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Kratom, a plant that produces opioid-like effects, has gained popularity in the U.S. for self-treating symptoms of chronic pain, mood disorders, and substance-use disorders (SUDs). Most data on kratom are from surveys into which current kratom-using adults could self-select; such surveys may underrepresent people who have used kratom and chosen to stop. Available data also do not adequately assess important psychosocial factors surrounding kratom use. In this study, U.S. adults who reported past 6-month alcohol, opioid, and/or stimulant use (N = 1,670) were recruited via Amazon Mechanical Turk between September and December 2020. Of the 1,510 evaluable respondents, 202 (13.4%) reported lifetime kratom use. Kratom-using adults, relative to others, were typically younger, male, unpartnered, without children, and had lower income. They had higher rates of chronic pain (31.7% vs. 21.9%, p = .003), childhood adversity, anxiety, and depression (p < .001), and lower perceived social rank (d = .19, .02-.22) and socioeconomic status (d = .37 .16-.26). They also reported higher use rates for most substances (except alcohol); this included medically supervised and unsupervised use of prescription opioids and diverted opioid agonist therapy (OAT) medications. Most (83.2%) met diagnostic criteria for any past-year SUD. Those reporting kratom use were less likely to reside in an urban/suburban area. The strongest predictors of kratom use were use of other drugs: cannabidiol (OR = 3.73), psychedelics (OR = 3.39), and nonmedical prescription opioids (OR = 1.72). Another strong predictor was lifetime OAT utilization (OR = 2.31). Despite seemingly poorer psychosocial functioning and health among respondents reporting lifetime kratom use, use of other substances may be the strongest indicators of kratom use. (PsycInfo Database Record (c) 2021 APA, all rights reserved).

Sleep impairment is a common comorbid and debilitating symptom for persons with opioid use disorder (OUD). Research into underlying mechanisms and efficacious treatment interventions for OUD-related sleep problems requires both precise and physiologic measurements of sleep-related outcomes and impairment. This pilot examined the feasibility of a wireless sleep electroencephalography (EEG) monitor (Sleep Profiler™) to measure sleep outcomes and architecture among participants undergoing supervised opioid withdrawal. Sleep outcomes were compared to a self-reported sleep diary and opioid withdrawal ratings. Participants (n = 8, 100% male) wore the wireless EEG 85.6% of scheduled nights. Wireless EEG detected measures of sleep architecture including changes in total, NREM and REM sleep time during study phases, whereas the diary detected changes in wakefulness only. Direct comparisons of five overlapping outcomes revealed lower sleep efficiency and sleep onset latency and higher awakenings and time spent awake from the wireless EEG versus sleep diary. Associations were evident between wireless EEG and increased withdrawal severity, lower sleep efficiency, less time in REM and non-REM stages 1 and 2, and more hydroxyzine treatment; sleep diary was associated with total sleep time and withdrawal only. Data provide initial evidence that a wireless EEG is a feasible and useful tool for objective monitoring of sleep in persons experiencing acute opioid withdrawal. Data are limited by the small and exclusively male sample, but provide a foundation for using wireless EEG sleep monitors for objective evaluation of sleep-related impairment in persons with OUD in support of mechanistic and treatment intervention research. (PsycInfo Database Record (c) 2022 APA, all rights reserved).

The purpose of this study was to determine the extent that language skills contribute to kindergarten children's classroom-based friendship networks. We assessed language skills and collected friendship data via individual interviews of 419 children from 21 kindergarten classrooms. Using social network analysis, we found that language skills were significantly associated with friendship centrality and reciprocity after controlling for classroom and child-level factors. Children classified as at risk for specific language impairment (SLI) were significantly less central to friendship networks, and the odds of a reciprocal friendship tie were more than 50% lower compared to children who were not classified as at risk. Of children at risk, girls were significantly more central than boys. We couch our results within limitations of our study and provide recommendations for future research. (PsycInfo Database Record (c) 2022 APA, all rights reserved).

© 2020, The Author(s), under exclusive licence to Springer Nature Limited.Lithium is a first-line medication for bipolar disorder (BD), but only one in three patients respond optimally to the drug. Since evidence shows a strong clinical and genetic overlap between depression and bipolar disorder, we investigated whether a polygenic susceptibility to major depression is associated with response to lithium treatment in patients with BD. Weighted polygenic scores (PGSs) were computed for major depression (MD) at different GWAS p value thresholds using genetic data obtained from 2586 bipolar patients who received lithium treatment and took part in the Consortium on Lithium Genetics (ConLi+Gen) study. Summary statistics from genome-wide association studies in MD (135,458 cases and 344,901 controls) from the Psychiatric Genomics Consortium (PGC) were used for PGS weighting. Response to lithium treatment was defined by continuous scores and categorical outcome (responders versus non-responders) using measurements on the Alda scale. Associations between PGSs of MD and lithium treatment response were assessed using a linear and binary logistic regression modeling for the continuous and categorical outcomes, respectively. The analysis was performed for the entire cohort, and for European and Asian sub-samples. The PGSs for MD were significantly associated with lithium treatment response in multi-ethnic, European or Asian populations, at various p value thresholds. Bipolar patients with a low polygenic load for MD were more likely to respond well to lithium, compared to those patients with high polygenic load [lowest vs highest PGS quartiles, multi-ethnic sample: OR = 1.54 (95% CI: 1.18–2.01) and European sample: OR = 1.75 (95% CI: 1.30–2.36)]. While our analysis in the Asian sample found equivalent effect size in the same direction: OR = 1.71 (95% CI: 0.61–4.90), this was not statistically significant. Using PGS decile comparison, we found a similar trend of association between a high genetic loading for MD and lower response to lithium. Our findings underscore the genetic contribution to lithium response in BD and support the emerging concept of a lithium-responsive biotype in BD.

This article describes the articulation, development, and deployment of a machine learning (ML) model-driven value solution for chronic kidney disease (CKD) in a health system. The ML model activated an electronic medical record (EMR) trigger that alerted CKD patients to seek primary care. Simultaneously, primary care physicians (PCPs) received an alert that a CKD patient needed an appointment. Using structured checklists, PCPs addressed and controlled comorbid conditions, reconciled drug dosing and choice to CKD stage, and ordered prespecified laboratory and imaging tests pertinent to CKD. After completion of checklist prescribed tasks, PCPs referred patients to nephrology. CKD patients had multiple comorbidities and ML recognition of CKD provided a facile insight into comorbid burden. Operational results of this program have exceeded expectations and the program is being expanded to the entire health system. This paradigm of ML-driven, checklist-enabled care can be used agnostic of EMR platform to deliver value in CKD through structured engagement of complexity in health systems.

Rationale & Objective Longer and more frequent hemodialysis sessions are associated with both benefits and harms. However, their relative importance to patients and how they influence acceptability for patients have not been quantified. Study Design Discrete-choice experiment in which a scenario followed by 12 treatment choice sets were presented to patients in conjunction with varying information about the clinical impact of the treatments offered. Setting and Participants Patients with kidney failure treated with maintenance dialysis for ≥1 year in 5 UK kidney centers. Predictors Length and frequency of hemodialysis sessions, and their prior reported associations with survival, quality of life, need for fluid restriction, hospitalization, and vascular access complications. Outcomes Selection of longer (4.5hr) or more frequent hemodialysis (4 sessions per week) regimens versus remaining on 3 sessions per week with session lengths of 4 hours. Analytical Approach Multinomial mixed effects logistic regression estimating the relative influence of different levels of the predictors on the selection of longer and more frequent dialysis, controlling for patient demographic characteristics. Results Among 183 prevalent in-centre haemodialysis patients (mean 4.7 years on dialysis, mean age of 63.7 years), 38.3% (70/183) always chose to remain on regimens of 3 sessions per week with session duration of 4 hours. Depicted associations of increasing survival and quality of life, reduced need for fluid restriction, and avoiding additional access complications were all significantly associated with choosing longer or more frequent treatment regimes. Younger age, fatigue, previous experience of vascular access complications, absence of heart failure, and shorter travel time to dialysis centers were associated with preference for 4 sessions per week. Patients expressed willingness to trade up to 2 years of life to avoid regimens of 4 sessions per week or access complications. After applying estimated treatment benefits and harms from existing literature, the fully adjusted model revealed that 27.1% would choose longer regimens delivered 3 times per week and 34.3% would choose 4hrs 4 times per week. Analogous estimates for younger fatigued patients living near their unit were 23.5% and 62.5%, respectively. Limitations Estimates were based on stated preferences rather than observed behaviors. Predicted acceptance of regimens was derived from data on treatment benefits and harms largely sourced from observational studies. Conclusions Predicted acceptance of longer and more frequent HD regimens substantially exceeds their use in current clinical practice. These findings underscore the need for robust data on clinical effectiveness of these more intensive regimens and more extensive consideration of patient choice in the selection of dialysis regimens.

BACKGROUND: Vaginal Lactobacillus is considered protective of some adverse reproductive health outcomes, including preterm birth. However, factors that increase or decrease the likelihood of harboring Lactobacillus in the vaginal microbiome remain largely unknown. In this study, we sought to identify risk and protective factors associated with vaginal Lactobacillus predominance within a cohort of pregnant African American women. MATERIALS AND METHODS: Vaginal microbiome samples were self-collected by African American women (N = 436) during their 8–14th week of pregnancy. Sociodemographic information and measures of health behaviors, including substance use, antibiotic exposure, sexual practices, frequency of vaginal intercourse, and the use of vaginal products, were collected through participant self-report. The V3–V4 region of the 16S rRNA gene was targeted for amplification and sequencing using Illumina HiSeq, with bacterial taxonomy assigned using the PECAN classifier. Univariate and a series of multivariate logistic regression models identified factors predictive of diverse vaginal microbiota or Lactobacillus predominance. RESULTS: Participants who used marijuana in the past 30 days (aOR 1.80, 95% CI 1.08–2.98) were more likely to have diverse non-Lactobacillus-predominant vaginal microbiota, as were women not living with their partners (aOR 1.90, 95% CI 1.20–3.01). Cohabitating or marijuana usage were not associated with type of Lactobacillus (non-iners Lactobacillus vs. Lactobacillus iners) predominance (aOR 1.11, 95% CI 0.52–2.38 and aOR 0.56, 95% CI 0.21–1.47, respectively). CONCLUSIONS: Living with a partner is conducive to vaginal Lactobacillus predominance. As such, cohabitation may be in important covariate to consider in vaginal microbiome studies.

Summary Background Virtual Surgical Planning (VSP) is increasingly used in maxillomandibular osseous free flap reconstruction. Non-commercial (‘in-house') VSP may offer the same level of accuracy and other benefits, without the inflated costs and time delays inherent in using commercial providers. Comparisons between commercial and in-house methods are lacking. This study aims to determine the accuracy of VSP, comparing in-house and commercially planned cases, and to explore predictors of reconstruction error. Methods 76 patients who had a virtually planned maxillomandibular reconstruction between January 2012 and July 2020 were retrospectively identified. The pre-operative digital plan was compared to the post-operative CT scan in terms of: length of bone segments, angle between adjacent segments and intercondylar and intergonial angle distances (mandibular reconstructions only). Results 44 patients fulfilled the inclusion criteria. The mean intergonial and intercondylar distances error was 1.7 ± 1.01mm, mean segment length error was 1.3 ± 1.40mm, and mean angles error was 1.9 ± 2.32 degrees. The difference in error of in-house VSP compared to commercial VSP was not statistically significant for intercondylar and intergonial distance (p=0.76), segment length (p=0.15), or angle between segments (p=0.92). Increased error was associated with osteoradionecrosis as the indication for surgery, greater number of segments, and secondary reconstructions. Conclusion VSP is an accurate method of maxillary and mandibular reconstruction. In-house VSP may be similar in accuracy to commercial VSP options. Higher levels of inaccuracy are likely to occur in more complex reconstructions, particularly secondary reconstructions, and in the setting of osteoradionecrosis.

Traumatic brain injury (TBI) and blunt thoracic aortic injury (BTAI) are the top two leading causes of death after blunt force trauma. Patients presenting with concomitant BTAI and TBI pose a specific challenge with respect to management strategy, because the optimal hemodynamic parameters are conflicting between the two pathologies. Early thoracic endovascular aortic repair (TEVAR) is often performed, even for minimal aortic injuries, to allow for the higher blood pressure parameters required for TBI management. However, the optimal timing of TEVAR for the treatment of BTAI in patients with concomitant TBI remains an active matter of controversy.The Aortic Trauma Foundation international prospective multicenter registry was used to identify all patients who had undergone TEVAR for BTAI in the setting of TBI from 2015 to 2020. The primary outcomes included delayed ischemic or hemorrhagic stroke, in-hospital mortality, and aortic-related mortality. The outcomes were examined among patients who had undergone TEVAR at emergent (6 vs ≥6 hours) or urgent (24 vs ≥24 hours) intervals.A total of 100 patients (median age, 43 years; 79% men; median injury severity score, 41) with BTAI (Society for Vascular Surgery BTAI grade 1, 3%; grade 2, 10%; grade 3, 78%; grade 4, 9%) and concomitant TBI who had undergone TEVAR were identified. Emergent repair was performed for 51 patients (51%). Comparing emergent repair (6 hours) to urgent repair (≥6 hours), no difference was found in delayed cerebral ischemic events (2.0% vs 4.1%; P = .614), in-hospital mortality (15.7% vs 22.4%; P = .389), or aortic-related mortality (2.0% vs 2.0%; P = .996) and no patient had experienced delayed hemorrhagic stroke. Likewise, repairs conducted in an urgent (24 hours) setting showed no differences compared with those completed in an emergent (≥24 hours) setting regarding delayed ischemic stroke (2.6% vs 4.3%; P = .548), in-hospital mortality (18.2% vs 21.7%; P = .764), or aortic-related mortality (1.3% vs 4.3%; P = .654), and no patient had experienced delayed hemorrhagic stroke.In contrast to prior retrospective efforts, results from the Aortic Trauma Foundation international prospective multicenter registry have demonstrated that neither emergent nor urgent TEVAR for patients with concomitant BTAI and TBI was associated with delayed stroke, in-hospital mortality, or aortic-related mortality. In these patients, the timing of TEVAR did not have an effect on the outcomes. Therefore, the decision to intervene should be guided by individual patient factors rather than surgical timing.

This review highlights recent advances in the understanding of eosinophils and eosinophilic diseases, particularly eosinophilic gastrointestinal diseases during the last year. The increasing incidence of diseases marked by eosinophilia has been documented and highlighted the need to understand eosinophil biology and eosinophilic contributions to disease. Significant insight into the nature of eosinophilic diseases has been achieved using next-generation sequencing technologies, proteomic analysis, and machine learning to analyze tissue biopsies. These technologies have elucidated mechanistic underpinnings of eosinophilic inflammation, delineated patient endotypes, and identified patient responses to therapeutic intervention. Importantly, recent clinical studies using monoclonal antibodies that interfere with type 2 cytokine signaling or deplete eosinophils point to multiple and complex roles of eosinophils in tissues. Several studies identified distinct activation features of eosinophils in different tissues and disease states. The confluence of these studies supports a new paradigm of tissue-resident eosinophils that have pro- and anti-inflammatory immunomodulatory roles in allergic disease. Improved understanding of unique eosinophil activation states is now poised to identify novel therapeutic targets for eosinophilic diseases.

Meningiomas are largely indolent tumors with a benign clinical course, but a minority exhibit aggressive behavior characterized by rapid growth, neurologic deficits, and increased mortality. Identifying high-risk patients requiring intervention is challenging, but recent insights into meningioma biology provide a useful guide for decision making. Standard of care for recurrent or biologically aggressive tumors consists of surgery and radiation therapy. Systemic therapies targeting vascular endothelial growth factor signaling and somatostatin analogues are potential options for those with refractory disease but display only modest activity. New paradigms in meningioma clinical trial design provide hope for improved options in the future.

Glioblastoma has emerged as an immunotherapy-refractory tumor based on negative phase III studies of anti-programmed cell death-1 therapy among newly diagnosed as well as recurrent patients. In addition, although much work on vaccine and cellular approaches is ongoing, therapeutic benefit with these approaches has been underwhelming. Much scientific insight into the multitiered layers of immunosuppression exploited by glioblastoma tumors is emerging that sheds light on the explanation for the disappointing results to date and highlights possible therapeutic avenues that may offer a better likelihood of therapeutic benefit for immune-based therapies.

Since the late 19th century, the immune system has increasingly garnered interest as a novel avenue for cancer therapy, particularly given scientific breakthroughs in recent decades delineating the fundamental role of the immune system in tumorigenesis. The immunoediting hypothesis has articulated this role, describing three phases of the tumor-immune system interaction: Elimination, Equilibrium, and Escape wherein tumors progress from active immunologic surveillance and destruction through dynamic immunologic stasis to unfettered growth. The primary goals of immunotherapy are to restrict and revert progression through these phases, thereby improving the immune system's ability to control tumor growth. In this review, we detail the development and foundation of the cancer immunoediting hypothesis and apply this hypothesis to the dynamic immunotherapy field that includes checkpoint blockade, vaccine therapy, and adoptive cell transfer.

To determine the impact of aortic root replacement (ARR) with a stentless bioprosthetic valve on midterm outcomes compared to a stented bioprosthetic valve-graft conduit. This was an observational study of aortic root operations from 2010 to 2018. All patients with a complete ARR for nonendocarditis reasons were included, while patients undergoing valve-sparing root replacements or primary aortic valve replacement or repair were excluded. Of the patients with a complete ARR, bioprosthetic valve implants were included, while mechanical valve implants were excluded. Patients were dichotomized into the stented ARR group and the stentless ARR group. A total of 1:1 nearest neighbor propensity matching was employed to assess the association of stentless valves with short-term and midterm outcomes. A total of 455 patients underwent a complete ARR with a bioprosthetic valve implant for nonendocarditis reasons, of which 212 (46.6%) received a stented valve, while 243 (53.4%) received a stentless valve. After matching, postoperative outcomes were similar across each group (P > 0.05), including operative mortality and adverse neurologic events. Median follow-up for the entire cohort was 4.41 years (95% CI: 4.01, 4.95). At 1 year follow-up, aortic regurgitation ≥ 2+ and ejection fraction were similar across each group (P > 0.05); however, the stentless valve group had lower aortic valve velocity and transvalvular pressure gradient. Finally, reoperations and survival were similar for each group over the study's follow-up (P > 0.05). Stentless valves may provide hemodynamic benefits after ARR; however, the clinical impact of those benefits for survival and reoperation may not yet be evident in the midterm.

Background Metabolic syndrome is associated with formation of calcium oxalate (CaOx) uroliths in humans. Objectives To investigate the association between obesity and hyperlipidemia with CaOx lower urinary tract uroliths in client‐owned dogs. Animals Dogs with (n = 55, U [uroliths]‐dogs) and without (n = 39, UF [uroliths‐free]‐dogs) CaOx lower urinary tract uroliths. Methods Case‐control study. U‐dogs were retrospectively enrolled and compared to UF‐dogs. Body condition score (BCS; 1‐9 scoring scale), serum triglyceride (TG) and total cholesterol (CH) concentrations and glycemia (after >12‐hour food withholding) were recorded in both groups. Results On univariate logistic regression, when excluding Miniature Schnauzers, odds of having uroliths increased by a factor of 3.32 (95% CI 1.38‐11.12) for each mmol/L of TG (P = .027), of 39 (95% CI 9.27‐293.22) for each mmol/L of glycemia (P

PURPOSE: Decision aids have been found to improve patients’ knowledge of treatments and decrease decisional regrets. Despite these benefits, there is not widespread use of decision aids for newly diagnosed prostate cancer (PCa). This analysis investigates factors that impact men’s choice to use a decision aid for newly diagnosed prostate cancer. MATERIALS AND METHODS: This is a retrospective analysis of a PCa registry from the Michigan Urological Surgery Improvement Collaborative (MUSIC). We included data from men with newly diagnosed, clinically localized PCa seen from 2018-21 at practices offering a PCa decision aid (Personal Patient Profile-Prostate; P3P). The primary outcome was men’s registration to use P3P. We fit a multilevel logistic regression model with patient-level factors and included urologist specific random intercepts. We estimated the intra-class correlation (ICC) and predicted the probability of P3P registration among urologists. RESULTS: A total of 2629 men were seen at practices that participated in P3P and 1174 (45%) registered to use P3P. Forty-one percent of the total variance of P3P registration was attributed to clustering of men under a specific urologist’s care. In contrast, only 1.5% of the variance of P3P registration was explained by patient factors. Our model did not include data on socioeconomic, literacy or psychosocial factors, which limits the interpretation of the results. CONCLUSIONS: These results suggest that urologists’ effect far outweighs patient factors in a man’s decision to enroll in P3P. Strategies that encourage providers to increase decision aid adoption in their practices are warranted.

Though surgical biopsies provide direct access to tissue for genomic characterization of brain cancer, they are invasive and pose significant clinical risks. Brain cancer management via blood-based liquid biopsies is a minimally invasive alternative; however, the blood-brain barrier (BBB) restricts the release of brain tumor-derived molecular biomarkers necessary for sensitive diagnosis. Methods: A mouse glioblastoma multiforme (GBM) model was used to demonstrate the capability of focused ultrasound (FUS)-enabled liquid biopsy (sonobiopsy) to improve the diagnostic sensitivity of brain tumor-specific genetic mutations compared with conventional blood-based liquid biopsy. Furthermore, a pig GBM model was developed to characterize the translational implications of sonobiopsy in humans. Magnetic resonance imaging (MRI)-guided FUS sonication was performed in mice and pigs to locally enhance the BBB permeability of the GBM tumor. Contrast-enhanced T1-weighted MR images were acquired to evaluate the BBB permeability change. Blood was collected immediately after FUS sonication. Droplet digital PCR was used to quantify the levels of brain tumor-specific genetic mutations in the circulating tumor DNA (ctDNA). Histological staining was performed to evaluate the potential for off-target tissue damage by sonobiopsy. Results: Sonobiopsy improved the detection sensitivity of EGFRvIII from 7.14% to 64.71% and TERT C228T from 14.29% to 45.83% in the mouse GBM model. It also improved the diagnostic sensitivity of EGFRvIII from 28.57% to 100% and TERT C228T from 42.86% to 71.43% in the porcine GBM model. Conclusion: Sonobiopsy disrupts the BBB at the spatially-targeted brain location, releases tumor-derived DNA into the blood circulation, and enables timely collection of ctDNA. Converging evidence from both mouse and pig GBM models strongly supports the clinical translation of sonobiopsy for the minimally invasive, spatiotemporally-controlled, and sensitive molecular characterization of brain cancer.

Physical frailty and impaired cognition are common in patients with cirrhosis. Physical frailty can be assessed using performance-based tests, but the extent to which impaired cognition may impact performance is not well characterized. We assessed the relationship between impaired cognition and physical frailty in patients with cirrhosis. We enrolled 1,623 ambulatory adult patients with cirrhosis waiting for liver transplantation at 10 sites. Frailty was assessed with the liver frailty index (LFI; "frail," LFI≥4.4). Cognition was assessed at the same visit with the number connection test (NCT); continuous "impaired cognition" was examined in primary analysis, with longer NCT (more seconds) indicating worse impaired cognition. For descriptive statistics, "impaired cognition" was NCT≥45seconds. Linear regression associated frailty and impaired cognition; competing risk regression estimated subhazard ratios (sHRs) of wait-list mortality (i.e., death/delisting for sickness). Median NCT was 41seconds, and 42% had impaired cognition. Median LFI (4.2 vs. 3.8) and rates of frailty (38% vs. 20%) differed between those with and without impaired cognition. In adjusted analysis, every10-second NCTincrease associated with a0.08-LFIincrease (95% confidence interval [CI], 0.07-0.10). In univariable analysis, both frailty (sHR, 1.63; 95% CI, 1.43-1.87) and impaired cognition (sHR, 1.07; 95% CI, 1.04-1.10) associated with wait-list mortality. After adjustment, frailty but not impaired cognition remained significantly associated with wait-list mortality (sHR, 1.55; 95% CI, 1.33-1.79). Impaired cognition mediated 7.4% (95% CI, 2.0%-16.4%) of the total effect of frailty on 1-year wait-list mortality. Conclusion: Patients with cirrhosis with higher impaired cognition displayed higher rates of physical frailty, yet frailty independently associated with wait-list mortality while impaired cognition did not. Our data provide evidence for using the LFI to understand mortality risk in patients with cirrhosis, even when concurrent impaired cognition varies.

Background: Despite advances in surgery and pharmacotherapy, there remains significant residual ischemic risk after coronary artery bypass grafting surgery. Methods: In REDUCE-IT (Reduction of Cardiovascular Events With Icosapent Ethyl–Intervention Trial), a multicenter, placebo-controlled, double-blind trial, statin-treated patients with controlled low-density lipoprotein cholesterol and mild to moderate hypertriglyceridemia were randomized to 4 g daily of icosapent ethyl or placebo. They experienced a 25% reduction in risk of a primary efficacy end point (composite of cardiovascular death, myocardial infarction, stroke, coronary revascularization, or hospitalization for unstable angina) and a 26% reduction in risk of a key secondary efficacy end point (composite of cardiovascular death, myocardial infarction, or stroke) when compared with placebo. The current analysis reports on the subgroup of patients from the trial with a history of coronary artery bypass grafting. Results: Of the 8179 patients randomized in REDUCE-IT, a total of 1837 (22.5%) had a history of coronary artery bypass grafting, with 897 patients randomized to icosapent ethyl and 940 to placebo. Baseline characteristics were similar between treatment groups. Randomization to icosapent ethyl was associated with a significant reduction in the primary end point (hazard ratio [HR], 0.76 [95% CI, 0.63–0.92]; P =0.004), in the key secondary end point (HR, 0.69 [95% CI, 0.56–0.87]; P =0.001), and in total (first plus subsequent or recurrent) ischemic events (rate ratio, 0.64 [95% CI, 0.50–0.81]; P =0.0002) compared with placebo. This yielded an absolute risk reduction of 6.2% (95% CI, 2.3%–10.2%) in first events, with a number needed to treat of 16 (95% CI, 10–44) during a median follow-up time of 4.8 years. Safety findings were similar to the overall study: beyond an increased rate of atrial fibrillation/flutter requiring hospitalization for at least 24 hours (5.0% vs 3.1%; P =0.03) and a nonsignificant increase in bleeding, occurrences of adverse events were comparable between groups. Conclusions: In REDUCE-IT patients with a history of coronary artery bypass grafting, treatment with icosapent ethyl was associated with significant reductions in first and recurrent ischemic events. Registration: URL: https://www.clinicaltrials.gov ; Unique identifier: NCT01492361.

BACKGROUND Women with HIV face challenges in engaging in HIV care post partum. We aimed to examine changes in engagement in HIV care through clinic attendance before, during, and after pregnancy, compared with matched women with HIV who had never had a recorded pregnancy. METHODS In this cohort study, we describe changes in engagement in HIV care before, during, and after pregnancy among women with HIV from the UK Collaborative HIV Cohort (CHIC) study from 25 HIV clinics in the UK with a livebirth reported to the National Surveillance of HIV in Pregnancy and Childhood between Jan 1, 2000, and Dec 31, 2017. To investigate whether changes were specific to HIV, we compared these changes to those over equivalent periods among non-pregnant women with HIV in the UK CHIC study matched for ethnicity, year of conception, age, CD4 cell count, viral suppression, and antiretroviral therapy use. Analyses were via logistic regression using generalised estimated equations with an interaction between case-control status (pregnant women vs non-pregnant women) and pregnancy or pseudo pregnancy (for non-pregnant women) stage. FINDINGS 1116 matched pairs of pregnant and non-pregnant women were included (median age 34 years [IQR 30-38], 80·1% Black African, 12·5% white). 69 330 person-months of follow-up were recorded, 25 412 in the before stage, 18 897 during, and 25 021 after pregnancy or pseudo pregnancy stages. Among pregnant women, the proportion of time engaged in care increased during pregnancy (8477 [90·5%] of 9371 person-months) and after pregnancy (10 501 [84·6%] of 12 407), compared with before pregnancy (9979 [78·5%] of 12 707). Among non-pregnant women in the control group, engagement in HIV care remained stable across the three equivalent stages (9688 [76·3%] of 12 705 person-months before pseudo pregnancy; 7463 [78·3%] of 9526 during pseudo pregnancy; and 9892 [78·4%] of 12 614 after pseudo pregnancy). The association of engagement in HIV care with pregnancy or pseudo pregnancy stage differed significantly by case-control status (pinteraction

Opioid use disorder (OUD) is a significant health problem, and understanding mechanisms of various aspects of OUD including drug use and withdrawal is important. Preclinical models provide an ideal opportunity to evaluate mechanisms underlying opioid withdrawal. Current models are limited by their reliance upon forced opioid administration, focus on the acute (and not protracted) syndrome, and exclusion of females. In this study, male and female rats self-administered heroin (maintenance dose of 12.5 μg/kg/infusion) and opioid withdrawal after abrupt discontinuation was measured. In Phase 1, acute withdrawal symptoms were rated in male and female rats at 0, 16, 48, and 72 hr after the last self-administration session. Total somatic signs increased until 48 hr (predominantly in females), and heroin intake positively correlated with total somatic signs at the 48 and 72 hr timepoints. Measures of hyperactivity and anxiety-like behavior increased by 16 and 48 hr, respectively. In Phase 2, symptoms were assessed at baseline, acute, and protracted (168 and 312 hr after self-administration) timepoints in a subset of male and female rats from Phase 1. The total number of somatic signs did not differ across timepoints, though females displayed significantly higher body temperature at all timepoints compared with males, indicating sex-specific protracted withdrawal symptomatology. These data provide a thorough characterization of rodent opioid withdrawal symptomatology after self-administration and abrupt discontinuation that serve as a foundation for future studies designed to mimic the human experience, and demonstrate the importance of characterizing acute and protracted withdrawal with sex-specificity in preclinical models of opioid self-administration. (PsycInfo Database Record (c) 2021 APA, all rights reserved).

Purpose: Cancer remains the most common cause of disease-related death among young people and carries a significant burden. In the absence of prior state-based Australian epidemiological studies, t...

Spinal osteomyelitis predominantly affects the anterior vertebral column. Pyogenic infection seldom results in significant deformity but rather the more insidious causes such as tuberculosis. The typical deformity is a single plane kyphosis, other than when the infection affects the more mobile and more loaded lumbar spine where facet subluxation may result in a three-dimensional torsional deformity. Management is dictated by whether the disease process is active versus healed disease, the skeletal maturity of the patient and whether there is ongoing spinal growth expected and associated neurological deficit. Surgical strategies may be anterior only, such as in the sub-axial cervical and thoracic active disease, combined anterior and posterior procedures at the cervico-thoracic and thoracic‐lumbar junctions, but the posterior circumferential vertebral column resection (VCR) is increasingly utilized for rigid healed disease, especially with late presenters and in those patients who have associated neurological impairment.

RATIONALE: People with cystic fibrosis (CF) experience acute worsening of respiratory symptoms and lung function known as pulmonary exacerbations. Treatment with intravenous antimicrobials is common; however, there is scant evidence to support a standard treatment duration. OBJECTIVES: To test differing durations of intravenous antimicrobials for CF exacerbations. METHODS: STOP2 (Standardized Treatment of Pulmonary Exacerbations 2) was a multicenter, randomized, controlled clinical trial in exacerbations among adults with CF. After 7–10 days of treatment, participants exhibiting predefined lung function and symptom improvements were randomized to 10 or 14 days’ total antimicrobial duration; all others were randomized to 14 or 21 days’ duration. MEASUREMENTS AND MAIN RESULTS: The primary outcome was percent predicted FEV(1) (ppFEV(1)) change from treatment initiation to 2 weeks after cessation. Among early responders, noninferiority of 10 days to 14 days was tested; superiority of 21 days compared with 14 days was compared for the others. Symptoms, weight, and adverse events were secondary. Among 982 randomized people, 277 met improvement criteria and were randomized to 10 or 14 days of treatment; the remaining 705 received 21 or 14 days of treatment. Mean ppFEV(1) change was 12.8 and 13.4 for 10 and 14 days, respectively, a ‒0.65 difference (95% CI [‒3.3 to 2.0]), excluding the predefined noninferiority margin. The 21- and 14-day arms experienced 3.3 and 3.4 mean ppFEV(1) changes, a difference of ‒0.10 (‒1.3 to 1.1). Secondary endpoints and sensitivity analyses were supportive. CONCLUSIONS: Among adults with CF with early treatment improvement during exacerbation, ppFEV(1) after 10 days of intravenous antimicrobials is not inferior to 14 days. For those with less improvement after one week, 21 days is not superior to 14 days. Clinical trial registered with www.clinicaltrials.gov (NCT02781610).

A 79-year-old male presented for removal of what was proven to be a keratoacanthoma. Additional tissue removed deep to the initial lesion revealed intravascular basal cell carcinoma (BCC). Intravascular BCC is exceedingly rare with only 8 cases previously reported in the literature. Intravascular BCC may be associated with more aggressive subtypes. Intravascular infiltration is more common in metastatic BCC, but this finding may not imply causality. More data are required in order to determine prognostic implications of intravascular BCC and to develop a protocol for managing patients with this unique finding.

Objective To perform a meta-analysis of all-cause, cause-specific and gender-specific standardized mortality ratio and crude mortality rate for people with multiple sclerosis. We also examined the temporal trends in this data. Methods Medline, Cochrane Library and Scopus were searched. Keywords were "multiple sclerosis" and "standardized mortality ratio" or "Standardized Mortality Ratio". We included longitudinal studies with available data on the number of deaths, follow-up period, person years and reports of standardized mortality ratio (SMR). Crude mortality ratio (CMR) was calculated and SMR was extracted. CMRs and log-SMR were pooled by the method of inverse variance. Meta-regression models were used to investigate temporal trends. Results Fifty-seven articles were screened. Fifteen studies were included covering a period 1949-2013 (160,000 patients; 21,225 deaths). The all-cause SMR for people with MS was 2.61 (95% CI 2.58 to 2.65). For men this was 2.47 (95% CI 2.42 to 2.52) and for women 2.57 (95% CI 2.53 to 2.61). The CMR was 13.45/1000 person years. Cause-specific SMR was 1.74 (1.67 to 1.81) for CVD, 4.70 (4.45 to 4.87) for respiratory disease and infection, 1.81 (1.64 to 2.0) for accident and suicide and 0.99 (0.93 to 1.06) for cancer. Meta-regression analysis of the SMR compared to midpoint follow-up year revealed no relationship (co-efficient 0.001, p = .98). Conclusions People with multiple sclerosis (MS) have reduced overall survival and increased risk of death from cardiovascular, respiratory and infectious disease as well as accidents and suicide. This does not appear to have changed over the last 65 years.

Objective To report the 30-day outcomes of patients with perioperative SARS-CoV-2 infection undergoing surgery in the USA. Summary background data Uncertainty regarding the postoperative risks of patients with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) exists. Methods As part of the COVIDSurg multicenter study, all patients aged ≥17 years undergoing surgery between January 1 and June 30, 2020 with perioperative SARS-CoV-2 infection in 70 hospitals across 27 states were included. The primary outcomes were 30-day mortality and pulmonary complications. Multivariable analyses (adjusting for demographics, comorbidities, and procedure characteristics) were performed to identify predictors of mortality. Results A total of 1,581 patients were included; more than half of them were males (n= 822, 52.0%) and older than 50 years (n=835, 52.8%). Most procedures (n=1,261, 79.8%) were emergent, and laparotomies (n= 538, 34.1%). The mortality and pulmonary complication rates were 11.0 and 39.5%, respectively. Independent predictors of mortality included age ≥70 years (OR 2.46, 95% CI [1.65-3.69]), male sex (2.26 [1.53-3.35]), ASA grades 3-5 (3.08 [1.60-5.95]), emergent surgery (2.44 [1.31-4.54]), malignancy (2.97 [1.58-5.57]), respiratory comorbidities (2.08 [1.30-3.32]), and higher Revised Cardiac Risk Index (1.20 [1.02-1.41]). While statewide elective cancelation orders were not associated with a lower mortality, a sub-analysis showed it to be associated with lower mortality in those who underwent elective surgery (0.14 [0.03-0.61]). Conclusions Patients with perioperative SARS-CoV-2 infection have a significantly high risk for postoperative complications, especially elderly males. Postponing elective surgery and adopting non-operative management, when reasonable, should be considered in the USA during the pandemic peaks.

BACKGROUND: Early vocational rehabilitation following spinal cord injury (SCI) improves return to work (RTW) outcomes, but there is limited information about who benefits from such interventions, why and in what contexts. OBJECTIVE: We aimed to describe demographic and clinical characteristics and RTW outcomes of adults with SCI who received early vocational rehabilitation. We sought to identify key mechanisms of early vocational rehabilitation. METHODS: This is a cross-sectional survey of people with SCI recruited from the New Zealand Spinal Trust Vocational Rehabilitation Service, who had sustained an SCI within the previous five years. RESULTS: Of the 37 people who responded to the survey, 54% returned to paid work (90% of whom retained their pre-injury employment). Those in autonomous roles returned to work faster with greater odds of returning to their pre-injury employer and role. Participants highlighted the importance of feeling hopeful about RTW while still in the spinal unit as a key mechanism of effect within the early vocational intervention. CONCLUSIONS: Findings suggested key mechanisms of early vocational intervention could be framed by models of hope. However, for gains to be optimised, continuity of support beyond the acute stage was suggested as an area for future research.

Background The Children's Oncology Group (COG) adopted cisplatin, 5-flourouracil, and vincristine (C5V) as standard therapy after the INT-0098 legacy study showed statistically equivalent survival but less toxicity in comparison with cisplatin and doxorubicin. Subsequent experience demonstrated doxorubicin to be effective in patients with recurrent disease after C5V, and this suggested that it could be incorporated to intensify therapy for patients with advanced disease. Methods In this nonrandomized, phase 3 COG trial, the primary aim was to explore the feasibility and toxicity of a novel therapeutic cisplatin, 5-flourouracil, vincristine, and doxorubicin (C5VD) regimen with the addition of doxorubicin to C5V for patients considered to be at intermediate risk. Patients were eligible if they had unresectable, nonmetastatic disease. Patients with a complete resection at diagnosis and local pathologic evidence of small cell undifferentiated histology were also eligible for an assessment of feasibility. Results One hundred two evaluable patients enrolled between September 14, 2009, and March 12, 2012. Delivery of C5VD was feasible and tolerable: the mean percentages of the target doses delivered were 96% (95% CI, 94%-97%) for cisplatin, 96% (95% CI, 94%-97%) for 5-fluorouracil, 95% (95% CI, 93%-97%) for doxorubicin, and 90% (95% CI, 87%-93%) for vincristine. Toxicity was within expectations, with death as a first event in 1 patient. The most common adverse events were febrile neutropenia (n = 55 [54%]), infection (n = 48 [47%]), mucositis (n = 31 [30%]), hypokalemia (n = 39 [38%]), and elevated aspartate aminotransferase (n = 28 [27%]). The 5-year event-free and overall survival rates for the 93 patients who did not have complete resection at diagnosis were 88% (95% CI, 79%-93%) and 95% (95% CI, 87%-98%), respectively. Conclusions The addition of doxorubicin to the previous standard regimen of C5V is feasible, tolerable, and efficacious, and this suggests that C5VD is a good regimen for future clinical trials.

Background For children with hearing loss, the primary goal of hearing aids is to provide improved access to the auditory environment within the limits of hearing aid technology and the child's auditory abilities. However, there are limited data examining aided speech recognition at very low (40 decibels A [dBA]) and low (50 dBA) presentation levels. Purpose Due to the paucity of studies exploring aided speech recognition at low presentation levels for children with hearing loss, the present study aimed to (1) compare aided speech recognition at different presentation levels between groups of children with “normal” hearing and hearing loss, (2) explore the effects of aided pure tone average and aided Speech Intelligibility Index (SII) on aided speech recognition at low presentation levels for children with hearing loss ranging in degree from mild to severe, and (3) evaluate the effect of increasing low-level gain on aided speech recognition of children with hearing loss. Research Design In phase 1 of this study, a two-group, repeated-measures design was used to evaluate differences in speech recognition. In phase 2 of this study, a single-group, repeated-measures design was used to evaluate the potential benefit of additional low-level hearing aid gain for low-level aided speech recognition of children with hearing loss. Study Sample The first phase of the study included 27 school-age children with mild to severe sensorineural hearing loss and 12 school-age children with “normal” hearing. The second phase included eight children with mild to moderate sensorineural hearing loss. Intervention Prior to the study, children with hearing loss were fitted binaurally with digital hearing aids. Children in the second phase were fitted binaurally with digital study hearing aids and completed a trial period with two different gain settings: (1) gain required to match hearing aid output to prescriptive targets (i.e., primary program), and (2) a 6-dB increase in overall gain for low-level inputs relative to the primary program. In both phases of this study, real-ear verification measures were completed to ensure the hearing aid output matched prescriptive targets. Data Collection and Analysis Phase 1 included monosyllabic word recognition and syllable-final plural recognition at three presentation levels (40, 50, and 60 dBA). Phase 2 compared speech recognition performance for the same test measures and presentation levels with two differing gain prescriptions. Conclusion In phase 1 of the study, aided speech recognition was significantly poorer in children with hearing loss at all presentation levels. Higher aided SII in the better ear (55 dB sound pressure level input) was associated with higher Consonant-Nucleus-Consonant word recognition at a 40 dBA presentation level. In phase 2, increasing the hearing aid gain for low-level inputs provided a significant improvement in syllable-final plural recognition at very low-level inputs and resulted in a nonsignificant trend toward better monosyllabic word recognition at very low presentation levels. Additional research is needed to document the speech recognition difficulties children with hearing aids may experience with low-level speech in the real world as well as the potential benefit or detriment of providing additional low-level hearing aid gain.

Background: Surveys suggest wide-spread use of MART-1 in MMS for CM among Mohs surgeons, but no previous systematic review has investigated the efficacy of this specific procedure. Methods: A systematic search and meta-analysis of retrospective studies on MMS with MART-1 was performed from Pubmed, Medline, and Cochrane databases for articles published from their inception to October 30, 2020. We performed a chi-squared analysis of homogenized data to examine the relationship between recurrence location and rate of recurrence. A risk of bias was obtained with the ROBINS-I tool. [PROSPERO ID: CRD42020221826] Results: Among the included studies, there were a total of 15 (0.52%) local recurrences of melanoma in-situ and invasive melanoma after MMS with MART-1. Conclusions: This review has served to demonstrate that MMS with MART-1 immunostaining in frozen sections is a technique that produces satisfactory recurrence rates for melanoma in-situ and invasive melanoma.

Athletes are at risk for a variety of injuries not typically sustained in everyday life. The team physician must be capable of not only identifying and treating injuries as they occur, but he or she must be armed with the knowledge to minimize the risk of injuries before they occur. This review serves to provide an overview of the various sport-specific injuries typically encountered by team physicians. Injuries are grouped by body part and/or organ system, when possible. We do not aim to cover in detail the various treatments for these injuries; rather, we hope that this article provides a comprehensive overview of sport-specific injury, and demonstrate the well-roundedness in skills that must be possessed by team physicians.

BACKGROUND Stroke risk factors after blunt cerebrovascular injury (BCVI) are ill-defined. We hypothesized that factors associated with stroke for BCVI would include medical therapy (ie: Aspirin®), radiographic features, and protocolization of care. METHODS An EAST-sponsored, 16 center, prospective, observational trial was undertaken. Stroke risk factors were analyzed individually for vertebral artery (VA) and internal carotid artery (ICA) BCVI. BCVI were graded on the standard 1-5 scale. Data was from the initial hospitalization only. RESULTS 777 BCVIs were included. Stroke rate was 8.9% for all BCVI, with an 11.7% rate of stroke for ICA BCVI and a 6.7% rate for VA BCVI. Use of a management protocol (p = 0.01), management by the trauma service (p = 0.04), antiplatelet therapy over the hospital stay (p < 0.001), and Aspirin® therapy specifically over the hospital stay (p < 0.001) were more common in ICA BCVI without stroke compared with those with stroke. Antiplatelet therapy over the hospital stay (p < 0.001) and Aspirin® therapy over the hospital stay (p < 0.001) were more common in VA BCVI without stroke than with stroke. Percentage luminal stenosis was higher in both ICA BCVI (p = 0.002) and VA BCVI (p < 0.001) with stroke. Decrease in percentage luminal stenosis (p < 0.001), resolution of intraluminal thrombus (p = 0.003), and new intraluminal thrombus (p = 0.001) were more common in ICA BCVI with stroke than without, while resolution of intraluminal thrombus (p = 0.03) and new intraluminal thrombus (p = 0.01) were more common in VA BCVI with stroke than without. CONCLUSIONS Protocol driven management by the trauma service, antiplatelet therapy (specifically Aspirin®), and lower percentage luminal stenosis were associated with lower stroke rates, while resolution and development of intraluminal thrombus were associated with higher stroke rates. Further research will be needed to incorporate these risk factors into lesion specific BCVI management.Study Type/Level of EvidenceOriginal article, prognostic and epidemiological, Level III.

OBJECTIVE The purpose of this study was to investigate whether neurosurgical intervention for traumatic brain injury (TBI) is associated with reduced risks of death and clinical deterioration in a low-income country with a relatively high neurosurgical capacity. The authors further aimed to assess whether the association between surgical intervention and acute poor outcomes differs according to TBI severity and various patient factors. METHODS Using TBI registry data collected from a national referral hospital in Uganda between July 2016 and April 2020, the authors performed Cox regression analyses of poor outcomes in admitted patients who did and did not undergo surgery for TBI, with surgery as a time-varying treatment variable. Patients were further stratified by TBI severity using the admission Glasgow Coma Scale (GCS) score: mild TBI (mTBI; GCS scores 13–15), moderate TBI (moTBI; GCS scores 9–12), and severe TBI (sTBI; GCS scores 3–8). Poor outcomes constituted Glasgow Outcome Scale scores 2–3, deterioration in TBI severity between admission and discharge (e.g., mTBI to sTBI), and death. Several clinical and demographic variables were included as covariates. Patients were observed for outcomes from admission through hospital day 10. RESULTS Of 1544 patients included in the cohort, 369 (24%) had undergone surgery. Rates of poor outcomes were 4% (n = 13) for surgical patients and 12% (n = 144) among nonsurgical patients (n = 1175). Surgery was associated with a 59% reduction in the hazard for a poor outcome (HR 0.41, 95% CI 0.23–0.72). Age, pupillary nonreactivity, fall injury, and TBI severity at admission were significant covariates. In models stratifying by TBI severity at admission, patients with mTBI had an 80% reduction in the hazard for a poor outcome with surgery (HR 0.20, 95% CI 0.04–0.90), whereas those with sTBI had a 65% reduction (HR 0.35, 95% CI 0.14–0.89). Patients with moTBI had a statistically nonsignificant 56% reduction in hazard (HR 0.44, 95% CI 0.17–1.17). CONCLUSIONS In this setting, the association between surgery and rates of poor outcomes varied with TBI severity and was influenced by several factors. Patients presenting with mTBI had the greatest reduction in the hazard for a poor outcome, followed by those presenting with sTBI. However, patients with moTBI had a nonsignificant reduction in the hazard, indicating greater variability in outcomes and underscoring the need for closer monitoring of this population. These results highlight the importance of accurate, timely clinical evaluation throughout a patient’s admission and can inform decisions about whether and when to perform surgery for TBI when resources are limited.

BACKGROUND CONTEXT Anterior cervical discectomy and fusion (ACDF) is a well-established procedure that has long been considered the standard treatment for degenerative disc disease (DDD). Despite positive clinical outcomes, accelerated rates of adjacent segment disease (ASD) in ACDF, especially in two-level surgery, has led spinal surgeons to increasingly use anterior cervical disc replacement (ACDR) as an alternative. However, long-term success may be limited by the properties inherent to the devices utilized. The use of metal-on-metal (MM) bearings in total joint replacement, for example, has been hypothesized to significantly decrease volumetric wear rates, but subsequent complications associated with metallosis have prompted joint surgeons toward using metal-on-plastic (MP) or ceramic implants more commonly. Furthermore, MP implants in total hip arthroplasty have been associated with superior clinical outcomes and durability when compared to MM implants. Although highlighted in joint arthroplasty studies, long-term outcomes between differing biomaterial composites in ACDR have not been thoroughly investigated. PURPOSE The purpose of this study was to evaluate the rates of ASD, reoperation rates, complications and patient reported clinical outcomes of MM vs MP artificial discs in two-level ACDR for the treatment of cervical DDD. STUDY DESIGN/SETTING Meta-analysis and systematic review. PATIENT SAMPLE A total of 980 patients (442 MM, 538 MP). OUTCOME MEASURES 1) Rate of ASD, 2) reoperation rate, 3) complications, 4) patient reported clinical outcomes (NDI, VAS-neck, VAS-arm). Methods A systematic search strategy of three electronic databases (PubMed, CINAHL Plus and SCOPUS) was conducted utilizing terms related to 2-level ACDR. All studies included were published in the past 5 years, had a sample size of >10 patients, and reported data on adjacent segment disease. Cadaver studies, non-English manuscripts and studies in which only single-level ACDR was investigated were excluded. A total of 7 studies were included in this analysis. Studies were analyzed for demographic data, clinical outcome scores (NDI, VAS-neck and VAS-arm), rates of ASD, complications and reoperation proportions. A random-effects model of meta-analysis was used for groups that were determined to be heterogenous and a fixed-effects model was utilized for groups that were not. An overlap of 95% confidence intervals suggests no statistically significant difference at the p Results Seven studies were included with data on 980 patients (442 MM, 538 MP). The study population was 52.84% female, with a mean age of 48.01 years, and a mean follow-up of 85.66 months. The mean improvement in NDI was 34.42 (95% CI, 32.49-36.36) and 29.72 (95% CI, 27.15-32.29) for the MM and MP groups, respectively. The mean improvement in VAS-neck was 11.20 (95% CI, 10.69-11.70) and 8.78 (95% CI, 7.81-9.74) for the MM and MP groups, respectively. The mean improvement in VAS-arm was 10.73 (95% CI, 9.83-11.63) and 8.49 (95% CI, 7.59-9.39) for the MM and MP groups, respectively. Reoperation was needed in 1.36% (95% CI, 0.61-2.99) of patients who underwent ACDR with an MM implant compared to 5.33% (95% CI, 3.68-7.65) of patients with an MP implant. The MM cohort had a larger proportion of patients with ASD who underwent subsequent surgery at an adjacent level (7.89% MM vs 1.91% MP). Heterotopic ossification and dysphagia were the most common complications in both groups, and the incidence of each was significantly higher in the MP cohort. Conclusions Our present meta-analysis suggests that the use of MM artificial discs in 2-level ACDR results in superior clinical outcome scores with a lower complication profile and reoperation rate, but higher rates of ASD compared to MP discs after a follow-up period of 5 years or more. FDA DEVICE/DRUG STATUS This abstract does not discuss or include any applicable devices or drugs.

Funder: UK Dementia Research Institute, Amyotrophic lateral sclerosis overlapping with frontotemporal dementia (ALS/FTD) is a fatal and currently untreatable disease characterized by rapid cognitive decline and paralysis. Elucidating initial cellular pathologies is central to therapeutic target development, but obtaining samples from presymptomatic patients is not feasible. Here, we report the development of a cerebral organoid slice model derived from human induced pluripotent stem cells (iPSCs) that recapitulates mature cortical architecture and displays early molecular pathology of C9ORF72 ALS/FTD. Using a combination of single-cell RNA sequencing and biological assays, we reveal distinct transcriptional, proteostasis and DNA repair disturbances in astroglia and neurons. We show that astroglia display increased levels of the autophagy signaling protein P62 and that deep layer neurons accumulate dipeptide repeat protein poly(GA), DNA damage and undergo nuclear pyknosis that could be pharmacologically rescued by GSK2606414. Thus, patient-specific iPSC-derived cortical organoid slice cultures are a reproducible translational platform to investigate preclinical ALS/FTD mechanisms as well as novel therapeutic approaches.

Pituitary tumors are the second most common primary brain tumors. Functional tumors demonstrate increased PD-L1 expression, but expression of other checkpoint regulators has not been characterized. We sought to characterize the immune microenvironment of human pituitary tumors to identify new treatment opportunities. 72 pituitary tumors were evaluated for expression of the immune regulatory markers programmed death ligand 1 (PD-L1), programmed death ligand 2 (PD-L2), V-domain Ig suppressor of T cell activation (VISTA), lymphocyte activation gene 3 (LAG3) and tumor necrosis factor receptor superfamily member 4 (OX40) by immunohistochemistry (IHC). Lymphocyte infiltration, macrophage infiltration, and angiogenesis were analyzed using IHC. Expression of pituitary tumor initiating cell marker CD15 and mismatch repair proteins MutS protein homolog 2 (MSH2) and MutS protein homolog 6 (MSH6) was also assessed. Pituitary tumors were infiltrated by macrophages and T cells, and they expressed varying levels of PD-L1, PD-L2, VISTA, LAG3, and OX40. Functional tumors and tumors with high expression of tumor stem cell markers had higher immune cell infiltration and greater expression of immunosuppressive checkpoint regulators. Increased PD-L1 and LAG3 and reduced VISTA were observed in primary tumors compared to recurrent tumors. Immune cell infiltration and checkpoint regulator expression vary depending on functional status and presence of pituitary tumor initiating cells. Functional tumors may have a particularly immunosuppressive microenvironment. Further studies of immune checkpoint blockade of pituitary tumors, particularly functional tumors, are warranted, though combination therapy may be required.

Purpose Immune checkpoint inhibition (ICI) has demonstrated clinically significant efficacy when combined with chemotherapy in triple negative breast cancer (TNBC). Although many patients derived benefit, others do not respond to immunotherapy, therefore relying upon innovative combinations to enhance response. Local therapies such as radiation therapy (RT) and cryotherapy are immunogenic and potentially optimize responses to immunotherapy. Strategies combining these therapies and ICI are actively under investigation. This review will describe the rationale for combining ICI with targeted local therapies in breast cancer. Methods A literature search was performed to identify pre-clinical and clinical studies assessing ICI combined with RT or cryotherapy published as of August 2021 using PubMed and ClinicalTrials.gov. Results Published studies of ICI with RT and IPI have demonstrated safety and signals of early efficacy. Conclusion RT and cryotherapy are local therapies that can be integrated safely with ICI and has shown promise in early trials. Randomized phase II studies testing both of these approaches, such as P-RAD (NCT04443348) and ipilimumab/nivolumab/cryoablation for TNBC (NCT03546686) are current enrolling. The results of these studies are paramount as they will provide long term data on the safety and efficacy of these regimens.

Objective Delays in seeking health care for dengue are associated with poor health outcomes. Despite this, the factors influencing such delays remain unclear, rendering interventions to improve health care-seeking for dengue ineffective. This systematic review aimed to synthesise the factors influencing health care-seeking of patients with dengue and form a comprehensive framework. Methods This review included both qualitative and quantitative studies. Studies were obtained by searching five databases, contacting field experts, and performing backward reference searches. The best-fit meta-synthesis approach was used during data synthesis, where extracted data were fitted into the social-ecological model. Sub-analyses were conducted to identify the commonly reported factors and their level of statistical significance. Results Twenty studies were selected for meta-synthesis. Eighteen factors influencing health care-seeking in dengue were identified and categorised under four domains: individual (11 factors), interpersonal (1 factor), organisational (4 factors), and community (2 factors). The most reported factors were knowledge of dengue, access to health care, quality of health service and resource availability. Overall, more barriers to dengue health seeking than facilitators were found. History of dengue infection and having knowledge of dengue were found to be ambiguous as they both facilitated and hindered dengue health care-seeking. Contrary to common belief, women were less likely to seek help for dengue than men. Conclusions The factors affecting dengue health care-seeking behaviour are diverse, can be ambiguous and are found across multiple social-ecological levels. Understanding these complexities is essential for the development of effective interventions to improve dengue health care-seeking behaviour.

STUDY OBJECTIVE: Vasopressin may be administered to treat vasospasm follow aneurysmal subarachnoid hemorrhage (aSAH). Few data support this practice, and it has recently been associated with clinically significant hyponatremia. The objectives of this study were to describe five cases of suspected vasopressin-induced hyponatremia after aSAH and to review the literature on this adverse effect. DESIGN: Single-center, observational case series of intensive care unit (ICU) patients SETTINGS: Ten-bed neurological intensive care unit at Maine Medical Center in Portland, Maine PATIENTS: Convenience sample of patients with aSAH treated with a vasopressin for symptomatic, radiologically-confirmed vasospasm MEASUREMENTS AND MAIN RESULTS: A total of five patients were included in the case series with a median age of 57 (51, 65) years and all were female. The median Glasgow coma scale score was 15 (11, 15) on admission and the Hunt and Hess scale score was 3, (3, 4). All patients were treated with endovascular coiling of their aneurysm. Vasopressin was administered to treat symptomatic, radiographically-confirmed vasospasm on median post-bleed day (PBD) 10 (10, 15) at a fixed-dose of 0.03 units/min. Serum sodium at baseline was 140 (140, 144) mEq/L and decreased to 129 (126, 129) mEq/L within 26 (17, 83) hours of vasopressin initiation for a median change of −16 (−10, −16) mEq/L. Serum sodium returned to baseline within 18 (14, 22) hours of stopping the infusion. CONCLUSIONS: Vasopressin administration to treat vasospasm after aSAH may be associated with clinically significant hyponatremia within 24 hours of starting the infusion. Hyponatremia appears to resolve within 24 hours of stopping the vasopressin infusion. Additional study in a larger sample size is needed to determine if a causal relationship exists.

Despite some success in secondary brain metastases, targeted or immune-based therapies have shown limited efficacy against primary brain malignancies such as glioblastoma (GBM). Although the intratumoral heterogeneity of GBM is implicated in treatment resistance, it remains unclear whether this diversity is observed within brain metastases and to what extent cancer cell–intrinsic heterogeneity sculpts the local immune microenvironment. Here, we profiled the immunogenomic state of 93 spatially distinct regions from 30 malignant brain tumors through whole-exome, RNA, and T-cell receptor sequencing. Our analyses identified differences between primary and secondary malignancies, with gliomas displaying more spatial heterogeneity at the genomic and neoantigen levels. In addition, this spatial diversity was recapitulated in the distribution of T-cell clones in which some gliomas harbored highly expanded but spatially restricted clonotypes. This study defines the immunogenomic landscape across a cohort of malignant brain tumors and contains implications for the design of targeted and immune-based therapies against intracranial malignancies. Significance: This study describes the impact of spatial heterogeneity on genomic and immunologic characteristics of gliomas and brain metastases. The results suggest that gliomas harbor significantly greater intratumoral heterogeneity of genomic alterations, neoantigens, and T-cell clones than brain metastases, indicating the importance of multisector analysis for clinical or translational studies. This article is highlighted in the In This Issue feature, p. 1

BackgroundSchools are the primary setting for the delivery of adolescent HPV vaccination in Australia. Although this strategy has achieved generally high vaccination coverage, gaps persist for reasons that are mostly unknown. This study sought to identify school-level correlates of low vaccination course initiation and completion in New South Wales, Tasmania, and Western Australia to inform initiatives to increase uptake.MethodsInitiation was defined as the number of first doses given in a school in 2016 divided by vaccine-eligible student enrolments. Completion was the number of third doses given in a school in 2015-2016 divided by the number of first doses. Low initiation and completion were defined as coverage ≤ 25thpercentile of all reporting schools. We investigated correlations between covariates using Spearman's rank correlation coefficients. Due to multicollinearity, we used univariable logistic regression to investigate associations between school characteristics and low coverage.ResultsMedian initiation was 84.7% (IQR: 75.0%-90.4%) across 1,286 schools and median completion was 93.8% (IQR: 86.0%-97.3%) across 1,295 schools. There were strong correlations between a number of school characteristics, particularly higher Indigenous student enrolments and lower attendance, increasing remoteness, higher postcode socioeconomic disadvantage, and smaller school size. Characteristics most strongly associated with low initiation in univariate analyses were small school size, location in Tasmania, and schools catering for special educational needs. Low completion was most strongly associated with schools in Tasmania and Western Australia, remote location, small size, high proportion of Indigenous student enrolments, and low attendance rates.ConclusionThis study provides indicative evidence that characteristics of schools and school populations are associated with the likelihood of low initiation and completion of the HPV vaccination course. The findings will guide further research and help target initiatives to improve vaccination uptake in schools with profiles associated with lower coverage.

Low serum 1,25-dihydroxyvitamin D (1,25(OH)2D) in end-stage renal disease (ESRD) is considered a consequence of elevated fibroblast growth factor 23 (FGF23) and concomitant reduced activity of renal 1α-hydroxylase (CYP27B1). Current ESRD treatment strategies to increase serum calcium and suppress secondary hyperparathyroidism involve supplementation with vitamin D analogues that circumvent 1α-hydroxylase. This overlooks the potential importance of 25-hydroxyvitamin D (25(OH)D) deficiency as a contributor to low serum 1,25(OH)2D. We investigated the effects of vitamin D (cholecalciferol) supplementation (40,000 IU for 12 weeks and maintenance dose of 20,000 IU fortnightly), on multiple serum vitamin D metabolites (25(OH)D, 1,25(OH)2D3 and 24,25(OH)2D3) in 55 haemodialysis patients. Baseline and 12 month data were compared using related-samples Wilcoxon signed rank test. All patients remained on active vitamin D analogues as part of routine ESRD care. 1,25(OH)2D3 levels were low at baseline (normal range: 60–120 pmol/L). Cholecalciferol supplementation normalised both serum 25(OH)D and 1,25(OH)2D3. Median serum 25(OH)D increased from 35.1 nmol/L (IQR: 23.0–47.5 nmol/L) to 119.9 nmol/L (IQR: 99.5–143.3 nmol/L) (P < 0.001). Median serum 1,25(OH)2D3 and 24,25(OH)2D3 increased from 48.3 pmol/L (IQR: 35.9–57.9 pmol/L) and 3.8 nmol/L (IQR: 2.3–6.0 nmol/L) to 96.2 pmol/L (IQR: 77.1–130.6 pmol/L) and 12.3 nmol/L (IQR: 9–16.4 nmol/L), respectively (P < 0.001). A non-significant reduction in daily active vitamin D analogue dose occurred, 0.94 µmcg at baseline to 0.77 µmcg at 12 months (P = 0.73). The ability to synthesise 1,25(OH)2D3 in ESRD is maintained but is substrate dependent, and serum 25(OH)D was a limiting factor at baseline. Therefore, 1,25(OH)2D3 deficiency in ESRD is partly a consequence of 25(OH)D deficiency, rather than solely due to reduced 1α-hydroxylase activity as suggested by current treatment strategies.

SARS-CoV-2 has profoundly affected the way healthcare is delivered and has created significant strain on medical facilities globally. As a result, hospitals have had to continuously adapt in order to provide optimal patient care while minimizing the risk of SARS-CoV-2 transmission, particularly in the surgical setting. Texas Children's Hospital developed a set of protocols for surgical screening and clearance of patients in the context of the COVID-19 pandemic. These screening protocols were designed to mitigate the risk of exposing patients and healthcare providers to SARS-CoV-2 and have evolved significantly as a result of the emerging changes in medicine, technology, and governmental regulations. In this article, we share the reasoning behind the development, implementation, and successive modification of our institutional screening protocols.

Purpose Little is currently known about how early intervention vocational rehabilitation (EIVR) works for people with newly acquired neurological conditions such as traumatic brain injury, acquired brain injury and spinal cord injury. This study aims, from a realist framework, to identify relevant literature and develop an initial programme theory to understand how EIVR might work for people experiencing acquired neurological disability. Realist reviews are ideally placed to address the identified knowledge gap as they assist in gaining a deeper understanding of how the intervention works, for whom it works best, and the contexts that promote the activation of desired outcomes. Methods We used a seven-step iterative process to synthesise literature using a realist approach. The steps included: development of initial programme theory, literature search, article selection, extracting and data organising, synthesis of evidence and programme theory refinement. We performed a literature search using the following databases: Cinahl, Embase, EMcare, Medline, PsychInfo and Scopus. Articles were selected if they contributed to the knowledge describing what is EIVR and how it works in newly acquired neurological conditions. Data were extracted and synthesised to develop a programme theory for EIVR. Results Following screening of 448 references, 37 documents were eligible for data extraction. We developed a refined programme theory of EIVR consisting of three contexts (prioritisation of exploring work options, return to work discussed as an option, and workplace support), nine mechanisms (ensuring rehabilitation teams’ culture, fostering hope, exploring options, optimising self-efficacy, maintaining worker identity, staying connected, setting goals, engaging employer, and flexing roles) and three outcomes (confidence in ability to work, psychological adjustment, and engagement in solution focussed options). Conclusions This appears to be the first paper to explore how EIVR works, for whom and in what situations. We have produced a programme theory that may provide an initial understanding of EIVR following acquired neurological conditions.

Background Meningiomas are the most common primary intracranial tumor in adults. Clinical care is currently guided by the World Health Organization (WHO) grade assigned to meningiomas, a 3-tiered grading system based on histopathology features, as well as extent of surgical resection. Clinical behavior, however, often fails to conform to the WHO grade. Additional prognostic information is needed to optimize patient management. Methods We evaluated whether chromosomal copy-number data improved prediction of time-to-recurrence for patients with meningioma who were treated with surgery, relative to the WHO schema. The models were developed using Cox proportional hazards, random survival forest, and gradient boosting in a discovery cohort of 527 meningioma patients and validated in 2 independent cohorts of 172 meningioma patients characterized by orthogonal genomic platforms. Results We developed a 3-tiered grading scheme (Integrated Grades 1-3), which incorporated mitotic count and loss of chromosome 1p, 3p, 4, 6, 10, 14q, 18, 19, or CDKN2A. 32% of meningiomas reclassified to either a lower-risk or higher-risk Integrated Grade compared to their assigned WHO grade. The Integrated Grade more accurately identified meningioma patients at risk for recurrence, relative to the WHO grade, as determined by time-dependent area under the curve, average precision, and the Brier score. Conclusion We propose a molecularly integrated grading scheme for meningiomas that significantly improves upon the current WHO grading system in prediction of progression-free survival. This framework can be broadly adopted by clinicians with relative ease using widely available genomic technologies and presents an advance in the care of meningioma patients.

To evaluate for inter-individual differences in financial distress and identify demographic, clinical, and symptom characteristics associated with higher levels of financial distress. Patients (n = 387) were enrolled prior to breast cancer surgery and followed for 12 months. Financial distress was measured using a 0 (no problem) to 10 (severe problem) numeric rating scale. Hierarchical linear modeling was used to evaluate for inter-individual differences in trajectories of financial distress and characteristics associated with financial distress at enrollment and over 12 months. Patients’ mean age was 55.0 (± 11.7) years and the majority underwent breast conservation surgery (80.6%). Mean financial distress score prior to surgery was 3.3 (± 3.4; range 0 to 10). Unconditional model for financial distress demonstrated no significant changes over time (-0.006/month). Younger age, lower income, receipt of an axillary lymph node dissection and adjuvant chemotherapy, and lower attentional function were associated with higher preoperative levels of financial distress. Risk factors identified in this study can be used to inform clinicians regarding the need to initiate financial discussions and social work referrals for some patients. Additional clinical or system level interventions should be considered for vulnerable groups with these risk factors.

Kidney fibrosis constitutes the shared final pathway of nearly all chronic nephropathies, but biomarkers for the non-invasive assessment of kidney fibrosis are currently not available. To address this, we characterize five candidate biomarkers of kidney fibrosis: Cadherin-11 (CDH11), Sparc-related modular calcium binding protein-2 (SMOC2), Pigment epithelium-derived factor (PEDF), Matrix-Gla protein, and Thrombospondin-2. Gene expression profiles in single-cell and single-nucleus RNA-sequencing (sc/snRNA-seq) datasets from rodent models of fibrosis and human chronic kidney disease (CKD) were explored, and Luminex-based assays for each biomarker were developed. Plasma and urine biomarker levels were measured using independent prospective cohorts of CKD: the Boston Kidney Biopsy Cohort, a cohort of individuals with biopsy-confirmed semiquantitative assessment of kidney fibrosis, and the Seattle Kidney Study, a cohort of patients with common forms of CKD. Ordinal logistic regression and Cox proportional hazards regression models were used to test associations of biomarkers with interstitial fibrosis and tubular atrophy and progression to end-stage kidney disease and death, respectively. Sc/snRNA-seq data confirmed cell-specific expression of biomarker genes in fibroblasts. After multivariable adjustment, higher levels of plasma CDH11, SMOC2, and PEDF and urinary CDH11 and PEDF were significantly associated with increasing severity of interstitial fibrosis and tubular atrophy in the Boston Kidney Biopsy Cohort. In both cohorts, higher levels of plasma and urinary SMOC2 and urinary CDH11 were independently associated with progression to end-stage kidney disease. Higher levels of urinary PEDF associated with end-stage kidney disease in the Seattle Kidney Study, with a similar signal in the Boston Kidney Biopsy Cohort, although the latter narrowly missed statistical significance. Thus, we identified CDH11, SMOC2, and PEDF as promising non-invasive biomarkers of kidney fibrosis.

OBJECTIVE The internal high-dose volume varies widely for a given prescribed dose during stereotactic radiosurgery (SRS) to treat brain metastases (BMs). This may be altered during treatment planning, and the authors have previously shown that this improves local control (LC) for non–small cell lung cancer BMs without increasing toxicity. Here, they seek to identify potentially actionable dosimetric predictors of LC after SRS for melanoma BM. METHODS The records of patients with unresected melanoma BM treated with single-fraction Gamma Knife RS between 2006 and 2017 were reviewed. LC was assessed on a per-lesion basis, defined as stability or a decrease in lesion size. Outcome-oriented approaches were utilized to determine optimal dichotomization for dosimetric variables relative to LC. Univariable and multivariable Cox regression analysis was implemented to evaluate the impact of collected parameters on LC. RESULTS Two hundred eighty-seven melanoma BMs in 79 patients were identified. The median age was 56 years (range 31–86 years). The median follow-up was 7.6 months (range 0.5–81.6 months), and the median survival was 9.3 months (range 1.3–81.6 months). Lesions were optimally stratified by volume receiving at least 30 Gy (V30) greater than or equal to versus less than 25%. V30 was ≥ and < 25% in 147 and 140 lesions, respectively. For all patients, 1-year LC was 83% versus 66% for V30 ≥ and < 25%, respectively (p = 0.001). Stratifying by volume, lesions 2 cm or less (n = 215) had 1-year LC of 82% versus 70% (p = 0.013) for V30 ≥ and < 25%, respectively. Lesions > 2 to 3 cm (n = 32) had 1-year LC of 100% versus 43% (p = 0.214) for V30 ≥ and < 25%, respectively. V30 was still predictive of LC even after controlling for the use of immunotherapy and targeted therapy. Radionecrosis occurred in 2.8% of lesions and was not significantly associated with V30. CONCLUSIONS For a given prescription dose, an increased internal high-dose volume, as indicated by measures such as V30 ≥ 25%, is associated with improved LC but not increased toxicity in single-fraction SRS for melanoma BM. Internal dose escalation is an independent predictor of improved LC even in patients receiving immunotherapy and/or targeted therapy. This represents a dosimetric parameter that is actionable at the time of treatment planning and warrants further evaluation.