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Failure by fatigue is one mechanism by which ligaments can rupture, with the accumulation of damage gradually degrading the ligament strength. Baseball pitchers who perform repeated high-level throwing continuously subject the medial ligament complex of the elbow to extreme levels of loading, which can lead to fatigue and eventual rupture. This study sought to investigate this behavior and quantify the fatigue properties of the anterior bundle of the medial collateral ligament (AMCL) with respect to valgus elbow torque. Eleven pairs of cadaveric elbow specimens were used for this study. One side of each pair was tested in vertical elongation at four flexion angles and then tested to failure at 90° of flexion. The contralateral specimens were tested in valgus fatigue at 90° of flexion using a specialized apparatus with application of known moments based on the elongation failure load. The average tensile failure load for the AMCL was 595.3 ± 201.9 N. During cycling, the average increase in the maximum valgus rotation angle was 4.77° ± 2.82°. The average maximum stretch of the AMCL middle band increased from 1.066 ± 0.017 to 1.076 ± 0.018 near the time of fatigue failure. The average cycles to failure for specimens tested at 90% and 80% of the estimated failure torque were 3211 ± 4721.33 and 25063 ± 30487.58, respectively. The nonlinear non-dimensional fatigue life and damage accretion results work in conjunction to predict the fatigue properties for a valgus elbow motion of arbitrary torque magnitude at 90° of elbow flexion., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Background: Malposition of the sesamoids relative to the first metatarsal head may relate to intersesamoid crista underdevelopment or erosion. Using 3-dimensional models created from weightbearing CT (WBCT) scans, the current work examined crista volume and its relationship to first metatarsal pronation and sesamoid station., Methods: Thirty-eight hallux valgus (HV) patients and 10 normal subjects underwent weightbearing or simulated WBCT imaging. The crista was outlined by the inferior articular surface, and a line was drawn to connect the lowest point of each sulcus on either side of the intersesamoidal crista throughout the length of the crista. The volume was calculated. Sesamoid station and first metatarsal pronation were calculated from the 3D reconstructions. The mean crista volumes between HV and normal patients were statistically compared, as were the crista volume and pronation angle between sesamoid stations., Results: The mean crista volume in HV patients was 80.10 ± 35 mm 3 and in normal subjects was 150.64 ± 24 mm 3 , which differed significantly between the 2 groups ( P < .001). Mean crista volumes were found to be statistically significantly different between the sesamoid stations ( P < .001) with decreasing crista volumes significantly and strongly correlated with increasing sesamoid station ( r = -0.80, P < .001). There was no difference in the mean pronation angle between the 4 sesamoid stations ( P = .37). The pronation angle was not associated with crista volume ( P = .52)., Conclusion: HV patients have lower mean crista volume than normal patients. Crista volume is correlated with sesamoid station. Pronation of the first metatarsal was not associated with crista volume., Clinical Relevance: Crista volume may offer an additional determinant for the severity of hallux valgus.

Description: The Scientific Medical Policy Committee (SMPC) of the American College of Physicians (ACP) developed these living, rapid practice points to summarize the current best available evidence on the antibody response to SARS-CoV-2 infection and protection against reinfection with SARS-CoV-2. This is version 2 of the ACP practice points, which serves to update version 1, published on 16 March 2021. These practice points do not evaluate vaccine-acquired immunity or cellular immunity., Methods: The SMPC developed this version of the living, rapid practice points based on an updated living, rapid, systematic review conducted by the Portland VA Research Foundation and funded by the Agency for Healthcare Research and Quality., Practice Point 1: Do not use SARS-CoV-2 antibody tests for the diagnosis of SARS-CoV-2 infection., Practice Point 2: Do not use SARS-CoV-2 antibody tests to predict the degree or duration of natural immunity conferred by antibodies against reinfection, including natural immunity against different variants., Retirement From Living Status: Although natural immunity remains a topic of scientific interest, this topic is being retired from living status given the availability of effective vaccines for SARS-CoV-2 and widespread recommendations for and prevalence of their use. Currently, vaccination is the best clinical recommendation for preventing infection, reinfection, and serious illness from SARS-CoV-2 and its variants.

Objective: To identify the most predictive parameters of ovarian malignancy and develop a machine learning (ML) based algorithm to preoperatively distinguish between a benign and malignant pelvic mass., Methods: Retrospective study of 70 predictive parameters collected from 140 women with a pelvic mass. The women were split into a 3:1 "training" to "testing" dataset. Feature selection was performed using Gini impurity through an embedded random forest model and principal component analysis. Nine unique ML classifiers were assessed across a variety of model-specific hyperparameters using 25 bootstrap resamples of the training data. Model predictions were then combined into an ensemble stack by LASSO regression. The final ensemble stack and individual classifiers were then applied to the testing dataset to assess model performance., Results: Feature selection identified HE4, CA125, and transferrin as three predictive parameters of malignancy. Assessment of the ensemble stack on the testing dataset outperformed all individual ML classifiers in predicting malignancy. The ensemble stack demonstrated an accuracy of 97.1%, a receiver operating characteristic (ROC) area under the curve (AUC) of 0.951, and a sensitivity of 93.3% with a specificity of 100%., Conclusions: Combining the measurement of three distinct biomarkers with the stacking of multiple ML classifiers into an ensemble can provide valuable preoperative diagnostic predictions for patients with a pelvic mass.

Background: CA125 is the gold standard serum biomarker for monitoring patients with epithelial ovarian cancer (EOC). Human epididymal protein 4 (HE4) is a novel serum biomarker for EOC patients., Objective: The objective of this trial was to examine the utility of measuring serum HE4 levels for monitoring EOC patients and to compare HE4 performance parameters to serum CA125., Methods: A retrospective trial using residual longitudinal serum samples drawn during treatment and monitoring from EOC patients. Serum CA125 and HE4 levels were analyzed at each time point, and a velocity of change was calculated and correlated with clinical status. The null hypothesis was that HE4 is inferior to CA125, and this was tested using concordance and two-sided Fisher's exact testing. McNemar's test was used to assess the overall agreement of the two assays with the clinical status., Results: A total of 129 patients with 272 separate clinical periods and 1739 events (serum samples) were evaluated. Using a 25% change in serum biomarker levels to indicate change in disease status, the accuracy and NPV determined for HE4 versus CA125 were 81.8% versus 82.6% (p = 0.846) and 87.4% versus 89.7% (p = 0.082), respectively. Concordance comparison of HE4 accuracy / CA125 accuracy was 0.990, indicating HE4 was not inferior to CA125 (McNemar's test p-value = 0.522). Performing a velocity of change analysis, the accuracy and NPV determined for HE4 versus CA125 were 78.3% versus 78.6% (p = 0.995) and 74.9% versus 76.3% (p = 0.815), respectively. Concordance comparison of HE4 velocity accuracy / CA125 velocity accuracy was 0.996, again indicating HE4 was not inferior to CA125 (McNemar's test p-value = 0.884). The combination of HE4 and CA125 velocity changes showed a similar accuracy of 81.3% (p = 0.797 compared to HE4 and CA125 alone) and NPV of 81.1% (p≥0.172 compared to HE4 and CA125 alone), and an increased sensitivity of 70.5% (p≤0.070 compared to HE4 and CA125 alone)., Conclusion: HE4 is equivalent to CA125 for monitoring of EOC patients. The combination of CA125 and HE4 velocities is superior to either marker alone.

Background: Digital nerves will experience tension under normal daily activities, and understanding the amount of tension experienced in these nerves relates directly to the necessary strength in nerve repairs. To begin quantification of tension, the tension borne by the median and digital nerves in cadaveric hands was quantified under conditions of finger hyperextension, nerve distraction, and finger flexion. Methods: Five cadaveric hands were mounted in a special fixture that allowed finger hyperextension and flexion and could apply known distractions while the tension borne by each digital nerve was measured. Sequential dissection exposed the digital nerves so that measurements of tension in the median, common, and proper digital nerves were conducted with finger hyperextension, nerve distraction, and finger flexion. Results: Metacarpophalangeal (MCP) hyperextension of 30° created mean nerve tensions up to 0.64 N, 5 mm of nerve distraction created mean nerve tensions up to 1.23 N, and 90° of MCP flexion relieved up to a mean of 1.18 N of nerve tension. Conclusions: In situ tension is present in the median and digital nerves with digital motion. Finger hyperextension and nerve distraction produce tension, whereas finger flexion reduces tension. Existing nerve repairs are strong enough to withstand in situ nerve tensions produced by reasonable digital motion if the original nerve length is present.

Repair of severed nerves without autograft or allograft has included suture, suture with glue alone, suture with conduit and suture with glue augmentation to conduit, where use of conduit is considered for separation of the nerve ends from 5 mm to 3 cm. Repairs must not only serve acutely to provide apposition of nerve ends but must enable the healing of the nerve. Using biological conduit can place suture at the ends of the conduit while fibrin glue alone eliminates suture but with limited strength. The combination of conduit and glue offers the growth guidance of conduit with sufficient strength from the glue to maintain the nerve within the conduit. The role of fibrin glue in the integrity of the repair remains an open question, however. We sought to determine the factors in the strength of a glue-conduit-nerve construct and include consideration of standard suture repair. Fresh-frozen cadaveric digital nerves were repaired with suture alone, with glue alone or with suture and glue together and then loaded to failure. Previously tested specimens with conduit, suture and glue were considered for comparison. The suture alone (2.02 N) and suture with glue (2.24 N) were not statistically different from each other but were statistically stronger than glue alone (0.15 N). When compared to the earlier results of the strength of conduit with glue (0.65 N), these simple results show that the glue and conduit act together. The increased area over which the glue adheres to the nerve and conduit creates a composite structure stronger than either alone., (Copyright © 2022 by ASME.)

The next two decades are expected to open the door to the first coincident detections of electromagnetic (EM) and gravitational-wave (GW) signatures associated with massive black-hole (MBH) binaries heading for coalescence. These detections will launch a new era of multimessenger astrophysics by expanding this growing field to the low-frequency GW regime and will provide an unprecedented understanding of the evolution of MBHs and galaxies. They will also constitute fundamentally new probes of cosmology and would enable unique tests of gravity. The aim of this Living Review is to provide an introduction to this research topic by presenting a summary of key findings, physical processes and ideas pertaining to EM counterparts to MBH mergers as they are known at the time of this writing. We review current observational evidence for close MBH binaries, discuss relevant physical processes and timescales, and summarize the possible EM counterparts to GWs in the precursor, coalescence, and afterglow stages of a MBH merger. We also describe open questions and discuss future prospects in this dynamic and quick-paced research area., (© The Author(s) 2022.)

Background: Children with advanced cancer and their primary caregivers may experience severe stress and anxiety in coping with their life-threatening condition. As a way to help reduce these stressors and increase overall quality of life, research suggests that animal-assisted interactions may be beneficial when integrated into palliative care., Aims: This pilot study aims to provide evidence for the feasibility and efficacy of a randomised clinical trial using animal-assisted interactions to help improve the quality of life for children with an advanced life-threatening condition and their primary caregivers. This protocol paper outlines the basis of the research, goals, experimental design and methodology.

Objectives: To provide a consensus statement describing best practices and evidence regarding head and neck cancer survivorship., Methods: Key topics regarding head and neck cancer survivorship were identified by the multidisciplinary membership of the American Head and Neck Society Survivorship, Supportive Care & Rehabilitation Service. Guidelines were generated by combining expert opinion and a review of the literature and categorized by level of evidence., Results: Several areas regarding survivorship including dysphonia, dysphagia, fatigue, chronic pain, intimacy, the ability to return to work, financial toxicity, lymphedema, psycho-oncology, physical activity, and substance abuse were identified and discussed. Additionally, the group identified and described the role of key clinicians in survivorship including surgical, medical and radiation oncologists; dentists; primary care physicians; psychotherapists; as well as physical, occupational, speech, and respiratory therapists., Conclusion: Head and neck cancer survivorship is complex and requires a multidisciplinary approach centered around patients and their caregivers. As survival related to head and neck cancer treatment improves, addressing post-treatment concerns appropriately is critically important to our patient's quality of life. There continues to be a need to define effective and efficient programs that can coordinate this multidisciplinary effort toward survivorship., Competing Interests: None of the authors have any conflicts of interest., (© 2021 The Authors. Laryngoscope Investigative Otolaryngology published by Wiley Periodicals LLC on behalf of The Triological Society.)

Introduction: Non-operative management of pelvic ring injuries in the elderly is associated with a high risk of one-year mortality. The majority of these injuries are the result of a low-energy mechanism, however, due to the multiple medical comorbidities in this patient population the injuries are associated with a high degree of morbidity. The purpose of this study was to determine the one-year mortality risk after operative treatment of pelvic ring injuries in a geriatric patient population and the effect of patient and injury characteristics on the risk of mortality., Patients and Methods: We performed a retrospective review of patients over the age of 70 who underwent operative fixation of a pelvic ring injury at two Level 1 trauma centers between January 2016 and June 2019. Medical records were reviewed for patient and injury characteristics including: Charlson Comorbidity Index (CCI), American Society of Anesthesiologists (ASA) physical status score or Injury Severity Score (ISS), hospital and intensive care unit (ICU) length of stay (LOS). The primary outcome of interest was the one-year mortality risk following operative treatment. Secondary outcomes included the effect of patient and injury characteristics on the one-year mortality risk and the hospital LOS., Results: Ninety patients were included with an average age of 79.8  ±  6.5 years. The overall mortality was 8.9% (n = 8) and was significantly associated with the CCI. There was no significant effect related to the ASA physical status score or ISS. The average hospital LOS was 9.2 ± 7.3 days and was associated with the CCI, ASA physical status score, and ISS., Discussion: Non-operative management of pelvic ring injuries in geriatric patients is associated with a high risk of one-year mortality. Our findings suggest operative treatment of these fractures is associated with an acceptable risk of one-year mortality that falls below the commonly reported range for non-operatively managed injuries. Furthermore, the risk of mortality was significantly associated with the patient's pre-injury state as determined by the CCI., Competing Interests: Declaration of Competing Interest The authors have no disclosures to declare., (Copyright © 2021. Published by Elsevier Ltd.)

Objectives: To compare the compressive force generated by a 3.5-mm compression plate with and without provisional fixation using a 2.0-mm minifragment plate., Methods: Fourth generation composite large humeral sawbones underwent transection and were divided into 2 groups. The first group underwent fixation with a 3.5-mm compression plate; the second group underwent provisional fixation with a 2.0-mm plate followed by definitive fixation using a 3.5-mm plate. Using a load cell, the compressive force generated was measured after insertion of each of 2 eccentrical placed screws and the total compression recorded., Results: There was no difference in the force generated after each successive compression screw (P = 0.59 and 0.58, respectively). Likewise, there was no significant difference in the total compression generated when the preload was accounted for (P = 0.93)., Conclusion: Provisional minifragment fixation does not have any adverse effect on the forces generated during compression plating. These findings suggest that provisional minifragment plates do not need to be removed before definitive fixation., Competing Interests: The authors report no conflict of interest., (Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.)

Comprehensive and meaningful policy analysis in the field of physical activity is difficult, not least because of the variable influence of other policy domains. However, in 2011 a Policy Assessment Tool (PAT) was developed by members of the WHO European Network for the Promotion of Health-Enhancing Physical Activity (HEPA Europe) and tested in several different countries. In 2014, Wales joined a global initiative, active healthy kids (AHK) Global Alliance, that supported the development of country level 'Report Cards' scoring a range of indicators that influence physical activity amongst children and young people, one of which was labelled 'Government Strategies and Investments'. For the first two Report Cards this indicator and its associated 'score' was informed subjectively by expert consensus. In 2018, it was decided to utilize the Policy Audit Tool Version 2 (PAT v2) developed by HEPA Europe to aid analysis and to develop and test a scoring rubric aligned to the tool. The subsequent process indicated that the tool could be applied and translated into a 'grade' that could be used in conjunction with the other indicators of the AHK Report Card to generate overall Report Card grades. The use of both the HEPA PAT v2 and the scoring rubric offers an opportunity to provide greater consistency and potential for developing both comparative and trend data when assessing policy impact on physical activity in children and young people. These tools should be utilized by the AHK Global Alliance in future Report Cards., (© The Author(s) 2020. Published by Oxford University Press. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

In response to the COVID-19 pandemic, the Scientific Medical Policy Committee (SMPC) of the American College of Physicians (ACP) began developing "practice points" to provide clinical advice based on the best available evidence for the public, patients, clinicians, and public health professionals. As one of the first organizations in the United States to develop evidence-based clinical guidelines, ACP continues to lead and advance the science of evidence-based medicine by implementing new methods to rapidly publish practice points and maintain them as living advice that regularly assesses and incorporates new evidence. The overarching aim of practice points is to answer targeted key questions for which there is a timely need to synthesize evidence for decision making. The SMPC believes these methods can potentially be adapted to address various clinical and public health topics beyond the COVID-19 pandemic. This article presents an overview of the SMPC's living, rapid practice points development process, which includes a rapid systematic review, use of the GRADE (Grading of Recommendations Assessment, Development and Evaluation) method, use of stringent policies on the disclosure of interests and management of conflicts of interest, incorporating a public (nonclinician) perspective, and maintenance of the documents as living through ongoing surveillance and synthesis of new evidence as it emerges.

Background: There is no consensus in the foot and ankle literature regarding how to measure pronation of the first metatarsal in patients with hallux valgus. The primary purpose of this study was to compare 2 previously published methods for measuring pronation of the first metatarsal and a novel 3-dimensional measurement of pronation to determine if different measurements of pronation are associated with each other., Methods: Thirty patients who underwent a modified Lapidus procedure for their hallux valgus deformity were included in this study. Pronation of the first metatarsal was measured on weightbearing computed tomography (WBCT) scans using the α angle with reference to the floor, a 3-dimensional computer-aided design (3D CAD) calculation with reference to the second metatarsal, and a novel method, called the triplanar angle of pronation (TAP), that included references to both the floor (floor TAP) and base of the second metatarsal (second TAP). Pearson's correlation coefficients were used to determine if the 3 calculated angles of pronation correlated to each other., Results: Preoperative and postoperative α angle and 3D CAD had no correlation with each other ( r = 0.094, P = .626 and r = 0.076, P = .694, respectively). Preoperative and postoperative second TAP and 3D CAD also had no correlation ( r = 0.095, P = .624 and r = 0.320, P = .09, respectively). However, preoperative and postoperative floor TAP and α angle were found to have moderate correlations ( r = 0.595, P = .001 and r = 0.501, P = .005, respectively)., Conclusion: The calculation of first metatarsal pronation is affected by the reference and technique used, and further work is needed to establish a consistent measurement for the foot and ankle community., Level of Evidence: Level III, retrospective cohort study.

The concerted actions of the CNS and the immune system are essential to coordinating the outcome of neuroinflammatory responses. Yet, the precise mechanisms involved in this crosstalk and their contribution to the pathophysiology of neuroinflammatory diseases largely elude us. Here, we show that the CNS-endogenous hedgehog pathway, a signal triggered as part of the host response during the inflammatory phase of multiple sclerosis and experimental autoimmune encephalomyelitis, attenuates the pathogenicity of human and mouse effector CD4 T cells by regulating their production of inflammatory cytokines. Using a murine genetic model, in which the hedgehog signalling is compromised in CD4 T cells, we show that the hedgehog pathway acts on CD4 T cells to suppress the pathogenic hallmarks of autoimmune neuroinflammation, including demyelination and axonal damage, and thus mitigates the development of experimental autoimmune encephalomyelitis. Impairment of hedgehog signalling in CD4 T cells exacerbates brain-brainstem-cerebellum inflammation and leads to the development of atypical disease. Moreover, we present evidence that hedgehog signalling regulates the pathogenic profile of CD4 T cells by limiting their production of the inflammatory cytokines granulocyte-macrophage colony-stimulating factor and interferon-γ and by antagonizing their inflammatory program at the transcriptome level. Likewise, hedgehog signalling attenuates the inflammatory phenotype of human CD4 memory T cells. From a therapeutic point of view, our study underlines the potential of harnessing the hedgehog pathway to counteract ongoing excessive CNS inflammation, as systemic administration of a hedgehog agonist after disease onset effectively halts disease progression and significantly reduces neuroinflammation and the underlying neuropathology. We thus unveil a previously unrecognized role for the hedgehog pathway in regulating pathogenic inflammation within the CNS and propose to exploit its ability to modulate this neuroimmune network as a strategy to limit the progression of ongoing neuroinflammation., (© The Author(s) (2021). Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Objectives: To compare the strength of the inverted triangle (IT) versus the L-shaped cannulated screw fixation technique for stabilizing a Pauwels 2 femoral neck fracture. To demonstrate the risk to the blood supply to the femoral head from a posterior-superior screw., Methods: The IT construct was compared with the L-shaped design in 10 composite femurs. A Pauwels 2 fracture was made with a 5 mm gap. Each specimen was loaded over 5000 cycles, measuring angular/shear displacement then loaded to failure. The data were analyzed using Mann-Whitney U test. Three separate fresh frozen cadavers were injected with low-viscosity epoxy. The intraosseous bloody supply was inspected in each femoral head (no fixation, IT, L-shaped)., Results: There was no difference in angular ( P  = .3) or shear displacement ( P  = .99) between either screw design after cyclical loading. Also, there was not statistical difference in load to failure testing between either construct ( P  = .99). The average load to failure in the IT group was 3204.4 N. The average was 3180.2 N in the L-shaped design. We demonstrated the presence of the intraosseous portion of the lateral epiphyseal vessel in the specimen without screw fixation. This was preserved in the specimen with the L-shaped design but absent in the specimen following IT fixation., Conclusions: The strength of the L-shaped construct was not statistically different than the strength of the IT design. The posterior-superior screw may put the main blood supply to the femoral head at risk and should be avoided., Competing Interests: The authors have no conflicts of interest to disclose., (Copyright © 2021 The Authors. Published by Wolters Kluwer Health, Inc. on behalf of the Orthopaedic Trauma Association.)

Multiple sclerosis (MS) is an idiopathic demyelinating disease in which meningeal inflammation correlates with accelerated disease progression. The study of meningeal inflammation in MS has been limited because of constrained access to MS brain/spinal cord specimens and the lack of experimental models recapitulating progressive MS. Unlike induced models, a spontaneously occurring model would offer a unique opportunity to understand MS immunopathogenesis and provide a compelling framework for translational research. We propose granulomatous meningoencephalomyelitis (GME) as a natural model to study neuropathological aspects of MS. GME is an idiopathic, progressive neuroinflammatory disease of young dogs with a female bias. In the GME cases examined in this study, the meninges displayed focal and disseminated leptomeningeal enhancement on magnetic resonance imaging, which correlated with heavy leptomeningeal lymphocytic infiltration. These leptomeningeal infiltrates resembled tertiary lymphoid organs containing large B cell clusters that included few proliferating Ki67 + cells, plasma cells, follicular dendritic/reticular cells, and germinal center B cell-like cells. These B cell collections were confined in a specialized network of collagen fibers associated with the expression of the lympho-organogenic chemokines CXCL13 and CCL21. Although neuroparenchymal perivascular infiltrates contained B cells, they lacked the immune signature of aggregates in the meningeal compartment. Finally, meningeal B cell accumulation correlated significantly with cortical demyelination reflecting neuropathological similarities to MS. Hence, during chronic neuroinflammation, the meningeal microenvironment sustains B cell accumulation that is accompanied by underlying neuroparenchymal injury, indicating GME as a novel, naturally occurring model to study compartmentalized neuroinflammation and the associated pathology thought to contribute to progressive MS., (Copyright © 2021 by The American Association of Immunologists, Inc.)

Background: The rotator cable (RCa) is an important articular-sided structure of the cuff capsular complex that helps prevent suture pull out during rotator cuff repairs (RCRs) and plays a role in force transmission. Yet, the RCa cannot be located during bursal-sided RCRs. The purpose of this study is to develop a method to locate the RCa in the subacromial space and compare its bursal- and articular-sided dimensions., Methods: In 20 fresh-frozen cadaveric specimens, the RCa was found from the articular side, outlined with stitches, and then evaluated from the bursal side using an easily identifiable reference point, the intersection of a line bisecting the supraspinatus (SS) tendon and posterior SS myotendinous junction (MTJ). Four bursal-sided lengths were measured on the SS-bisecting line as well as the RCa's outside anteroposterior base. For the articular-sided measurements, the rotator cuff capsular complex was detached from bone and optically scanned creating 3D solid models. Using the 3D models, 4 articular-sided lengths were made, including the RCa's inside and outside anteroposterior base., Results: The RCa's medial arch was located 9.9 ± 5.6 mm from the reference point in 10 intact specimens and 4.1 ± 2.4 mm in 10 torn specimens (P = .007). The RCa's width was 10.9 ± 2.1 mm, and the distance from the lateral edge of the RCa to the lateral SS insertion was 13.9 ± 4.8 mm. The bursal- and articular-sided outside anteroposterior base measured 48.1 ± 6.4 mm and 49.6 ± 6.5 mm, respectively (P = .268). The average inside anteroposterior base measurement was 37.3 ± 5.9 mm., Discussion: The medial arch of the RCa can be reliably located during subacromial arthroscopy using the reference point, analogous to the posterior SS MTJ. The RCa is located 10 mm in intact and 4 mm in torn tendons (P = .007) from the posterior SS MTJ. If the above 6-mm shift in location of the RCa is not taken into consideration during rotator cuff suture placement, it could negatively affect time zero repair strength. The inside anteroposterior base of the RCa measures on average 37 mm; therefore, rotator cuff tears measuring >37 mm are at risk of rupturing part or all of the RCa's 2 humeral attachments, which if not recognized and addressed could impact postoperative function., (Copyright © 2021 Journal of Shoulder and Elbow Surgery Board of Trustees. Published by Elsevier Inc. All rights reserved.)

Description: The widespread availability of SARS-CoV-2 antibody tests raises important questions for clinicians, patients, and public health professionals related to the appropriate use and interpretation of these tests. The Scientific Medical Policy Committee (SMPC) of the American College of Physicians developed these rapid, living practice points to summarize the current and best available evidence on the antibody response to SARS-CoV-2 infection, antibody durability after initial infection with SARS-CoV-2, and antibody protection against reinfection with SARS-CoV-2., Methods: The SMPC developed these rapid, living practice points based on a rapid and living systematic evidence review done by the Portland VA Research Foundation and funded by the Agency for Healthcare Research and Quality. Ongoing literature surveillance is planned through December 2021. When new studies are identified and a full update of the evidence review is published, the SMPC will assess the new evidence and any effect on the practice points., Practice Point 1: Do not use SARS-CoV-2 antibody tests for the diagnosis of SARS-CoV-2 infection., Practice Point 2: Antibody tests can be useful for the purpose of estimating community prevalence of SARS-CoV-2 infection., Practice Point 3: Current evidence is uncertain to predict presence, level, or durability of natural immunity conferred by SARS-CoV-2 antibodies against reinfection (after SARS-CoV-2 infection).

Description: Antimicrobial overuse is a major health care issue that contributes to antibiotic resistance. Such overuse includes unnecessarily long durations of antibiotic therapy in patients with common bacterial infections, such as acute bronchitis with chronic obstructive pulmonary disease (COPD) exacerbation, community-acquired pneumonia (CAP), urinary tract infections (UTIs), and cellulitis. This article describes best practices for prescribing appropriate and short-duration antibiotic therapy for patients presenting with these infections., Methods: The authors conducted a narrative literature review of published clinical guidelines, systematic reviews, and individual studies that addressed bronchitis with COPD exacerbations, CAP, UTIs, and cellulitis. This article is based on the best available evidence but was not a formal systematic review. Guidance was prioritized to the highest available level of synthesized evidence., Best Practice Advice 1: Clinicians should limit antibiotic treatment duration to 5 days when managing patients with COPD exacerbations and acute uncomplicated bronchitis who have clinical signs of a bacterial infection (presence of increased sputum purulence in addition to increased dyspnea, and/or increased sputum volume)., Best Practice Advice 2: Clinicians should prescribe antibiotics for community-acquired pneumonia for a minimum of 5 days. Extension of therapy after 5 days of antibiotics should be guided by validated measures of clinical stability, which include resolution of vital sign abnormalities, ability to eat, and normal mentation., Best Practice Advice 3: In women with uncomplicated bacterial cystitis, clinicians should prescribe short-course antibiotics with either nitrofurantoin for 5 days, trimethoprim-sulfamethoxazole (TMP-SMZ) for 3 days, or fosfomycin as a single dose. In men and women with uncomplicated pyelonephritis, clinicians should prescribe short-course therapy either with fluoroquinolones (5 to 7 days) or TMP-SMZ (14 days) based on antibiotic susceptibility., Best Practice Advice 4: In patients with nonpurulent cellulitis, clinicians should use a 5- to 6-day course of antibiotics active against streptococci, particularly for patients able to self-monitor and who have close follow-up with primary care.

Galectin-3 (Gal-3) has a long, aperiodic, and dynamic proline-rich N-terminal tail (NT). The functional role of the NT with its numerous prolines has remained enigmatic since its discovery. To provide some resolution to this puzzle, we individually mutated all 14 NT prolines over the first 68 residues and assessed their effects on various Gal-3-mediated functions. Our findings show that mutation of any single proline (especially P37A, P55A, P60A, P64A/H, and P67A) dramatically and differentially inhibits Gal-3-mediated cellular activities (i.e., cell migration, activation, endocytosis, and hemagglutination). For mechanistic insight, we investigated the role of prolines in mediating Gal-3 oligomerization, a fundamental process required for these cell activities. We showed that Gal-3 oligomerization triggered by binding to glycoproteins is a dynamic process analogous to liquid-liquid phase separation (LLPS). The composition of these heterooligomers is dependent on the concentration of Gal-3 as well as on the concentration and type of glycoprotein. LLPS-like Gal-3 oligomerization/condensation was also observed on the plasma membrane and disrupted endomembranes. Molecular- and cell-based assays indicate that glycan binding-triggered Gal-3 LLPS (or LLPS-like) is driven mainly by dynamic intermolecular interactions between the Gal-3 NT and the carbohydrate recognition domain (CRD) F-face, although NT-NT interactions appear to contribute to a lesser extent. Mutation of each proline within the NT differentially controls NT-CRD interactions, consequently affecting glycan binding, LLPS, and cellular activities. Our results unveil the role of proline polymorphisms (e.g., at P64) associated with many diseases and suggest that the function of glycosylated cell surface receptors is dynamically regulated by Gal-3., Competing Interests: The authors declare no competing interest.

Background: Partial avulsions of the short and/or long head of the distal biceps tendon cause pain and loss of strength. The goal of the present study was to quantify the loss of supination and flexion strength following a series of surgical releases designed to simulate partial and complete short and long head traumatic avulsions., Methods: Mechanical testing was performed to measure supination moment arms and flexion force efficiency on 18 adult fresh-frozen specimens in pronation, neutral, and supination. The distal biceps footprint length was divided into 4 equal segments. In 9 specimens (the distal-first group), the tendon was partially cut starting distally by releasing 25%, 50%, and 75% of the insertion site. In the other 9 specimens (the proximal-first group), the releases started proximally. Mechanical testing was performed before and after each release., Results: Significant decreases in the supination moment arm occurred after a 75% release in the distal-first release group; the decrease was 24% in pronation (p = 0.003) and 10% in neutral (p = 0.043). No significant differences in the supination moment arm (p ≥ 0.079) or in flexion force efficiency (p ≥ 0.058) occurred in the proximal-first group., Conclusions: A simulated complete short head avulsion significantly decreased the supination moment arm and therefore supination strength., Clinical Relevance: A mechanical case can be made for repair of partial distal biceps tendon avulsions when the rupture involves ≥75% of the distal insertion site., Competing Interests: Disclosure: The authors indicated that no external funding was received for any aspect of this work. On the Disclosure of Potential Conflicts of Interest forms, which are provided with the online version of the article, one or more of the authors checked “yes” to indicate that the author had a relevant financial relationship in the biomedical arena outside the submitted work (http://links.lww.com/JBJS/G324)., (Copyright © 2021 by The Journal of Bone and Joint Surgery, Incorporated.)

We examined seasonal and geographic effects on vitamin D [25(OH)D] levels, association with attention-deficit/hyperactivity disorder (ADHD) symptom severity, and effects of supplementation in 222 children age 7-10 with rigorously diagnosed ADHD. 25(OH)D insufficiency rates were 47.2 % in Ohio and 28.5 % 400 miles south in North Carolina. Nadir of 25(OH)D levels was reached by November in Ohio, not until January in NC. Thirty-eight children with insufficiency/deficiency took vitamin D (1000-2000 IU/day for a month); levels rose 52 %. Although inattention did not correlate with 25(OH)D at screen nor improve significantly with supplementation, inattention improvement after supplementation correlated with 25(OH)D increase (rho = 0.41, p = 0.012). A clinically significant proportion of children with ADHD have insufficient 25(OH)D even at summer's end, more so in the winter and north of the 37th parallel. The significant correlation of inattention improvement with 25(OH)D increase suggests further research on 25(OH)D as ADHD treatment., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Galectin-3 is crucial to many physiological and pathological processes. The generally accepted dogma is that galectins function extracellularly by binding specifically to β(1→4)-galactoside epitopes on cell surface glycoconjugates. Here, we used crystallography and NMR spectroscopy to demonstrate that negatively charged homogalacturonans (HG, linear polysaccharides of α(1→4)-linked-D-galacturonate (GalA)) bind to the galectin-3 carbohydrate recognition domain. The HG carboxylates at the C6 positions in GalA rings mandate that this saccharide bind galectin-3 in an unconventional, "topsy-turvy" orientation that is flipped by about 180o relative to that of the canonical β-galactoside lactose. In this binding mode, the reducing end GalA β-anomer of HGs takes the position of the nonreducing end galactose residue in lactose. This novel orientation maintains interactions with the conserved tryptophan and seven of the most crucial lactose-binding residues, albeit with different H-bonding interactions. Nevertheless, the HG molecular orientation and new interactions have essentially the same thermodynamic binding parameters as lactose. Overall, our study provides structural details for a new type of galectin-sugar interaction that broadens glycospace for ligand binding to Gal-3 and suggests how the lectin may recognize other negatively charged polysaccharides like glycoaminoglycans (e.g. heparan sulfate) on the cell surface. This discovery impacts on our understanding of galectin-mediated biological function., (© The Author(s) 2020. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Calix[4]arene PTX008 is an angiostatic agent that inhibits tumor growth in mice by binding to galectin-1, a β-galactoside-binding lectin. To assess the affinity profile of PTX008 for galectins, we used 15 N, 1 H HSQC NMR spectroscopy to show that PTX008 also binds to galectin-3 (Gal-3), albeit more weakly. We identified the contact site for PTX008 on the F-face of the Gal-3 carbohydrate recognition domain. STD NMR revealed that the hydrophobic phenyl ring crown of the calixarene is the binding epitope. With this information, we performed molecular modeling of the complex to assist in improving the rather low affinity of PTX008 for Gal-3. By removing the N-dimethyl alkyl chain amide groups, we produced PTX013 whose reduced alkyl chain length and polar character led to an approximately eightfold stronger binding than PTX008. PTX013 also binds Gal-1 more strongly than PTX008, whereas neither interacts strongly, if at all, with Gal-7. In addition, PTX013, like PTX008, is an allosteric inhibitor of galectin binding to the canonical ligand lactose. This study broadens the scope for galectin targeting by calixarene-based compounds and opens the perspective for selective galectin blocking., (© 2020 Wiley-VCH GmbH.)

Programmed DNA double-strand breaks (DSBs) made during meiosis are repaired by recombination with the homologous chromosome to generate, at selected sites, reciprocal crossovers that are critical for the proper separation of homologs in the first meiotic division. Backup repair processes can compensate when the normal meiotic recombination processes are non-functional. We describe a novel backup repair mechanism that occurs when the homologous chromosome is not available in Drosophila melanogaster meiosis. In the presence of a previously described mutation (Mcm5A7) that disrupts chromosome pairing, DSB repair is initiated by homologous recombination but is completed by non-homologous end joining (NHEJ). Remarkably, this process yields precise repair products. Our results provide support for a recombination intermediate recently proposed in mouse meiosis, in which an oligonucleotide bound to the Spo11 protein that catalyzes DSB formation remains bound after resection. We propose that this oligonucleotide functions as a primer for fill-in synthesis to allow scarless repair by NHEJ. We argue that this is a conserved repair mechanism that is likely to be invoked to overcome occasional challenges in normal meiosis., (© The Author(s) 2021. Published by Oxford University Press on behalf of Nucleic Acids Research.)

While studies have documented the influence of caregiver and care recipient factors on caregiver health, it is important to address the potential impact of neighborhood contexts. This study estimated the cross-sectional associations between neighborhood characteristics and mental health among caregivers cohabiting with Alzheimer's disease care recipients that were experiencing severe or non-severe neuropsychiatric symptoms (NPSs) (e.g., aggression/anxiety). We obtained data collected in 2010 on caregivers and care recipients ( n = 212) from a subset of South Carolina's Alzheimer's Disease Registry. Neighborhood measures (within 1 mile of the residence) came from the American Community Survey and the Rural-Urban Commuting Area Code. We categorized the neighborhood median household income into tertiles, namely, "low" (<$31,000), "medium" ($31,000-40,758), and "high" (>$40,758), and rurality as "large urban," "small urban," and "rural." We used negative binomial regression to estimate the prevalence ratios (PRs) and 95% confidence intervals (CIs) for caregiver mental health using neighborhood characteristics. The mean age was 58 ± 10.3 years, 85% were women, and 55% were non-Hispanic Black. Among the caregivers cohabiting with a recipient experiencing severe NPS, higher distress was experienced by caregivers living in low- (PR = 1.61 (95% CI = 1.26-2.04)) and medium- (PR = 1.45 (95% CI = 1.17-1.78)) vs. high-income neighborhoods after an adjustment. These results suggest that neighborhood characteristics may amplify other social stressors experienced by caregivers.

Background: Lesions of the long head of the biceps can be successfully treated with biceps tenotomy or tenodesis when surgical management is elected. The advantage of a tenodesis is that it prevents the potential development of a cosmetic deformity or cramping muscle pain. Proponents of a subpectoral tenodesis believe that "groove pain" may remain a problem after suprapectoral tenodesis as a result of persistent motion of the tendon within the bicipital groove., Purpose/hypothesis: To evaluate the motion of the biceps tendon within the bicipital groove before and after a suprapectoral intra-articular tenodesis. The hypothesis was that there would be minimal to no motion of the biceps tendon within the bicipital groove after tenodesis., Study Design: Controlled laboratory study., Methods: Six fresh-frozen cadaveric arms were dissected to expose the long head of the biceps tendon as well as the bicipital groove. Inclinometers and fiducials (optical markers) were used to measure the motions of the scapula, forearm, and biceps tendon through a full range of shoulder and elbow motions. A suprapectoral biceps tenodesis was then performed, and the motions were repeated. The motion of the biceps tendon was quantified as a function of scapular or forearm motion in each plane, both before and after the tenodesis., Results: There was minimal motion of the native biceps tendon during elbow flexion and extension but significant motion during all planes of scapular motion before tenodesis, with the most motion occurring during shoulder flexion-extension (20.73 ± 8.21 mm). The motion of the biceps tendon after tenodesis was significantly reduced during every plane of scapular motion compared with the native state ( P < .01 in all planes of motion), with a maximum motion of only 1.57 mm., Conclusion: There was a statistically significant reduction in motion of the biceps tendon in all planes of scapular motion after the intra-articular biceps tenodesis. The motion of the biceps tendon within the bicipital groove was essentially eliminated after the suprapectoral biceps tenodesis., Clinical Relevance: This arthroscopic suprapectoral tenodesis technique can significantly reduce motion of the biceps tendon within the groove in this cadaveric study, possibly reducing the likelihood of groove pain in the clinical setting., Competing Interests: One or more of the authors has declared the following potential conflict of interest or source of funding: The anchors used for tenodesis in this study were donated by Arthrex. B.J.K. has received research support from Arthrex; educational support from Mid-Atlantic Surgical Systems and Smith & Nephew; and hospitality payments from Biomet and Exactech. S.A. has received research support, consulting fees, and speaking fees from Arthrex and educational support from Mid-Atlantic Surgical Systems. AOSSM checks author disclosures against the Open Payments Database (OPD). AOSSM has not conducted an independent investigation on the OPD and disclaims any liability or responsibility relating thereto., (© The Author(s) 2021.)

Decision makers can be described as economically rational (making consistent choices), or economically irrational (making choices that vary with the options available). As the extent to which animals can and do make rational versus irrational decisions remains unclear, we tested the decision-making strategies of female Nasonia vitripennis parasitic wasps in two behavioural contexts: oviposition and foraging. In our first experiment, to determine whether oviposition preferences changed depending on the options available, we presented females with a high and a medium-quality blow fly host to parasitize, and gave some females an additional low or very low quality 'decoy' host. Presence of decoy options did not affect females' oviposition choices, either in willingness to parasitize a host or the number of offspring laid. In our second experiment, we tested the effects of a low-quality decoy option on foraging preference for a high and a medium-quality sucrose concentration option. Here, presence of the low-quality decoy enhanced female preference for the high-quality option. Females therefore made economically rational decisions when ovipositing and economically irrational decisions when foraging. This difference in decision outcomes suggests that the cost/benefit ratio of making one type of decision over another may differ with the behavioural task., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Objectives: Diversity is needed within the aging and Alzheimer's disease and related dementias (ADRD) research and practice workforce to comprehensively address health inequities faced by underrepresented minority (URM) older adults. We conducted a scoping review of training programs designed to diversify the pool of researchers and practitioners in the field of aging and ADRD. Methods: Online database searches yielded 3976 articles published from 1999 to 2019. Fourteen studies met the inclusion criteria. Results: All programs were from the United States and included URM populations. Nine programs included students, one targeted university faculty, and four targeted clinical staff. Only five programs were guided by theory. Discussion: Our review identified URMs' desire for culturally diverse and representative mentorship, the need for career development support at various training stages, and the importance of incorporating theory to program design. It also identified key characteristics for future program development, creation of systematic evaluation standards, and opportunities for promotion.

Background: The measurement of serum HE4 levels has emerged as a sensitive and specific biomarker for epithelial ovarian cancers (EOCs). However, serum levels in women diagnosed with various histologic subtypes of EOC and in women with metastatic non-ovarian primary malignancies have not been widely reported., Objective: The goal of this study was to identify how serum HE4 levels vary in women diagnosed with different histologic subtypes of EOC and non-ovarian malignancies., Methods: Data from six prospective pelvic mass clinical trials was combined and an evaluation of serum HE4 levels in women diagnosed with a malignancy was performed. For all patients, serum was obtained prior to surgery and final pathology, including primary tumor site, histologic subtype, grade and stage, were recorded. The mean, median, standard deviation, maximum, and minimum HE4 levels were determined for each group., Results: A total of 984 patients were included in this study, with the average patient age being 60 years old. There were 230 premenopausal and 754 postmenopausal patients. Serum HE4 levels were elevated (≥70.0 pMol) in 85%of EOCs, 40%of LMP tumors, 21%of non-EOCs (germ cell tumors), 25%of cervical cancers, and 47%of non-gynecologic metastatic cancers. Analysis of histologic subtypes revealed 90%(n = 391) of serous, 85%(n = 73) of endometrioid, 45%(n = 42) of mucinous, 86%(n = 51) of mixed tumors, and 69%(n = 36) of clear cell tumors had elevated serum HE4 levels., Conclusions: Serum HE4 levels are most often elevated in women with high grade serous and endometrioid EOCs, and though serum elevations are seen more often with advanced stage disease, HE4 is also often elevated in early stage disease and lower grade tumors.

Objectives: The purpose of this mechanical study was to compare 2 methods of augmented stabilization of Pauwels type III femoral neck fractures., Methods: Ten matched pairs of young cadaveric femurs were cut 22 cm distal to the lesser trochanter. All specimens received a 70-degree osteotomy, which was stabilized with a 135-degree sliding hip screw. One of each pair received augmented fixation with a 6.5 mm fully threaded cannulated screw. The other specimen in the matched pair had additional fixation with a 3.5 mm 5-hole tubular plate placed at the inferior-medial femoral neck. Each specimen was tested under cyclic axial loading conditions (5000 cycles between 200 and 1400 N at 2 cycles/sec) and subsequently loaded to failure. The angular displacement (varus), interfragmentary (shear) displacement, and failure loads were calculated., Results: In the augmented plate group, 7 specimens failed by angular displacement and 3 failed by shear displacement. In the augmented screw group, 8 specimens failed by angular displacement and 2 by shear displacement. The plate group was found to have significantly less angular displacement, regardless of completed cycles, than the augmented screw group (0.75 ± 0.35 degrees vs. 2.15 ± 1.99 degrees averaged across completed cycles, P < 0.01). Similarly, the plate group was found to have significantly less shear displacement, regardless of completed cycles, than the augmented screw group (0.77 ± 0.70 mm vs. 1.22 ± 0.92 mm averaged across completed cycles, P = 0.01). The average failure load of the plate group (4930 ± 1578 N) was also larger but not significantly different from the screw group (3824 ± 2140 N), P = 0.12., Conclusions: Augmenting sliding hip screw stabilization of a Pauwels type III fracture with a medial plate applied to the femoral neck significantly decreases angular displacement and shear displacement compared with augmentation with a derotational screw., Competing Interests: All other authors certify that they have no commercial associations (eg, consultancies, stock ownership, equity interest, patent/licensing arrangements, etc.) that might pose a conflict of interest in connection with the submitted article., (Copyright © 2020 Wolters Kluwer Health, Inc. All rights reserved.)

Objectives: To compare displacement between the cuneiforms and metatarsals for a typical Lisfranc screw and a transmetatarsal base screw under biomechanical loading., Methods: Eight pairs of cadaveric feet (16 total) were evaluated. The Lisfranc ligamentous structures were transected in all specimens. All feet were repaired with screws traversing the first and second tarsometatarsal joints. A Lisfranc screw was placed from the first cuneiform to the second metatarsal in 8 specimens. A transmetatarsal base screw from the first metatarsal to the second metatarsal was placed in the remaining 8 corresponding feet. The repairs were randomized by side. Markers were placed on the dorsum of the midfoot for optical tracking. The feet were mounted into a load frame and loaded on the plantar forefoot to 100, 400, 800, and 1100 N. Displacement was measured and recorded using 3D camera tracking., Results: Displacement between the first cuneiform and second metatarsal base was found to be significantly less (P = 0.02) with the transmetatarsal screw than the Lisfranc screw. There were no significant differences between displacements at any other articulations., Conclusions: This study demonstrates biomechanical superiority using a modified transmetatarsal base screw compared with the highly used Lisfranc screw for fixation of ligamentous Lisfranc injuries.

Purpose of Review: Traumatic brain injury (TBI) is highly prevalent among service members and Veterans (SMVs) and associated with changes in blood-based biomarkers. This manuscript reviews candidate biomarkers months/years following military-associated TBI., Recent Findings: Several blood-based biomarkers have been investigated for diagnostic or prognostic use to inform care years after military-associated TBI. The most promising include increased levels of plasma/serum and exosomal proteins reflecting neuronal, axonal and/or vascular injury, and inflammation, as well as altered microRNA expression and auto-antibodies of central nervous system markers. Diagnostic and prognostic biomarkers of remote TBI outcomes remain in the discovery phase. Current evidence does not yet support single or combination biomarkers for clinical diagnostic use remotely after injury, but there are promising candidates that require validation in larger, longitudinal studies. The use of prognostic biomarkers of future neurodegeneration, however, holds much promise and could improve treatments and/or preventive measures for serious TBI outcomes.

Glycosaminoglycan chains of keratan sulfate proteoglycans appear to be physiologically significant by pairing with tissue lectins. Here, we used NMR spectroscopy and molecular dynamics (MD) simulations to characterize interactions of corneal keratan sulfate (KS), its desulfated form, as well as di-, tetra- (N-acetyllactosamine and lacto-N-tetraose) and octasaccharides with adhesion/growth-regulatory galectins, in particular galectin-3 (Gal-3). The KS contact region involves the lectin canonical binding site, with estimated K D values in the low µM range and stoichiometry of ~ 8 to ~ 20 galectin molecules binding per polysaccharide chain. Compared to Gal-3, the affinity to Gal-7 is relatively low, signaling preferences among galectins. The importance of the sulfate groups was delineated by using desulfated analogs that exhibit relatively reduced affinity. Binding studies with two related di- and tetrasaccharides revealed a similar decrease that underscores affinity enhancement by repetitive arrangement of disaccharide units. MD-based binding energies of KS oligosaccharide-loaded galectins support experimental data on Gal-3 and -7, and extend the scope of KS binding to Gal-1 and -9N. Overall, our results provide strong incentive to further probe the relevance of molecular recognition of KS by galectins in terms of physiological processes in situ, e.g. maintaining integrity of mucosal barriers, intermolecular (lattice-like) gluing within the extracellular meshwork or synaptogenesis.

Human galectin-7 (Gal-7; also termed p53-induced gene 1 product) is a multifunctional effector by productive pairing with distinct glycoconjugates and protein counter-receptors in the cytoplasm and nucleus, as well as on the cell surface. Its structural analysis by NMR spectroscopy detected doubling of a set of particular resonances, an indicator of Gal-7 existing in two conformational states in slow exchange on the chemical shift time scale. Structural positioning of this set of amino acids around the P4 residue and loss of this phenomenon in the bioactive P4L mutant indicated cis-trans isomerization at this site. Respective resonance assignments confirmed our proposal of two Gal-7 conformers. Mapping hydrogen bonds and considering van der Waals interactions in molecular dynamics simulations revealed a structural difference for the N-terminal peptide, with the trans-state being more exposed to solvent and more mobile than the cis-state. Affinity for lactose or glycan-inhibitable neuroblastoma cell surface contact formation was not affected, because both conformers associated with an overall increase in order parameters (S2). At low µM concentrations, homodimer dissociation is more favored for the cis-state of the protein than its trans-state. These findings give direction to mapping binding sites for protein counter-receptors of Gal-7, such as Bcl-2, JNK1, p53 or Smad3, and to run functional assays at low concentration to test the hypothesis that this isomerization process provides a (patho)physiologically important molecular switch for Gal-7., (© 2020 The Author(s).)

Purpose: We examined the capacity of the pan-fibroblast growth factor receptor (FGFR) inhibitor AZD4547 to augment radiation response across a panel of head and neck squamous cell carcinoma (HNSCC) cell lines and xenografts., Methods and Materials: FGFR1, FGFR2, and FGFR3 RNA in situ hybridization expression was assessed in a cohort of HNSCC patient samples, cell lines, and patient-derived xenografts (PDXs). In vitro effects of AZD4547 and radiation on cell survival, FGFR signaling, apoptosis, autophagy, cell cycle, and DNA damage repair were evaluated. Reverse phase protein array was used to identify differentially phosphorylated proteins in cells treated with AZD4547. In vivo tumor responses were evaluated in cell lines and PDX models., Results: FGFR1, FGFR2, and FGFR3 RNA in situ hybridization were expressed in 41%, 81%, and 89% of 107 oropharynx patient samples. Sensitivity to AZD4547 did not directly correlate with FGFR protein or RNA expression. In sensitive cell lines, AZD4547 inhibited p-MAPK in a time-dependent manner. Significant radiosensitization with AZD4547 was observed in cell lines that were sensitive to AZD4547. The mechanism underlying these effects appears to be multifactorial, involving inhibition of the MTOR pathway and subsequent enhancement of autophagy and activation of apoptotic pathways. Significant tumor growth delay was observed when AZD4547 was combined with radiation compared with radiation or drug alone in an FGFR-expressing HNSCC cell line xenograft and PDX., Conclusions: These findings suggest that AZD4547 can augment the response of radiation in FGFR-expressing HNSCC in vivo model systems. FGFR1 and FGFR2 may prove worthy targets for radiosensitization in HNSCC clinical investigations., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Adolescent alcohol exposure increases the risk of developing alcohol use disorders (AUDs), yet the mechanisms responsible for this vulnerability remain largely unknown. One potential target for alcohol-induced changes is the circuitry that modulates negative affect and stress, two sexually dependent drivers of alcohol relapse. The bed nucleus of the stria terminalis (BNST) is a sexually dimorphic region that critically regulates negative affective- and stress-induced relapse. Group I metabotropic glutamate receptors (mGluR) are a target of interest due to their regulation of stress, anxiety behaviors, and BNST plasticity. The current studies investigate sex-dependent sensitivity to the effects of adolescent intermittent ethanol vapor exposure (AIE) on negative affect during acute and protracted alcohol withdrawal and following stress in adulthood. This work also assessed whether BNST group I mGluR-mediated long-term depression (LTD) was disrupted at these timepoints. During acute withdrawal, AIE altered LTD induced by the group I mGluR antagonist DHPG in females, but not males. During adulthood, stress unmasked persistent changes in DHPG-induced LTD and behavior that were not present under basal conditions. Females with an AIE history demonstrated enhanced negative affective-like behavior in the novelty-induced hypophagia test following restraint stress-a phenotype that could be blocked with systemic mGluR5 allosteric antagonism via MTEP. Conversely, males with an AIE history demonstrated elevated freezing in a contextual fear conditioning paradigm. These studies demonstrate long-lasting, sex-dependent phenotypes produced by AIE and suggest pharmaceutical interventions for alcohol use and comorbid disorders may be more effective if designed with sex differences in mind.

Hypothesis and Background: Injuries to the elbow medial ulnar collateral ligament (mUCL) pose a diagnostic challenge, with the moving valgus stress test (MVST) currently accepted as the gold-standard clinical test. This study sought to biomechanically evaluate the change in length of the ulnar collateral ligament (UCL) during flexion-extension using a null hypothesis that the mUCL will not experience a greater change in length with movement than with static loading., Methods: Seven fresh-frozen human cadaveric elbows were tested with static and dynamic valgus stress. We measured (1) ligament length with a multi-camera optical system, (2) elbow flexion with an incremental encoder, and (3) valgus deviation with an electronic inclinometer. With a force applied to the wrist to simulate a clinical stress examination, the elbow was flexed and extended in a physiological elbow simulator to mimic the flexion and extension of the MVST., Results: The simulated MVST produced more elongation of the UCL compared with static stress testing (P < .001). Ninety degrees of flexion produced the highest mean change, and the anterior and posterior bands demonstrated different length change characteristics. Comparison of dynamic flexion and extension showed a statistically significant difference in change in length: The mUCL reached the greatest change during extension, with the greatest changes during extension near 90° of flexion., Discussion and Conclusion: The MVST produces significantly more elongation of the mUCL than either a static test or a moving test in flexion. This study provides biomechanical evidence of the validity of the MVST as a superior examination technique for injuries to the UCL., (Copyright © 2020 Journal of Shoulder and Elbow Surgery Board of Trustees. Published by Elsevier Inc. All rights reserved.)

FGFRs are commonly altered in non-small cell lung cancer (NSCLC). FGFRs activate multiple pathways including RAS/RAF/MAPK, PI3K/AKT, and STAT, which may play a role in the cellular response to radiation. We investigated the effects of combining the selective FGFR 1-3 tyrosine kinase inhibitor AZD4547 with radiation in cell line and xenograft models of NSCLC. NSCLC cell lines were assessed with proliferation, clonogenic survival, apoptosis, autophagy, cell cycle, and DNA damage signaling and repair assays. In vivo xenografts and IHC were used to confirm in vitro results. NSCLC cell lines demonstrated varying degrees of FGFR protein and mRNA expression. In vitro clonogenic survival assays showed radiosensitization with AZD4547 in two NSCLC cell lines. In these two cell lines, an increase in apoptosis and autophagy was observed with combined radiation and AZD4547. The addition of AZD4547 to radiation did not significantly affect γH2AX foci formation. Enhanced xenograft tumor growth delay was observed with the combination of radiation and AZD4547 compared with radiation or drug alone. IHC results revealed inhibition of pMAPK and pS6 and demonstrated an increase in apoptosis in the radiation plus AZD4547 group. This study demonstrates that FGFR inhibition by AZD4547 enhances the response of radiation in FGFR-expressing NSCLC in vitro and in vivo model systems. These results support further investigation of combining FGFR inhibition with radiation as a clinical therapeutic strategy., (©2020 American Association for Cancer Research.)

Background: The RNA-binding motif protein 3 (RBM3) has been shown to be up-regulated in several types of cancer, including prostate cancer (PCa), compared to normal tissues. Increased RBM3 nuclear expression has been linked to improved clinical outcomes., Aims: Given that RBM3 has been hypothesized to play a role in critical nuclear functions such as chromatin remodeling, DNA damage response, and other post-transcriptional processes, we sought to: (1) quantify RBM3 protein levels in archival PCa samples; (2) develop a nuclear morphometric model to determine if measures of RBM3 protein levels and nuclear features could be used to predict disease aggressiveness and biochemical recurrence., Methods & Results: This study utilized two tissue microarrays (TMAs) stained for RBM3 that included 80 total cases of PCa stratified by Gleason score. A software-mediated image processing algorithm identified RBM3-positive cancerous nuclei in the TMA samples and calculated twenty-two features quantifying RBM3 expression and nuclear architecture. Multivariate logistic regression (MLR) modeling was performed to determine if RBM3 levels and nuclear structural changes could predict PCa aggressiveness and biochemical recurrence (BCR). Leave-one-out cross validation (LOOCV) was used to provide insight on how the predictive capabilities of the feature set might behave with respect to an independent patient cohort to address issues such as model overfitting. RBM3 expression was found to be significantly downregulated in highly aggressive GS ≥ 8 PCa samples compared to other Gleason scores ( P < 0.0001) and significantly down-regulated in recurrent PCa samples compared to non-recurrent samples ( P = 0.0377). An eleven-feature nuclear morphometric MLR model accurately identified aggressive PCa, yielding a receiver operating characteristic area under the curve (ROC-AUC) of 0.90 ( P < 0.0001) in the raw data set and 0.77 (95% CI: 0.83-0.97) for LOOCV testing. The same eleven-feature model was then used to predict recurrence, yielding a ROC-AUC of 0.92 ( P = 0.0004) in the raw data set and 0.76 (95% CI: 0.64-0.87) for LOOCV testing., Conclusions: The RBM3 biomarker alone is a strong prognostic marker for the prediction of aggressive PCa and biochemical recurrence. Further, RBM3 appears to be down-regulated in aggressive and recurrent tumors., Competing Interests: Conflicts of Interest Statement: All authors declare that they have no competing interests.