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ABSTRACT: Objective: To evaluate the impact of the COVID-19 pandemic on the psychosocial functioning of individuals with cleft lip and/or palate (CL/P). Methods: Patients with CL/P ≥ 6 years old were prospectively recruited from the Cleft and Craniofacial Clinic of a tertiary children's hospital. From July-October 2021, eligible patients (or their parent/guardian) were sent a survey regarding their psychosocial functioning before and after the start of the pandemic. Main Outcome Measure: The difference between prepandemic and intrapandemic patient-reported outcome scores. Results: Thirty-six patients (20 female, age: 15.9 ± 9.8 years) responded. Most had cleft lip and palate (77.8%), responded online (69.4%), interacted remotely via both voice- and video-conferencing (62.9%), and wore masks routinely (77.1%). Similar numbers of patients responded independently (27.8%), responded with the help of a parent/guardian (36.1%), or had a parent/guardian respond on their behalf (36.1%). General social-emotional well-being (p = 0.004, rrb = 0.659) and satisfaction with facial appearance (p = 0.044, rrb = 0.610) significantly improved after the start of the pandemic. Compared to their general intrapandemic social-emotional well-being scores, patients reported higher scores while wearing a mask (rrb = 0.827) and lower scores while interacting remotely (rrb = 0.605), although all were still significantly improved compared to their prepandemic scores (p ≤ 0.010). Patients also reported significant improvement in social functioning while wearing a mask (p = 0.036, rrb = 0.519), whereas they did not when considering their general intrapandemic feelings/experiences (p = 0.269, rrb = 0.211). Conclusion: Patients with CL/P demonstrated significant improvement in overall social-emotional well-being, satisfaction with facial appearance, and social functioning after the start of the COVID-19 pandemic, particularly when wearing a mask.

Abstract Background Mild traumatic brain injury (mTBI) can result in lasting brain damage that is often too subtle to detect by qualitative visual inspection on conventional MR imaging. Although a number of FDA-cleared MR neuroimaging tools have demonstrated changes associated with mTBI, they are still under-utilized in clinical practice. Methods We investigated a group of 65 individuals with predominantly mTBI (60 mTBI, 48 due to motor-vehicle collision, mean age 47 ± 13 years, 27 men and 38 women) with MR neuroimaging performed in a median of 37 months post-injury. We evaluated abnormalities in brain volumetry including analysis of left-right asymmetry by quantitative volumetric analysis, cerebral perfusion by pseudo-continuous arterial spin labeling (PCASL), white matter microstructure by diffusion tensor imaging (DTI), and neurometabolites via magnetic resonance spectroscopy (MRS). Results All participants demonstrated atrophy in at least one lobar structure or increased lateral ventricular volume. The globus pallidi and cerebellar grey matter were most likely to demonstrate atrophy and asymmetry. Perfusion imaging revealed significant reductions of cerebral blood flow in both occipital and right frontoparietal regions. Diffusion abnormalities were relatively less common though a subset analysis of participants with higher resolution DTI demonstrated additional abnormalities. All participants showed abnormal levels on at least one brain metabolite, most commonly in choline and N-acetylaspartate. Conclusion We demonstrate the presence of coup-contrecoup perfusion injury patterns, widespread atrophy, regional brain volume asymmetry, and metabolic aberrations as sensitive markers of chronic mTBI sequelae. Our findings expand the historic focus on quantitative imaging of mTBI with DTI by highlighting the complementary importance of volumetry, arterial spin labeling perfusion and magnetic resonance spectroscopy neurometabolite analyses in the evaluation of chronic mTBI.

Six muscle-specific ground beef products along with conventional chuck ground beef were evaluated for proximate composition, objective color, descriptive flavor attributes, texture attributes, fatty acid composition, and volatile com- pound profile. Ground products were derived from beef chuck shoulder clods, chuck boneless short ribs, whole briskets, loin tenderloin tips, loin top sirloin caps, round sirloin tip knuckles, and 81:19 chuck-sourced trimmings. Each grind type was formulated to a target fat percent of 15%. Proximate analysis determined actual fat content to range from 12.0% to 19.5%. Percent fat was tested as a covariate and included in model statements when significant. Sirloin caps, brisket, and 81:19 chuck each had greater beefy/brothy ratings compared with shoulder clods and tenderloins (P < 0.05). Tenderloin grinds also had lower browned/grilled, buttery/beef fat attributes compared to all others (P < 0.05). Additionally, tenderloins had greater sour/acidic flavor compared to all others (P < 0.05). Oleic acid (C18:1 cis-9) percent was lower in tenderloin compared to all others (P < 0.05). Percent C18:1 cis-9 of 81:19 chuck was comparable with short rib and sirloin cap grinds (P > 0.05) but lower than shoulder clods, brisket, and knuckles (P < 0.05). Tenderloin grinds had the greatest percent of stearic acid (C18:0) compared to all others (P < 0.05). Tenderloin grinds also expressed the greatest content of 1-hexanol, hexanal, acetic acid, and 3-methylbutanal (P < 0.05). Methional content was greater from 81:19 chuck compared to all others (P < 0.05). Likewise, the knuckle had greater dimethyl sulfide compared to all other grinds (P < 0.05). Interestingly, short rib grinds frequently had the lowest (P < 0.05) or were comparable (P > 0.05) with other grinds low in the quantity of multiple volatile compounds. The results of this study imply that muscle source influences flavor and flavor-related compounds of ground beef. Therefore, processors and retailers may manage muscle sources and thus ground beef flavor through subprimal selection.

There is an established idea – found in science fiction, architectural studios, and scientific papers alike – of stainable buildings crafted from bio-based materials, colonized by plant and animal life, and blending seamlessly into the natural surroundings. Such buildings might one day be built, maintained and remodelled by swarms of autonomous robots, allowing them to evolve in response to the changing needs of their inhabitants. Inspired by that vision, this paper contributes to the field of swarm intelligence with a focus on robotic construction and human-swarm interaction. Along with a short literature review on robotic building, swarm intelligence and biocompatible building materials, the paper presents an open-source simulation of abstracted termite-like swarm construction. The focus is mainly on human-swarm interaction, specifically how to influence the emergent behaviour of an autonomous swarm in order to elicit a desired outcome while retaining the robustness and adaptability of a self-organized system. The simulator is used to demonstrate a set of four autonomous swarm behaviours that are representative of construction tasks.

This study examines the impact of Maine’s 2019 Medicaid expansion through the Affordable Care Act on hospitals’ uncompensated care costs. The author finds that this expansion reduced uncompensated care costs by an average of 26 percent per year, leading to a $126 million reduction in uncompensated care costs during the first two years of the COVID-19 pandemic. The most pronounced reduction in costs occurred across larger, general acute care hospitals. When comparing bad debt vs charity care, the reduction in uncompensated care costs is driven by a steep decline in reported charity care costs. This decline offsets increases in bad debt expenses in 2020 across smaller, critical access hospitals. The results highlight Medicaid expansion’s effectiveness in lowering uncompensated care costs during the first two years of the COVID-19 pandemic in Maine

Background. The HIV Organ Policy Equity Act legalizes organ procurement from donors with HIV (HIV D+). A prior survey of Organ Procurement Organizations (OPOs) estimated >2000 HIV D+ referrals/year; however, only 30–35 HIV D+/year have had organs procured. Given this gap, we sought to understand HIV D+ referrals and procurements in practice. Methods. We prospectively collected data on all OPO-reported HIV D+ referrals, including reasons for nonprocurement. We evaluated trends and compared HIV D+ characteristics by procurement status using regression, chi-squared tests, and Wilcoxon rank-sum tests. Results. From December 23, 2015 to May 31, 2021, there were 710 HIV D+ referrals from 49 OPOs, of which 171 (24%) had organs procured. HIV D+ referrals increased from 7 to 15 per month (P

Agricultural stewardship programs that incentivize practices such as winter cover cropping (WCC), grassland set-asides (GLSA), and hedgerows (HR) for intensive annual agricultural production are often implemented to improve both soil conditions and provision of wildlife habitat in coastal agricultural systems of the Fraser River Delta, British Columbia (BC). Although these programs have been shown to support numerous ecosystem services, it is unclear how they contribute to regenerative agricultural outcomes. Regenerative agricultural practices aim to increase soil carbon inputs and reduce carbon dioxide losses which in turn improves soil structure, optimizes soil water regulation, and provides climate mitigation and resiliency of agricultural systems. The objectives of this study were to quantify the effects of agricultural stewardship programs for regenerative outcomes through indicators of climate mitigation and adaptation. Twenty-six fields in the southwestern, BC were grouped by those that participated in stewardship programs between 1992 and 2016 and those that did not. In the spring of 2018, soil samples were collected; soil organic carbon (SOC) concentrations were measured, and stocks were calculated; pedo-transfer functions were used to estimate soil water regulation indicators; and differences among stewardship program and non-program fields were statistically analyzed using a linear mixed effects model. The SOC (mg kg−1) from 0 to 15 cm was greater with implementation of stewardship programs. Topsoil equivalent soil mass SOC stocks (t/ha) were 71 % and 63 % greater in HR and WCC + GLSA program fields, respectively, compared to non-program fields. Soil workability threshold was 25 % and 14 % greater in HR and WCC + GLSA program fields, respectively, compared to non-program. Our results indicate that stewardship programs that include hedgerows and grassland set-asides promote accrual of soil carbon and improved soil water regulation and show that these programs can effectively enhance regenerative outcomes and improve agroecosystem resilience in this important agricultural region.

Abstract Genomic and transcriptomic data have been generated across a wide range of prostate cancer (PCa) study cohorts. These data can be used to better characterize the molecular features associated with clinical outcomes and to test hypotheses across multiple, independent patient cohorts. In addition, derived features, such as estimates of cell composition, risk scores, and androgen receptor (AR) scores, can be used to develop novel hypotheses leveraging existing multi-omic datasets. The full potential of such data is yet to be realized as independent datasets exist in different repositories, have been processed using different pipelines, and derived and clinical features are often not provided or not standardized. Here, we present the curatedPCaData R package, a harmonized data resource representing >2900 primary tumor, >200 normal tissue, and >500 metastatic PCa samples across 19 datasets processed using standardized pipelines with updated gene annotations. We show that meta-analysis across harmonized studies has great potential for robust and clinically meaningful insights. curatedPCaData is an open and accessible community resource with code made available for reproducibility.

The SET binding protein 1 (SETBP1) gene encodes a transcription factor (TF) involved in various cellular processes. Variants in SETBP1 can result in three different diseases determined by the introduction (germline vs. somatic) and location of the variant. Germline variants cause the ultra-rare pediatric Schinzel Giedion Syndrome (SGS) and SETBP1 haploinsufficiency disorder (SETBP1-HD), characterized by severe multisystemic abnormalities with neurodegeneration or a less severe brain phenotype accompanied by hypotonia and strabismus, respectively. Somatic variants in SETBP1 are associated with hematological malignancies and cancer development in other tissues in adults. To better understand the tissue-specific mechanisms involving SETBP1, we analyzed publicly available RNA-sequencing (RNA-seq) data from the Genotype-Tissue Expression (GTEx) project. We found SETBP1 and its known target genes were widely expressed across 31 adult human tissues. K-means clustering identified three distinct expression patterns of SETBP1 targets across tissues. Functional enrichment analysis (FEA) of each cluster revealed gene sets related to transcriptional regulation, DNA binding, and mitochondrial function. TF activity analysis of SETBP1 and its target TFs revealed tissue-specific TF activity, underscoring the role of tissue context-driven regulation and suggesting its impact in SETBP1-associated disease. In addition to uncovering tissue-specific molecular signatures of SETBP1 expression and TF activity, we provide a Shiny web application to facilitate exploring TF activity across human tissues for 758 TFs. This study provides insight into the landscape of SETBP1 expression and TF activity across 31 non-diseased human tissues and reveals tissue-specific expression and activity of SETBP1 and its targets. In conjunction with the web application we constructed, our framework enables researchers to generate hypotheses related to the role tissue backgrounds play with respect to gene expression and TF activity in different disease contexts.

Purpose: The purpose of this study was to use a smartphone app to collect gait metrics in patients undergoing hip arthroscopy for femoroacetabular impingement syndrome (FAIS) and determine when gait metrics return to preoperative levels and if gait metrics correlate with postoperative hip-specific patient-reported outcomes. Methods: Patients undergoing primary hip arthroscopy for FAIS from August 2021 to December 2022 were prospectively enrolled. Patients downloaded the iPhone app, rHip, at ∼6 months postoperatively, enabling retroactive access to Apple Health data. Gait metrics included step count, step length, and walking speed. Each patient’s preoperative baseline was compared to that individual’s successive postoperative week metrics. All patients underwent a standard 4-stage rehabilitation protocol. We compared metrics from beginning to end of each phase (i.e., week 1 to 6 for phase 1) and evaluated correlations with patient outcomes. Results: Fifty patients (40 women; age: 31.9 ± 14.5 years) were included. Patients had significantly reduced step count from postoperative weeks 1 to 5 and improved upon baseline at weeks 13 and 16 to 26. Patients had significantly reduced step length from postoperative weeks 1 to 4 and improved upon baseline at weeks 16 and 20. Patients had significantly lower walking speed from postoperative weeks 1 to 6 and improved upon baseline at week 20 (P < .05). Step count significantly improved over phase 1 rehabilitation (P < .05). Step length and walking speed significantly improved over each of phases 1 to 3 (P < .05 for all). Preoperatively, weak correlations were noted between step length and Patient-Reported Outcomes Measurement Information System (PROMIS) for Physical Function (PF)/Pain, as well as walking speed and Hip Outcome Score–Activities of Daily Living (HOS-ADL)/PROMIS-Pain. At 3 months, moderate correlations were noted between step count and HOS-ADL/12-item international Hip Outcome Tool (iHOT-12), step length and HOS-ADL/PROMIS-PF, and walking speed and HOS-ADL/iHOT-12/PROMIS-PF/PROMIS-Pain. At 6 months, weak to moderate correlations were noted between all 3 gait metrics and HOS-ADL. Conclusions: A smartphone app was capable of capturing health data gait metrics. Patients undergoing hip arthroscopy for FAIS returned to baseline levels in step count, step length, and walking speed after phase 1 (6 weeks) of rehabilitation. The most consistent correlations between gait metrics and step count were seen at 3 months, although only weak to moderate. Gait metrics similarly had weak to moderate correlations with HOS-ADL at 6 months. Level of Evidence: Level IV, case series.

High-resolution subsurface marine mapping tools, including chirp and 3D seismic, enable the reconstruction of ancient landscapes that have been buried and subsequently submerged by marine transgression. However, the established methods for paleotopographic reconstruction require time consuming field and data interpretation efforts. Here we present a novel methodology using machine learning to estimate Marine Isotope Stage 2 (MIS2) paleotopography over a large (22 000 km2) area of the Northern Gulf of Mexico with meter-scale accuracy (2.7 m mean prediction error, 4.3 m 1-σ mean uncertainty). A relatively small area (3300 km2) of high-resolution (30 × 30 m) interpreted paleotopography is used as training and validation data, while modern bathymetry and MIS2 paleovalley location (binary deep/shallow paleotopography) are used as predictors. This approach merges the high-resolution of modern mapping techniques and the broad coverage of low-resolution legacy geophysical data. Machine learning-modeled paleotopography is not a substitute for precise high-resolution paleotopography reconstruction techniques, but it can be used to reasonably approximate paleotopography over large areas with greatly reduced expense and expertise.

Background & Aims: Tumor necrosis factor (TNF) superfamily member tumor necrosis factor–like protein 1A (TL1A) has been associated with the susceptibility and severity of inflammatory bowel diseases. However, the function of the tumor necrosis factor–like protein 1A and its receptor death receptor 3 (DR3) in the development of intestinal inflammation is incompletely understood. We investigated the role of DR3 expressed by intestinal epithelial cells (IECs) during intestinal homeostasis, tissue injury, and regeneration. Methods: Clinical phenotype and histologic inflammation were assessed in C57BL/6 (wild-type), Tl1a-/- and Dr3-/- mice in dextran sulfate sodium (DSS)-induced colitis. We generated mice with an IEC-specific deletion of DR3 (Dr3ΔIEC) and assessed intestinal inflammation and epithelial barrier repair. In vivo intestinal permeability was assessed by fluorescein isothiocyanate dextran uptake. Proliferation of IECs was analyzed by bromodeoxyuridine incorporation. Expression of DR3 messenger RNA was assessed by fluorescent in situ hybridization. Small intestinal organoids were used to determine ex vivo regenerative potential. Results: Dr3-/- mice developed more severe colonic inflammation than wild-type mice in DSS-induced colitis with significantly impaired IEC regeneration. Homeostatic proliferation of IECs was increased in Dr3-/- mice, but blunted during regeneration. Cellular localization and expression of the tight junction proteins Claudin-1 and zonula occludens-1 were altered, leading to increased homeostatic intestinal permeability. Dr3ΔIEC mice recapitulated the phenotype observed in Dr3-/- mice with increased intestinal permeability and IEC proliferation under homeostatic conditions and impaired tissue repair and increased bacterial translocation during DSS-induced colitis. Impaired regenerative potential and altered zonula occludens-1 localization also were observed in Dr3ΔIEC enteroids. Conclusions: Our findings establish a novel function of DR3 in IEC homeostasis and postinjury regeneration independent of its established role in innate lymphoid cells and T-helper cells.

The molecular mechanisms underlying the formation of biomolecular condensates have not been fully elucidated. Here the authors show that the LLPS propensity, dynamics, and encapsulation efficiency of designed peptide condensates can be tuned by subtle changes to the peptide composition.

Warming across the low Arctic is increasing tundra vegetation productivity and facilitating the expansion of upright shrubs. We modeled the effects of warming on habitat suitability in green alder, dwarf birch, Labrador tea, bog bilberry, and lingonberry and assessed the influence of data type (true absence or pseudo-absence) on species distribution models (SDMs). We generated SDMs using the two absence data types under current (1970–2000) and future (2061–2080) climate projections. Our results show that warming leads to range expansion of all shrubs, though responses vary in magnitude and extent, with mean increases in suitability ranging from 0.080 (Labrador tea) to 0.369 (lingonberry) with true absences. Differences in driving variables and suitability projections suggest that physiological and ecological variability between species mediate responses to warming. Between data types, we observed inconsistencies in model performance, suitability projections, and variable importance. Bog bilberry and lingonberry exhibited larger differences in suitability (0.201 and 0.288, respectively), whereas alder showed similar responses (difference of 0.01). These results are important to consider when assessing changes in habitat suitability or identifying environmental or climatic determinants of species’ distributions. We suggest further development of open data repositories, facilitating access to true absence data to support conservation and land use planning.

Long-term dynamics of the humoral response to HCV in cured individuals aren’t well understood. Here, Nishio et al. show that virus-neutralizing antibody levels decrease in potency and breadth after cure of chronic hepatitis C, while HCV-specific memory B cells persist.

Surgical repair of proximal hamstring injuries can relieve pain and restore lower extremity function in active individuals. Whereas traditional surgical techniques are performed via an open approach, more recent endoscopic proximal hamstring repair techniques have proven safe, effective, and potentially associated with fewer complications than open repair. One theorized disadvantage of existing endoscopic techniques is reduced security at the suture-tendon interface, as compared to open surgery, during which a running suture technique, such as a Krackow stitch, may be employed. In this article, we present a technique for increasing suture purchase by performing an all-endoscopic, running, locking stitch during proximal hamstring repair.

Background: Allograft anterior cruciate ligament (ACL) reconstruction, while it may have a higher failure rate in younger and more active populations, continues to serve as a viable graft option for the appropriately indicated patient. Efficient bone-patellar tendon-bone (BTB) allograft preparation is beneficial to reduce operating time and ensure optimal reconstruction with bony fixation. Indications: ACL reconstruction with BTB allograft is indicated for skeletally mature and older patients, patients who are less active and have fewer physical demands, patients who have had previously harvested autograft, circumstances where an autograft harvest is inadequate, patients with multiligament knee injuries, and patients who prefer allograft use. Technique Description: The central third of the BTB allograft is harvested, aiming for a graft diameter of 10 mm along the tendon. The tibial bone plug is first cut to a length of 25 to 30 mm and width of 10 mm with the saw at a 70° angle to the bone. The patellar bone plug is cut to a length of 25 mm and width of 10 mm with the saw at a 45° angle to the bone. The bone plugs are mobilized, and soft tissue is dissected to free the graft. The graft is trimmed until it fits through a 10-mm sizer on each side. A single hole is created with a k-wire in the patellar bone plug, and a #5 Ethibond suture is passed. On the tibial bone plug, 2 holes are made perpendicular to one another, and a #2 Fiberwire suture is passed through each of these holes. These sutures allow for facilitated graft passage and tensioning. Once the graft is affixed with interference screws, the graft is arthroscopically evaluated throughout range of motion. Results: ACL reconstruction with BTB allograft provides high success rates in appropriately selected patients. Data demonstrate more optimal mechanical properties by harvesting the central third of the allograft tendon in younger donors. Non-irradiated and less chemically processed grafts are also preferred to optimize biomechanical properties. Discussion/Conclusion: Bone-patellar tendon-bone allograft with 2 bone plugs offers a reliable alternative to other allografts or autografts. Preparing the allograft in a fashion similar to an autograft harvest may increase familiarity with techniques and facilitate surgical efficiency and graft passage. Patient Consent Disclosure Statement: The author(s) attests that consent has been obtained from any patient(s) appearing in this publication. If the individual may be identifiable, the author(s) has included a statement of release or other written form of approval from the patient(s) with this submission for publication.

The contemporary treatment of hamstring avulsions has been evolving, as more patients are being identified as having persistently symptomatic partial hamstring tears recalcitrant to nonoperative treatment. The endoscopic hamstring repair allows surgeons improved visualization of the footprint, as well as safe dissection of the sciatic nerve. The present technique article provides a step-by-step technical note to allow for safe and effective surgical treatment of partial hamstring tears.

Background: Many of the current total hip arthroplasty (THA) planning tools only consider sagittal pelvic tilt in the standing and relaxed sitting positions. Considering that the risk of postoperative dislocation is higher when bending forward or in sit-to-stand move, sagittal pelvic tilt in the flexed seated position may be more relevant for preoperative planning. We hypothesized that there was a significant difference in sagittal pelvic tilt between the relaxed sitting and flexed seated positions as measured by the sacral slope in preoperative and postoperative full-body radiographs. Methods: This was a multicenter retrospective analysis of the preoperative and postoperative simultaneous biplanar full-body radiographs of 93 primary THA patients in standing, relaxed sitting, and flexed seated positions. The sagittal pelvic tilt was measured using the sacral slope relative to the horizontal line. Results: The mean difference between the preoperative sacral slope in the relaxed sitting position and the flexed seated position was 11.3° (−13° to 43°) (P < .0001). This difference was >10° in 52 patients (56%) and >20° in 18 patients (19.4%). The mean difference between the postoperative sacral slope in a relaxed sitting position and the sacral slope in a flexed seated position was 11.3° (P < .0001). This difference was >10° in 51 patients (54.9%) and >30° in 14 patients (15.1%) postoperatively. Conclusions: There was a significant difference in sagittal pelvic tilt between the relaxed and flexed seated positions. A flexed seated view provides valuable information that might be more relevant for preoperative THA planning in order to prevent postoperative THA instability.

Abstract Background Airspace disease as seen on chest X-rays is an important point in triage for patients initially presenting to the emergency department with suspected COVID-19 infection. The purpose of this study is to evaluate a previously trained interpretable deep learning algorithm for the diagnosis and prognosis of COVID-19 pneumonia from chest X-rays obtained in the ED. Methods This retrospective study included 2456 (50% RT-PCR positive for COVID-19) adult patients who received both a chest X-ray and SARS-CoV-2 RT-PCR test from January 2020 to March of 2021 in the emergency department at a single U.S. institution. A total of 2000 patients were included as an additional training cohort and 456 patients in the randomized internal holdout testing cohort for a previously trained Siemens AI-Radiology Companion deep learning convolutional neural network algorithm. Three cardiothoracic fellowship-trained radiologists systematically evaluated each chest X-ray and generated an airspace disease area-based severity score which was compared against the same score produced by artificial intelligence. The interobserver agreement, diagnostic accuracy, and predictive capability for inpatient outcomes were assessed. Principal statistical tests used in this study include both univariate and multivariate logistic regression. Results Overall ICC was 0.820 (95% CI 0.790–0.840). The diagnostic AUC for SARS-CoV-2 RT-PCR positivity was 0.890 (95% CI 0.861–0.920) for the neural network and 0.936 (95% CI 0.918–0.960) for radiologists. Airspace opacities score by AI alone predicted ICU admission (AUC = 0.870) and mortality (0.829) in all patients. Addition of age and BMI into a multivariate log model improved mortality prediction (AUC = 0.906). Conclusion The deep learning algorithm provides an accurate and interpretable assessment of the disease burden in COVID-19 pneumonia on chest radiographs. The reported severity scores correlate with expert assessment and accurately predicts important clinical outcomes. The algorithm contributes additional prognostic information not currently incorporated into patient management.

BackgroundEffective consultation-liaison psychiatry (CLP) is proactive, collaborative, and requires providers to have proficiency with therapeutic skills beyond nosology and medication management. Motivational interviewing (MI) is an evidenced-based intervention that should be considered essential for CLP trainees to learn. Given that the demands of training and patient care are already experienced as stressful for many psychiatry trainees, the authors endeavored to create a MI training program that was integrated into trainees’ normal CLP workflow.MethodTwenty-two trainees on an inpatient CLP rotation participated in a six-week MI training program that was incorporated into their regular workflow. The program included didactic sessions with role-playing, as well as on-demand between-session coaching via an expert in MI. Trainee participation and perceptions of MI were measured via a questionnaire that was administered prior to each training session.ResultsTrainee participation in the didactic sessions was inconsistent. Questionnaire data revealed positive baseline perceptions of motivational interviewing and its usefulness in inpatient medical settings. Additionally, as trainees participated in the program, perceived knowledge of motivational interviewing as well as awareness of motivational issues among their patients increased. Finally, participation in program was not perceived as disruptive to daily workflow for the participants.DiscussionThis the first documented attempt at implementing a MI training program for CLP trainees that was integrated into their regular workflow. Preliminary data identified some encouraging trends, but also unexpected challenges. These lessons could inform how these types of training programs are implemented moving forward.

Background: Proximal hamstring ruptures meeting operative criteria may be treated through endoscopic, open, or combined techniques. Open techniques allow for facilitated tendon visualization and mobilization with ease of suture passage. Indications: Proximal hamstring repairs are indicated for complete 3 tendon avulsions; partial avulsions with 2 or more tendons involved with more than 2 cm of retraction in young, active patients; and partial avulsion injuries or chronic tears that remain refractory to conservative treatment. Technique Description: Through an incision along the gluteal crease, the tendon stump is identified and mobilized. Anchors are placed in the prepped ischium and sutures are passed through the tendon in a running fashion. The tendon is secured to its origin in a docking technique. Results: Patients undergoing hamstring repair have high satisfaction rates and patient-reported outcome scores. Competitive and elite athletes have demonstrated reliable return-to-sport rates at presurgical levels. Discussion: Open proximal hamstring repairs produce reliable results. The open technique is advantageous for its ease of tendon mobilization, direct visualization, and suture passage. Patient Consent Disclosure Statement: The author(s) attests that consent has been obtained from any patient(s) appearing in this publication. If the individual may be identifiable, the author(s) has included a statement of release or other written form of approval from the patient(s) with this submission for publication.

With an increasing amount of biological data available publicly, there is a need for a guide on how to successfully download and use this data. The 10 simple rules for using public biological data are: (1) use public data purposefully in your research; (2) evaluate data for your use case; (3) check data reuse requirements and embargoes; (4) be aware of ethics for data reuse; (5) plan for data storage and compute requirements; (6) know what you are downloading; (7) download programmatically and verify integrity; (8) properly cite data; (9) make reprocessed data and models Findable, Accessible, Interoperable, and Reusable (FAIR) and share; and (10) make pipelines and code FAIR and share. These rules are intended as a guide for researchers wanting to make use of available data and to increase data reuse and reproducibility.

There are over 6,000 different rare diseases estimated to impact 300 million people worldwide. As genetic testing becomes more common practice in the clinical setting, the number of rare disease diagnoses will continue to increase, resulting in the need for novel treatment options. Identifying treatments for these disorders is challenging due to a limited understanding of disease mechanisms, small cohort sizes, interindividual symptom variability, and little commercial incentive to develop new treatments. A promising avenue for treatment is drug repurposing, where FDA-approved drugs are repositioned as novel treatments. However, linking disease mechanisms to drug action can be extraordinarily difficult and requires a depth of knowledge across multiple fields, which is complicated by the rapid pace of biomedical knowledge discovery. To address these challenges, The Hugh Kaul Precision Medicine Institute developed an artificial intelligence tool, mediKanren, that leverages the mechanistic insight of genetic disorders to identify therapeutic options. Using knowledge graphs, mediKanren enables an efficient way to link all relevant literature and databases. This tool has allowed for a scalable process that has been used to help over 500 rare disease families. Here, we provide a description of our process, the advantages of mediKanren, and its impact on rare disease patients.

Background Few studies have examined age and sex differences in the receipt of cardiac diagnostic and interventional procedures in patients hospitalized with acute myocardial infarction and trends in these possible differences during recent years. Methods and Results Data from patients hospitalized with a first acute myocardial infarction at the major medical centers in the Worcester, Massachusetts, metropolitan area were utilized for this study. Logistic regression analysis was used to examine age (

Abstract Background We aimed to define the clinical and variant spectrum and to provide novel molecular insights into the DHX30-associated neurodevelopmental disorder. Methods Clinical and genetic data from affected individuals were collected through Facebook-based family support group, GeneMatcher, and our network of collaborators. We investigated the impact of novel missense variants with respect to ATPase and helicase activity, stress granule (SG) formation, global translation, and their effect on embryonic development in zebrafish. SG formation was additionally analyzed in CRISPR/Cas9-mediated DHX30-deficient HEK293T and zebrafish models, along with in vivo behavioral assays. Results We identified 25 previously unreported individuals, ten of whom carry novel variants, two of which are recurrent, and provide evidence of gonadal mosaicism in one family. All 19 individuals harboring heterozygous missense variants within helicase core motifs (HCMs) have global developmental delay, intellectual disability, severe speech impairment, and gait abnormalities. These variants impair the ATPase and helicase activity of DHX30, trigger SG formation, interfere with global translation, and cause developmental defects in a zebrafish model. Notably, 4 individuals harboring heterozygous variants resulting either in haploinsufficiency or truncated proteins presented with a milder clinical course, similar to an individual harboring a de novo mosaic HCM missense variant. Functionally, we established DHX30 as an ATP-dependent RNA helicase and as an evolutionary conserved factor in SG assembly. Based on the clinical course, the variant location, and type we establish two distinct clinical subtypes. DHX30 loss-of-function variants cause a milder phenotype whereas a severe phenotype is caused by HCM missense variants that, in addition to the loss of ATPase and helicase activity, lead to a detrimental gain-of-function with respect to SG formation. Behavioral characterization of dhx30-deficient zebrafish revealed altered sleep-wake activity and social interaction, partially resembling the human phenotype. Conclusions Our study highlights the usefulness of social media to define novel Mendelian disorders and exemplifies how functional analyses accompanied by clinical and genetic findings can define clinically distinct subtypes for ultra-rare disorders. Such approaches require close interdisciplinary collaboration between families/legal representatives of the affected individuals, clinicians, molecular genetics diagnostic laboratories, and research laboratories.

Abstract Few prospective studies have evaluated the relation between fat-soluble vitamins and glioma risk. Using three cohorts—UK Biobank (UKB), Nurses’ Health Study (NHS), and Health Professionals Follow-Up Study (HPFS), we investigated associations of pre-diagnostic concentrations of fat-soluble vitamins D, A, and E with incident glioma. In 346,785 participants (444 cases) in UKB, associations with vitamin D (25-hydroxyvitamin D [25(OH)D]) were evaluated by Cox proportional hazards regression. In NHS (52 cases, 104 controls) and HPFS (32 cases, 64 controls), associations with 25(OH)D, vitamin A (retinol), and vitamin E (α- and γ-tocopherol) were assessed using conditional logistic regression. Our results suggested plasma concentrations of 25(OH)D and retinol were not associated with glioma risk. Comparing the highest to lowest tertile, the multivariable hazard ratio (MVHR) for 25(OH)D was 0.87 (95% confidence interval [CI] 0.68–1.11) in UKB and the multivariable risk ratio (MVRR) was 0.97 (95% CI 0.51–1.85) in NHS and HPFS. In NHS and HPFS, the MVRR for the same comparison for retinol was 1.16 (95% CI 0.56–2.38). Nonsignificant associations were observed for α-tocopherol (MVRRtertile3vs1 = 0.61, 95% CI 0.29–1.32) and γ-tocopherol (MVRR tertile3vs1 = 1.30, 95% CI 0.63–2.69) that became stronger in 4-year lagged analyses. Further investigation is warranted on a potential association between α- and γ-tocopherol and glioma risk.

Alzheimer's disease (AD) is the most common neurodegenerative disease and affects persons of all races, ethnic groups, and sexes. The disease is characterized by neuronal loss leading to cognitive decline and memory loss. There is no cure and the effectiveness of existing treatments is limited and depends on the time of diagnosis. The long prodromal period, during which patients' ability to live a normal life is not affected despite neuronal loss, often leads to a delayed diagnosis because it can be mistaken for normal aging of the brain. In order to make a substantial impact on AD patient survival, early diagnosis may provide a greater therapeutic window for future therapies to slow AD-associated neurodegeneration. Current gold standards for disease detection include magnetic resonance imaging and positron emission tomography scans, which visualize amyloid β and phosphorylated tau depositions and aggregates. Liquid biopsies, already an active field of research in precision oncology, are hypothesized to provide early disease detection through minimally or non-invasive sample collection techniques. Liquid biopsies in AD have been studied in cerebrospinal fluid, blood, ocular, oral, and olfactory fluids. However, most of the focus has been on blood and cerebrospinal fluid due to biomarker specificity and sensitivity attributed to the effects of the blood-brain barrier and inter-laboratory variation during sample collection. Many studies have identified amyloid β and phosphorylated tau levels as putative biomarkers, however, advances in next-generation sequencing-based liquid biopsy methods have led to significant interest in identifying nucleic acid species associated with AD from liquid tissues. Differences in cell-free RNAs and DNAs have been described as potential biomarkers for AD and hold the potential to affect disease diagnosis, treatment, and future research avenues.

Background: Cardiogenic shock (CS) is associated with high mortality. We report on a “Shock Team” approach of combined interdisciplinary expertise for decision making, expedited assessment, and treatment. Methods: We reviewed 100 patients admitted in CS over 52 months. Patients managed under a Code Shock Team protocol (n = 64, treatment) from 2016 to 2019 were compared with standard care (n = 36, control) from 2015 to 2016. The cohort was predominantly male (78% treatment, 67% control) with a median age of 55 years (interquartile range [IQR], 43-64) for treatment vs 64 years (IQR, 48-69) for control (P = 0.01). New heart failure was more common in the treatment group: 61% vs 36%, P = 0.02. Acute myocardial infarction comprised 13% of patients in CS. There were no significant differences between treatment and control in markers of clinical acuity, including median left ventricular ejection fraction (18% vs 20%), prevalence of moderate-severe right ventricular dysfunction (64% vs 56%), median peak serum lactate (5.3 vs 4.7 mmol/L), acute kidney injury (70% vs 75%), or acute liver injury (50% vs 31%). Inotropes, dialysis, and invasive ventilation were required in 92%, 33%, and 66% of patients, respectively. Temporary mechanical circulatory support was used in 45% of treatment and 28% of control patients (P = 0.08). There were no significant differences in median hospital length of stay (17.5 days), 30-day survival (71%), or survival to hospital discharge (66%). Over 240 days (IQR, 14,847) of median follow-up, survival was 67% for treatment vs 42% for control (hazard ratio, 0.53; 95% confidence interval, 0.28-0.99; P = 0.03). Conclusion: A multidisciplinary Code Shock Team approach for CS is feasible and may be associated with improved long-term survival. Résumé: Contexte: Le choc cardiogénique (CC) est associé à une mortalité élevée. Nous décrivons une approche où la prise de décision, l’évaluation rapide des cas et le traitement sont confiés à une « équipe de choc » interdisciplinaire. Méthodologie: Nous avons examiné les cas de 100 patients hospitalisés en raison d’un CC sur une période de 52 mois. Les patients pris en charge par une équipe interdisciplinaire selon un protocole d’intervention déclenché par un code-choc (n = 64, groupe traité) de 2016 à 2019 ont été comparés à des patients ayant reçu des soins courants (n = 36, groupe témoin) de 2015 à 2016. Les patients de la cohorte étaient majoritairement de sexe masculin (78 % dans le groupe traité, 67 % dans le groupe témoin) et l’âge médian était de 55 ans (intervalle interquartile [IIQ] : 43-64) au sein du groupe traité par rapport à 64 ans (IIQ : 48-69) au sein du groupe témoin (p = 0,01). Les nouveaux cas d’insuffisance cardiaque étaient plus fréquents dans le groupe traité : 61 % vs 36 % (p = 0,02). Les patients hospitalisés en raison d’un CC avaient subi un infarctus aigu du myocarde dans 13 % des cas. Aucune différence significative n’a été relevée entre le groupe traité et le groupe témoin au chapitre des marqueurs d’acuité clinique, y compris la fraction médiane d’éjection ventriculaire gauche (18 % vs 20 %), la prévalence d’une dysfonction modérée ou sévère du ventricule droit (64 % vs 56 %), la concentration maximale médiane de lactate sérique (5,3 vs 4,7 mmol/l), l’insuffisance rénale aiguë (70 % vs 75 %) ou l’insuffisance hépatique aiguë (50 % vs 31 %). L’administration d’inotropes, la dialyse et la ventilation effractive ont été nécessaires chez 92 %, 33 % et 66 % des patients, respectivement. Une assistance circulatoire mécanique temporaire a été utilisée chez 45 % des patients du groupe traité et 28 % des patients du groupe témoin (p = 0,08). Aucune différence significative n’a été notée en ce qui concerne la durée médiane des hospitalisations (17,5 jours), la survie à 30 jours (71 %) ou la survie à la sortie de l’hôpital (66 %). Au cours d’une période de suivi médiane de 240 jours (IIQ : 14 847), le taux de survie était de 67 % dans le groupe traité vs 42 % dans le groupe témoin (rapport des risques instantanés : 0,53; intervalle de confiance à 95 % : 0,28-0,99; p = 0,03). Conclusion: Dans les cas de CC, l’intervention d’une équipe interdisciplinaire déclenchée par un code-choc est réalisable et pourrait être associée à une amélioration de la survie à long terme.

Fibro-adipose vascular anomaly (FAVA) is a recently described complex and painful benign lesion found in young adults and the pediatric population composed of intramuscular vascular, fibrous, and adipose tissues. A previous report has identified the presence of somatic mosaic mutations in the gene for the catalytic subunit of phosphatidylinositol 3-kinase (PIK3CA) in cases of FAVA. Herein, we present a case of FAVA found in a 23-year-old male patient who presented with chronic wrist pain associated with a mass, and we identified an associated somatic activating mutation (H1047R) in PIK3CA. We briefly review the relevant literature surrounding the identification and histology of FAVA, the known mutational spectrum, downstream signaling pathways, and relevant treatment modalities. Our case highlights the association between FAVA and somatic mosaic activating PIK3CA mutations.

The challenges faced with current fluorescence imaging agents have motivated us to study two nanostructures based on a hydrophobic dye, 6H-pyrrolo[3,2-b:4,5-b’]bis [1,4]benzothiazine (TRPZ). TRPZ is a heteroacene with a rigid, pi-conjugated structure, multiple reactive sites, and unique spectroscopic properties. Here we coupled TRPZ to a tert-butyl carbamate (BOC) protected 2,2-bis(hydroxymethyl)propanoic acid (bisMPA) dendron via azide-alkyne Huisgen cycloaddition. Deprotection of the protected amine groups on the dendron afforded a cationic terminated amphiphile, TRPZ-bisMPA. TRPZ-bisMPA was nanoprecipitated into water to obtain nanoparticles (NPs) with a hydrodynamic radius that was

Abstract Levodopa-induced dyskinesias (LID) are a prevalent side effect of chronic treatment with levodopa (L-DOPA) for the motor symptoms of Parkinson’s disease (PD). It has long been hypothesized that serotonergic neurons of the dorsal raphe nucleus (DRN) are capable of L-DOPA uptake and dysregulated release of dopamine (DA), and that this “false neurotransmission” phenomenon is a main contributor to LID development. Indeed, many preclinical studies have demonstrated LID management with serotonin receptor agonist treatment, but unfortunately, promising preclinical data has not been translated in large-scale clinical trials. Importantly, while there is an abundance of convincing clinical and preclinical evidence supporting a role of maladaptive serotonergic neurotransmission in LID expression, there is no direct evidence that dysregulated DA release from serotonergic neurons impacts LID formation. In this study, we ectopically expressed the DA autoreceptor D2Rs (or GFP) in the DRN of 6-hydroxydopamine (6-OHDA) lesioned rats. No negative impact on the therapeutic efficacy of L-DOPA was seen with rAAV-D2Rs therapy. However, D2Rs treated animals, when subjected to a LID-inducing dose regimen of L-DOPA, remained completely resistant to LID, even at high doses. Moreover, the same subjects remained resistant to LID formation when treated with direct DA receptor agonists, suggesting D2Rs activity in the DRN blocked dyskinesogenic L-DOPA priming of striatal neurons. In vivo microdialysis confirmed that DA efflux in the striatum was reduced with rAAV-D2Rs treatment, providing explicit evidence that abnormal DA release from DRN neurons can affect LID. This is the first direct evidence of dopaminergic neurotransmission in DRN neurons and its modulation with rAAV-D2Rs gene therapy confirms the serotonin hypothesis in LID, demonstrating that regulation of serotonergic neurons achieved with a gene therapy approach offers a novel and potent antidyskinetic therapy.

Background:. Congenital midline nasal masses are rare anomalies and are typically benign nasal dermoid sinus cysts (NDSCs). Rhabdomyosarcomas (RMSs) are even less common, and only a fraction affect sites like the external nose, nasal cavity, nasopharynx, and paranasal sinuses. We review the clinical presentation and treatment of nasal, nasopharyngeal, and paranasal RMSs and report the first documented midline presentation. Methods:. We queried PubMed for articles with titles containing the terms rhabdomyosarcoma or sarcoma botryoides and nose, nasal, paranasal, sinonasal, nasopharynx, or nasopharyngeal. We then searched the references of each included article using the same parameters and continued this process iteratively until no new articles were found. Results:. The paranasal sinuses were the most commonly affected site, followed by the nasopharynx, nasal cavity, and external nose. Two patients presented with involvement of the external nose, but each presented with involvement of the right ala rather than a midline mass. The rates of intracranial extension and/or skull base involvement were comparable to those of NDSCs. The alveolar subtype was most common, followed by the embryonal subtype. Conclusions:. Most midline nasal masses are benign; however, we report the first documented presentation of an RMS as a midline nasal mass. Accordingly, RMS should be included in the differential diagnosis of midline nasal masses in the pediatric population. Surgery for midline nasal masses is sometimes delayed due to the risks of interfering with developing structures and early anesthesia. However, early surgical treatment should be considered given this new differential and its predilection for early metastasis.

Plasminogen activator inhibitor type-2 (PAI-2), a member of the serpin family, is dramatically upregulated during pregnancy and in response to inflammation. Although PAI-2 exists in glycosylated and non-glycosylated forms in vivo, the majority of in vitro studies of PAI-2 have exclusively involved the intracellular non-glycosylated form. This study shows that exposure to inflammation-associated hypochlorite induces the oligomerisation of PAI-2 via a mechanism involving dityrosine formation. Compared to plasminogen activator inhibitor type-1 (PAI-1), both forms of PAI-2 are more resistant to hypochlorite-induced inactivation of its protease inhibitory activity. Holdase-type extracellular chaperone activity plays a putative non-canonical role for PAI-2. Our data demonstrate that glycosylated PAI-2 more efficiently inhibits the aggregation of Alzheimer’s disease and preeclampsia-associated amyloid beta peptide (Aβ), compared to non-glycosylated PAI-2 in vitro. However, hypochlorite-induced modification of non-glycosylated PAI-2 dramatically enhances its holdase activity by promoting the formation of very high-molecular-mass chaperone-active PAI-2 oligomers. Both PAI-2 forms protect against Aβ-induced cytotoxicity in the SH-SY5Y neuroblastoma cell line in vitro. In the villous placenta, PAI-2 is localised primarily to syncytiotrophoblast with wide interpersonal variation in women with preeclampsia and in gestational-age-matched controls. Although intracellular PAI-2 and Aβ staining localised to different placental cell types, some PAI-2 co-localised with Aβ in the extracellular plaque-like aggregated deposits abundant in preeclamptic placenta. Thus, PAI-2 potentially contributes to controlling aberrant fibrinolysis and the accumulation of misfolded proteins in states characterised by oxidative and proteostasis stress, such as in Alzheimer’s disease and preeclampsia.

BackgroundAdvocates use the hashtag #GlobalHealth on Twitter to draw users' attention to prominent themes on global health, to harness their support, and to advocate for change.ObjectivesWe aimed to describe #GlobalHealth tweets pertinent to given major health issues.MethodsTweets containing the hashtag #GlobalHealth (N = 157,951) from January 1, 2014, to April 30, 2015, were purchased from GNIP Inc. We extracted 5 subcorpora of tweets, each with 1 of 5 co-occurring disease-specific hashtags (#Malaria, #HIV, #TB, #NCDS, and #NTDS) for further analysis. Unsupervised machine learning was applied to each subcorpus to categorize the tweets by their underlying topics and obtain the representative tweets of each topic. The topics were grouped into 1 of 4 themes (advocacy; epidemiological information; prevention, control, and treatment; societal impact) or miscellaneous. Manual categorization of most frequent users was performed. Time zones of users were analyzed.FindingsIn the entire #GlobalHealth corpus (N = 157,951), there were 40,266 unique users, 85,168 retweets, and 13,107 unique co-occurring hashtags. Of the 13,087 tweets across the 5 subcorpora with co-occurring hashtag #malaria (n = 3640), #HIV (n = 3557), #NCDS (noncommunicable diseases; n = 2373), #TB (tuberculosis; n = 1781), and #NTDS (neglected tropical diseases; n = 1736), the most prevalent theme was prevention, control, and treatment (4339, 33.16%), followed by advocacy (3706, 28.32%), epidemiological information (1803, 13.78%), and societal impact (1617, 12.36%). Among the top 10 users who tweeted the highest number of tweets in the #GlobalHealth corpus, 5 were individual professionals, 3 were news media, and 2 were organizations advocating for global health. The most common users' time zone was Eastern Time (United States and Canada).ConclusionsThis study highlighted the specific #GlobalHealth Twitter conversations pertinent to malaria, HIV, tuberculosis, noncommunicable diseases, and neglected tropical diseases. These conversations reflect the priorities of advocates, funders, policymakers, and practitioners of global health on these high-burden diseases as they presented their views and information on Twitter to their followers.

Abstract Background Approximately 33% of the patients with lumbar spinal stenosis (LSS) who undergo surgery are not satisfied with their postoperative clinical outcomes. Therefore, identifying predictors for postoperative outcome and groups of patients who will benefit from the surgical intervention is of significant clinical benefit. However, many of the studied predictors to date suffer from subjective recall bias, lack fine digital measures, and yield poor correlation to outcomes. Methods This study utilized smart-shoes to capture gait parameters extracted preoperatively during a 10 m self-paced walking test, which was hypothesized to provide objective, digital measurements regarding the level of gait impairment caused by LSS symptoms, with the goal of predicting postoperative outcomes in a cohort of LSS patients who received lumbar decompression and/or fusion surgery. The Oswestry Disability Index (ODI) and predominant pain level measured via the Visual Analogue Scale (VAS) were used as the postoperative clinical outcome variables. Results The gait parameters extracted from the smart-shoes made statistically significant predictions of the postoperative improvement in ODI (RMSE =0.13, r=0.93, and p

Amrita Jesurasa, Kelly Mackenzie, Hannah Jordan, Elizabeth C Goyder School of Health and Related Research (ScHARR), University of Sheffield, Regent Court, Sheffield, UK Background: The “flipped classroom,” a pedagogical model where typical lecture and homework elements are reversed, is being advocated in medical education to support the teaching of a large curriculum. However, research into the use of this model in postgraduate medical education, which requires the application of acquired knowledge, is limited. The aim of this study was to explore the barriers and facilitators to engagement with the flipped classroom model in preparation for the written element of postgraduate membership examinations. Methods: Three focus groups (n=14) were held between February and June 2016. Participants were drawn from a membership examination preparation course, run by the University of Sheffield. Two of the groups (n=10) involved “students” (public health registrars) while the other focus group (n=4) was held with “tutors” (experienced registrars and consultants). The focus groups were audiorecorded and transcribed verbatim. Transcripts were thematically analyzed by using both predetermined and emergent themes. Results: Key themes that emerged from the data included variation in learning and teaching styles of individuals as well as the feasibility and flexibility of the overall course design. However, management of students’ expectations was found to be the fundamental factor, which underpinned the engagement. Conclusion: The complex interaction of factors affecting engagement in this study highlights the need to consider the appropriateness of the flipped classroom model. However, this must be balanced by the potential benefits of the approach for delivering a large curriculum. Recognizing the central importance of managing expectations at the outset would be useful when considering this model in postgraduate medical education. Keywords: flipped classroom, membership examination, postgraduate

The female reproductive system ages before any other organ system in the body. This phenomenon can have tangible clinical implications leading to infertility, miscarriages, birth defects and systemic deterioration due to estrogen loss. “Fibroinflammation” is a hallmark of aging tissues; there is an increase in inflammatory cytokines and fibrotic tissue in the aging ovarian stroma. We systematically evaluated immunomodulatory factors in human follicular fluid, which, like the stroma, is a critical ovarian microenvironment directly influencing the oocyte. Using a cytokine antibody array, we identified a unique fibroinflammatory cytokine signature in follicular fluid across an aging series of women (27.7–44.8 years). This signature (IL-3, IL-7, IL-15, TGFβ1, TGFβ3 and MIP-1) increased with chronologic age, was inversely correlated to anti-Müllerian hormone (AMH) levels, and was independent of body mass index (BMI). We focused on one specific protein, TGFβ3, for further validation. By investigating this cytokine in human cumulus cells and ovarian tissue, we found that the age-dependent increase in TGFβ3 expression was unique to the ovarian stroma but not other ovarian sub-compartments. This study broadens our understanding of inflammaging in the female reproductive system and provides a defined fibroinflammatory aging signature in follicular fluid and molecular targets in the ovary with potential clinical utility.

WASp-interacting protein (WIP), a regulator of actin cytoskeleton assembly and remodeling, is a cellular multi-tasker and a key member of a network of protein–protein interactions, with significant impact on health and disease. Here, we attempt to complement the well-established understanding of WIP function from cell biology studies, summarized in several reviews, with a structural description of WIP interactions, highlighting works that present a molecular view of WIP’s protein–protein interactions. This provides a deeper understanding of the mechanisms by which WIP mediates its biological functions. The fully disordered WIP also serves as an intriguing example of how intrinsically disordered proteins (IDPs) exert their function. WIP consists of consecutive small functional domains and motifs that interact with a host of cellular partners, with a striking preponderance of proline-rich motif capable of interactions with several well-recognized binding partners; indeed, over 30% of the WIP primary structure are proline residues. We focus on the binding motifs and binding interfaces of three important WIP segments, the actin-binding N-terminal domain, the central domain that binds SH3 domains of various interaction partners, and the WASp-binding C-terminal domain. Beyond the obvious importance of a more fundamental understanding of the biology of this central cellular player, this approach carries an immediate and highly beneficial effect on drug-design efforts targeting WIP and its binding partners. These factors make the value of such structural studies, challenging as they are, readily apparent.

Descriptive trained sensory attributes, fatty acids, and volatile compounds were determined to characterize the effects of dry-aging on ground beef. Beef shoulder clods were ground to include 100% fresh beef, 100% dry-aged beef, and a 50% fresh and 50% dry-aged ground beef blend. Samples comprised of 100% dry-aged beef were rated greatest (P < 0.001) for browned/grilled, earthy/mushroom, and nutty/roasted-nut flavors; however, panelists also detected greater (P ≤ 0.011) incidences of sour/acidic and bitter flavors. The addition of dry-aged beef increased (P < 0.001) hardness and reduced (P < 0.001) tenderness. Dry-aging also caused a shift in saturated fatty acids, where shorter chain saturated fatty acids (≤ 16:0) were reduced (P ≤ 0.034) compared to stearic acid (18:0). Meanwhile, increases of trans-octadecenoic acid (18:1 trans) and decreases of cis monounsaturated fatty acids were present in dry-aged beef. Concentrations of 18:2 conjugated linoleic isomers were greatest (P < 0.001) in fresh beef and decreased with the incorporation of dry-aged beef. Several lipid-derived volatile compounds were greater (P < 0.05) in dry-aged beef compared with fresh beef, implying a greater degree of lipid degradation among dry-aged beef. Increases (P ≤ 0.031) were determined for 3- and 2-methyl butanal with the addition of dry-aged beef. Intermediates of the Maillard reaction, 2,3-butanedione and acetoin, were determined to be greatest (P ≤ 0.046) from dry-aged beef. Alterations of fatty acids and volatile compounds with dry-aging were determined to be related with intensity of individual flavor attributes. Overall, it may be concluded that inclusion of dry-aged beef impacts flavor profile through altered fatty acid profiles and flavor related compounds. These results support the idea that dry-aging may be utilized to impart an altered ground beef flavor experience.

The events underlying senescence induced by critical telomere shortening are not fully understood. Here we provide evidence that TERRA, a non-coding RNA transcribed from subtelomeres, contributes to senescence in yeast lacking telomerase (tlc1Δ). Levels of TERRA expressed from multiple telomere ends appear elevated at senescence, and expression of an artificial RNA complementary to TERRA (anti-TERRA) binds TERRA in vivo and delays senescence. Anti-TERRA acts independently from several other mechanisms known to delay senescence, including those elicited by deletions of EXO1, TEL1, SAS2, and genes encoding RNase H enzymes. Further, it acts independently of the senescence delay provided by RAD52-dependent recombination. However, anti-TERRA delays senescence in a fashion epistatic to inactivation of the conserved histone methyltransferase Dot1. Dot1 associates with TERRA, and anti-TERRA disrupts this interaction in vitro and in vivo. Surprisingly, the anti-TERRA delay is independent of the C-terminal methyltransferase domain of Dot1 and instead requires only its N-terminus, which was previously found to facilitate release of telomeres from the nuclear periphery. Together, these data suggest that TERRA and Dot1 cooperate to drive senescence.