A Tiny Pocket Packs a Punch: Leveraging Pyridones for the Discovery of CNS-Penetrant Aza-indazole IRAK4 Inhibitors.

We herein report the discovery, synthesis, and evolution of a series of indazoles and azaindazoles as CNS-penetrant IRAK4 inhibitors. Described is the use of structure-based and property-based drug design strategically leveraged to guide the property profile of a key series into a favorable property space while maintaining potency and selectivity. Our rationale that led toward functionalities with potency improvements, CNS-penetration, solubility, and favorable drug-like properties is portrayed. In vivo evaluation of an advanced analogue showed significant, dose-dependent modulation of inflammatory cytokines in a mouse model. In pursuit of incorporating a highly engineered bridged ether that was crucial to metabolic stability in this series, significant synthetic challenges were overcome to enable the preparation of the analogues.

Discovery of BIO-8169─A Highly Potent, Selective, and Brain-Penetrant IRAK4 Inhibitor for the Treatment of Neuroinflammation.

Interleukin receptor associated kinase 4 (IRAK4) plays an important role in innate immune signaling through Toll-like and interleukin-1 receptors and represents an attractive target for the treatment of inflammatory diseases and cancer. We previously reported the development of a potent, selective, and brain-penetrant imidazopyrimidine series of IRAK4 inhibitors. However, lead molecule BIO-7488 (1) suffered from low solubility which led to variable PK, compound accumulation, and poor in vivo tolerability. Herein, we describe the discovery of a series of pyridone analogs with improved solubility which are highly potent, selective and demonstrate desirable PK profiles including good oral bioavailability and excellent brain penetration. BIO-8169 (2) reduced the in vivo production of pro-inflammatory cytokines, was well tolerated in safety studies in rodents and dog at margins well above the predicted efficacious exposure and showed promising results in a mouse model for multiple sclerosis.

Advancing diabetes surveillance ecosystems: a case study of India.

Professional society and expert guidelines recommend the achievement of glycaemic, blood pressure, and cholesterol targets to prevent the microvascular and macrovascular complications of diabetes. The WHO Diabetes Compact recommends that countries meet and monitor these targets for diabetes management. Surveillance-ie, continuous, systematic measurement, analysis, and interpretation of data-is a crucial component of public health. In this Personal View, we use the case of India as an illustration of the challenges and future directions needed for a diabetes surveillance system that documents national progress and persistent gaps. To address the growing burdens of diabetes and cardiometabolic diseases, the Government of India has launched programmes such as the National Programme for Prevention and Control of Non-Communicable Diseases. Different surveys have provided estimates of the diabetes care continuum of awareness, treatment, and control at the national, state, and, very recently, district level. We reviewed the literature to analyse how these surveys have varied in both their data collection methods and the reported estimates of the diabetes care continuum. We propose an integrated surveillance and monitoring framework to augment decentralised decision making, leveraging the complementary strengths of different surveys and electronic health record databases, such as data obtained by the National Programme for Prevention and Control of Non-Communicable Diseases, and building on methodological advances in model-based small-area estimation and data fusion. Such a framework could aid state and district administrators in monitoring the progress of diabetes screening and management initiatives, and benchmarking against national and global standards in all countries.

The Discovery of 7-Isopropoxy-2-(1-methyl-2-oxabicyclo[2.1.1]hexan-4-yl)-N-(6-methylpyrazolo[1,5-a]pyrimidin-3-yl)imidazo[1,2-a]pyrimidine-6-carboxamide (BIO-7488), a Potent, Selective, and CNS-Penetrant IRAK4 Inhibitor for the Treatment of Ischemic Stroke.

Interleukin receptor-associated kinase 4 (IRAK4) is a key node of signaling within the innate immune system that regulates the production of inflammatory cytokines and chemokines. The presence of damage-associated molecular patterns (DAMPs) after tissue damage such as stroke or traumatic brain injury (TBI) initiates signaling through the IRAK4 pathway that can lead to a feed-forward inflammatory loop that can ultimately hinder patient recovery. Herein, we describe the first potent, selective, and CNS-penetrant IRAK4 inhibitors for the treatment of neuroinflammation. Lead compounds from the series were evaluated in CNS PK/PD models of inflammation, as well as a mouse model of ischemic stroke. The SAR optimization detailed within culminates in the discovery of BIO-7488, a highly selective and potent IRAK4 inhibitor that is CNS penetrant and has excellent ADME properties.

Migraine headache: When to consider these newer agents.

These agents are as effective as traditional acute and preventive treatments, cause fewer adverse effects, and can simplify regimens.

Impacts of census differential privacy for small-area disease mapping to monitor health inequities.

The U.S. Census Bureau will implement a modernized privacy-preserving disclosure avoidance system (DAS), which includes application of differential privacy, on publicly released 2020 census data. There are concerns that the DAS may bias small-area and demographically stratified population counts, which play a critical role in public health research, serving as denominators in estimation of disease/mortality rates. Using three DAS demonstration products, we quantify errors attributable to reliance on DAS-protected denominators in standard small-area disease mapping models for characterizing health inequities. We conduct simulation studies and real data analyses of inequities in premature mortality at the census tract level in Massachusetts and Georgia. Results show that overall patterns of inequity by racialized group and economic deprivation level are not compromised by the DAS. While early versions of DAS induce errors in mortality rate estimation that are larger for Black than non-Hispanic white populations in Massachusetts, this issue is ameliorated in newer DAS versions.

U.S. Adult Critical Care Beds Per Capita: A 2021 County-Level Cross-Sectional Study.

Per capita geographic distribution of adult critical care beds can be utilized for healthcare resources assessments. OBJECTIVES: Describe the per capita distribution of staffed adult critical care beds across the United States. DESIGN SETTING AND PARTICIPANTS: Cross-sectional epidemiologic assessment of November 2021 hospital data from the Department of Health and Human Services' Protect Public Data Hub. MAIN OUTCOMES AND MEASURES: Staffed adult critical care beds per adult population. RESULTS: The percent of hospitals reporting was high and varied by state/territory (median, 98.6% of states' hospitals reporting; interquartile range [IQR], 97.8-100%). There was a total of 4,846 adult hospitals accounting for 79,876 adult critical care beds in the United States and its territories. Crudely aggregated at the national-level, this calculated to 0.31 adult critical care beds per 1,000 adults. The median crude per capita density of adult critical care beds per 1,000 adults across U.S. counties was 0.00 per 1,000 adults (county, IQR 0.00-0.25; range, 0.00-8.65). Spatially smoothed county-level estimates were obtained using Empirical Bayes and Spatial Empirical Bayes approaches, resulting in an estimated 0.18 adult critical care beds per 1,000 adults (range from both methodological estimates, 0.00-8.20). When compared to counties in the lower quartile of adult critical care bed density, counties in the upper quartile had higher average adult population counts (mean 159,000 vs 32,000 adults per county) and a choropleth map demonstrated high densities of beds in urban centers with low density across rural areas. CONCLUSIONS AND RELEVANCE: Among U.S. counties, the density of critical care beds per capita was not uniformly distributed, with high densities concentrated in highly populated urban centers and relative scarcity in rural areas. As it is unknown what defines deficiency and surplus in terms of outcomes and costs, this descriptive report serves as an additional methodological benchmark for hypothesis-driven research in this area.

Mapping Uncharted Terrain: A Systematic Review of Complementary and Integrative Health Communication Using Observational Data in Biomedical Settings.

Complementary and integrative health (CIH) use is diverse and highly prevalent worldwide. Prior research of CIH communication in biomedical encounters address safety, efficacy, symptom management, and overall wellness. Observational methods are rarely used to study CIH communication and avoid recall bias, preserve ecological validity, and contextualize situated clinical communication. Following PRISMA guidelines, we systematically reviewed studies at the intersection of social scientific observational research and findings about CIH communication between clinicians, patients, and caregivers in biomedical settings. We identified international, peer-reviewed publications from seven databases between January 2010 and December 2020. Titles and abstracts were first screened for inclusion, then full studies were coded using explicit criteria. We used a standard checklist was modified to assess article quality. Ten of 11,793 studies examined CIH communication using observational methods for CIH communication in biomedical settings. Studies used a range of observational techniques, including participant and non-participant observation, which includes digital audio or video recordings. Results generated two broad sets of findings, one focused on methodological insights and another on CIH communication. Despite methodological and topic similarities, included studies addressed CIH communication as a process and as proximal and intermediate health outcomes. We recommend how observational studies of CIH communication can better highlight relationships between communication processes and health outcomes. Current research using observational methods offers an incomplete picture of CIH communication in biomedical settings. Future studies should standardize how observational techniques are reported to enhance consistency and comparability within and across biomedical settings to improve comparability.

Disparities in Nicotine Addictiveness and Cancer Harm Perceptions Among U.S. Adults: A Trend Analysis Using the Health Information National Trends Survey.

INTRODUCTION: Recent research has found widespread misperceptions about nicotine. This study tests perceptions among U.S. adults with respect to nicotine addictiveness and cancer harm, while distinguishing between nicotine misperceptions (ie an incorrect response) and "don't know" (DK) responses. AIMS AND METHODS: Data from three cycles of the Health Information National Trends Survey, fielded in 2015, 2017, and 2019 were merged for analysis. Weighted multinominal logistic regression models were conducted where nicotine addictiveness and cancer harm beliefs (DK, incorrect, and correct responses) were regressed on survey year and demographic variables. We also tested for interactions between survey year and demographic variables to assess if previously identified disparities had evolved during these years. RESULTS: Analyses showed lower odds of misperceptions about nicotine addictiveness, but higher odds of misperceptions about nicotine cancer harm in 2019 compared to 2015. There was no change in DK responses during these years. Disparities by sociodemographics and tobacco use status were observed, mostly for cancer harm. Survey year significantly interacted with age in the model for cancer harm, which was driven primarily by increased incorrect responses and decreased DK responses over time among the youngest age group (18-34 years). There were no significant interactions between survey year and race and ethnicity or level of educational attainment. CONCLUSIONS: Disparities in nicotine addictiveness and cancer harm perceptions reflect the uneven distribution of knowledge in the U.S. adult population. Nicotine cancer harm misperceptions are increasing and educational efforts to address this misperception are warranted. IMPLICATIONS: Future educational efforts targeting nicotine addictiveness beliefs may benefit by focusing on DK responders. The growing trend of misperceptions of nicotine's role in cancer harm may negatively impact perceptions about nicotine replacement therapy and low nicotine content cigarettes. Future efforts should focus on correcting nicotine cancer harm misperception, particularly among young adults.

IMPELLA VERSUS EXTRACORPOREAL MEMBRANE OXYGENATION IN CARDIOGENIC SHOCK: A SYSTEMATIC REVIEW AND META-ANALYSIS.

ABSTRACT: Background: Cardiogenic shock (CS) carries high mortality. The roles of specific mechanical circulatory support (MCS) systems are unclear. We compared the clinical outcomes of Impella versus extracorporal membrane oxygenation (ECMO) in patients with CS. Methods: This is a systematic review and meta-analysis that was conducted in accordance with Preferred Reporting Items for Systematic Reviews and Meta Analyses guidelines. We searched PubMed, Cochrane Central Register, Embase, Web of Science, Google Scholar, and ClinicalTrials.gov (inception through May 10, 2022) for studies comparing the outcomes of Impella versus ECMO in CS. We used random-effects models to calculate risk ratios (RRs) with 95% confidence interval (CIs). End points included in-hospital, 30-day, and 12-month all-cause mortality, successful weaning from MCS, bridge to transplant, all reported bleeding, stroke, and acute kidney injury. Results: A total of 10 studies consisting of 1,827 CS patients treated with MCS were included in the analysis. The risk of in-hospital all-cause mortality was significantly lower with Impella compared with ECMO (RR, 0.80; 95% CI, 0.65-1.00; P = 0.05), whereas there was no statistically significant difference in 30-day (RR, 0.97, 95% CI, 0.82-1.16; P = 0.77) and 12-month mortality (RR, 0.90; 95% CI, 0.74-1.11; P = 0.32). There were no significant differences between the two groups in terms of successful weaning (RR, 0.97; 95% CI, 0.81-1.15; P = 0.70) and bridging to transplant (RR, 0.88; 95% CI, 0.58-1.35; P = 0.56). There was less risk of bleeding and stroke in the Impella group compared with the ECMO group. Conclusions: In patients with CS, the use of Impella is associated with lower rates of in-hospital mortality, bleeding, and stroke than ECMO. Future randomized studies with adequate sample sizes are needed to confirm these findings.

Eight weeks of lentil consumption attenuates insulin resistance progression without increased gastrointestinal symptom severity: A randomized clinical trial.

Lentils lower acute glycemic responses and promote satiety, benefits that may aid in chronic disease prevention. However, perceived gastrointestinal (GI) effects may deter inclusion of dietary pulses in the diet. We hypothesized that 8 weeks of lentil-based vs meat-based meals would improve glycemic control and improve satiety in metabolically at-risk, nondiabetic adults. Because GI symptoms are rarely reported, we also explored the temporal effects of symptom severity. Adults with an increased waist circumference (male > 40 inches, female > 35 inches) participated in an 8-week dietary intervention that included 5 prepared midday meals each week that were isocaloric but varied in cooked green lentil dosage: 0 g (CON), 300 g (MOD), or 600 g (HI). Assessments included glucose and insulin integrated area under the curve measured during a 75-g carbohydrate tolerance test, hepatic Homeostatic Model of Insulin Resistance (HOMA-IR), and peripheral insulin resistance. On 1 randomized day each week, satiety was assessed at 4:00 pm and GI symptoms at 8:00 pm. A linear model assessed changes in glycemic and GI measures by meal group. Thirty adults (mean ± SD; age, 41.6 ± 11.7 years, body mass index, 35.1 ± 6.3) completed the intervention. HOMA-IR increased in CON (+1.2 units) and decreased in a dose-dependent manner in MOD (-0.9 units, P = .03) and HI (-1.5 units, P < .01) relative to CON. Most participants (87.4%) reported no to mild GI symptoms. Of these, flatulence was mild on average with bloating, abdominal discomfort, and cramping severity 0.3, 0.5, and 0.5 units lower (P < .001). We observed a dose-dependent reduction on rising hepatic insulin resistance and low GI symptom severity with long-term lentil consumption in metabolically at-risk adults.

Complete Genome of Aeromonas encheleia Strain SOD01 Isolated from an Urban Freshwater Stream.

We isolated Aeromonas encheleia strain SOD01 from an urban freshwater stream in Providence, RI. De novo assembly of PacBio RSII data followed by polishing with Illumina MiSeq data generated a complete 4,450,115 bp genome with 61.8% GC content. PGAP annotation predicted 3,877 protein-coding genes, 127 tRNA, and 31 rRNA.

Transfer from spatial education to verbal reasoning and prediction of transfer from learning-related neural change.

Current debate surrounds the promise of neuroscience for education, including whether learning-related neural changes can predict learning transfer better than traditional performance-based learning assessments. Longstanding debate in philosophy and psychology concerns the proposition that spatial processes underlie seemingly nonspatial/verbal reasoning (mental model theory). If so, education that fosters spatial cognition might improve verbal reasoning. Here, in a quasi-experimental design in real-world STEM classrooms, a curriculum devised to foster spatial cognition yielded transfer to improved verbal reasoning. Further indicating a spatial basis for verbal transfer, students' spatial cognition gains predicted and mediated their reasoning improvement. Longitudinal fMRI detected learning-related changes in neural activity, connectivity, and representational similarity in spatial cognition-implicated regions. Neural changes predicted and mediated learning transfer. Ensemble modeling demonstrated better prediction of transfer from neural change than from traditional measures (tests and grades). Results support in-school "spatial education" and suggest that neural change can inform future development of transferable curricula.

Synthesis of N-Substituted 3-Amino-2-pyridones.

Pyridones are versatile building blocks in organic synthesis and a privileged motif in drug discovery. However, N-substituted 2-pyridones bearing an α-tertiary carbon, cyclopropyl, or heterocycle off of the pyridone nitrogen atom remain challenging to prepare. Herein, we describe the efficient synthesis of a large variety of N-substituted 2-pyridones from ethyl nitroacetate and readily available primary amine building blocks, which can be utilized on a large scale and in parallel medicinal chemistry applications.

Management of hospitalized patients with mild to moderate diabetic ketoacidosis using a continuous insulin infusion protocol on a medical surgical ward and observation level of care: A retrospective cohort study.

Although the practice of using rapid-acting subcutaneous insulin for the management of mild-to-moderate diabetic ketoacidosis is becoming increasingly popular, the continuous insulin infusion remains widely utilized, and its real-world applicability and safety on a medical surgical unit (Med Surg) and observation level of care are unclear. We assessed whether a continuous insulin infusion protocol for mild-to-moderate diabetic ketoacidosis on Med Surg/observation level of care over a 6.5-year period was associated with adverse outcomes. A retrospective cohort study of adults hospitalized with mild-to-moderate diabetic ketoacidosis was conducted at 2 community hospitals in Northern California, USA, from January 2014 to May 2020. Demographic and clinical variables were collected using an electronic health record. Admission to Med Surg/observation was compared to intensive care unit admission for the outcomes of 30-day readmission, presence of hypoglycemia, rate of hypoglycemic episodes, in-hospital and 30-day mortality, and length of stay using bivariate analysis. Among 227 hospital encounters (mean age 41 years, 52.9% women, 79.3% type 1 diabetes, 97.4% utilization of continuous insulin infusion), 19.4% were readmitted within 30 days, and 20.7% developed hypoglycemia. For Med Surg/observation encounters compared to the intensive care unit, there were no statistically significant differences in the risk of readmission (RR 1.48, 95% CI, 0.86-2.52), hypoglycemia (RR 1.17, 95% CI, 0.70-1.95), or increased length of stay (RR 0.71, 95% CI, 0.55-1.02); there was a lower risk of hypoglycemic events during hospitalization (RR 0.69, 95% CI, 0.54-0.96). Continuous insulin infusion utilization may be a safe option for treatment of mild-to-moderate diabetic ketoacidosis on Med Surg/observation level of care. Further investigation is needed.

Effects of physical activity interventions for caregivers of adults: A meta-analysis.

OBJECTIVES: Caregivers of adults afflicted with a variety of chronic physical and mental health conditions are at risk for poorer well-being and reduced health related to chronic stress. Physical activity (PA) interventions may alleviate aspects of this burden, as well as provide benefits to physical health. However, notable limitations exist in the previous reviews that have attempted to synthesize the evidence for the benefits of PA interventions. METHOD: A meta-analysis was conducted investigating and quantifying the impact of PA interventions on different domains of mental and physical health for caregivers of adults, including only randomized and nonrandomized control trials. RESULTS: A comprehensive search yielded 25 studies. PA interventions led to small-to-medium effects (Hedges' g = .37, 95% confidence interval [.18, .56]) on mental health, with the most notable impact on quality of life (Hedges' g = .74, 95% CI [48, 1.01]). PA interventions led to trivial effects on physical health (Hedges' g = .15, 95% CI [.01, .31]), with small but significant effects found for mobility outcomes (Hedges' g = .28, 95% CI [.10, .47]). Yoga interventions yielded large effects (g = .85, 95% CI [.52, 1.17], p < .001) compared to other forms of PA (g = .24, 95% CI [.40, .43], p = .018), primarily within the domain of mental health. CONCLUSIONS: PA interventions appear to be effective for improving caregiver health, particularly in relation to psychological health. Further high-quality research using standardized measures for outcome comparison is needed to determine the type, formats, and length of PA interventions that best serve different caregiving populations. (PsycInfo Database Record (c) 2022 APA, all rights reserved).

Effect of Experiential Communication Skills Education on Graduate Medical Education Trainees' Communication Behaviors: A Systematic Review.

PURPOSE: A better understanding of how communication skills education impacts trainees' communication skills is important for continual improvement in graduate medical education (GME). Guided by the Kirkpatrick Model, this review focused on studies that measured communication skills in either simulated or clinical settings. The aim of this systematic review was to examine the effect of experiential communication skills education on GME trainees' communication behaviors. METHOD: Five databases were searched for studies published between 2001 and 2021 using terms representing the concepts of medical trainees, communication, training, and skills and/or behaviors. Included studies had an intervention design, focused only on GME trainees as learners, used experiential methods, and had an outcome measure of communication skills behavior that was assessed by a simulated or standardized patient (SP), patient, family member, or outside observer. Studies were examined for differences in outcomes based on study design; simulated versus clinical evaluation setting; outside observer versus SP, patient, or family member evaluator; and length of training. RESULTS: Seventy-seven studies were ultimately included. Overall, 54 (70%) studies reported some positive findings (i.e., change in behavior). There were 44 (57%) single-group pre-post studies, 13 (17%) nonrandomized control studies, and 20 (26%) randomized control studies. Positive findings were frequent in single-group designs (80%) and were likely in nonrandomized (62%) and randomized (55%) control trials. Positive findings were likely in studies evaluating communication behavior in simulated (67%) and clinical (78%) settings as well as in studies with outside observer (63%) and SP, patient, and family member (64%) evaluators. CONCLUSIONS: This review demonstrates strong support that experiential communication skills education can impact GME trainees' communication behaviors. Marked heterogeneity in communication trainings and evaluation measures, even among subgroups, did not allow for meta-analysis or comparative efficacy evaluation of different studies. Future studies would benefit from homogeneity in curricular and evaluation measures.

Statistical implications of endogeneity induced by residential segregation in small-area modelling of health inequities.

Health inequities are assessed by health departments to identify social groups disproportionately burdened by disease and by academic researchers to understand how social, economic, and environmental inequities manifest as health inequities. To characterize inequities, group-specific small-area health data are often modeled using log-linear generalized linear models (GLM) or generalized linear mixed models (GLMM) with a random intercept. These approaches estimate the same marginal rate ratio comparing disease rates across groups under standard assumptions. Here we explore how residential segregation combined with social group differences in disease risk can lead to contradictory findings from the GLM and GLMM. We show that this occurs because small-area disease rate data collected under these conditions induce endogeneity in the GLMM due to correlation between the model's offset and random effect. This results in GLMM estimates that represent conditional rather than marginal associations. We refer to endogeneity arising from the offset, which to our knowledge has not been noted previously, as "offset endogeneity". We illustrate this phenomenon in simulated data and real premature mortality data, and we propose alternative modeling approaches to address it. We also introduce to a statistical audience the social epidemiologic terminology for framing health inequities, which enables responsible interpretation of results.

Discovery of Phospholipase D Inhibitors with Improved Drug-like Properties and Central Nervous System Penetrance.

Phospholipase D (PLD) is a phospholipase enzyme responsible for hydrolyzing phosphatidylcholine into the lipid signaling molecule, phosphatidic acid, and choline. From a therapeutic perspective, PLD has been implicated in human cancer progression as well as a target for neurodegenerative diseases, including Alzheimer's. Moreover, knockdown of PLD rescues the ALS phenotype in multiple Drosophila models of ALS (amyotrophic lateral sclerosis) and displays modest motor benefits in an SOD1 ALS mouse model. To further validate whether inhibiting PLD is beneficial for the treatment of ALS, a brain penetrant small molecule inhibitor with suitable PK properties to test in an ALS animal model is needed. Using a combination of ligand-based drug discovery and structure-based design, a dual PLD1/PLD2 inhibitor was discovered that is single digit nanomolar in the Calu-1 cell assay and has suitable PK properties for in vivo studies. To capture the in vivo measurement of PLD inhibition, a transphosphatidylation pharmacodynamic LC-MS assay was developed, in which a dual PLD1/PLD2 inhibitor was found to reduce PLD activity by 15-20-fold.

Couple and family therapists' experiences with Telehealth during the COVID-19 pandemic: a phenomenological analysis.

In designing this study, we aimed to obtain a rich, phenomenological understanding of the experiences of couple and family therapists who transitioned their practice to telehealth due to the COVID-19 pandemic. Twelve experienced therapists from the U.S., Spain and Australia were interviewed in depth about their experiences of this transition, particularly how they developed and maintained therapeutic alliances in a virtual context with couples and families suffering pandemic-related hardships. The qualitative analysis identified 40 themes reflecting participants' initial impressions of telehealth and their positive and negative reactions and adjustments to practicing remotely. Upon overcoming some initial wariness about providing services virtually, many participants described advantages to this way of working with families. Indeed, participants were creative in adjusting to this novel therapy modality, finding new ways to connect emotionally with their clients, to work meaningfully with children, to assess in-session dynamics, and to ensure their clients' privacy and safety. Notably, several participants commented on the relatively slower development of alliances with new cases and the challenge of repairing split alliances between family members. Many of these difficulties were described as due to having minimal access to their clients' raw emotions and the inability to use typical systemic interventions, such as moving family members around physically. Participants also reflected on being a "participant observer" to the upheaval caused by the pandemic, a distressing experience they shared with the families in their care.