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.

The MCL1 inhibitor S63845 is tolerable and effective in diverse cancer models.

Avoidance of apoptosis is critical for the development and sustained growth of tumours. The pro-survival protein myeloid cell leukemia 1 (MCL1) is overexpressed in many cancers, but the development of small molecules targeting this protein that are amenable for clinical testing has been challenging. Here we describe S63845, a small molecule that specifically binds with high affinity to the BH3-binding groove of MCL1. Our mechanistic studies demonstrate that S63845 potently kills MCL1-dependent cancer cells, including multiple myeloma, leukaemia and lymphoma cells, by activating the BAX/BAK-dependent mitochondrial apoptotic pathway. In vivo, S63845 shows potent anti-tumour activity with an acceptable safety margin as a single agent in several cancers. Moreover, MCL1 inhibition, either alone or in combination with other anti-cancer drugs, proved effective against several solid cancer-derived cell lines. These results point towards MCL1 as a target for the treatment of a wide range of tumours.

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.

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.

Gastropericardial fistula: radiologic findings and literature review.

BACKGROUND: Gastropericardial fistula, a rare condition characterized by an abnormal communication between the stomach and the pericardium, is an emergency as sequelae such as cardiac tamponade and sepsis may lead to hemodynamic instability and death. We aimed to summarize the surgical and radiologic findings of the reported cases published to date, describe their pertinent surgical history, and present an algorithm for diagnosis. METHODS: The Pubmed database was searched using the terms: gastropericardial, pericardiogastric, pneumopericardium, pericardial, and pneumopericardium with the term "fistula" added to each term. The search was limited to January 2000-October 2015 and English language publications. RESULTS: Thirty five cases were identified. The most common etiology was prior esophageal and/or gastric surgery (80% of cases; esophagectomy = 26%/gastrointestinal reflux disease associated surgery = 23%/bariatric surgery = 11%/partial gastrectomy = 6%/other = 20%). The average duration between presentation and surgery was 7.3 ± 6.2 years (SD). Radiology typically played a crucial role in diagnosis with computed tomography most commonly demonstrated to be the most appropriate modality to demonstrate the fistula and assist in surgical planning. Contrast studies were frequently helpful to confirm the diagnosis. Chest x-ray findings including pneumopericardium and pericardial thickening were contributory but nonspecific. Esophagoduodenoscopy characterized the fistula in cases where imaging was equivocal and may provide therapeutic options. CONCLUSIONS: We present the clinical radiologic findings of the 35 cases of gastropericardial fistula reported. This is the first literature review of gastropericardial fistula to focus on the effectiveness of these various diagnostic modalities and to present an algorithm for diagnosis.

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.

"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.

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.

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.

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.

The geometric classification of rotator cuff tears: a system linking tear pattern to treatment and prognosis.

A valuable classification system allows for communication among surgeons and/or other investigators and offers information on treatment and prognosis. It provides a means for comparison of epidemiologic data and treatment outcomes. There is no current standard classification for rotator cuff tears. Authors and practicing orthopaedists use a variety of descriptions when communicating about cuff tears. Older classifications do not use 3-dimensional information derived from the present use of arthroscopy and magnetic resonance imaging. The new geometric classification offers guidance on treatment and prognosis. Type 1, crescent-shaped tears are repaired end to bone and have a good to excellent prognosis. Type 2, longitudinal (L- or U-shaped) tears are repaired side to side with margin convergence and have a good to excellent prognosis. Type 3, massive contracted tears have coronal and sagittal dimensions greater than 2 x 2 cm on preoperative magnetic resonance imaging; are repaired with interval slides or partial repair; and have a fair to good prognosis. Type 4, rotator cuff arthropathy tears have end-stage degenerative changes of the glenohumeral joint and have articulation of the humeral head with the undersurface of the acromion; are irreparable; and require arthroplasty if surgery is considered. This classification describes complete tears of the superior and posterior rotator cuff, supraspinatus, infraspinatus, and teres minor. Additional notation can be made regarding the presence of related pathology including tears of the subscapularis, biceps, or labrum; instability or arthritic change of the glenohumeral or acromioclavicular joints; or fatty degeneration of the cuff.

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.

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.

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.