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Objective: To evaluate age, sex, race, osteoarthritis (OA) severity, metabolic factors, and bone health as risk factors for erosive hand OA at baseline and its incidence over a 48-month period., Methods: This was a longitudinal cohort study that included participants from the Osteoarthritis Initiative (OAI) with complete hand radiographs from baseline and 48-month visits who were eligible at baseline for incident erosive hand OA (i.e., had or were at risk for knee OA [criterion for OAI inclusion] and did not currently have erosive hand OA). Individuals were classified as having erosive hand OA if the Kellgren/Lawrence (K/L) grade was ≥2 in at least 1 interphalangeal joint on 2 different fingers and central erosion was present in at least 1 joint., Results: Of the 3,365 individuals without prevalent erosive hand OA at baseline, 86 (2.6%) developed erosive hand OA during the 48-month period. Risk factors included older age (relative risk [RR] per SD 1.63 [95% confidence interval 1.35-1.97]), female sex (RR 2.47 [95% confidence interval 1.52-4.02]), greater OA severity (sum K/L grade 13.9 versus 5.3; P < 0.001), and less cortical width (1.38 mm versus 1.52 mm; P < 0.001). After 48 months, subjects who had developed erosive hand OA were characterized by greater progression of radiographic OA (i.e., joint space narrowing, K/L grade progression [RR 1.35], and loss of cortical thickness [RR 1.23]), adjusted for age, sex, race, body mass index, and baseline OA severity (sum K/L grade)., Conclusion: These findings demonstrate that erosive hand OA is more common in older women and is strongly associated with severity of articular structural damage and its progression. Individuals who develop erosive hand OA have thinner bones prior to erosive hand OA development and as it progresses, suggesting that erosive hand OA is a disorder of skeletal frailty., (© 2021, American College of Rheumatology.)

Pitch-based carbon fibers are of considerable interest as high-performance materials. There are reports over the last several decades detailing (i) methods of improving pitch-based carbon fiber performance, and (ii) reducing the cost of production via novel processing techniques. However, there remain considerable challenges in producing high-performance pitch-based carbon fibers consistently on an industrial scale. This is arguably due to the difficulty of scaling the melt-spinning process to compensate for variability in pitch feedstock quality and a lack of understanding of processing-structure-performance relationships. This work focuses on the early stages of heat treatment (pyrolysis) of isotropic pitch and its effect on the chemical, thermal, and rheological properties of the pitch, which help determine its processability. More specifically, we quantify significant changes in chemical structure, M w , T g , T s , and shear and extensional rheology as a function of pyrolysis time at 400 °C. The extensional rheology, in particular, shows that the 'stretchability' of the pitch samples strongly depends on pyrolysis severity, and is important for characterizing 'drawability'. Using a novel analysis of the uniaxial stretching kinematics, we show an isothermal 'drawability window' that allows for the largest axial and radial Hencky strains at constant rate. We hypothesize that this extensional drawability window could facilitate the successful processing of pitch into high quality fiber, minimizing the trial-and-error approach currently used in the field.

This paper presents a hybrid electromechanical transformer that passively transfers electrical power between galvanically isolated ports by coupling electrodynamic and piezoelectric transducers. The use of these two complementary electromechanical transduction methods along with a high-Q mechanical resonance affords very large transformations of voltage, current, or impedance at particular electrical frequencies. A chip-size prototype is designed, simulated, fabricated, and experimentally characterized. The 7.6 mm × 7.6 mm × 1.65 mm device achieves an open-circuit voltage gain of 31.4 and 48.7 when operating as a step-up transformer at 729.5 Hz and 1015 Hz resonance frequencies, respectively. When operating as a step-down transformer, the resonance frequencies and the corresponding voltage gains are 728 Hz, 1002 Hz, and 0.0097, 0.0128, respectively. In one operational mode, the system shows a minimum power dissipation of only 0.9 µW corresponding to a power conversion efficiency of 11.8%.

Background: Patellofemoral joint (PFJ) disease is a common ailment in elite athletes. Our aim is to report the frequency of superolateral Hoffa's fat pad (SHFP) edema, and PFJ cartilage damage and bone marrow lesions (BML), among Olympian athletes, and to study the association between measurements of trochlear morphology and vertical patellar position and a) PFJ cartilage damage or BML, and b) SHFP edema., Methods: All knee MRI, performed in the Olympic Village and polyclinics, of participating athletes in the 2016 Olympic Games of Rio de Janeiro were included. MRI were scored for PFJ cartilage damage and BML, and SHFP edema. Trochlear morphology measurements included sulcus angle, trochlear angle, lateral trochlear inclination, and medial trochlear inclination. Insall-Salvati ratio was also assessed., Results: One hundred twenty-one knee MRIs were included (62 female, 51.2 %). The highest frequencies of PFJ cartilage damage, combination of PFJ cartilage damage and BML, and SHFP edema were found among Beach Volleyball and Volleyball athletes. SHFP edema was more common among female compared to male Olympian athletes. We found no statistically significant associations between different measurements of trochlear morphology/vertical patellar position, and 1. SHFP edema, and 2. PFJ cartilage damage/BML., Conclusion: SHFP edema and the combination of PFJ cartilage damage and BML are highly frequent among Olympic athletes especially those competing in Beach volleyball and Volleyball. SHFP edema is more common among female athletes. Further studies are needed to determine whether PFJ cartilage damage has a stronger association to sports disciplines rather than trochlear morphology., Competing Interests: Ali Guermazi is shareholder of Boston Imaging Core Lab (BICL), LLC, and a consultant to MerckSerono, AstraZeneca, Pfizer, Novartis, Regeneron and TissueGene. Frank Roemer is a shareholder of BICL, LLC and a consultant to Calibr - California Institute of Biomedical Research. Lars Engebretsen is a consultant to Arthrex and Smith and Nephew. Andrew J. Kompel, Kirstin Small, Stacy E. Smith, and Mohamed Jarraya have nothing to disclose.

Ibrutinib has superior progression-free survival compared with bendamustine plus rituximab (BR) in older CLL patients, however, differences in treatment duration, six monthly BR cycles versus continuous ibrutinib, complicate adverse event (AE) comparisons. We introduce the AE burden score (AE sc ) to compare AEs, calculated for each patient by summing over products of reporting period length and grade for each all-cause grade 1-4 AE and dividing by the length of time over which AEs are assessed. A total of 176 patients received BR and 361 ibrutinib alone or with six cycles of rituximab. At 38 months median follow-up, 64% remained on ibrutinib. Median AE sc was higher with BR versus ibrutinib in the first six cycles (7.2 versus 4.9, p < 0.0001). Within ibrutinib arms, median AE sc decreased significantly to 3.7 after six cycles (p < 0.0001). 10% and 14% of BR and ibrutinib patients discontinued treatment for AEs. In ibrutinib arms, cumulative incidence of grade 3 or higher atrial fibrillation, hypertension, and infection (AEs of clinical interest) at 12 months was 4.5%, 17.5%, and 12.8%, respectively, and increased more slowly thereafter to 7.7%, 25.4%, and 20.5% at 36 months. Analytical tools including the AE sc and cumulative incidence of AEs can help to better characterize AE burden over time. ClinicalTrials.gov identifier: NCT01886872., (© 2021. The Author(s), under exclusive licence to Springer Nature Limited.)

Background: Pharmacologic thromboprophylaxis (PTP) is the mainstay prevention strategy for venous thromboembolism (VTE). PTP agents traditionally dosed, like unfractionated heparin (UFH) and enoxaparin (ENOX), are associated with failure and bleeding in obese and underweight patients, respectively. Objectives: This study aimed to describe the prevalence of unadjusted ENOX and UFH dosing for PTP based on anthropometric measures. Patients/Methods :This was a post-hoc, multicenter, cross-sectional analysis of critically ill adults receiving PTP with ENOX or UFH. The primary outcome was the prevalence of unadjusted PTP based on body mass index (BMI) and total body weight (TBW). Definitions for dose adjustments were developed based on existing literature. A secondary outcome was to identify factors associated with unadjusted dosing per BMI and TBW using multivariable generalized linear mixed-effect models. Results: The nested cohort included 172 patients (ENOX=46, UFH=126). Unadjusted PTP was observed in 118 patients (68.6%) based on BMI and 74 (43%) per TBW. When comparing UFH to ENOX, more patients who received UFH had doses unadjusted by BMI (78.6% vs. 41.3%, p<0.05) but not TBW (43.7% vs. 41.3%). Factors independently associated with unadjusted PTP per BMI were receipt of UFH (OR 6.93, 95% CI 1.06-8.77) or a BMI underweight or overweight/obese (OR 10.45, 95% CI 4.38-24.92). Having a TBW <50kg or >100kg (OR 4.85, 95% CI 2.15-10.96) were independently associated with unadjusted PTP based on TBW. Conclusions: Unadjusted dosing of PTP occurs frequently in critically ill adults receiving ENOX or UFH. This was seen in body size extremes by both BMI and TBW., (© Individual authors.)

Background: The transfer of training to the workplace is the aim of training interventions. Three primary factors influence transfer: trainee characteristics, training design and work environment influences. Within medical education, the work environment factors influencing transfer of training remain underexplored. Burke and Hutchins' review of training transfer outlined five work environment influences: opportunity to perform, supervisor/peer support, strategic link, transfer climate and accountability. This study aimed to explore the ways in which work environment factors influence the transfer of training for medical trainees., Methods: Internal Medicine Training in Scotland includes a three-day boot camp involving simulation-based mastery learning of procedural skills, immersive simulation scenarios and communication workshops. Following ethical approval, trainees were invited to take part in interviews at least three months after following their boot camp. Interviews were semi-structured, anonymised, transcribed verbatim and analysed using template analysis. Member checking interviews were performed to verify findings., Results: A total of 26 trainees took part in interviews between January 2020 and January 2021. Trainees reported a lack of opportunities to perform procedures in the workplace and challenges relating to the transfer climate, including a lack of appropriate equipment and resistance to change in the workplace. Trainees described a strong sense of personal responsibility to transfer and they felt empowered to change practice in response to the challenges faced., Conclusions: This study highlights barriers to transfer of training within the clinical workplace including procedural opportunities, a transfer climate with challenging equipment availability and, at times, an unsupportive workplace culture. Trainees are driven by their own sense of personal responsibility; medical educators and healthcare leaders must harness this enthusiasm and take heed of the barriers to assist in the development of strategies to overcome them., (© 2021. The Author(s).)

Tumor-initiating stem cells (TSCs) are critical for drug resistance and immune escape. However, the mutual regulations between TSC and tumor microenvironment (TME) remain unclear. Using DNA-label retaining, single-cell RNA sequencing (scRNA-seq), and other approaches, we investigated intestinal adenoma in response to chemoradiotherapy (CRT), thus identifying therapy-resistant TSCs (TrTSCs). We find bidirectional crosstalk between TSCs and TME using CellPhoneDB analysis. An intriguing finding is that TSCs shape TME into a landscape that favors TSCs for immunosuppression and propagation. Using adenoma-organoid co-cultures, niche-cell depletion, and lineaging tracing, we characterize a functional role of cyclooxygenase-2 (Cox-2)-dependent signaling, predominantly occurring between tumor-associated monocytes and macrophages (TAMMs) and TrTSCs. We show that TAMMs promote TrTSC proliferation through prostaglandin E2 (PGE2)-PTGER4(EP4) signaling, which enhances β-catenin activity via AKT phosphorylation. Thus, our study shows that the bidirectional crosstalk between TrTSC and TME results in a pro-tumorigenic and immunosuppressive contexture., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2021 The Author(s). Published by Elsevier Inc. All rights reserved.)

Preexisting heart failure (HF) in patients with sepsis is associated with worse clinical outcomes. Core sepsis management includes aggressive volume resuscitation followed by vasopressors (and potentially inotropes) if fluid is inadequate to restore perfusion; however, large fluid boluses and vasoactive agents are concerning amid the cardiac dysfunction of HF. This review summarizes evidence regarding the influence of HF on sepsis clinical outcomes, pathophysiologic concerns, resuscitation targets, hemodynamic interventions, and adjunct management (ie, antiarrhythmics, positive pressure ventilatory support, and renal replacement therapy) in patients with sepsis and preexisting HF. Patients with sepsis and preexisting HF receive less fluid during resuscitation; however, evidence suggests traditional fluid resuscitation targets do not increase the risk of adverse events in HF patients with sepsis and likely improve outcomes. Norepinephrine remains the most well-supported vasopressor for patients with sepsis with preexisting HF, while dopamine may induce more cardiac adverse events. Dobutamine should be used cautiously given its generally detrimental effects but may have an application when combined with norepinephrine in patients with low cardiac output. Management of chronic HF medications warrants careful consideration for continuation or discontinuation upon development of sepsis, and β-blockers may be appropriate to continue in the absence of acute hemodynamic decompensation. Optimal management of atrial fibrillation may include β-blockers after acute hemodynamic stabilization as they have also shown independent benefits in sepsis. Positive pressure ventilatory support and renal replacement must be carefully monitored for effects on cardiac function when HF is present.

Background: This analysis assessed combined safety data from 4 clinical studies of teduglutide in pediatric patients with short-bowel syndrome-associated intestinal failure (SBS-IF)., Methods: Safety data from teduglutide-treated patients in 4 clinical trials were pooled. The completed 12-week and 24-week phase 3 core studies (NCT01952080/EudraCT 2013-004588-30 and NCT02682381/EudraCT 2015-002252-27) enrolled children aged 1-17 years with SBS-IF. Patients could elect to enroll in ongoing open-label extensions (NCT02949362/EudraCT 2016-000863-17 and NCT02954458/EudraCT 2016-000849-30). Interim data from ongoing studies were included., Results: Safety data are reported for 89 pediatric patients treated with teduglutide for a median (range) of 51.7 (5.0-94.7) weeks. Adverse events (AEs) were reported in all patients; the most common were vomiting (51.7%), pyrexia (43.8%), upper respiratory tract infection (41.6%), and cough (33.7%). Thirty-five patients (39.3%) had AEs considered related to teduglutide treatment; abdominal pain and vomiting were most frequent (5.6% each). Three serious AEs in 3 patients (3.4%) were considered related to teduglutide treatment: ileus, d-lactic acidosis, and gastrointestinal obstruction due to hard stools. All 3 events resolved. One cecal polyp was detected, which was not biopsied or found on repeat colonoscopy. No cases of neoplasia occurred., Conclusion: Based on integrated data from 4 clinical studies, including long-term follow-up for ≤161 weeks, teduglutide had a safety profile consistent with the individual core pediatric studies and as expected for pediatric patients with SBS-IF who never received teduglutide. The most frequent AEs reflected treatment with teduglutide, complications of the underlying disease, and typical childhood illnesses., (© 2020 American Society for Parenteral and Enteral Nutrition.)

Objective: To determine whether temperature screening is useful in detecting and reducing workplace transmission of SARS-CoV-2., Methods: A survey was conducted to determine whether temperature screening successfully identified workers with coronavirus disease 2019 (COVID-19) among a convenience sample of medical directors of multinational corporations in a wide range of industries., Results: More than 15 million screenings were performed by 14 companies. Fewer than 700 episodes of fever were identified. Of these, only about 53 cases of COVID-19 were detected. By contrast about 2000 workers with diagnosed COVID-19 were in the workplace and not detected by screening., Conclusions: One case of COVID-19 was identified by screening for approximately every 40 cases that were missed. Worksite temperature screening was ineffective for detecting workers with COVID-19 and is not recommended., Competing Interests: Stave, Smith, Hymel, and Heron have no relationships/conditions/circumstances that present potential conflict of interest., (Copyright © 2021 American College of Occupational and Environmental Medicine.)

Data addressing prognostication in patients with HIV related Burkitt lymphoma (HIV-BL) currently treated remain scarce. We present an international analysis of 249 (United States: 140; United Kingdom: 109) patients with HIV-BL treated from 2008 to 2019 aiming to identify prognostic factors and outcomes. With a median follow up of 4.5 years, the 3-year progression-free survival (PFS) and overall survival (OS) were 61% (95% confidence interval [CI] 55% to 67%) and 66% (95%CI 59% to 71%), respectively, with similar results in both countries. Patients with baseline central nervous system (CNS) involvement had shorter 3-year PFS (36%) compared to patients without CNS involvement (69%; P < .001) independent of frontline treatment. The incidence of CNS recurrence at 3 years across all treatments was 11% with a higher incidence observed after dose-adjusted infusional etoposide, doxorubicin, vincristine, prednisone, cyclophosphamide (DA-EPOCH) (subdistribution hazard ratio: 2.52; P = .03 vs other regimens) without difference by CD4 count 100/mm3. In multivariate models, factors independently associated with inferior PFS were Eastern Cooperative Oncology Group (ECOG) performance status 2-4 (hazard ratio [HR] 1.87; P = .007), baseline CNS involvement (HR 1.70; P = .023), lactate dehydrogenase >5 upper limit of normal (HR 2.09; P < .001); and >1 extranodal sites (HR 1.58; P = .043). The same variables were significant in multivariate models for OS. Adjusting for these prognostic factors, treatment with cyclophosphamide, vincristine, doxorubicin, and high-dose methotrexate, ifosfamide, etoposide, and high-dose cytarabine (CODOX-M/IVAC) was associated with longer PFS (adjusted HR [aHR] 0.45; P = .005) and OS (aHR 0.44; P = .007). Remarkably, HIV features no longer influence prognosis in contemporaneously treated HIV-BL., (© 2021 by The American Society of Hematology.)

Circadian rhythms are nearly ubiquitous throughout nature, suggesting they are critical for survival in diverse environments. Organisms inhabiting largely arrhythmic environments, such as caves, offer a unique opportunity to study the evolution of circadian rhythms in response to changing ecological pressures. Populations of the Mexican tetra, Astyanax mexicanus, have repeatedly invaded caves from surface rivers, where individuals must contend with perpetual darkness, reduced food availability, and limited fluctuations in daily environmental cues. To investigate the molecular basis for evolved changes in circadian rhythms, we investigated rhythmic transcription across multiple independently-evolved cavefish populations. Our findings reveal that evolution in a cave environment has led to the repeated disruption of the endogenous biological clock, and its entrainment by light. The circadian transcriptome shows widespread reductions and losses of rhythmic transcription and changes to the timing of the activation/repression of core-transcriptional clock. In addition to dysregulation of the core clock, we find that rhythmic transcription of the melatonin regulator aanat2 and melatonin rhythms are disrupted in cavefish under darkness. Mutants of aanat2 and core clock gene rorca disrupt diurnal regulation of sleep in A. mexicanus, phenocopying circadian modulation of sleep and activity phenotypes of cave populations. Together, these findings reveal multiple independent mechanisms for loss of circadian rhythms in cavefish populations and provide a platform for studying how evolved changes in the biological clock can contribute to variation in sleep and circadian behavior., Competing Interests: The authors have declared that no competing interests exist.

Introduction: The American Association of Colleges of Pharmacy Pharmacy Practice Section appointed a task force charged with developing a formal, national mentorship program for association section members. This manuscript provides insight into the creation of a mentorship program in a professional organization., Methods: Eighteen task force volunteers were divided into four sub-teams, along with a chair and vice chair. Sub-team responsibilities were segmented into the following: (1) mission and vision development, (2) structure and content, (3) assessment and impact, and (4) dissemination and scholarship. Task force members were surveyed to generate recommendations for creating a formal mentorship program within a professional organization and reflect on the process., Results: Seven of 14 eligible task force members completed the questionnaire (50% response rate). Most participants were mid-career, involved in a range of development aspects, and represented both committee members and leadership within the task force. The average time commitment was 15-19 hours over the year. The most common resource utilized was published literature and guidance documents. Identified needs included validated assessment tools, a wider range of exemplary programs to review, and guidance on broader organizational support. Strengths included organization and sub-team structure. Areas for improvement included coordination between sub-teams and resources available. Participants noted the challenges of creating a program to meet the diverse needs of a large membership., Conclusions: This manuscript demonstrates the feasibility and evidence-based approach in creation of a mentorship program within a national organization., Competing Interests: Declaration of competing interest The authors have no reported conflicts of interest or funding sources to disclose. The content is solely the responsibility of the authors and does not necessarily represent the official views of the American Association of Colleges of Pharmacy., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Aim: To determine the features cited by motor phenotyping experts when identifying dystonia in people with cerebral palsy (CP)., Method: Dystonia identification in CP, particularly when comorbid with spasticity, can be difficult. The dystonia diagnostic criterion standard remains subjective visual identification by expert consensus. For this qualitative study, we conducted an inductive thematic analysis of consensus-building discussions between three pediatric movement disorder physicians as they identified the presence or absence of dystonia in gait videos of 40 participants with spastic CP and periventricular leukomalacia., Results: Unanimous consensus about the presence or absence of dystonia was achieved for 34 out of 40 videos. Two main themes were present during consensus-building discussions as videos were evaluated for dystonia: (1) unilateral leg or foot adduction that was variable over time, and (2) difficulty in identifying dystonia. Codes contributing to the first theme were more likely to be cited by a discussant when they felt dystonia was present (as opposed to absent) in a video (χ 2 test, p=0.004)., Discussion: These results describe the gait features cited by experts during consensus-building discussion as they identify dystonia in ambulatory people with CP. Qualitative thematic analysis of these discussions could help codify the subjective process of dystonia diagnosis., (© 2021 Mac Keith Press.)

Pathology associated with the plantaris includes rupture of the tendon and an association with mid-substance Achilles tendinopathy in some patients. There have only been two previous case reports in the literature in English language describing snapping of the plantaris tendon. We present a case report of a 15-year-old female competitive dancer who described pain and an audible popping at the medial margin of the Achilles tendon while squatting. Physical examination revealed visible and audible popping of the plantaris, and ultrasonography confirmed the diagnosis. After symptoms persisted despite nonsurgical treatment with physical therapy, the patient underwent an open plantaris tenotomy. By 8 weeks after surgery, she had resumed dancing. Twenty-three months after her operation, she reported an excellent outcome and full recovery with no limitations to her physical activity. She reported having no pain, a Foot and Ankle Ability Measure Activities of Daily Living Subscale score of 100, and a Foot and Ankle Ability Measure Sports Subscale score of 100. This case demonstrates a successful course of treatment for this uncommon pathology within the context of a competitive dancer., (Copyright © 2021 The Authors. Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Orthopaedic Surgeons.)

Overuse of computed tomography (CT) is a prevalent problem across multiple disciplines in healthcare and is common in the workup of odontogenic infections. To address this problem, an imaging pathway was created through collaboration of the oral maxillofacial surgery and emergency medicine departments to reduce unnecessary CT orders. A prospective study was implemented to assess the success of the imaging pathway to guide in the selection of the most appropriate radiological imaging modality when managing an odontogenic infection. Subjects included were adults, presenting through the emergency department for confirmed odontogenic infection. The primary outcome was the rate of unnecessary CT scans performed after the introduction of the pathway. Statistics were performed via the t-test, χ 2 test, and multiple regression analysis; P < 0.05 was considered significant. Between February 1 and December 15, 2019, 100 patients met the inclusion criteria and were enrolled. The rate of unnecessary CT scans was 25.6%, compared to 56.6% prior to the introduction of the imaging pathway. The pathway did not misclassify any patient to not receive a CT when it was medically necessary. Use of the imaging pathway has the potential to reduce unnecessary CT imaging for odontogenic infections, without negatively affecting patient outcomes., (Copyright © 2020 International Association of Oral and Maxillofacial Surgeons. Published by Elsevier Inc. All rights reserved.)

Cerebral palsy (CP) neurologic care and research efforts typically focus on children. However, most people with CP are adults. Adults with CP are at increased risk of new neurologic conditions, such as stroke and myelopathy, that require ongoing neurologic surveillance to distinguish them from baseline motor impairments. Neurologic factors could also contribute to the motor function decline, chronic pain, and chronic fatigue that are commonly experienced by adults with CP. Based on a systematic literature review, we suggest (1) guidelines for neurologic surveillance and neurologist referral and (2) clinical research questions regarding the evolving neurologic risks for adults with CP. ANN NEUROL 2021;89:860-871., (© 2021 American Neurological Association.)

Purpose: Burkitt lymphoma (BL) has unique biology and clinical course but lacks a standardized prognostic model. We developed and validated a novel prognostic index specific for BL to aid risk stratification, interpretation of clinical trials, and targeted development of novel treatment approaches., Methods: We derived the BL International Prognostic Index (BL-IPI) from a real-world data set of adult patients with BL treated with immunochemotherapy in the United States between 2009 and 2018, identifying candidate variables that showed the strongest prognostic association with progression-free survival (PFS). The index was validated in an external data set of patients treated in Europe, Canada, and Australia between 2004 and 2019., Results: In the derivation cohort of 633 patients with BL, age ≥ 40 years, performance status ≥ 2, serum lactate dehydrogenase > 3× upper limit of normal, and CNS involvement were selected as equally weighted factors with an independent prognostic value. The resulting BL-IPI identified groups with low (zero risk factors, 18% of patients), intermediate (one factor, 36% of patients), and high risk (≥ 2 factors, 46% of patients) with 3-year PFS estimates of 92%, 72%, and 53%, respectively, and 3-year overall survival estimates of 96%, 76%, and 59%, respectively. The index discriminated outcomes regardless of HIV status, stage, or first-line chemotherapy regimen. Patient characteristics, relative size of the BL-IPI groupings, and outcome discrimination were consistent in the validation cohort of 457 patients, with 3-year PFS estimates of 96%, 82%, and 63% for low-, intermediate-, and high-risk BL-IPI, respectively., Conclusion: The BL-IPI provides robust discrimination of survival in adult BL, suitable for use as prognostication and stratification in trials. The high-risk group has suboptimal outcomes with standard therapy and should be considered for innovative treatment approaches.

Introduction: Nontechnical skills (NTS) have been acknowledged to be important for medical students and can be linked to improved clinical performance. However, existing tools to evaluate these within a simulated setting address only a limited number of NTS. The Medical Students' Nontechnical Skills (Medi-StuNTS) behavioral marker system (BMS) outlines 5 categories of NTS for medical students. This study aimed to seek evidence for completeness and content validity to refine the BMS and to ascertain which NTS are essential for medical students., Methods: We asked 128 workshop participants if they felt there were any missing or irrelevant items in Medi-StuNTS system. A subject matter expert panel (n = 10) rated how essential they considered each item in the BMS. An Item-Content Validity Index was calculated for each skill element and the Scale-Content Validity Index was calculated as a measure of content validity of the full system., Results: Of the workshop participants, 78.9% felt that there were no missing items and 93% felt that there were no irrelevant items. Potentially missing items highlighted were as follows: "working in a hierarchy," "leadership," "awareness of the emotional state of other team members," and "nonverbal communication." Fourteen of 16 skill elements achieved the recommended level for content validity (Item-Content Validity Index ≥ 0.78), and the Scale-Content Validity Index was higher than the acceptable level (≥0.8)., Conclusions: Evidence for completeness and content validity of Medi-StuNTS has been demonstrated. There is a far wider range of NTS that seem to be essential for medical students than those assessed by tools developed before Medi-StuNTS. Medi-StuNTS provides comprehensive cover of the essential NTS required by medical students, with specific reference to the skill categories "self-awareness" and "escalating care," which do not feature in other tools for assessing NTS in this group., Competing Interests: The authors declare no conflict of interest., (Copyright © 2020 Society for Simulation in Healthcare.)

Carbon nanothreads, which are one-dimensional sp 3 -rich polymers, combine high tensile strength with flexibility owing to subnanometer widths and diamond-like cores. These extended carbon solids are constructed through pressure-induced polymerization of sp 2 molecules such as benzene. Whereas a few examples of carbon nanothreads have been reported, the need for high onset pressures (≥17 GPa) to synthesize them precludes scalability and limits scope. Herein, we report the scalable synthesis of carbon nanothreads based on molecular furan, which can be achieved through ambient temperature pressure-induced polymerization with an onset reaction pressure of only 10 GPa due to its lessened aromaticity relative to other molecular precursors. When slowly compressed to 15 GPa and gradually decompressed to 1.5 GPa, a sharp 6-fold diffraction pattern is observed in situ , indicating a well-ordered crystalline material formed from liquid furan. Single-crystal X-ray diffraction (XRD) of the reaction product exhibits three distinct d -spacings from 4.75 to 4.9 Å, whose size, angular spacing, and degree of anisotropy are consistent with our atomistic simulations for crystals of furan nanothreads. Further evidence for polymerization was obtained by powder XRD, Raman/IR spectroscopy, and mass spectrometry. Comparison of the IR spectra with computed vibrational modes provides provisional identification of spectral features characteristic of specific nanothread structures, namely syn , anti , and syn/anti configurations. Mass spectrometry suggests that molecular weights of at least 6 kDa are possible. Furan therefore presents a strategic entry toward scalable carbon nanothreads.

Objective: While weight-bearing radiographs are considered the optimal method for evaluation of joint spaces in osteoarthritis, non-weight-bearing radiographs are often performed. The purpose of this study is to evaluate the rate of follow-up radiographs in patients receiving non-weight-bearing radiographs for chronic knee pain in the outpatient setting, compared with patients receiving weight-bearing radiographs., Materials and Methods: Consecutive patients who received non-weight-bearing knee radiographs for chronic knee pain between January 1, 2018, and June 15, 2019, were included. Exclusion criteria included trauma, concern for infection or tumor, and post-surgical radiographs. An age- and sex-matched control group of 100 patients who received weight-bearing knee radiographs was compiled. The proportion of follow-up radiographs within 1 year was compared between the study and control groups with chi-squared tests., Results: Four hundred non-weight-bearing knee radiographic examinations were included. There were 74/400 (18.5%) follow-up radiographs within 12 months. All follow-up radiographs were weight-bearing. In the control group, 4/100 (4%) had follow-up weight-bearing radiographs within 1 year (p < 0.001)., Conclusion: Outpatients who underwent non-weight-bearing knee radiographs for chronic pain had a higher frequency of repeat imaging than those who initially underwent weight-bearing knee radiographs. These results suggest that non-weight-bearing knee radiographs are of lower clinical utility compared with weight-bearing radiographs.

Introduction: Many clinical faculty members are challenged by competing factors of scholarly productivity, education, service obligations, and patient care. A team-based approach has the potential to synergistically increase productivity and mitigate factors associated with burnout., Methods: The purpose of this report is to discuss a prototype for a small, team-based, practice-oriented collaborative approach to advancing critical care pharmacy practice through research and education. Productivity was evaluated in the areas of scholarship and teaching., Results: This team was formed in 2017 and includes five critical care faculty across four campuses from a single academic institution. This collaborative has published peer-reviewed articles, secured grant funding, and developed novel teaching modalities., Conclusions: Challenges encountered include timeline adherence, development of uniform data collection processes, clarifying roles and expectations for different projects, and authorship. This team may act as a prototype for clinical faculty teams to enhance engagement and scholarship productivity in a practice-based setting., (Published by Elsevier Inc.)

Problem: No South Australian study has previously investigated the role of midwives in the promotion and provision of antenatal influenza immunisation., Background: Influenza acquired in pregnancy can have serious sequalae for both mother and foetus. Recent studies have demonstrated that influenza vaccine in pregnancy is both safe and effective. Despite this, evidence suggests that vaccine uptake in pregnancy is suboptimal in both Australia and worldwide., Aim: The aim of this study was to investigate the role of midwives in the promotion and provision of antenatal influenza vaccine and, to provide a statistical and thematic description of the barriers and enablers midwives encounter., Methods: This mixed method study incorporated a cross sectional on-line survey and in-depth interviews conducted with midwives, employed in urban and regional South Australia., Findings: Quantitative data were available for 137 midwives and 10 midwives participated in the interviews. Recruitment for the interview phase was through the last question on the survey. Whilst all midwives indicated that education and vaccine promotion were part of their role, immunisation knowledge varied between Registered Nurse/Midwives (RM/RN) 80% and Registered Midwives (RM) 48.90% ( p  = 0.001). Quantitative data showed that only 43% of midwives felt sufficiently educated to provide the vaccine. Midwives who had received formal immunisation training were more likely to recommend the vaccine 93.7% ( p  = 0.001). Qualitative data confirmed these results and identified the lack of immunisation education as a barrier to practise., Conclusion: Midwives identified an immunisation knowledge deficit. Midwives who had received immunisation education were more likely to actively promote and provide the vaccine to pregnant women. These findings indicate the need for more immunisation education of midwives in both tertiary and practice settings., (© 2020 Australian College of Midwives. Published by Elsevier Ltd. All rights reserved.)

What Is Known and Objective: Advanced Cardiovascular Life Support (ACLS) is an integrated, team-based approach to optimizing patient outcomes during acute cardiovascular events. Due to the fast-paced, high-stress environment, inherent strengths may impact performance and confidence with ACLS skills. The objective of this study was to assess pharmacist perceptions regarding strengths deemed important during emergency cardiovascular response., Methods: An electronic survey was administered to members of the American College of Clinical Pharmacists Critical Care, Cardiology, Internal Medicine, Emergency Medicine and Pediatrics Practice and Research Network listservs. The survey assessed the top 5 strengths deemed important for being part of an emergency response team, a pharmacist's role in ACLS and a team leader's role in ACLS. The primary outcome was top strengths required for pharmacist involvement in ACLS. Descriptive statistics were used to present survey results., Results: Of the 359 responses included, nearly all respondents had been certified by the American Heart Association in ACLS and/or Pediatric Advanced Life Support (PALS). The top CliftonStrengths ® themes considered important for a pharmacist's role in ACLS were communication, adaptability, analytical, focus and responsibility. The top CliftonStrengths ® themes considered important for the team leader's role in ACLS were communication, command, analytical, focus and adaptability. The top CliftonStrengths ® themes important for an emergency response team were communication, adaptability, focus, analytical and command., What Is New and Conclusions: By determining the personality traits perceived to be associated with high performance in ACLS, approaches can be taken to personalize student learning in order to train "practice-ready" pharmacists that can be integral members of the ACLS team., (© 2020 John Wiley & Sons Ltd.)

We examined adults with untreated Burkitt lymphoma (BL) from 2009 to 2018 across 30 US cancer centers. Factors associated with progression-free survival (PFS) and overall survival (OS) were evaluated in univariate and multivariate Cox models. Among 641 BL patients, baseline features included the following: median age, 47 years; HIV+, 22%; Eastern Cooperative Oncology Group (ECOG) performance status (PS) 2 to 4, 23%; >1 extranodal site, 43%; advanced stage, 78%; and central nervous system (CNS) involvement, 19%. Treatment-related mortality was 10%, with most common causes being sepsis, gastrointestinal bleed/perforation, and respiratory failure. With 45-month median follow-up, 3-year PFS and OS rates were 64% and 70%, respectively, without differences by HIV status. Survival was better for patients who received rituximab vs not (3-year PFS, 67% vs 38%; OS, 72% vs 44%; P < .001) and without difference based on setting of administration (ie, inpatient vs outpatient). Outcomes were also improved at an academic vs community cancer center (3-year PFS, 67% vs 46%, P = .006; OS, 72% vs 53%, P = .01). In multivariate models, age ≥ 40 years (PFS, hazard ratio [HR] = 1.70, P = .001; OS, HR = 2.09, P < .001), ECOG PS 2 to 4 (PFS, HR = 1.60, P < .001; OS, HR = 1.74, P = .003), lactate dehydrogenase > 3× normal (PFS, HR = 1.83, P < .001; OS, HR = 1.63, P = .009), and CNS involvement (PFS, HR = 1.52, P = .017; OS, HR = 1.67, P = .014) predicted inferior survival. Furthermore, survival varied based on number of factors present (0, 1, 2 to 4 factors) yielding 3-year PFS rates of 91%, 73%, and 50%, respectively; and 3-year OS rates of 95%, 77%, and 56%, respectively. Collectively, outcomes for adult BL in this real-world analysis appeared more modest compared with results of clinical trials and smaller series. In addition, clinical prognostic factors at diagnosis identified patients with divergent survival rates., (© 2021 by The American Society of Hematology.)

Objective: To validate a semi-automated software method of quantifying knee osteoarthritis (KOA) related effusion-synovitis (ES) and Hoffa-synovitis (HS) on MRI., Materials and Methods: 301 subjects were randomly selected from the FNIH sub cohort, a nested case control study within the Osteoarthritis Initiative (OAI), and distributed into 4 groups based on pain and radiographic progression. Measurements of ES and HS volume were made by 2 readers. Criterion validation was assessed through comparison with the MRI Osteoarthritis Knee Score (MOAKS) and the Spearman correlation coefficient r value. Reader reliability was measured on a subset of 30 subjects and intra-class correlation coefficients (ICCs). Clinical validity was assessed based on case control status using logistic regression and the area under the curve (AUC)., Results: ES volume was highly correlated with MOAKS Scores (r ​= ​0.74), as was the HS measure but to a lesser extent (r ​= ​0.55). For ES, the intra-reader and intra-reader precision ICCs were 0.83 and 0.95 respectively and 0.98 and 0.96 for HS. For clinical validity, we found similar AUC values when comparing the software method to MOAKS. The average reader time was less than 15 ​min per knee for both ES and HS., Conclusion: We have demonstrated the validity of an efficient, accurate, and rapid ES and HS measurement method for KOA using MRI. To our knowledge, this is the first such software to measure both ES and HS. This method will offer an objective and efficient tool for clinical trials and other epidemiologic studies of KOA., Competing Interests: The authors declare that they have no conflict of interest., (© 2021 The Authors.)

Although immunohistochemistry of tissue sections has been the gold standard for analyzing tissue structure and cellular localization, this approach has significant shortcomings when it comes to analyzing complex and heterogeneous tissues such as the bone marrow with rare cells like hematopoietic stem cells (HSCs). Hence, studying rare cells and their relationship with the surrounding heterogenous microenvironment requires visualization of specifically labeled cells within large intact tissues in three dimensions. Here, we describe a whole mount sternal bone marrow imaging method which has enabled detailed quantitative and qualitative analysis of rare HSCs within the sternal tissue. The methodology is broadly applicable for examining the 3D architecture of niche cells in relation to HSCs.

Due to their shared genetic history, antibodies from the same clonotype often bind to the same epitope. This knowledge is used in immune repertoire mining, where known binders are used to search bulk sequencing repertoires to identify new binders. However, current computational methods cannot identify epitope convergence between antibodies from different clonotypes, limiting the sequence diversity of antigen-specific antibodies that can be identified. We describe how the antibody binding site, the paratope, can be used to cluster antibodies with common antigen reactivity from different clonotypes. Our method, paratyping, uses the predicted paratope to identify these novel cross clonotype matches. We experimentally validated our predictions on a pertussis toxoid dataset. Our results show that even the simplest abstraction of the antibody binding site, using only the length of the loops involved and predicted binding residues, is sufficient to group antigen-specific antibodies and provide additional information to conventional clonotype analysis. Abbreviations : BCR: B-cell receptor; CDR: complementarity-determining region; PTx: pertussis toxoid.

Background: Fluid overload is associated with poor outcomes, but mitigating its occurrence poses significant challenges., Objective: This study sought to assess the impact of hidden fluid volume on fluid overload., Methods: This study was a multi-center, retrospective evaluation of adults admitted to a medical or surgical intensive care unit for at least 72 h. Patients were divided into tertiles (low, moderate, and high) based on the hidden fluid volume received. Hidden fluids were defined as intravenous medications, line flushes, blood products, and enteral nutrition. The primary outcome was the incidence of fluid overload at intensive care unit (day 3). Secondary outcomes included mechanical-ventilation free days and association of hidden fluid volume with fluid overload, length of stay, and mortality., Results: A total of 219 (73 per tertile) were included, with hidden fluid volume comprising ⩽2500, 2501-4400, and >4400 mL in the low, moderate, and high tertiles, respectively. Incidence of fluid overload was significantly different across groups (low: 3%, moderate: 14%, high: 25%; p < 0.001). No difference existed in mechanical-ventilation free days or in-hospital mortality across tertiles. In binary logistic regression, hidden fluid volume received at 3 days was independently associated with fluid overload (odds ratio = 1.40, 95% confidence interval = 1.15-1.70)., Conclusion: The volume of hidden fluid volume administered by intensive care unit day 3 independently predicted development of fluid overload., Competing Interests: Declaration of conflicting interests: The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article., (© The Author(s) 2020.)

Familial hemiplegic migraine is an episodic neurological disorder characterized by transient sensory and motor symptoms and signs. Mutations of the ion pump α2-Na/K ATPase cause familial hemiplegic migraine, but the mechanisms by which α2-Na/K ATPase mutations lead to the migraine phenotype remain incompletely understood. Here, we show that mice in which α2-Na/K ATPase is conditionally deleted in astrocytes display episodic paralysis. Functional neuroimaging reveals that conditional α2-Na/K ATPase knockout triggers spontaneous cortical spreading depression events that are associated with EEG low voltage activity events, which correlate with transient motor impairment in these mice. Transcriptomic and metabolomic analyses show that α2-Na/K ATPase loss alters metabolic gene expression with consequent serine and glycine elevation in the brain. A serine- and glycine-free diet rescues the transient motor impairment in conditional α2-Na/K ATPase knockout mice. Together, our findings define a metabolic mechanism regulated by astrocytic α2-Na/K ATPase that triggers episodic motor paralysis in mice.

Objective: Symptomatic knee osteoarthritis (OA) and meniscal tear are often treated with weight-bearing exercises and without ordering advanced imaging (e.g. MRI). This may lead to missed diagnoses of subchondral insufficiency fracture of the knee (SIFK). Failure to diagnose SIFK has treatment implications, as patients with SIFK are typically managed with a period of reduced weight-bearing. The primary objective of this study is to determine the prevalence of undiagnosed SIFK among persons treated non-operatively for knee pain and suspected meniscal tear(s)., Methods: The randomized controlled trial, TeMPO (Treatment of Meniscal Problems and Osteoarthritis), enrolls subjects whose clinicians suspect concomitant meniscal tear and knee OA. TeMPO participants undergo MRI ordered by the study to confirm meniscal tear. All study-ordered MRIs revealing a fracture were reviewed by two study radiologists who noted features of the fracture and joint. We report prevalence of SIFK and clinical and imaging features on these subjects with 95% confidence intervals., Results: Ten of the 340 study-ordered MRIs had SIFK, resulting in an estimated prevalence of 2.94% (95% CI: 1.15%, 4.71%). Eight of the ten participants with SIFK had fractures located medially. The femur was involved in five of these participants, tibia in four, and both in one. Five of the ten participants did not have meniscal tears., Conclusions: This is the only reported estimate of undiagnosed SIFK in adults with knee pain, to our knowledge. Approximately 3% of patients managed with weight-bearing exercise for suspected meniscal tear may have SIFK, a diagnosis typically treated with reduced weight-bearing approaches., Competing Interests: Competing Interest Statement Drs. Katz and Losina have research grants with Flexion and Samumed. Dr. Losina has a grant with Pfizer and performs consulting work for Velocity, and Regeneron. Dr. Chen has personal fees from SLACK publishing, Stryker, bOne, Pfizer, Avanos, Irrisept, Convatec, 3M, Recro, Heraeus, DePuy-Ethicon, GLG, and UpToDate. Dr. Chen is on the advisory board of Hyalex, is an associate editor of The Journal of Bone and Joint Surgery, and has equity with Sonoran Biosciences, Graftworx, and Joint Purification Systems.

Melphalan at a dose of 200 mg/m 2 (MEL200) remains the standard high dose therapy before autologous stem cell transplantation (ASCT) for multiple myeloma (MM). Intensifying the high dose regimen has shown promising results. We report here 7-year follow up of our novel high dose regimen of busulfan and melphalan followed by bortezomib (BuMelVel). Forty-three MM patients received BuMelVel high dose therapy with pharmacokinetic adjusted busulfan. Outcomes were compared to a matched control cohort from the CIBMTR database ( n  = 162) receiving MEL200. The primary endpoint was progression free survival. Five year PFS was 47% v 30% (95% CI; 32-62) in favor or the BuMelVel group (95% CI; 23-37) ( p  = 0.05). In multivariate analysis for PFS, BuMelVel (HR 0.65; 95% CI 0.44-0.97)( p  = 0.036) was predictive. Similar to recent reports of double alkylator therapy, although depth of response was similar between the BuMelVel group and MEL200, the BUMELVEL group experienced an improved PFS.

Intravenous fluids (IVFs) are the most common drugs administered in the intensive care unit. Despite the ubiquitous use, IVFs are not benign and carry significant risks associated with under- or overadministration. Hypovolemia is associated with decreased organ perfusion, ischemia, and multi-organ failure. Hypervolemia and volume overload are associated with organ dysfunction, delayed liberation from mechanical ventilation, and increased mortality. Despite appropriate provision of IVF, adverse drug effects such as electrolyte abnormalities and acid-base disturbances may occur. The management of volume status in critically ill patients is both dynamic and tenuous, a process that requires frequent monitoring and high clinical acumen. Because patient-specific considerations for fluid therapy evolve across the continuum of critical illness, a standard approach to the assessment of fluid needs and prescription of IVF therapy is necessary. We propose the principle of "fluid stewardship," guided by 4 rights of medication safety: right patient, right drug, right route, and right dose. The successful implementation of fluid stewardship will aid pharmacists in making decisions regarding IVF therapy to optimize hemodynamic management and improve patient outcomes. Additionally, we highlight several areas of focus for future research, guided by the 4 rights construct of fluid stewardship.

Acute injuries to the ankle are frequently encountered in the setting of the emergency room, sport, and general practice. This ACR Appropriateness Criteria defines best practices for imaging evaluation for several variants of patients presenting with acute ankle trauma. The variants include scenarios when Ottawa Rules can be evaluated, when there are exclusionary criteria, when Ottawa Rules cannot be evaluated, as well as specific injuries. Clinical scenarios are followed by the imaging choices and their appropriateness with an accompanying narrative explanation to help physicians to order the most appropriate imaging test. The American College of Radiology Appropriateness Criteria are evidence-based guidelines for specific clinical conditions that are reviewed annually by a multidisciplinary expert panel. The guideline development and revision include an extensive analysis of current medical literature from peer reviewed journals and the application of well-established methodologies (RAND/UCLA Appropriateness Method and Grading of Recommendations Assessment, Development, and Evaluation or GRADE) to rate the appropriateness of imaging and treatment procedures for specific clinical scenarios. In those instances where evidence is lacking or equivocal, expert opinion may supplement the available evidence to recommend imaging or treatment., (Copyright © 2020 American College of Radiology. Published by Elsevier Inc. All rights reserved.)

Introduction: Non-technical skills are recognised to play an integral part in safe and effective patient care. Medi-StuNTS (Medical Students' Non-Technical Skills) is a behavioural marker system developed to enable assessment of medical students' non-technical skills. This study aimed to assess whether newly trained raters with high levels of clinical experience could achieve reliability coefficients of >0.7 and to compare differences in inter-rater reliability of raters with varying clinical experience., Methods: Forty-four raters attended a workshop on Medi-StuNTS before independently rating three videos of medical students participating in immersive simulation scenarios. Data were grouped by raters' levels of clinical experience. Inter-rater reliability was assessed by calculating intraclass correlation coefficients (ICC)., Results: Eleven raters with more than 10 years of clinical experience achieved single-measure ICC of 0.37 and average-measures ICC of 0.87. Fourteen raters with more than or equal to 5 years and less than 10 years of clinical experience achieved single-measure ICC of 0.09 and average-measures ICC of 0.59. Nineteen raters with less than 5 years of clinical experience achieved single-measure ICC of 0.09 and average-measures ICC 0.65., Conclusions: Using 11 newly trained raters with high levels of clinical experience produced highly reliable ratings that surpassed the prespecified inter-rater reliability standard; however, a single rater from this group would not achieve sufficiently reliable ratings. This is consistent with previous studies using other medical behavioural marker systems. This study demonstrated a decrease in inter-rater reliability of raters with lower levels of clinical experience, suggesting caution when using this population as raters for assessment of non-technical skills., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2021. No commercial re-use. See rights and permissions. Published by BMJ.)

As opportunistic omnivores, humans are evolutionarily adapted to obtain calories and nutrients from both plant and animal food sources. Today, many people overconsume animal products, often-processed meats high in saturated fats and chemical additives. Alternatively, strict veganism can cause nutritional deficiencies and predispose to osteopenia, sarcopenia, and anemia. A logical compromise is a plant-rich diet with fish/seafood as principal sources of animal food. This paper reviews cumulative evidence regarding diet and health, incorporating data from landmark clinical trials of the Mediterranean diet and recommendations from recent authoritative guidelines, to support the hypothesis that a Pesco-Mediterranean diet is ideal for optimizing cardiovascular health. The foundation of this diet is vegetables, fruits, nuts, seeds, legumes, whole grains, and extra-virgin olive oil with fish/seafood and fermented dairy products. Beverages of choice are water, coffee, and tea. Time-restricted eating is recommended, whereby intermittent fasting is done for 12 to 16 h each day., (Copyright © 2020 The Authors. Published by Elsevier Inc. All rights reserved.)

Mouse embryonic stem cells (ESCs) cultured in defined medium resemble the pre-implantation epiblast in the ground state, with full developmental capacity including the germline. β-Catenin is required to maintain ground state pluripotency in mouse ESCs, but its exact role is controversial. Here, we reveal a Tcf3-independent role of β-catenin in restraining germline and somatic lineage differentiation genes. We show that β-catenin binds target genes with E2F6 and forms a complex with E2F6 and HMGA2 or E2F6 and HP1γ. Our data indicate that these complexes help β-catenin restrain and fine-tune germ cell and neural developmental potential. Overall, our data reveal a previously unappreciated role of β-catenin in preserving lineage differentiation integrity in ground state ESCs., (Copyright © 2020 The Authors. Published by Elsevier Inc. All rights reserved.)

Background The overall rate of hip fractures not identified on radiographs but that require surgery (ie, surgical hip fractures) remains unclear in elderly patients who are suspected to have such fractures based on clinical findings. Moreover, the importance of advanced imaging in these patients has not been comprehensively assessed. Purpose To estimate the frequency of radiographically occult hip fracture in elderly patients, to define the higher-risk subpopulation, and to determine the diagnostic performance of CT and bone scanning in the detection of occult fractures by using MRI as the reference standard. Materials and Methods A literature search was performed to identify English-language observational studies published from inception to September 27, 2018. Studies were included if patients were clinically suspected to have hip fracture but there was no radiographic evidence of surgical hip fracture (including absence of any definite fracture or only presence of isolated greater trochanter [GT] fracture). The rate of surgical hip fracture was reported in each study in which MRI was used as the reference standard. The pooled rate of occult fracture, diagnostic performance of CT and bone scanning, and strength of evidence (SOE) were assessed. Results Thirty-five studies were identified (2992 patients; mean age, 76.8 years ± 6.0 [standard deviation]; 66% female). The frequency of radiographically occult surgical hip fracture was 39% (1110 of 2835 patients; 95% confidence interval [CI]: 35%, 43%) in studies of patients with no definite radiographic fracture and 92% (134 of 157 patients; 95% CI: 83%, 98%) in studies of patients with radiographic evidence of isolated GT fracture (moderate SOE). The frequency of occult fracture was higher in patients aged at least 80 years (44%, 529 of 1184), those with an equivocal radiographic report (58%, 71 of 126), and those with a history of trauma (41%, 977 of 2370) (moderate SOE). CT and bone scanning yielded comparable diagnostic performance in the detection of radiographically occult hip fracture ( P = .67), with a sensitivity of 79% and 87%, respectively (low SOE). Conclusion Elderly patients with acute hip pain and negative or equivocal findings at initial radiography have a high frequency of occult hip fractures. Therefore, the performance of advanced imaging (preferably MRI) may be clinically appropriate in all such patients. © RSNA, 2020 Online supplemental material is available for this article.

Species introductions provide opportunities to quantify rates and patterns of evolutionary change in response to novel environments. Alewives ( Alosa pseudoharengus ) are native to the East Coast of North America where they ascend coastal rivers to spawn in lakes and then return to the ocean. Some populations have become landlocked within the last 350 years and diverged phenotypically from their ancestral marine population. More recently, alewives were introduced to the Laurentian Great Lakes (~150 years ago), but these populations have not been compared to East Coast anadromous and landlocked populations. We quantified 95 years of evolution in foraging traits and overall body shape of Great Lakes alewives and compared patterns of phenotypic evolution of Great Lakes alewives to East Coast anadromous and landlocked populations. Our results suggest that gill raker spacing in Great Lakes alewives has evolved in a dynamic pattern that is consistent with responses to strong but intermittent eco-evolutionary feedbacks with zooplankton size. Following their initial colonization of Lakes Ontario and Michigan, dense alewife populations likely depleted large-bodied zooplankton, which drove a decrease in alewife gill raker spacing. However, the introduction of large, non-native zooplankton to the Great Lakes in later decades resulted in an increase in gill raker spacing, and present-day Great Lakes alewives have gill raker spacing patterns that are similar to the ancestral East Coast anadromous population. Conversely, contemporary Great Lakes alewife populations possess a gape width consistent with East Coast landlocked populations. Body shape showed remarkable parallel evolution with East Coast landlocked populations, likely due to a shared response to the loss of long-distance movement or migrations. Our results suggest the colonization of a new environment and cessation of migration can result in rapid parallel evolution in some traits, but contingency also plays a role, and a dynamic ecosystem can also yield novel trait combinations., (© 2020 The Authors. Evolutionary Applications published by John Wiley & Sons Ltd.)

Background: Histological and epidemiological data suggest that increased signal intensity at the proximal patellar tendon on magnetic resonance imaging is a response to tendon loading. As patellofemoral geometry is a mediator of loading, we examined the association between patellofemoral geometry and the prevalence of increased signal intensity at the patellar tendon in community-based middle-aged adults., Methods: Two hundred-one adults aged 25-60 years in a study of obesity and musculoskeletal health had the patellar tendon assessed from magnetic resonance imaging. Increased signal intensity at the proximal patellar tendon was defined as hyper-intense regions of characteristic pattern, size and distribution on both T1- and T2-weighted sequences. Indices of patellofemoral geometry, including Insall-Salvati ratio, patellofemoral congruence angle, sulcus angle, and lateral condyle-patella angle, were measured from magnetic resonance imaging using validated methods. Binary logistic regression was used to examine the association between patellofemoral geometrical indices and the prevalence of increased signal intensity at the patellar tendon., Results: The prevalence of increased signal intensity at the patellar tendon was 37.3%. A greater Insall-Salvati ratio (odds ratio 0.80, 95% confidence interval 0.66-0.97 per 0.1 change in the ratio, p = 0.02), indicative of a higher-riding patella, and a larger patellofemoral congruence angle (odds ratio 0.91, 95% confidence interval 0.85-0.98 per 5 degree change in the angle, p = 0.01), indicating a more laterally placed patella, were associated with reduced odds of increased signal intensity at the patellar tendon. Sulcus angle and lateral condyle-patella angle were not significantly associated with the odds of increased signal intensity at the patellar tendon., Conclusions: In community-based asymptomatic middle-aged adults, increased signal intensity at the patellar tendon was common and associated with Insall-Salvati ratio and patellofemoral congruence angle, suggesting a biomechanical mechanism. Such work is likely to inform tissue engineering and cell regeneration approaches to improving outcomes in those with tendon pathology.

Aberrant migration of inhibitory interneurons can alter the formation of cortical circuitry and lead to severe neurologic disorders including epilepsy, autism, and schizophrenia. However, mechanisms involved in directing the migration of interneurons remain incompletely understood. Using a mouse model, we performed live-cell confocal microscopy to explore the mechanisms by which the c-Jun NH 2 -terminal kinase (JNK) pathway coordinates leading process branching and nucleokinesis, two cell biological processes that are essential for the guided migration of cortical interneurons. Pharmacological inhibition of JNK signaling disrupts the kinetics of leading process branching, rate and amplitude of nucleokinesis, and leads to the rearward mislocalization of the centrosome and primary cilium to the trailing process. Genetic loss of Jnk from interneurons also impairs leading process branching and nucleokinesis, suggesting that important mechanics of interneuron migration depend on the intrinsic activity of JNK. These findings highlight key roles for JNK signaling in leading process branching, nucleokinesis, and the trafficking of centrosomes and cilia during interneuron migration, and further implicates JNK signaling as an important mediator of cortical development., (Copyright © 2020 Smith et al.)

Temporomandibular disorders encompass multiple pathologies of the temporomandibular joint that manifest as middle/inner ear symptoms, headache, and/or localized TMJ symptoms. There is an important although somewhat limited role of imaging in the diagnostic evaluation of temporomandibular disorders. In this manuscript, we provide a comprehensive review of TMJ anatomy, outline potentially important features of TMJ disc ultrastructure and biochemistry in comparison with the intervertebral disc and knee meniscus, and provide imaging examples of the TMJ abnormalities currently evaluable with MRI and CT. In addition, we provide an overview of emerging and investigational TMJ imaging techniques in order to encourage further imaging research based on the biomechanical alterations of the TMJ disc.

The increase of antimicrobial resistance (AMR), and lack of new classes of licensed antimicrobials, have made alternative treatment options for AMR pathogens increasingly attractive. Recent studies have demonstrated anti-bacterial efficacy of a humanised monoclonal antibody (mAb) targeting the O25b O-antigen of Escherichia coli ST131. To evaluate the phenotypic effects of antibody binding to diverse clinical E. coli ST131 O25b bacterial isolates in high-throughput, we designed a novel mAb screening method using high-content imaging (HCI) and image-based morphological profiling to screen a mAb targeting the O25b O-antigen. Screening the antibody against a panel of 86 clinical E. coli ST131 O25:H4 isolates revealed 4 binding phenotypes: no binding (18.60%), weak binding (4.65%), strong binding (69.77%) and strong agglutinating binding (6.98%). Impaired antibody binding could be explained by the presence of insertion sequences or mutations in O-antigen or lipopolysaccharide core biosynthesis genes, affecting the amount, structure or chain length of the O-antigen. The agglutinating binding phenotype was linked with lower O-antigen density, enhanced antibody-mediated phagocytosis and increased serum susceptibly. This study highlights the need to screen candidate mAbs against large panels of clinically relevant isolates, and that HCI can be used to evaluate mAb binding affinity and potential functional efficacy against AMR bacteria.

Achieving a viable process for three-dimensional (3D) printing of ceramics is a sought-after goal in a wide range of fields including electronics and sensors for harsh environments, microelectromechanical devices, energy storage materials, and structural materials, among others. Low laser absorption of ceramic powders renders available additive manufacturing (AM) technologies for metals not suitable for ceramics. Polymer solutions that can be converted to ceramics (preceramic polymers) offer a unique opportunity to 3D-print ceramics; however, due to the low viscosity of these polymers, so far, their 3D printing has only been possible by combining them with specialized light-sensitive agents and subsequently cross-linking them layer by layer by rastering an optical beam. The slow rate, lack of scalability to large specimens, and specialized chemistry requirements of this optical process are fundamental limitations. Here, we demonstrate 3D printing of ceramics enabled by dispensing the preceramic polymer at the tip of a moving nozzle into a gel that can reversibly switch between fluid and solid states, and subsequently thermally cross-linking the entire printed part "at-once" while still inside the same gel. The solid gel, which is composed of mineral oil and silica nanoparticles, converts to fluid at the tip of the moving nozzle, allows the polymer solution to be dispensed, and quickly returns to a solid state to maintain the geometry of the printed polymer both during printing and the subsequent high-temperature (160 °C) cross-linking. We retrieve the cross-linked part from the gel and convert it to ceramic by high-temperature pyrolysis. This scalable process opens up new opportunities for low-cost and high-speed production of complex three-dimensional ceramic parts and will be widely used for high temperature and corrosive environment applications, including electronics and sensors, microelectromechanical systems, energy and structural applications.