"Does Religious Service Attendance Modify the Relationship between Everyday Discrimination and Risk of Obesity? Results from the Study on Stress, Spirituality and Health".

This study examined the association of everyday discrimination with risk of obesity and the potential modifying effect of religious service attendance. Participants included Black, South Asian, and white women in three cohort studies that belong to the Study on Stress, Spirituality and Health. Logistic regression models estimated odds of obesity classification (BMI ≥ 30) relative to experiences of everyday discrimination. In initial pooled analyses, high levels of discrimination were related to increased odds of obesity. Race-specific analyses revealed marginal associations for white and South Asian women. Among Black women, high levels of discrimination and religious service attendance were both associated with higher odds of obesity. However, among women who attended religious services frequently, higher levels of everyday discrimination were associated with slightly lower odds of obesity. These findings underline the complex association between obesity and religion/spirituality, suggesting that higher levels of discrimination may uniquely activate religious resources or coping strategies. Findings highlight the need for additional studies to examine the impact of everyday discrimination on risk of obesity across racial/ethnic communities and how religious practices or coping strategies might affect these dynamics.

Verification of Composite Beam Theory with Finite Element Model for Pretensioned Concrete Members with Prestressing FRP Tendons.

Composite beam theory was previously developed to establish an analytical solution for determining the transfer length of prestressed fiber-reinforced polymers (FRP) tendons in pretensioned concrete members. In the present study, a novel finite element (FE) modeling approach is proposed to provide further verification of the developed analytical method. The present FE model takes into account the friction coefficients obtained from pull-out tests on the FRP tendons and prestressed concrete members. Convergence analysis of two numerical simulations with different mesh densities is carried out as well. The results demonstrated that the transfer length predicted by the fine FE model with a friction coefficient of α = 0.3 for high pretension is in good agreement with the measured values and the analytical solutions. The consistency between the analytical solution and FE simulation not only further proves the reliability of composite beam theory but also demonstrates the importance of the bond-slip relationship in predicting the transfer length of pretensioned concrete members prestressed with FRP tendons.

Advanced Ultrasonic Inspection of Thick-Section Composite Structures for In-Field Asset Maintenance.

An investigation into the inspection capabilities of in-field advanced ultrasound detection for use on ultra-thick (20 to 100 mm) glass fibre-reinforced polyester composites is presented. Plates were manufactured using custom moulding techniques, such that delamination flaws were created at calibrated depths. The full matrix capture technique with an on-board total focussing method was used to detect flaws scanned by a 0.5 MHz linear array probe. Flaw through-thickness dimensions were altered to assess the threshold for crack face separation at which delaminations could be identified. Furthermore, part thickness and in-plane flaw dimensions were varied to identify the inspection capability limitations of advanced ultrasonics for thick composites. The results presented in this study demonstrate an inverse relationship between the ability to find delaminations and plate thicknesses, with inspections successful at depths up to 74 mm. When the delamination thickness exhibited surface-to-surface contact, the inspection capability was reduced to 35 mm. There was an exponential decay relationship between the accuracy of the flaw depth measurement and plate thickness, likely due to the necessity of low probe frequencies. The effective inspection depth was determined to be in the range of 1 to 20 times the wavelength. It is speculated that the accuracy of measurements could be improved using probes with novel coupling solutions, and detectors with optimised signal processing/filtration algorithms.

Leigh syndrome mimicking neuromyelitis optica spectrum disorder (NMOSD).

We report two children with molecularly confirmed mitochondrial disease mimicking Neuromyelitis Optica Spectrum Disorder (NMOSD). The first patient presented at the age of 15 months with acute deterioration following a pyrexial illness with clinical features localising to the brainstem and spinal cord. The second patient presented at 5 years with acute bilateral visual loss. In both cases, MOG and AQP4 antibodies were negative. Both patients died within a year of symptoms onset from respiratory failure. Arriving at an early genetic diagnosis is important for redirection of care and avoiding potentially harmful immunosuppressant therapies.

Fragment Merging Using a Graph Database Samples Different Catalogue Space than Similarity Search.

Fragment merging is a promising approach to progressing fragments directly to on-scale potency: each designed compound incorporates the structural motifs of overlapping fragments in a way that ensures compounds recapitulate multiple high-quality interactions. Searching commercial catalogues provides one useful way to quickly and cheaply identify such merges and circumvents the challenge of synthetic accessibility, provided they can be readily identified. Here, we demonstrate that the Fragment Network, a graph database that provides a novel way to explore the chemical space surrounding fragment hits, is well-suited to this challenge. We use an iteration of the database containing >120 million catalogue compounds to find fragment merges for four crystallographic screening campaigns and contrast the results with a traditional fingerprint-based similarity search. The two approaches identify complementary sets of merges that recapitulate the observed fragment-protein interactions but lie in different regions of chemical space. We further show our methodology is an effective route to achieving on-scale potency by retrospective analyses for two different targets; in analyses of public COVID Moonshot and Mycobacterium tuberculosis EthR inhibitors, potential inhibitors with micromolar IC50 values were identified. This work demonstrates the use of the Fragment Network to increase the yield of fragment merges beyond that of a classical catalogue search.

COVID-19-related changes in outpatient CPAP setup pathways for OSA are linked with decreased 30-day CPAP usage.

The COVID-19 pandemic changed continuous positive airway pressure (CPAP) setup pathways. We evaluated patients commenced on CPAP in 2019 (prepandemic) and 2020 (post-first UK wave). Face-to-face (F2F) setup numbers, with CPAP turned on, decreased from 613 patients (98.9%) in 2019, to 6 (1.1%) in 2020. In 2020, setups were F2F without CPAP turned on (403 (71.1%)), or remote (158 (27.9%)). Prepandemic median CPAP usage at first follow-up was 5.4 (2.7-6.9) hours/night and fell by 0.9 hours/night (95% CI 0.5 to 1.2, p<0.0001) in 2020. We found clinically relevant reductions in CPAP usage with pathway changes post-COVID-19.

Magnetic Resonance Imaging Findings of the Asymptomatic Shoulder May Impact Performance, Not Future Injury List Placement in Major League Baseball Pitchers.

Purpose: To evaluate preseason shoulder magnetic resonance images (MRIs) obtained from pitchers entering either major or minor league baseball (MLB) and correlate findings with subsequent injury, operative repair, and placement on the injured list (IL). Methods: Preseason-MRI of the throwing shoulders of professional-level baseball pitchers, taken during routine evaluations at a single organization (2004-2017) were retrospectively reviewed. Publicly available databases were queried to exclude pitchers with known injuries prior to pre-signing imaging. Three blinded reviewers reviewed all MRI scans independently to evaluate for the presence of abnormalities in the rotator cuff (RTC), labrum, capsule, long-head of the biceps tendon (LHBT), and humeral head. Binary imaging findings were correlated to future placement on the IL for subsequent shoulder complaints. Bivariate statistics using Student's t-tests and Fisher exact tests (both α = .05) were used in this study. Results: A total of 38 asymptomatic pitchers with shoulder MRIs were included. Pitchers had a mean (±SD) age of 28.2 ± 4.9 and had pitched an average of 119.6 ± 143.8 career games. Pitchers with partial articular-sided RTC tears (P = .04) or intra-articular BT hyperintensity (P = .04) on preseason MRI demonstrated an association with the need for future surgery. Pitchers with evidence of labral heterogeneity demonstrated greater total career pitch counts (10,034.1 vs 2,465.3; P = .04). Evidence of a posterior-superior humeral cyst was associated with decreased strikeouts per 9 innings (6.1 vs 8.0; P = .039) and total strikeout percentage (16.1% vs 23.2%; P = .04). Conclusion: Although there was a significant difference in the percent of various radiographic findings between the injured and healthy cohort, no MRI findings were predictive of future IL placement or duration of placement. The presence of a posterior superior humeral cyst was associated with decreased strikeout rates at 2 and 3 years, the presence of a labral tear was associated with decreased earned run average (ERA) at 3 years and decreased career strikeout percentages, and increased capsular signal was associated with decreased 5-year ERA. Level of Evidence: Level IV, retrospective study.

Experimental Study on the Interlaminar Fracture Properties of Carbon Fibre Reinforced Polymer Composites with a Single Embedded Toughened Film.

In this study, two types of single polymer films have been inserted in a composite laminate to examine their toughening effects on mechanical properties. The first is a thermoplastic polyurethane (PU) film, and the second is an adhesive epoxy film featuring a polyester net. The laminates were manufactured either using a co-curing (CC) process or a secondary bonding (SB) process used for the epoxy film. Mode I and mode II interlaminar fracture toughness were measured for laminates manufactured by both processes and compared with the corresponding reference laminate toughness. A significant increase in both mode I and mode II toughness resulted when introducing a single PU film, approximately 290% and 50%, respectively. Similarly, the epoxy film improved the interlaminar fracture properties; the CC process produced an increase of 175% for mode II toughness, while the SB adhesive film showed an increase of 75% for mode II toughness.

The Effect of Core Replacement on S64315, a Selective MCL-1 Inhibitor, and Its Analogues.

Following the identification of thieno[2,3-d]pyrimidine-based selective and potent inhibitors of MCL-1, we explored the effect of core swapping at different levels of advancement. During hit-to-lead optimization, X-ray-guided S-N replacement in the core provided a new vector, whose exploration led to the opening of the so-called deep-S2 pocket of MCL-1. Unfortunately, the occupation of this region led to a plateau in affinity and had to be abandoned. As the project approached selection of a clinical candidate, a series of core swap analogues were also prepared. The affinity and cellular activity of these compounds showed a significant dependence on the core structure. In certain cases, we also observed an increased and accelerated epimerization of the atropoisomers. The most potent core replacement analogues showed considerable in vivo PD response. One compound was progressed into efficacy studies and inhibited tumor growth.

SARS-CoV-2 Tests: Bridging the Gap between Laboratory Sensors and Clinical Applications.

This review covers emerging biosensors for SARS-CoV-2 detection together with a review of the biochemical and clinical assays that are in use in hospitals and clinical laboratories. We discuss the gap in bridging the current practice of testing laboratories with nucleic acid amplification methods, and the robustness of assays the laboratories seek, and what emerging SARS-CoV-2 sensors have currently addressed in the literature. Together with the established nucleic acid and biochemical tests, we review emerging technology and antibody tests to determine the effectiveness of vaccines on individuals.

Parents, Peers, and Trajectories of Cigarette Smoking: A Group-Based Approach.

This study examines the independent, relative, and additive associations between both parent and peer role models and longitudinal patterns of smoking across adolescence and early adulthood. An analysis of data from the National Longitudinal Study of Adolescent to Adult Health (N=10,166) reveals at least four distinct trajectories of smoking across ages 13-35: (1) non-smokers; (2) late peak (almost 10 cigarettes per day around age 30); (3) an early peak group that reached roughly 10 cigarettes per day around age 20 and declined; and (4) a high group that increased during adolescence and early adulthood and then remained high. Parent and peer smoking behaviors were associated with trajectory group membership net of controls for sociodemographic characteristics, parental SES, parent-child relations, and the availability of cigarettes in the family home. Parents and peers appear to have at least some independent associations net of each other, but their combined effects are powerful.

Religion and Spirituality among American Indian, South Asian, Black, Hispanic/Latina, and White Women in the Study on Stress, Spirituality, and Health.

Social scientists have increasingly recognized the lack of diversity in survey research on American religion, resulting in a dearth of data on religion and spirituality (R/S) in understudied racial and ethnic groups. At the same time, epidemiological studies have increasingly diversified their racial and ethnic representation, but have collected few R/S measures to date. With a particular focus on American Indian and South Asian women (in addition to Blacks, Hispanic/Latinas, and white women), this study introduces a new effort among religion and epidemiology researchers, the Study on Stress, Spirituality, and Health (SSSH). This multi-cohort study provides some of the first estimates of R/S beliefs and practices among American Indians and U.S. South Asians, and offers new insight into salient beliefs and practices of diverse racial/ethnic and religious communities.

Discovery of S64315, a Potent and Selective Mcl-1 Inhibitor.

Myeloid cell leukemia 1 (Mcl-1) has emerged as an attractive target for cancer therapy. It is an antiapoptotic member of the Bcl-2 family of proteins, whose upregulation in human cancers is associated with high tumor grade, poor survival, and resistance to chemotherapy. Here we report the discovery of our clinical candidate S64315, a selective small molecule inhibitor of Mcl-1. Starting from a fragment derived lead compound, we have conducted structure guided optimization that has led to a significant (3 log) improvement of target affinity as well as cellular potency. The presence of hindered rotation along a biaryl axis has conferred high selectivity to the compounds against other members of the Bcl-2 family. During optimization, we have also established predictive PD markers of Mcl-1 inhibition and achieved both efficient in vitro cell killing and tumor regression in Mcl-1 dependent cancer models. The preclinical candidate has drug-like properties that have enabled its development and entry into clinical trials.

Coding Basics and Guidelines for Musculoskeletal Office Evaluation and Management.

¼ In documenting a patient encounter, the orthopaedic evaluation consists of 3 key components: "History," "Physical Examination," and "Medical Decision-Making." ¼ The level of service coded must be supported by the complexity of the problem, the care provided, and the documentation of the encounter. ¼ Determining whether the patient is new or established is the first step in the evaluation and management (E/M) process and relies on same-practice/same-specialty rules. ¼ Careful attention must be paid to documentation and coding to allow for appropriate care of the patient and efficient use of the orthopaedist's time. The available step-by-step guidelines include all necessary criteria to accomplish this. ¼ Continue to monitor for the U.S. Centers for Medicare & Medicaid Services (CMS) changes to stay up-to-date on changes in the guidelines.

Exploring IDP-Ligand Interactions: tau K18 as A Test Case.

Over the past decade intrinsically disordered proteins (IDPs) have emerged as a biologically important class of proteins, many of which are of therapeutic relevance. Here, we investigated the interactions between a model IDP system, tau K18, and nine literature compounds that have been reported as having an effect on tau in order to identify a robust IDP-ligand system for the optimization of a range of biophysical methods. We used NMR, surface plasmon resonance (SPR) and microscale thermophoresis (MST) methods to investigate the binding of these compounds to tau K18; only one showed unambiguous interaction with tau K18. Several near neighbors of this compound were synthesized and their interactions with tau K18 characterized using additional NMR methods, including 1D ligand-observed NMR, diffusion-ordered spectroscopy (DOSY) and 19F NMR. This study demonstrates that it is possible to detect and characterize IDP-ligand interactions using biophysical methods. However, care must be taken to account for possible artefacts, particularly the impact of compound solubility and where the protein has to be immobilized.

Establishing Drug Discovery and Identification of Hit Series for the Anti-apoptotic Proteins, Bcl-2 and Mcl-1.

We describe our work to establish structure- and fragment-based drug discovery to identify small molecules that inhibit the anti-apoptotic activity of the proteins Mcl-1 and Bcl-2. This identified hit series of compounds, some of which were subsequently optimized to clinical candidates in trials for treating various cancers. Many protein constructs were designed to identify protein with suitable properties for different biophysical assays and structural methods. Fragment screening using ligand-observed NMR experiments identified several series of compounds for each protein. The series were assessed for their potential for subsequent optimization using 1H and 15N heteronuclear single-quantum correlation NMR, surface plasmon resonance, and isothermal titration calorimetry measurements to characterize and validate binding. Crystal structures could not be determined for the early hits, so NMR methods were developed to provide models of compound binding to guide compound optimization. For Mcl-1, a benzodioxane/benzoxazine series was optimized to a K d of 40 µM before a thienopyrimidine hit series was identified which subsequently led to the lead series from which the clinical candidate S 64315 (MIK 665) was identified. For Bcl-2, the fragment-derived series were difficult to progress, and a compound derived from a published tetrahydroquinone compound was taken forward as the hit from which the clinical candidate (S 55746) was obtained. For both the proteins, the work to establish a portfolio of assays gave confidence for identification of compounds suitable for optimization.

Structure-Guided Discovery of a Selective Mcl-1 Inhibitor with Cellular Activity.

Myeloid cell leukemia 1 (Mcl-1), an antiapoptotic member of the Bcl-2 family of proteins, whose upregulation when observed in human cancers is associated with high tumor grade, poor survival, and resistance to chemotherapy, has emerged as an attractive target for cancer therapy. Here, we report the discovery of selective small molecule inhibitors of Mcl-1 that inhibit cellular activity. Fragment screening identified thienopyrimidine amino acids as promising but nonselective hits that were optimized using nuclear magnetic resonance and X-ray-derived structural information. The introduction of hindered rotation along a biaryl axis has conferred high selectivity to the compounds, and cellular activity was brought on scale by offsetting the negative charge of the anchoring carboxylate group. The obtained compounds described here exhibit nanomolar binding affinity and mechanism-based cellular efficacy, caspase induction, and growth inhibition. These early research efforts illustrate drug discovery optimization from thienopyrimidine hits to a lead compound, the chemical series leading to the identification of our more advanced compounds S63845 and S64315.

Implementation of an ICU Recovery Clinic at a Tertiary Care Academic Center.

Post-ICU clinics may facilitate the care of survivors of critical illness, but there is a paucity of data describing post-ICU clinic implementation. We sought to describe implementation of our ICU recovery clinic, including an assessment of barriers and facilitators to clinic attendance. DESIGN: Adults admitted to the medical ICU of a large tertiary care academic hospital with shock and/or respiratory failure requiring mechanical ventilation were screened for participation in a newly formed ICU recovery clinic. Participant selection and attendance rates were tracked. Reasons for nonattendance were assessed by phone call in a subset of patients. SETTING: A newly formed ICU recovery clinic of a large tertiary care academic hospital. PATIENTS: All patients admitted to the medical ICU were screened. INTERVENTIONS: ICU recovery clinic appointments were scheduled for all eligible patients. A subset of nonattenders were called to assess reasons for nonattendance. MEASUREMENTS AND MAIN RESULTS: Over 2 years, we admitted 5,510 patients to our medical ICU. Three hundred sixty-two were screened into the recovery clinic. One-hundred sixty-six were not scheduled for clinic; major reasons included discharge to hospice/death in the hospital (n = 55) and discharge to a facility (n = 50). One-hundred ninety-six patients were scheduled for a visit and of those, 101 (52%) arrived to clinic. Reasons for nonattendance in a surveyed subset of nonattenders included patient's lack of awareness of the appointment (50%, n = 9/18), financial concerns (17%, n = 3/18), and transportation difficulty (17%, n = 3/18). CONCLUSIONS: ICU recovery clinics may address the needs of survivors of critical illness. Barriers to clinic attendance include high mortality rates, high rates of clinic appointment cancelations and nonattendance, and discharge to locations such as skilled nursing facilities or long-term acute care hospitals. Improved communication to patients about the role of the clinic may facilitate attendance and minimize canceled appointments.