aP-only schedule at approximately 1 month after the 6-month aP dose [GMR = 0·98, 95% credible interval (0·77 to 1·26); probability (GMR > 2/3) > 0·99; ITT analysis]. At 7 months old, the posterior median probability of quantitation for tetanus toxoid IgE was 0·22 (95% credible interval 0·12 to 0·34) in both the mixed schedule group and in the aP-only group. Despite exclusions, the results were consistent in the PP analysis. At 6 weeks old, irritability was the most common systemic solicited reaction reported in wP (65 [88%] of 74) versus aP (59 [82%] of 72) vaccinees. At the same age, severe systemic reactions were reported among 14 (19%) of 74 infants after wP and 8 (11%) of 72 infants after aP. There were 7 SAEs among 5 participants within the first 6 months of follow-up; on blinded assessment, none were deemed to be related to the study vaccines. Parental acceptance of mixed and aP-only schedules was high (71 [97%] of 73 versus 69 [96%] of 72 would agree to have the same schedule again). CONCLUSIONS: Compared to the aP-only schedule, the mixed schedule evoked noninferior PT-IgG responses, was associated with more severe reactions, but was well accepted by parents. Tetanus toxoid IgE responses did not differ across the study groups. TRIAL REGISTRATION: Trial registered at the Australian and New Zealand Clinical 207 Trial Registry (ACTRN12617000065392p).

Translational artificial intelligence-led optimization and realization of estimated discharge with a supportive weekend interprofessional flow team (TAILORED-SWIFT).

Weekend discharges occur less frequently than discharges on weekdays, contributing to hospital congestion. Artificial intelligence algorithms have previously been derived to predict which patients are nearing discharge based upon ward round notes. In this implementation study, such an artificial intelligence algorithm was coupled with a multidisciplinary discharge facilitation team on weekend shifts. This approach was implemented in a tertiary hospital, and then compared to a historical cohort from the same time the previous year. There were 3990 patients included in the study. There was a significant increase in the proportion of inpatients who received weekend discharges in the intervention group compared to the control group (median 18%, IQR 18-20%, vs median 14%, IQR 12% to 17%, P = 0.031). There was a corresponding higher absolute number of weekend discharges during the intervention period compared to the control period (P = 0.025). The studied intervention was associated with an increase in weekend discharges and economic analyses support this approach as being cost-effective. Further studies are required to examine the generalizability of this approach to other centers.

Translational PK/PD and the first-in-human dose selection of a PD1/IL15: an engineered recombinant targeted cytokine for cancer immunotherapy.

Introduction: Interleukin 15 (IL-15) is a potential anticancer agent and numerous engineered IL-15 agonists are currently under clinical investigation. Selective targeting of IL-15 to specific lymphocytes may enhance therapeutic effects while helping to minimize toxicities. Methods: We designed and built a heterodimeric targeted cytokine (TaCk) that consists of an anti-programmed cell death 1 receptor antibody (anti-PD-1) and an engineered IL-15. This "PD1/IL15" selectively delivers IL-15 signaling to lymphocytes expressing PD-1. We then investigated the pharmacokinetic (PK) and pharmacodynamic (PD) effects of PD1/IL15 TaCk on immune cell subsets in cynomolgus monkeys after single and repeat intravenous dose administrations. We used these results to determine the first-in-human (FIH) dose and dosing frequency for early clinical trials. Results: The PD1/IL15 TaCk exhibited a nonlinear multiphasic PK profile, while the untargeted isotype control TaCk, containing an anti-respiratory syncytial virus antibody (RSV/IL15), showed linear and dose proportional PK. The PD1/IL15 TaCk also displayed a considerably prolonged PK (half-life range ∼1.0-4.1 days) compared to wild-type IL-15 (half-life ∼1.1 h), which led to an enhanced cell expansion PD response. The PD was dose-dependent, durable, and selective for PD-1+ lymphocytes. Notably, the dose- and time-dependent PK was attributed to dynamic TMDD resulting from test article-induced lymphocyte expansion upon repeat administration. The recommended first-in-human (FIH) dose of PD1/IL15 TaCk is 0.003 mg/kg, determined based on a minimum anticipated biological effect level (MABEL) approach utilizing a combination of in vitro and preclinical in vivo data. Conclusion: This work provides insight into the complex PK/PD relationship of PD1/IL15 TaCk in monkeys and informs the recommended starting dose and dosing frequency selection to support clinical evaluation of this novel targeted cytokine.

mTOR inhibition enhances synaptic and mitochondrial function in Alzheimer's disease in an APOE genotype-dependent manner.

Apolipoprotein ε4 (APOE4) carriers develop brain metabolic dysfunctions decades before the onset of Alzheimer's disease (AD). A goal of the study is to identify if rapamycin, an inhibitor for the mammalian target of rapamycin (mTOR) inhibitor, would enhance synaptic and mitochondrial function in asymptomatic mice with human APOE4 gene (E4FAD) before they showed metabolic deficits. A second goal is to determine whether there may be genetic-dependent responses to rapamycin when compared to mice with human APOE3 alleles (E3FAD), a neutral AD genetic risk factor. We fed asymptomatic E4FAD and E3FAD mice with control or rapamycin diets for 16 weeks from starting from 3 months of age. Neuronal mitochondrial oxidative metabolism and excitatory neurotransmission rates were measured using in vivo 1H-[13C] proton-observed carbon-edited magnetic resonance spectroscopy, and isolated mitochondrial bioenergetic measurements using Seahorse. We found that rapamycin enhanced neuronal mitochondrial function, glutamate-glutamine cycling, and TCA cycle rates in the asymptomatic E4FAD mice. In contrast, rapamycin enhances glycolysis, non-neuronal activities, and inhibitory neurotransmission of the E3FAD mice. These findings indicate that rapamycin might be able to mitigate the risk for AD by enhancing brain metabolic functions for cognitively intact APOE4 carriers, and the responses to rapamycin are varied by APOE genotypes. Consideration of precision medicine may be needed for future rapamycin therapeutics.