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Background: The long-term outcomes following surgical resection for pancreatic ductal adenocarcinoma (PDAC) remains poor, with only 20% of patients surviving 5 years after pancreatectomy. Patient selection for surgery remains sub-optimal largely due to the absence of consideration of aggressive tumor biology. Objective: The aim of this study was to evaluate traditional staging criteria for PDAC in the setting of molecular subtypes. Methods: Clinicopathological data were obtained for 5 independent cohorts of consecutive unselected patients, totaling n = 1298, including n = 442 that underwent molecular subtyping. The main outcome measure was disease-specific survival following surgical resection for PDAC stratified according to the American Joint Commission for Cancer (TNM) staging criteria, margin status, and molecular subtype. Results: TNM staging criteria and margin status confers prognostic value only in tumors with classical pancreatic subtype. Patients with tumors that are of squamous subtype, have a poor outcome irrespective of favorable traditional pathological staging [hazard ratio (HR) 1.54, 95% confidence interval (CI) 1.04–2.28, P = 0.032]. Margin status has no impact on survival in the squamous subtype (16.0 vs 12.1 months, P = 0.374). There were no differences in molecular subtype or gene expression of tumors with positive resection margin status. Conclusions: Aggressive tumor biology as measured by molecular subtype predicts poor outcome following pancreatectomy for PDAC and should be utilized to inform patient selection for surgery.

Purpose Stevens-Johnson Syndrome (SJS) and Toxic Epidermal Necrolysis Syndrome (TENS) are severe and potentially lethal adverse drug reactions characterized by acute inflammation of the skin, mucous membranes, and ocular surface that typically occurs within weeks of a culprit drug ingestion. The purpose of this study is to report a retrospective trend analysis of SJS spectrum diagnoses and associated culprit drugs in patients admitted to the Loyola University Medical Center (LUMC) Burn Unit, the major referral center in the Chicagoland region for patients with SJS disease spectrum. Methods The electronic medical records (EMR) of 163 patients with a diagnosis of SJS/TENS admitted to the LUMC Burn Unit from 2000 to 2019 were reviewed. Clinical data in addition to the well-established algorithm of drug causality for epidermal necrolysis (ALDEN) allowed us to identify the single most probable culprit drug in 131 cases. Results From 2000 to 2019, the most common spectrum classification was TENS (48.1%), followed by SJS (33.6%) and SJS-TEN Overlap Syndrome (18.3%). Anticonvulsants were found to be the most probable culprit class in 30% of cases followed by Trimethoprim-Sulfamethoxazole in 19% of cases. Beta-lactams were the most probable culprit class in 11% of cases while NSAIDs and allopurinol were each the most probable culprit class/drug in 8.4% of cases. Conclusions This is one of the largest single center series of SJS/TENS cases in the United States. Further study into culprit drug distribution by region as well as continuous monitoring of trends is crucial in order to advise prescribing practices.

ObjectivesTo investigate the role of endogenous TSG-6 in human osteoarthritis (OA) and assess the disease-modifying potential of a TSG-6-based biological treatment in cell, explant and animal models of OA.MethodsKnee articular cartilages from OA patients were analysed for TSG-6 protein and mRNA expression using immunohistochemistry and RNAscope, respectively. The inhibitory activities of TSG-6 and its isolated Link module domain (Link_TSG6) on cytokine-induced glycosaminoglycan loss in OA cartilage explants were compared. Mesenchymal stem/stromal cell (MSC)-derived chondrocyte pellet cultures were used to determine the effects of Link_TSG6 and full-length TSG-6 on IL-1α-, IL-1β- or TNF-stimulated ADAMTS4, ADAMTS5 and MMP13 mRNA expression. Link_TSG6 was administered i.a. to the rat ACLTpMMx model and cartilage damage and tactile allodynia were assayed.ResultsTSG-6 is predominantly associated with chondrocytes in regions of cartilage damage and its expression is negatively correlated with MMP13, the major collagenase implicated in OA progression. Link_TSG6 is more potent than full-length TSG-6 at dose-dependently inhibiting cytokine-mediated matrix breakdown in human OA cartilage explants; about 50% of donor cartilages, from 59 tested, were responsive to Link_TSG6 treatment. Similarly, Link_TSG6 displayed more potent effects in 3D pellet cultures, suppressing aggrecanase and collagenase gene expression. Link_TSG6 treatment reduced touch-evoked pain and dose-dependently inhibited cartilage damage in a rodent model of surgically-induced OA.ConclusionsNative TSG-6 is associated with a low catabolic chondrocyte phenotype in OA cartilage. Link_TSG6, which has enhanced chondroprotective activity compared to the full-length TSG-6 protein, demonstrates potential as a disease modifying OA drug (DMOAD) and warrants further investigation and development.KEY MESSAGESWhat is already known about this subject?TSG-6, a protein with anti-inflammatory and protective effects in other tissues, is expressed in joints affected by osteoarthritis – a condition for which there are no disease-modifying drugs.What does this study add?A novel protective mechanism has been identified, whereby TSG-6 inhibits inflammatory cytokine-induced catabolic pathways in cartilage.The Link module of TSG-6 (Link_TSG6) has been shown to have greater potency than TSG-6 as an inhibitor of cartilage damage and is efficacious in a rat model of osteoarthritis.Data from cartilage explants indicate that OA patients can be stratified for Link_TSG6 responsiveness.How might this impact on clinical practice or future developments?Link_TSG6 has been identified as potential disease-modifying OA drug that mimics an intrinsic protective process.

Background Surgical approaches to the third ventricle (TV) have always represented a technical challenge in neurosurgery. Virtual reality (VR) is attaining increasing relevance in training programs and preoperative planning. The aim of this study is to demonstrate the worthwhile mutual contribution of VR simulations and specimen dissections to develop a new surgical approach to the TV. Methods The transcortical endoportal subchoroidal endoscope-assisted (TEPSEA) approach was planned and simulated thanks to VR (Surgical Theater©, LLC, Cleveland, Ohio), and then implemented on cadaver specimens by using the VBAS portal system (Viewsite™ Brain Access System TC Model, Vycor Medical™ Inc). We assessed anthropometric measurements during VR planning and evaluated surgical operability during anatomical dissections. Results Surgical field depths measured between 75.6 and 85.3 mm to mammillary bodies and habenular commissure, which were in mean 20.2 mm away. An 18-mm movement was estimated for 15°-posterior tilting of a 70-mm long VBAS. Excellent exposure and maneuverability were achieved within the TV through a 2.47 cm2 portal working area. The 30°-endoscope assistance expanded the access towards the anterior and posterior walls of the TV particularly to the infundibular recess, mammillary bodies, habenular commissure and pineal recess. Conclusions We documented the utility of a step-by-step VR planning and simulation followed by anatomical dissections to study surgical approaches to deep brain areas. The TEPSEA exploits the portal system and endoscopic assistance to access the entire TV minimizing cortical and white matter manipulation.

This comprehensive literature review represents a summary of all cases of clear cell carcinoma (CCC) of the salivary glands that are documented in the literature. PubMed was used to collect available reports of CCC; 97 reports detailing 254 cases, published between 1983 and 2020, were retrieved. Clinically the tumor manifests most commonly as a painless mass or swelling on the palate, and the duration of symptoms prior to seeking care ranges from 1 week to 6 years. Metastasis, both local and distant, was reported in 13.9% of 202 total cases. Local tumor recurrence was present in 18.8% of the cases. By histopathology, CCC shows a mixture of growth patterns including solid (25.1%), nested (78.6%), sheet-like (23.5%), cords (46.1%), and trabeculae (42.4%). Immunohistochemical studies are positive for one or more cytokeratins (99.1%), PAS (95.1%), EMA (77.8%), and p63 (96.3%), but negative for S-100 (96.3%), PASD (91.1%), SMA (91.0%), and calponin (95.1%). Molecular features were reported in 115 cases; 96.0% were positive for an EWSR1 rearrangement by EWSR1 break apart FISH testing and 14.8% were positive for the rearrangement EWSR1-ATF1 tested by qPCR or targeted RNA sequencing. Clinical patterns and genetic studies imply that this tumor is the extraosseous counterpart of clear cell odontogenic carcinoma, an intraosseous odontogenic tumor of the jaws.

Aortic stiffness increases with advancing age, more than doubling during the human life span, and is a robust predictor of cardiovascular disease (CVD) clinical events independent of traditional risk factors. The aorta increases in diameter and length to accommodate growing body size and cardiac output in youth, but in middle and older age the aorta continues to remodel to a larger diameter, thinning the pool of permanent elastin fibers, increasing intramural wall stress and resulting in the transfer of load bearing onto stiffer collagen fibers. Whereas aortic stiffening in early middle age may be a compensatory mechanism to normalize intramural wall stress and therefore theoretically “good” early in the life span, the negative clinical consequences of accelerated aortic stiffening beyond middle age far outweigh any earlier physiological benefit. Indeed, aortic stiffness and the loss of the “windkessel effect” with advancing age result in elevated pulsatile pressure and flow in downstream microvasculature that is associated with subclinical damage to high-flow, low-resistance organs such as brain, kidney, retina, and heart. The mechanisms of aortic stiffness include alterations in extracellular matrix proteins (collagen deposition, elastin fragmentation), increased arterial tone (oxidative stress and inflammation-related reduced vasodilators and augmented vasoconstrictors; enhanced sympathetic activity), arterial calcification, vascular smooth muscle cell stiffness, and extracellular matrix glycosaminoglycans. Given the rapidly aging population of the United States, aortic stiffening will likely contribute to substantial CVD burden over the next 2–3 decades unless new therapeutic targets and interventions are identified to prevent the potential avalanche of clinical sequelae related to age-related aortic stiffness.

BACKGROUND. Older adults with late-life depression (LLD) often experience incomplete or lack of response to first-line pharmacotherapy. The treatment of LLD could be improved using objective biological measures to predict response. Transcranial magnetic stimulation (TMS) can be used to measure cortical excitability, inhibition, and plasticity, which have been implicated in LLD pathophysiology, and associated with brain stimulation treatment outcomes in younger adults with depression. TMS measures have not yet been investigated as predictors of treatment outcomes in LLD, or pharmacotherapy outcomes in adults of any age with depression. METHODS. We assessed whether pre-treatment single-pulse and paired-pulse TMS measures, combined with clinical and demographic measures, predict venlafaxine treatment response in 76 outpatients with LLD. We compared the predictive performance of machine learning models including or excluding TMS predictors. RESULTS. Two single-pulse TMS measures predicted venlafaxine response: cortical excitability (neuronal membrane excitability), and the variability of cortical excitability (dynamic fluctuations in excitability levels). In cross-validation, models using a combination of these TMS predictors, clinical markers of treatment resistance, and age, classified patients with 73±11% balanced accuracy (average correct classification rate of responders and non-responders; permutation testing, p

Objective The aim of this study was to explore expert opinion to identify the components of sprinting technique they believed to be risk factors for hamstring strain injuries (HSI). Design Mixed-method research design. Methods The Concept Systems groupwisdom™ web platform was used to analyse and collect data. Participants brainstormed, sorted and rated the components of sprinting technique to consider in a HSI prevention strategy. Results Twenty-three experts (academic/researcher, physiotherapist, strength and conditioning coaches and sprint coaches) brainstormed 66 statements that were synthesised and edited to 60 statements. Nineteen participants sorted the statements into clusters and rated them for relative importance and confidence they could be addressed in a hamstring injury prevention program. Multidimensional scaling and cluster analysis identified a 8-cluster solution modified to a 5-cluster solution by the research team: Training prescription (10 statements, mean importance: 3.79 out of 5 and mean confidence: 3.79); Neuromuscular and tendon properties (9, 3.09, 3.08); Kinematics parameters/Technical skills (27, 2.99, 2.98); Kinetics parameters (10, 2.85, 2.92); and Hip mechanics (4, 2.70, 2.63). The statement: “low exposure to maximal sprint running” located in the cluster “Training prescription” received the highest mean importance (4.55) and confidence ratings (4.42) of all statements. Conclusion The five clusters of components of sprinting technique believed to be risk factors for HSIs in order of most to least important were: training prescription, neuromuscular and tendon properties, kinematics parameters/technical drills, kinetics parameters and hip mechanics.

Background Esophagectomy is associated with postoperative delirium, but its pathophysiology is not well defined. We conducted this study to measure the relationship among serum biomarkers of inflammation and neuronal injury and delirium incidence and severity in a cohort of esophagectomy patients. Methods Blood samples were obtained from patients preoperatively and on postoperative days 1 and 3 and were analyzed for S100 calcium-binding protein B, C-reactive protein (CRP), interleukin (IL) 8 and IL-10, tumor necrosis factor-α, and insulin-like growth factor 1. Delirium was assessed twice daily using the Richmond Agitation Sedation Scale and Confusion Assessment Method for Intensive Care Unit. Delirium severity was assessed once daily with the Delirium Rating Scale–Revised-98. Results Samples from 71 patients were included. Preoperative biomarker concentrations were not associated with postoperative delirium. Significant differences in change in concentrations from preoperatively to postoperative day 1 were seen in IL-8 (delirium, 38.6; interquartile range [IQR], 29.3-69.8; no delirium, 24.8; IQR, 16.0-41.7, P = .022), and IL-10 (delirium, 26.1; IQR, 13.9-36.7; no delirium, 12.4; IQR, 7.7-25.7; P = .025). Greater postoperative increase in S100 calcium-binding protein B (Spearman r = 0.289, P = .020) and lower levels of insulin-like growth factor 1 were correlated with greater delirium severity (Spearman r = −0.27, P = .040). Greater CRP change quartiles were associated with higher delirium incidence adjusting for severity of illness (odds ratio, 1.68; 95% confidence interval, 1.03-2.75; P = .037) or comorbidities (odds ratio, 1.70; 95% confidence interval, 1.05-2.76, P = .030). Conclusions Differences in change in serum CRP, IL-8, and IL-10 concentrations were associated with postoperative delirium, suggesting biomarker measurement early in the postoperative course is associated with delirium.

Several prognostic nomograms designed to predict survival after curative resection for colorectal cancer (CRC) have been proposed. Recently, routine pathological assessment has evolved with subtle changes to the AJCC staging system, and routine screening for mismatch repair deficiency (MMRd). Therefore we sought to develop and validate a new prognostic nomogram. All cause survival data from 4517 consecutive patients with primary CRC were used as independent training and validation cohorts to develop a final model including only: age, sex, tumour stage, nodal status, number of lymph nodes resected, apical node status, distant metastases, thin-walled vascular invasion, and MMR status. Patients were stratified into four risk groups to assess model discrimination and calibration. To assess discrimination, the area-under-the-curve (AUC) of a receiver-operator-curve (ROC), concordance-index (C-index), and D-index were calculated. The model was compared to the Memorial Sloan Kettering Cancer Center (MSKCC) CRC nomogram and the AJCC TNM staging. Based on the 5-year ROC analysis, the AUC for our model was 0.81 (0.79 and 0.74 for MSKCC and AJCC, respectively). Moreover, our model demonstrated a concordance index of 0.77 (95% CI 0.70-0.82) compared to 0.75 (95% CI 0.68-0.81) for MSKCC and 0.73 (95% CI 0.65-0.79) for AJCC. In conclusion, our new prognostic nomogram incorporates a larger number of clinically relevant prognostic markers, including MMR status, and therefore demonstrates improved predictive capability. As these factors are routinely assessed, it is hoped that this model will inform prognostication and difficult management decisions, such as patient selection for adjuvant therapy.

Purpose:\ud Low-dose whole lung radiotherapy (LDLR) has been proposed as a treatment for patients with acute respiratory distress syndrome associated with SARS-CoV-2 infection and clinical trials are underway. There is an urgent need for preclinical evidence to justify this approach and inform dose, scheduling and mechanisms of action.\ud \ud Materials and methods:\ud Female C57BL/6 mice were treated with intranasal bleomycin sulphate (7.5 or 11.25 units/kg, day 0), then exposed to whole lung radiation therapy (0.5, 1.0, 1.5 Gy or sham, day 3). Bodyweight was measured daily and lung tissue harvested for histology and flow cytometry on day 10. Computed tomography (CT) lung imaging was performed pre-radiation (day 3) and pre-endpoint (day 10).\ud \ud Results:\ud Bleomycin caused pneumonitis of variable severity which correlated with weight loss. LDLR at 1.0 Gy was associated with a significant increase in the proportion of mice recovering to 98% of initial bodyweight and a proportion of these mice exhibited less severe histopathological lung changes. Mice experiencing moderate initial weight loss were more likely to respond to LDLR than those experiencing severe initial weight loss. Additionally, LDLR (1.0 Gy) significantly reduced bleomycin-induced increases in interstitial macrophages, CD103+ dendritic cells and neutrophil-DC hybrids. Overall, bleomycin-treated mice exhibited significantly higher percentages of non-aerated lung in left than right lungs and LDLR (1.0 Gy) limited further reductions in aerated lung volume in right but not left lungs. LDLR at 0.5 and 1.5 Gy did not improve bodyweight, flow cytometric or radiological readouts of bleomycin-induced pneumonitis.\ud \ud Conclusions:\ud Our data support the concept that LDLR can ameliorate acute inflammatory lung injury, identify 1.0 Gy as the most effective dose and provide evidence that it is more effective in the context of moderate than severe pneumonitis. Mechanistically, LDLR at 1.0 Gy significantly suppressed bleomycin-induced accumulation of pulmonary interstitial macrophages, CD103+ dendritic cells and neutrophil-DC hybrids.

Currently, large numbers of clinical trials are performed to investigate different forms of experimental therapy for patients suffering from chronic spinal cord injury (SCI). However, for the enrollment process, there are different views on how the time period between injury and interventions should be determined. Herein, we sought to evaluate the impact of time-to-enrollment in chronic SCI clinical trials. A data set comprising 957 clinical studies from clinicalTrials.gov was downloaded and analyzed focusing on the eligibility criteria for post-injury time-to-enrollment. We also aggregated individual patient data from nine clinical trials of regenerative interventions for chronic SCI selected by a systematic literature search from 1990 to 2018. Characteristics of the studies were assessed and compared by dividing into three groups based on time-to-enrollment (group 1 ≤ 12 months, group 2 = 12-23 months and group 3 ≥ 24 months). In ClinicalTrials.gov registry, 445 trials were identified for chronic SCI where 87% (385) were unrestricted in the maximum post-injury time for trial eligibility. From systematic literature search, nine studies and 156 patients (group 1 = 30, group 2 = 55 and group 3 = 71) were included. The range of time-to-enrollment was 0.5 to 321 months in those studies. We also observed various degrees of motor and sensory improvement in between three time-to-enrollment groups. Our results indicate that enrolling wide ranges of time-to-enrollment in a group may present imprecise outcomes. Clinical trial designs should consider appropriate post-injury time frames to evaluate therapeutic benefit.

ObjectivesThis study aimed to investigate short-interval intracortical inhibition (SICI) and muscle function in the Triceps surae of runners with mid-portion Achilles tendinopathy (AT).MethodsRunners with (n=11) and without (n=13) AT were recruited. Plantar flexor isometric peak torque and rate of torque development (RTD) were measured using an isokinetic dynamometer. Triceps surae endurance was measured as single leg heel raise (SLHR) to failure test. SICI was assessed using paired-pulse transcranial magnetic stimulation during a sustained contraction at 10% of plantar flexor isometric peak torque.ResultsTriceps surae SICI was 14.3% (95%CI: -2.1 to 26.4) higher in AT than control group (57.9%, 95%CI: 36.2, to 79.6; and 43.6% 95%CI:16.2 to 71.1; p=0.032) irrespective of the tested muscle. AT performed 16 (95%CI: 7.9 to 23.3, pPerspectiveOur data suggest greater intracortical inhibition for the Triceps surae muscles for the AT group accompanied by reduced SLHR endurance, without deficits in isometric peak torque or RTD. The increased SICI observed in the AT group could be negatively influencing Triceps surae endurance; thus, rehabilitation aiming to reduce intracortical inhibition should be considered to improve patient outcomes. Furthermore, SLHR is a useful clinical tool to assess plantar flexor function in AT patients.

The COVID-19 pandemic has had unprecedented effects on lifestyle stability and physical and mental health. We examined the impact of preexisting posttraumatic stress disorder (PTSD), alcohol use disorder (AUD), and depression on biopsychosocial responses to the pandemic, including psychiatric symptoms, COVID-19 exposure, and housing/financial stability, among 101 U.S. military veterans enrolled in a longitudinal study of PTSD, a population of particular interest given veterans' trauma histories and defense-readiness training. Participants (83.2% male, 79.2% White, Mage = 59.28 years) completed prepandemic, clinician-administered psychiatric diagnostic interviews and a phone-based assessment between May and September 2020 using a new measure, the Rapid Assessment of COVID-19-Related Experiences (RACE), which was used to assess pandemic responses and its effects on mental and physical health; COVID-19 diagnosis and testing were also extracted from electronic medical records. Multivariate regressions showed that, controlling for demographic characteristics, prepandemic PTSD, β = .332; p = .003, and AUD symptoms, β = .228; p = .028, were associated with increased pandemic-related PTSD symptoms. Prepandemic AUD was associated with increased substance use during the pandemic, β = .391; p

BACKGROUND AND OBJECTIVES High-dose melphalan is an integral part of conditioning chemotherapy prior to both autologous and allogeneic hematopoietic cell transplantation. While underexposure may lead to relapse, overexposure may lead to toxicities include mucositis, diarrhea, bone marrow suppression, and rarely sinusoidal obstruction syndrome. In this study, we describe the population pharmacokinetics of high-dose melphalan as a first step towards individualized dosing. METHODS Melphalan samples were collected in patients receiving an allogeneic or autologous hematopoietic cell transplantation between August 2016 and August 2020 at the Memorial Sloan Kettering Cancer Center. A population-pharmacokinetic model was developed using NONMEM. RESULTS Based on a total of 3418 samples from 452 patients receiving a median cumulative dose of 140 mg/m2, a two-compartment population-pharmacokinetic model was developed. Fat-free mass was a covariate for clearance, central volume of distribution, and inter-compartmental clearance, while glomerular filtration rate predicted clearance. Simulation studies showed that based on fixed body surface area-based dosing, renal impairment has a higher impact in increasing melphalan exposure compared with obesity. CONCLUSIONS The proposed model adequately describes the population pharmacokinetics of melphalan in adult patients receiving a hematopoietic cell transplantation. This model can be used to define the therapeutic window of melphalan, and subsequently to develop individualized dosing regimens aiming for that therapeutic window in all patients.

Introduction Suicide is a leading cause of mortality in the United States and recent initiatives have sought to increase monitoring of suicide risk within healthcare systems. Working-age adults (22–64 years) admitted to nursing homes may be at risk for suicidal ideation, yet little is known about this population. Methods The national nursing home database, Minimum Dataset 3.0, was used to identify 323,436 working-age adults newly admitted to a nursing home in 2015. This cross-sectional study sought to describe sociodemographic and clinical characteristics, examine behavioral health treatment received, and determine resident characteristics associated with suicidal ideation at nursing home admission using logistic regression and reports adjusted odds ratios (aOR). Results Suicidal ideation was present among 1.27% of newly admitted working-age residents. Almost 25% of those with suicidal ideation had no psychiatric diagnosis. Factors associated with increased odds of suicidal ideation included younger age (aOR 1.90), admission from the community (aOR 1.92) or a psychiatric hospital (aOR 2.38), cognitive impairments (aOR 1.46), pain (aOR 1.40), rejection of care (aOR 1.91), and psychiatric comorbidity (aOR depression: 1.91, anxiety disorder: 1.11, bipolar disorder: 1.62, schizophrenia: 1.32, post-traumatic stress disorder: 1.17). Limitations Due to the cross-sectional nature of this study, no causal inferences about suicidal ideation and the explored covariates can be made. The Minimum Dataset 3.0 has only one measure of suicidal ideation the Patient Health Questionnaire. Conclusion Factors other than psychiatric diagnosis may be important in identifying newly admitted working-age nursing home residents who require on-going suicide screening and specialized psychiatric care.

Background: Previous studies of the effect of interaction between psychiatric disorders on suicide have reported mixed results. We investigated the joint effect of depression and various comorbid psychiatric disorders on suicide. Methods: We conducted a population-based case–cohort study with all suicide deaths occurring between 1 January 1995 and 31 December 2015 in Denmark (n = 14,103) and a comparison subcohort comprised of a 5% random sample of the source population at baseline (n = 265,183). We quantified the joint effect of pairwise combinations of depression and major psychiatric disorders (e.g., organic disorders, substance use disorders, schizophrenia, bipolar disorder, neurotic disorders, eating disorders, personality disorders, intellectual disabilities, developmental disorders, and behavioral disorders) on suicide using marginal structural models and calculated the relative excess risk due to interaction. We assessed for the presence of competing antagonism for negative relative excess risk due to interactions. Results: All combinations of depression and comorbid psychiatric disorders were associated with increased suicide risk. For example, the rate of suicide among men with depression and neurotic disorders was 20 times (95% CI = 15, 26) the rate in men with neither disorder. Most disorder combinations were associated with subadditive suicide risk, and there was evidence of competing antagonism in most of these cases. Conclusions: Subadditivity may be explained by competing antagonism. When both depression and a comorbid psychiatric disorder are present, they may compete to cause the outcome such that having 2 disorders may be no worse than having a single disorder with respect to suicide risk.

IntroductionClinical depression is usually treated in primary care with psychological therapies and antidepressant medication. However, when patients do not respond to at least two or more antidepressants within a depressive episode, they are considered to have treatment resistant depression (TRD). Previous small randomised controlled trials suggested that pramipexole, a dopamine D2/3 receptor agonist, may be effective for treating patients with unipolar and bipolar depression as it is known to influence motivational drive and reward processing. PAX-D will compare the effects of pramipexole vs placebo when added to current antidepressant medication for people with TRD. Additionally, PAX-D will investigate the mechanistic effect of pramipexole on reward sensitivity using a probabilistic decision-making task.Methods and analysisPAX-D will assess effectiveness in the short- term (during the first 12 weeks) and in the longer-term (48 weeks) in patients with TRD from the UK. The primary outcome will be change in self-reported depressive symptoms from baseline to week 12 post-randomisation measured using the Quick Inventory of Depressive Symptomatology Self-Report (QIDS-SR16). Performance on the decision-making task will be measured at week 0, week 2 and week 12. Secondary outcomes include anhedonia, anxiety and health economic measures including quality of life, capability, well-being and costs. PAX-D will also assess the adverse effects of pramipexole including impulse control difficulties.DiscussionPramipexole is a promising augmentation agent for TRD and may be a useful addition to existing treatment regimes. PAX-D will assess its effectiveness and test for a potential mechanism of action in patients with TRD.Trial registration numberISRCTN84666271

AIMS Amplification of the murine double minute-2 (MDM2) gene, which is usually detected with fluorescence in-situ hybridisation (FISH), is the key driving event for atypical lipomatous tumours (ALTs)/well-differentiated liposarcomas (WDLs). We sought to determine the concordance between the histopathological findings and MDM2 FISH in the diagnosis of ALT/WDL, and to identify the histological features of MDM2-amplified tumours lacking classic atypia. METHODS AND RESULTS We performed a retrospective analysis of all mature lipomatous lesions subjected to MDM2 FISH analysis at our institution. MDM2 FISH analysis was performed on 439 mature lipomatous lesions: 364 (82.9%) were negative and 75 (17%) were positive. In 17 of 75 (22.6%) ALTs/WDLs, cytological atypia was not identified on initial histological assessment, thus favouring lipoma. On review, these cases shared common histological features, consisting of a very low number of relatively small stromal cells within the tumour lobules, with mildly coarse chromatin and oval nuclei, admixed with unremarkable adipocytes in a tumour background devoid of fibroconnective septa, areas of fibrosis, or blood vessels. These cells matched the cells in which FISH showed MDM2 amplification. In contrast, 13 cases (3.5%) regarded as suspicious for ALT/WDL on the basis of histology lacked MDM2 amplification and were reclassified following the FISH findings. CONCLUSIONS We conclude that a subset of lipoma-like ALTs/WDLs are not associated with any of the features typically described in ALT/WDL. Our study also showed that tumours >100 mm are more likely to be ALT/WDL; however, a history of recurrence or concerning clinical/radiological features was not significantly associated with classification as ALT/WDL.

Thyroid abnormalities are well reported following childhood treatment for Hodgkin Lymphoma (HL). Limited information exists for adult patients and after modern treatments. We analyzed risks of thyroid disorders in 237 female participants treated at the Royal Marsden Hospital 1970-2015. Multivariable analyses of risk according to treatment and time-related factors, survival analyses, and Cox regression modeling were undertaken. Overall, 33.8% of patients reported thyroid disorders (hypothyroidism 30.0% and thyroid nodules 6.8%). Cumulative prevalence was 42.9% by 40 years follow-up. Risks were greatest after supradiaphragmatic radiotherapy (RR = 5.0, p

Background Primary sclerosing cholangitis (PSC) is a well-described risk factor for the development of cholangiocarcinoma (CCA). Early detection of CCA in these patients is of great importance because it expands options for therapeutic interventions, including liver transplantation. Current diagnostic tests for the evaluation of biliary strictures are limited to biliary brushing (BB) cytology and fluorescence in situ hybridization (FISH). Next-generation sequencing (NGS) has become an important diagnostic tool in oncology and may be a useful tool for diagnosing CCA on BBs. It is not clear how NGS performs when it is added to BB cytology and FISH in patients with PSC. Methods This study reports the authors' experience with NGS performed as a prospective cotest with cytology and FISH on BBs obtained from 60 patients with PSC followed at Massachusetts General Hospital. A duct with malignancy was defined as a high-risk (HR) stricture with either high-grade dysplasia or CCA. Results NGS was better than FISH and cytology in detecting HR strictures, which showed multiple genetic mutations in all cases. NGS provided specific mutational information, and NGS results were reproducible in longitudinal samples. Conclusions Adding NGS to BB cytology and FISH in the evaluation of biliary strictures for patients with PSC may provide additional information that could help to inform clinical management.

Cortical mechanisms may contribute to weakness in participants with previous hamstring strain injury. This study aims to examine intra-cortical inhibition (SICI) and corticospinal excitability in previously injured participants. In this cross-sectional study, TMS was used to examine SICI, silent period, silent period: MEP ratios and area under the stimulus response curve in the biceps femoris and medial hamstrings. Comparisons were made between participants with (n = 10) and without (n = 10) previous hamstring strain injury. Motor threshold and isometric knee flexor strength were also compared between participants and the relationship between strength and SICI in control and previously injured participants was examined. Isometric knee flexor strength was lower in previously injured limbs compared with control limbs (mean difference = − 41 Nm (− 26%) [95% CI = − 80 to − 2 Nm], p = 0.04, Cohen’s d = − 1.27) and contralateral uninjured limbs (mean difference = − 23 Nm (− 17%), [95% CI = − 40 to − 6 Nm], p = 0.01, Cohen’s d = − 0.57). Previously injured limbs exhibited smaller responses to paired pulse stimulation (i.e. greater levels of SICI) in the biceps femoris compared with control limbs (mean difference = − 19%, [95% CI = − 34 to − 5%], p = 0.007, Cohen’s d = − 1.33). Isometric knee flexor strength was associated with the level of SICI recorded in the biceps femoris in previously injured participants (coefficient = 23 Nm [95% CI = 7–40 Nm], adjusted R2 = 0.31, p = 0.01). There were no differences in markers of corticospinal excitability between previously injured and control limbs (all p > 0.24, all Cohen’s d

Objectives To investigate the utility of Magnetic Resonance Imaging (MRI) for prostate cancer diagnosis in the Australian setting. Patients and methods All consecutive men who underwent a prostate biopsy (transperineal or transrectal) at Royal Melbourne Hospital between July 2017 to June 2019 were included, totalling 332 patients. Data were retrospectively collected from patient records. For each individual patient, the risk of prostate cancer diagnosis at biopsy based on clinical findings was determined using the European Randomized study of Screening for Prostate Cancer (ERSPC) risk calculator, with and without incorporation of MRI findings. Results MRI has good diagnostic accuracy for clinically significant prostate cancer. A PI‐RADS 2 or lower finding has a negative predictive value of 96% for clinically significant cancer, and a PI‐RADS 3, 4 or 5 MRI scan has a sensitivity of 93%. However, MRI has a false negative rate of 6.5% overall for clinically significant prostate cancers. Pre‐ biopsy MRI may reduce the number of unnecessary biopsies, as up to 50.0% of negative or ISUP1 biopsies have MRI PI‐RADS 2 or lower. Incorporation of MRI findings into the ERSPC calculator improved predictive performance for all prostate cancer diagnoses (AUC 0.77 vs 0.71, P = .04), but not for clinically significant cancer (AUC 0.89 vs 0.87, P = .37). Conclusion MRI has good sensitivity and negative predictive value for clinically significant prostate cancers. It is useful as a pre‐biopsy tool and can be used to significantly reduce the number of unnecessary prostate biopsies. However, MRI does not significantly improve risk predictions for clinically significant cancers when incorporated into the ERSPC risk calculator.

Background Outpatient shoulder arthroplasty performed in an ambulatory surgery center has been shown to be a safe and cost-effective practice in appropriately selected patients. The decision to proceed with outpatient shoulder arthroplasty is based on a multitude of factors, including the patient's overall medical status, insurance type, social factors, and complexity of shoulder pathology. Currently, there is a paucity of literature that exists identifying the main drivers in determining in which setting, outpatient or inpatient, shoulder arthroplasty is performed. Methods A retrospective chart review of 1017 patients who underwent total shoulder arthroplasty (TSA) or reverse total shoulder arthroplasty at a single institution between January 2014 and February 2020 was performed. Each patient was screened for medical candidacy using a previously described evidenced-based patient selection algorithm based on age and cardiopulmonary risk factors. Clinical documentation and billing records were reviewed to determine the setting in which the shoulder arthroplasty was performed and the primary factors for determining inpatient shoulder arthroplasty. Results Overall 837 (82.3%) arthroplasties were performed inpatient, with at least a 23-hour hospital stay, and 180 (17.7%) were performed outpatient at a free-standing ambulatory orthopedic surgery center. The patient selection algorithm identified 522 (51.3%) patients as medical candidates for outpatient surgery. Poor candidacy based on medical risk stratification (495; 59.1%) and government insurance payors (231; 27.6%) were the most common reasons for a procedure to be performed in an inpatient setting. Among those deemed appropriate outpatient candidates but who had surgery in an inpatient setting, insurance status (231; 67.5%) was the most common reason, whereas additional medical or social concerns represented a smaller proportion (40; 11.7%). Eliminating shoulder arthroplasty as an inpatient-only code would have effectively transitioned 231 patients, 22.7% of the entire cohort, from an inpatient setting to an outpatient setting. Conclusions Medical stratification and insurance status both contribute significantly toward the decision to perform shoulder arthroplasty outpatient. Should policy change occur that eliminates shoulder arthroplasty from the Centers for Medicare and Medicaid Services inpatient-only distinction, a significant increase in outpatient shoulder arthroplasty volume would be expected. In the absence of insurance requirements, our data suggest that 40.4% of patients could safely undergo shoulder arthroplasty in an outpatient setting. Level of Evidence Level III

Inflammation and dyslipidemia are often present in polycystic ovary syndrome (PCOS). We determined the effect of saturated fat ingestion on circulating heat shock protein-70 (HSP-70) and mononuclear cell (MNC) toll-like receptor-2 (TLR2) gene expression, activator protein-1 (AP-1) activation, and matrix matalloproteinase-2 (MMP-2) protein in women with PCOS. Twenty reproductive-age women with PCOS (10 lean, 10 with obesity) and 20 ovulatory controls (10 lean, 10 with obesity) participated in the study. HSP-70 was measured in serum and TLR2 mRNA and protein, AP-1 activation, and MMP-2 protein were quantified in MNC from blood drawn while fasting and 2, 3, and 5 h after saturated fat ingestion. Insulin sensitivity was derived from an oral glucose tolerance test (IS(OGTT)). Androgen secretion was assessed from blood drawn while fasting and 24, 48, and 72 h after human chorionic gonadotropin (HCG) administration. In response to saturated fat ingestion, serum HSP-70, TLR2 gene expression, activated AP-1, and MMP-2 protein were greater in lean women with PCOS compared with lean controls and in women with PCOS and obesity compared with controls with obesity. Both PCOS groups exhibited lower IS(OGTT) and greater HCG-stimulated androgen secretion compared with control subjects of their respective weight classes. Lipid-stimulated proatherogenic inflammation marker responses were negatively correlated with IS(OGTT) and positively correlated with abdominal adiposity and HCG-stimulated androgen secretion. In PCOS, saturated fat ingestion stimulates proatherogenic inflammation independent of obesity. This effect is greater when PCOS is combined with obesity compared with obesity alone. Abdominal adiposity and hyperandrogenism may perpetuate proatherogenic inflammation. NEW & NOTEWORTHY This paper demonstrates that in polycystic ovary syndrome (PCOS), ingestion of saturated fat triggers a molecular pathway of inflammation known to drive atherogenesis. This effect is independent of obesity as it occurs in lean women with PCOS and not in lean ovulatory control subjects. Furthermore, the combined effects of PCOS and obesity are greater compared with obesity alone.

The cornerstone of management in patients with acute promyelocytic leukemia (APL) is early diagnosis and prompt initiation of treatment with an all-trans retinoic acid (ATRA)-based regimen. Identification of the t(15;17)(PML-RARA) chromosomal translocation through conventional cytogenetics fluorescence in-situ hybridization (FISH) or detection of the promyelocytic leukemia-retinoic acid receptor alpha (PML-RARα) fusion through RT-PCR represent the current standard of care for diagnosing APL. However, about 1–2% of patients with APL have a variant translocation involving other fusion partners with RARα besides PML. These patients present a unique diagnostic and clinical challenge in that conventional cytogenetics in addition to FISH and/or RT-PCR for PML-RARα may fail to identify these clinically relevant genetic lesions leading to an inappropriate diagnosis and treatment. We present two cases of patients who had APL with variant translocations whose bone marrow specimens were sent to the University of Michigan for enrollment in the MI-ONCOSEQ study (HUM00067928) after standard testing failed to identify PML-RARα or t(15;17) despite a phenotypic concern for this diagnosis. In these two patients, whole exome and transcriptome profiling via the MI-ONCOSEQ platform identified a PRKAR1A-RARα fusion in one patient and ZBTB16-RARα fusion in another patient. These cases illustrate the utility of whole exome and transcriptome profiling in diagnosing variant translocations in patients in whom there is a high clinical suspicion for APL based on hematopathology review.

The past two decades have built on the successes of the Human Genome Project identifying the impact of genetics and genomics on human traits. Given the importance of exercise in the physical and psychological health of individuals across the lifespan, using genomics to understand the impact of genes in the sports medicine field is an emerging field. Given the complexity of the systems involved, high-throughput genomics is required to understand genetic variants, their functions, and ultimately their effect on the body. Consequently, genomic studies have been performed across several domains of sports medicine with varying degrees of success. While the breadth of these is great, they focus largely on the following three areas: 1) performance; 2) injury susceptibility; and 3) sports associated chronic conditions, such as osteoarthritis. Herein, we review literature on genetics and genomics in sports medicine, offer suggestions to bolster existing studies, and suggest ways to ideally impact clinical care.

Background Endovenous laser ablation (EVLA) and foam sclerotherapy are effective and safe treatments for chronic venous disease with great saphenous vein (GSV) reflux. We report our experience combining both strategies as a merged approach to treat GSV incompetence to potentiate both methods' superiority and benefits. We aimed to determine the effectiveness of this treatment strategy. Methods A total of 246 limbs with GSV incompetence (C2-C6) treated with EVLA and foam sclerotherapy between January 2016 and December 2019 were retrospectively analyzed. Outcomes of interest were the International Union of Phlebology (IUP) type of anatomic closure (primary, primary assisted, secondary, and therapeutic failure), identified with ultrasound in the GSV after the procedure. Clinical and ultrasound follow-up was conducted at 2 weeks, 3, 6, and 12 months after intervention. We used the Fisher exact test to determine the significance of the association between the type of anatomic closure and the clinical stage according to the Clinical-Etiology-Anatomy-Pathophysiology classification. Results A total of 67% of the treated limbs were C2-C4 and 33% C5-C6. IUP primary closure was achieved in 229 limbs (93%), IUP primary assisted closure in 10 limbs (4%), IUP secondary closure in 1 limb (0.4%), and therapeutic failure in 6 limbs (2%). A total of 45 limbs (18%) required microthrombectomies of tributary veins due to local induration, 7 (2.8%) developed dyschromia, 4 (1.6%) had type 1 endovenous heat-induced thrombosis, and 1 limb (0.4%) developed deep vein thrombosis, which was successfully treated with anticoagulation. Conclusions Our results demonstrate a high occlusion rate of incompetent GSVs with combined EVLA and foam sclerotherapy with infrequent nonserious complications and one case of subclinical isolated popliteal deep vein thrombosis. Combined therapy effectiveness and safety are comparable with other endovenous treatments for chronic venous disease with GSV reflux. The use of both thermal and chemical ablation combines the benefits of both techniques.

PURPOSE Appendiceal cancer is a rare disease process with complex treatment strategies. The objective of this study was to identify mutation-based genetic subtypes that may differ from the current histological classification, compare the genetic make-up of primaries and metastases, and find novel targetable alterations. METHODS The analyses involved the curation and normalization of gene mutation panels from appendiceal adenocarcinoma and mucinous adenocarcinoma (n = 196) stored in the AACR GENIE Database v6.0. Genes mutated in less than one patient and tumors profiled with incomplete mutation panels were excluded from the study. The optimal number of AC subtypes was established using the Nonnegative Matrix Factorization algorithm. Statistical comparisons of mutation frequencies were performed using Pearson's χ2 test. RESULTS AC patients were stratified into five mutation subtypes, based on a final set of 41 cancer-related genes. AC0 had no mutations. The most frequently mutated genes varied between the subtypes were: AC1: KRAS (91.9%) and GNAS (77.4%); AC2: KRAS (52.5%), APC (32.5%), and GNAS (30%); AC3: KMT2D (38.7%), TP53 (38.7%), KRAS (35.5%), EP300 (22.6%); and AC4: TP53 (97.2%), KRAS (77.8%), and SMAD4 (36.1%). Additionally, AC3 was less likely to be mucinous (22.6% vs. 50.0-74.2%, p

The aim of this study was to determine the impacts of anterior cruciate ligament reconstruction (ACLR) and recent (

Compare long-term mortality, secondary intervention and secondary rupture following elective endovascular aneurysm repair (EVAR) and open surgical repair (OSR).EVAR has surpassed OSR as the most common procedure used to repair abdominal aortic aneurysm (AAA), but evidence regarding long-term outcomes is inconclusive.We included patients in linked clinical registry and administrative data undergoing EVAR or OSR for intact AAA between January 2010 and June 2019. We used an inverse probability of treatment-weighted survival analysis to compare all-cause mortality, cause-specific mortality, secondary interventions and secondary rupture, and evaluate the impact of secondary interventions and secondary rupture on all-cause mortality.The study included 3460 EVAR and 427 OSR patients. Compared to OSR, the EVAR all-cause mortality rate was lower in the first 30 days (adjusted hazard ratio [HR]=0.24, 95% confidence interval (CI) 0.15-0.36), but higher between 1 and 4 years (HR=1.31, 95% CI 1.14-1.51) and after 4 years (HR=1.45, 95% CI 1.25-1.67). Secondary intervention rates were higher over the first 30 days (HR=2.20, 95% CI 1.09-4.44), but lower between 1 and 4 years (HR=0.60, 95% CI 0.49-0.75). Secondary aortic intervention rates were higher across the entire follow-up period (HR=2.45, 95% CI 2.01-2.99). Secondary rupture rates did not differ significantly (HR=1.15, 95% CI 0.78-1.70). All-cause mortality beyond 1 year remained significantly higher for EVAR after adjusting for any secondary interventions, or secondary rupture.EVAR has an early survival benefit compared to OSR. However, elevated long-term mortality and higher rates of secondary aortic interventions and subsequent aneurysm repair suggest that EVAR may be a less durable method of aortic aneurysm exclusion.

Restrictive dermopathy (RD) is a rare and lethal laminopathy caused by mutations in LMNA or ZMPSTE24. This series reports 3 patients with RD and reviews the literature of the 113 previously reported cases, including highlights of the unique constellation of clinical findings in RD, as well as histologic, radiographic, and genetic features. Early recognition of these characteristic features is vital to establish a prompt diagnosis and provide adequate family counseling for this terminal condition.

Rationale Whether treatment with intravenous alteplase prior to mechanical thrombectomy (MT) in acute ischemic stroke patients with large vessel occlusion is beneficial remains unclear. Aim To determine whether patients experiencing acute ischemic stroke due to occlusion of the intracranial internal carotid artery or the M1 segment of the middle cerebral artery who are referred to an endovascular stroke center and who are candidates for intravenous alteplase will have non-inferior functional outcome at 90 days when treated with MT alone (direct MT) with stent retrievers compared to patients treated with combined intravenous thrombolysis (IVT) with alteplase plus MT (IVT + MT) with stent retrievers. Sample size To randomize 404 patients 1:1 to direct MT or combined IVT+MT. Methods and design A multicenter, prospective, randomized, open-label, blinded-endpoint (PROBE) trial utilizing an adaptive statistical design. Outcomes The primary efficacy endpoint is functional independence (modified Rankin Scale 0–2) at 90 days. Secondary clinical efficacy outcomes include change in National Institutes of Health Stroke Scale score from baseline to day 1 and health-related quality of life at 90 days. Secondary technical efficacy outcomes include successful reperfusion prior to start of MT and time from randomization to successful reperfusion. Safety outcomes include all serious adverse events, symptomatic intracranial hemorrhage, and mortality up to 90 days. Discussion SWIFT DIRECT will inform physicians whether direct MT in acute ischemic stroke patients with large vessel occlusion is equally or more efficacious than combined treatment with intravenous alteplase and MT. Trial registration ClinicalTrials.gov Identifier: NCT03192332

Background Exposure to high doses of ionizing radiation is among the few well-established brain tumour risk factors. We used data from the Interphone study to evaluate the effects of exposure to low-dose radiation from diagnostic radiological examinations on glioma, meningioma and acoustic neuroma risk. Methods Brain tumour cases (2644 gliomas, 2236 meningiomas, 1083 neuromas) diagnosed in 2000–02 were identified through hospitals in 13 countries, and 6068 controls (population-based controls in most centres) were included in the analysis. Participation across all centres was 64% for glioma cases, 78% for meningioma cases, 82% for acoustic neuroma cases and 53% for controls. Information on previous diagnostic radiological examinations was obtained by interviews, including the frequency, timing and indication for the examinations. Typical brain doses per type of examination were estimated based on the literature. Examinations within the 5 years before the index date were excluded from the dose estimation. Adjusted odds ratios were estimated using conditional logistic regression. Results No materially or consistently increased odds ratios for glioma, meningioma or acoustic neuroma were found for any specific type of examination, including computed tomography of the head and cerebral angiography. The only indication of an elevated risk was an increasing trend in risk of meningioma with the number of isotope scans, but no such trends for other examinations were observed. No gradient was found in risk with estimated brain dose. Age at exposure did not substantially modify the findings. Sensitivity analyses gave results consistent with the main analysis. Conclusions There was no consistent evidence for increased risks of brain tumours with X-ray examinations, although error from selection and recall bias cannot be completely excluded. A cautious interpretation is warranted for the observed association between isotope scans and meningioma.

Diverse representation in higher education leadership is critical to the Academy’s mission of teaching, research, and service. As academic leadership positions are rarely occupied by faculty from u...

Lefamulin is a novel antibiotic agent within the pleuromutilin derivative class approved for the treatment of community-acquired bacterial pneumonia (CABP) by the United States Food and Drug Administration (FDA) and the European Commission (EC) in 2019 and 2020, respectively. The objective of this article is to provide a summary of clinically relevant data underlying lefamulin, and to provide recommendations for its place in therapy. In vitro data establishes lefamulin's activity against a number of gram-positive, gram-negative, and atypical organisms relevant in the treatment of CABP, including S. pneumoniae, H. influenzae, M. catarrhalis, L. pneumophila, M. pneumoniae, and C. pneumoniae. Two phase 3 studies, the Lefamulin Evaluation Against Pneumonia (LEAP) trials, established non-inferiority of lefamulin against moxifloxacin in the treatment of CABP, including sequential transition from intravenous to oral therapy and across a broad set of patient demographics and severities. Pooled and post-hoc analyses have confirmed these effects for a variety of subgroups and secondary endpoints. Real-world study data post-approval has largely not yet emerged for lefamulin, and there is a need for further investigation into safety/efficacy for off-label indications such as acute bacterial skin and skin structure infections (ABSSSIs) and sexually transmitted infections (STIs). Further data regarding tolerability, particularly with longer term use, as well as the emergence of resistance over time are still undefined. This article is protected by copyright. All rights reserved.

The clinical success of periacetabular osteotomy (PAO) for the treatment of symptomatic acetabular dysplasia is well-documented. Conflicting evidence exists regarding the correlation of age with clinical outcomes. Hip disability and Osteoarthritis Outcome Score - global (HOOSglobal) is a recently validated patient-reported outcome measure following PAO. The purpose of this study is to asses HOOSglobal and Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) scores at early follow-up based on age at the time of PAO.A prospective multicenter cohort of 391 patients undergoing PAO with minimum 2-year follow-up (average 4.71 years) were identified. Patients were categorized into 4 age groups:20 years (N = 131), 20-29 (N = 102), 30-39 (N = 65), and ≥40 (N = 34). A 4 × 2 repeated measures analysis of variance (Age Group × Time) was used to compare preoperative and postoperative HOOSglobal and WOMAC scores between age groups. A multiple linear regression was used to identify predictors of postoperative HOOSglobal scores.HOOSglobal and WOMAC scores increased across all age groups; however, a statistically greater increase in preoperative to postoperative HOOSglobal and WOMAC scores was found in those ≥40 years compared to those20 (P.002), 20-29 (P = .01), and 30-39 years (P = .02). Higher preoperative HOOSglobal scores were predictive of greater postoperative HOOSglobal scores (P.001) but age (P = .65), gender (P = .80), body mass index (P = .50), and Tönnis Classification (P = .07) were not independent predictors of 1-year outcomes.The absence of differences in early postoperative patient-reported outcomes across multiple age ranges emphasizes that PAO in the setting of symptomatic acetabular dysplasia can be successful regardless of patient age alone. Therefore, age alone might not be an appropriate selection criterion when evaluating surgical candidates for PAO.II.

Elevated blood lactate levels are strongly associated with mortality in patients with cardiogenic shock. Recent evidence suggests that the degree and rate at which blood lactate levels decrease after the initiation of treatment may be equally important in patient prognosis. We performed a systematic review and meta-analysis to evaluate the usefulness of lactate clearance as a prognostic factor in cardiogenic shock.We performed searches of Ovid MEDLINE, Elsevier EMBASE, EBM Reviews-Cochrane Central Register of Controlled Trials, and Web of Science to identify studies comparing lactate clearance between survivors and nonsurvivors at one or more timepoints. Both prospective and retrospective studies were eligible for inclusion. Two study investigators independently screened, extracted data, and assessed the quality of all included studies. Twelve studies were included in the meta-analysis. The median lactate clearance at 6-8 hours was 21.9% (interquartile range [IQR] 14.6%-42.1%) in survivors and 0.6% (IQR -3.7% to 14.6%) in nonsurvivors. At 24 hours, the median lactate clearance was 60.7% (IQR 58.1%-76.3%) and 40.3% (IQR 30.2%-55.8%) in survivors and nonsurvivors, respectively. Accordingly, the pooled mean difference in lactate clearance between survivors and nonsurvivors at 6-8 hours was 17.3% (95% CI 11.6%-23.1%, P.001) at 6-8 hours and 27.9% (95% CI 14.1%-41.7%, P.001) at 24 hours.Survivors had significantly greater lactate clearance at 6-8 hours and at 24 hours compared with nonsurvivors, suggesting that lactate clearance is an important prognostic marker in cardiogenic shock.

Background Pancreatic cancer is the 8th commonest cancer and the 5th commonest cause of cancer-related death in Australia, with a 9% average 5-year survival. This study aims to investigate the effects of neoadjuvant treatment on overall survival (OS) and recurrence-free survival (RFS) in borderline resectable (BRPC) and locally advanced (LAPC) pancreatic adenocarcinoma followed by curative resection. Materials and methods Prospectively-collected demographic, medical, surgical and pathological data of patients with BRPC and LAPC treated with both neoadjuvant therapy (NAT) and surgery at a single tertiary referral centre in Australia were reviewed and analysed. Results Between 2012 and 2018, 60 patients, 34 with BRPC and 26 with LAPC, were treated with NAT followed by curative resection. The commonest neoadjuvant chemotherapy regimens were Gemcitabine + Abraxane (51.7%) and FOLFIRINOX (35.0%), with 48.3% of patients additionally receiving neoadjuvant radiotherapy. Median RFS was 30 months and median OS was 35 months. On multivariable analysis, inferior OS was predicted by enlarged loco-regional lymph nodes on initial computed tomography (p = 0.032), larger tumour size post-NAT (p = 0.006) and Common Terminology Criteria for Adverse Events post-NAT toxicity greater than grade 2 (p = 0.015). LAPC patients received more neoadjuvant chemotherapy (p = 0.008) and radiotherapy (p = 0.021) than BRPC and achieved a superior pathological response (p = 0.010). Conclusion Patients who respond to NAT likely have a favourable disease biology and will progress well following resection. It is these patients who should be selected for more aggressive upfront management, and those with resistant disease should be spared from high-risk surgery.

BACKGROUND: Right heart catheterization for invasive hemodynamics has shown only modest correlation with clinical outcomes. We designed a novel hemodynamic variable that incorporates ventricular output and filling pressure. We anticipated that the aortic pulsatility index (API) would correlate with clinical outcomes in patients with heart failure. METHODS AND RESULTS: We retrospectively analyzed consecutive patients undergoing right heart catheterization with milrinone drug study at our institution (February 2013 to November 2019). The API was calculated as (systolic blood pressure – diastolic blood pressure)/pulmonary capillary wedge pressure. The primary outcome was freedom from advanced therapies, defined as the need for inotropes, temporary mechanical circulatory support, a left ventricular assist device, or orthotopic heart transplantation, or death at 30 days. A total of 224 patient encounters, age 57 years (48–66 years; 34% women; 31% ischemic cardiomyopathy) were included. In univariable analysis, lower baseline API was significantly associated with progression to advanced therapies or death at 30-days (odds ratio 0.43, 95% confidence interval 0.30–0.61; P < .001) compared with those on continued medical management. Receiver operator characteristic analysis specified an optimal cutpoint of 1.45 for API. A Kaplan–Meier analysis indicated an association of API with the primary outcome (79% for API ≥ 1.45 vs 48% for API < 1.45). In multivariable analysis, higher API was strongly associated with freedom from advanced therapies or death (odds ratio 0.38, 95% confidence interval 0.22–0.65, P ≤ .001), even when adjusted for baseline characteristics and routine right heart catheterization measurements. CONCLUSIONS: The API is a novel invasive hemodynamic measurement that is associated independently with freedom from advanced therapies or death at 30-day follow-up.

Introduction:\ud Malignant pleural mesothelioma (MPM) is difficult to diagnose. An accurate blood biomarker could prompt specialist referral or be deployed in future screening. In earlier retrospective studies, SOMAscan proteomics (Somalogic, Boulder, CO) and fibulin-3 seemed highly accurate, but SOMAscan has not been validated prospectively and subsequent fibulin-3 data have been contradictory.\ud \ud Methods:\ud A multicenter prospective observational study was performed in 22 centers, generating a large intention-to-diagnose cohort. Blood sampling, processing, and diagnostic assessment were standardized, including a 1-year follow-up. Plasma fibulin-3 was measured using two enzyme-linked immunosorbent assays (CloudClone [used in previous studies] and BosterBio, Pleasanton, CA). Serum proteomics was measured using the SOMAscan assay. Diagnostic performance (sensitivity at 95% specificity, area under the curve [AUC]) was benchmarked against serum mesothelin (Mesomark, Fujirebio Diagnostics, Malvern, PA). Biomarkers were correlated against primary tumor volume, inflammatory markers, and asbestos exposure.\ud \ud Results:\ud A total of 638 patients with suspected pleural malignancy (SPM) and 110 asbestos-exposed controls (AECs) were recruited. SOMAscan reliably differentiated MPM from AECs (75% sensitivity, 88.2% specificity, validation cohort AUC 0.855) but was not useful in patients with differentiating non-MPM SPM. Fibulin-3 (by BosterBio after failed CloudClone validation) revealed 7.4% and 11.9% sensitivity at 95% specificity in MPM versus non-MPM SPM and AECs, respectively (associated AUCs 0.611 [0.557–0.664], p = 0.0015) and 0.516 [0.443–0.589], p = 0.671), both inferior to mesothelin. SOMAscan proteins correlated with inflammatory markers but not with asbestos exposure. Neither biomarker correlated with tumor volume.\ud \ud Conclusions:\ud SOMAscan may prove useful as a future screening test for MPM in asbestos-exposed persons. Neither fibulin-3 nor SOMAscan should be used for diagnosis or pathway stratification.

Historically, outcomes reporting for radioembolization with yttrium-90 (90Y) of hepatocellular carcinoma has included patients across the range of Barcelona Clinic Liver Cancer (BCLC) stages. With the potential for curative radiation segmentectomy for BCLC 0/A patients and evolution of systemic therapy for BCLC C patients, focused review by group is of increasing interest. In this review, we report on efficacy of 90Y in patients with intermediate (BCLC B) and advanced (BCLC C) hepatocellular carcinoma as well as expected toxicities. Additionally, we review existing trials comparing 90Y to transarterial chemoembolization and systemic treatments in these patient groups and outline future studies.

BACKGROUND: Treating hyperphosphatemia is a tenet of dialysis care. This trial assessed the safety and efficacy of tenapanor for the management of hyperphosphatemia. METHODS: In this 52-week phase 3 study (NCT03427125), participants receiving maintenance dialysis with both hyperphosphatemia (serum phosphate 6.0–10.0 mg/dl) and a 1.5 mg/dl increase after phosphate binder washout were randomized (3:1) to tenapanor 30 mg twice daily for 26 weeks (randomized treatment period) or sevelamer carbonate (52-week safety control). Participants completing 26 weeks of treatment with tenapanor were rerandomized (1:1) to tenapanor or placebo for 12 weeks (randomized withdrawal period), and were eligible to enter the 14-week safety extension period. With input from the US Food and Drug Administration, the primary efficacy end point was the difference in the change in serum phosphate from the end of the randomized treatment period to the end of the randomized withdrawal period, among participants who achieved ≥1.2 mg/dl decrease in serum phosphate during the randomized treatment period (efficacy analysis set). Efficacy was also evaluated in the intention-to-treat (ITT) analysis set. RESULTS: Of 564 eligible participants randomized to receive tenapanor (n=423) or sevelamer carbonate (n=141) during the randomized treatment period, 255 (60%) in the tenapanor group subsequently were rerandomized to tenapanor (n=128) or placebo (n=127) during the randomized withdrawal period. In the efficacy analysis set (n=131), the difference in estimated mean change in serum phosphate level between tenapanor and placebo from the beginning to the end of the randomized withdrawal period was −1.4 mg/dl (P

Z.R. is a 20-year-old White man with no prior relevant medical or surgical history. He presented to his pediatrician’s office in April 2020 with a 1-month history of thirst and polyuria and an unintentional weight loss of 25 lb. His weight was 167 lb, and he was 6 feet tall. He was not in distress, dehydrated, or hyperventilating. His vital signs and physical examination were normal, but point-of-care glucose levels were in the 300-mg/dL range, with urine positive for glucose and ketones. Z.R. is a college student majoring in sports medicine. He reports not smoking tobacco or drinking alcohol. At the time of his clinic visit, he was home from college and staying with parents during the coronavirus disease 2019 (COVID-19) pandemic lockdown. He had no family history of diabetes or autoimmune diseases. He is of Ashkenazi Jewish descent. The pediatrician contacted the endocrine service at 5:00 p.m. on a Thursday night. The pediatrician and endocrinologist mutually agreed that it would be in the best interests of the patient to avoid both an emergency department visit and a hospital stay. The COVID-19 outbreak was straining hospital resources and posing a potential nosocomial infection risk. Furthermore, telehealth resources were in place to safely and effectively manage Z.R.’s needs remotely. The endocrinologist contacted Z.R. and his parents and conducted an initial telehealth consultation by telephone that evening. The family was informed of the likely diagnosis of type 1 diabetes and agreed to initiate glucose monitoring and insulin administration that evening and that Z.R. would undergo laboratory testing the next morning. The value of blood glucose monitoring and continuous glucose monitoring (CGM) was discussed along with the requirement for insulin therapy. The endocrinologist also reviewed how to recognize and treat hypoglycemia, the basic nutrition principles of matching insulin to carbohydrates, and the potential …

To examine the mediating role of adiposity on the associations of diet quality with longitudinal changes in insulin sensitivity and beta-cell function.Adults at-risk for type 2 diabetes (T2D) in the PROMISE cohort had 4 assessments over 9 years (n = 442). Alternate Healthy Eating Index (AHEI) scores were used to assess diet quality. Generalized Estimating Equations (GEE) evaluated the associations between the AHEI and longitudinal changes in insulin sensitivity (HOMA2-%S and ISI) and beta-cell function (IGI/HOMA-IR and ISSI-2). The proportion of the mediating effect of waist circumference changes was estimated using the difference method. In the primary longitudinal analysis, AHEI was positively associated with insulin sensitivity and beta-cell function over time (% difference per standard deviation increase of AHEI for HOMA2-%S (β = 11.0, 95%CI 5.43-17.0), ISI (β = 10.4, 95%CI 4.35-16.8), IGI/HOMA-IR (β = 7.12, 95%CI 0.98-13.6) and ISSI-2 (β = 4.38, 95%CI 1.05-7.80), all p 0.05). There was no significant association between AHEI and dysglycemia incidence (OR = 0.95, 95%CI 0.77-1.17). Adjustments for longitudinal changes in waist circumference substantially attenuated all associations of AHEI with insulin sensitivity and beta-cell function. Mediation analysis indicated that waist circumference mediated 73%, 70%, 83% and 81% of the association between AHEI and HOMA2-%S, ISI, IGI/HOMA-IR, and ISSI-2, respectively (all p 0.01).In a Canadian population at-risk for T2D, AHEI score was positively associated with changes in insulin sensitivity and beta-cell function. These associations were substantially mediated by waist circumference, suggesting that changes in adiposity may represent an important pathway linking diet quality with risk phenotypes for T2D.

Pickett, CW, Nosaka, K, Zois, J, and Blazevich, AJ. Relationships between midthigh pull force development and 200-m race performance in highly trained kayakers. J Strength Cond Res 35(10): 2853-2861, 2021-While increased lower-limb force production during kayaking has been shown to be related to increased boat velocity, poor relationships between maximal deadlift test performances and 200-m race time have been observed previously. This discrepancy may result from either a lack of movement pattern or temporal force production specificity between the test and kayak paddling. The isometric midthigh pull (MTP) test is commonly used in strength testing and quantifies temporal and peak force production, with the lower limbs positioned in a more kayak-specific manner than the deadlift test. Midthigh pull force data collected from 11 high-level kayak athletes were analyzed for both reliability and correlations with 200-m race time and deadlift isoinertial strength 3 repetition maximum (3RM). Strong consideration was given to the collection, processing, and analysis of the MTP data, which markedly affected the study results. Correlations between race time and MTP peak force and rates of force development were poor to moderate (r = -0.49 to 0.07). Strong to very strong relationships (r = 0.66-0.79) were found between forces developed early in the MTP (0.15 seconds) and deadlift 3RM strength tests but were poor for later time-specific force development (r ≤ 0.12). However, poor reliability was found for force measured up to ≤0.25 seconds from the point of force onset (intraclass correlation coefficient0.8). Owing to the relatively weak relationships with 200-m race time, and the large variability of the data, it may not be wise to include the MTP in the testing and training of 200-m kayak athletes.

PURPOSE: More than half of patients with head and neck squamous cell carcinoma (HNSCC) experience a delay initiating guideline-adherent postoperative radiation therapy (PORT), contributing to excess mortality and racial disparities in survival. However, interventions to improve the delivery of timely, equitable PORT among patients with HNSCC are lacking. This study (1) describes the development of NDURE (Navigation for Disparities and Untimely Radiation thErapy), a navigation-based multilevel intervention (MLI) to improve guideline-adherent PORT and (2) evaluates its feasibility, acceptability, and preliminary efficacy. METHODS: NDURE was developed using the six steps of intervention mapping (IM). Subsequently, NDURE was evaluated by enrolling consecutive patients with locally advanced HNSCC undergoing surgery and PORT (n = 15) into a single-arm clinical trial with a mixed-methods approach to process evaluation. RESULTS: NDURE is a navigation-based MLI targeting barriers to timely, guideline-adherent PORT at the patient, healthcare team, and organizational levels. NDURE is delivered via three in-person navigation sessions anchored to case identification and surgical care transitions. Intervention components include the following: (1) patient education, (2) travel support, (3) a standardized process for initiating the discussion of expectations for PORT, (4) PORT care plans, (5) referral tracking and follow-up, and (6) organizational restructuring. NDURE was feasible, as judged by accrual (88% of eligible patients [100% Blacks] enrolled) and dropout (n = 0). One hundred percent of patients reported moderate or strong agreement that NDURE helped solve challenges starting PORT; 86% were highly likely to recommend NDURE. The rate of timely, guideline-adherent PORT was 86% overall and 100% for Black patients. CONCLUSION: NDURE is a navigation-based MLI that is feasible, is acceptable, and has the potential to improve the timely, equitable, guideline-adherent PORT.