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Objective: Essential tremor (ET) is a common neurological disorder that has been associated with 60% increased risk of developing dementia. The goals of the present study were to: (a) learn whether individuals with advanced ET symptoms seeking deep brain stimulation (DBS) surgery would fall into distinct cognitive subgroups, and (b) learn how empirically derived subgroups map onto criteria for mild cognitive impairment (MCI). Method: Patients with ET (N = 201; mean age = 68.9 ± 8.9 years) undergoing pre-surgical evaluation for DBS completed a multi-domain neurocognitive assessment consisting of memory, executive function, visuospatial skill, language, and processing speed. Two cluster analytic approaches (K-means, hierarchical) were independently conducted to classify cognitive patterns using domain composites. Demographics, clinical characteristics, and proportion of cases meeting neuropsychologically defined criteria for MCI were examined among clusters. Results: A three-cluster solution reflected a Low Executive group (N = 64), Low Memory Multi-Domain group (N = 41), and Cognitively Normal group (N = 96). The Cognitively Normal group was older and more educated, with a higher Dementia Rating Scale-2 score. In total, 27.4% of participants met criteria for MCI. Of the MCI cases, most were in the Low Executive (41.8%) or Low Memory Multi-Domain groups (49.1%). In the latter, 65.9% of its members were classified as MCI versus 35.9% in the Low Executive group. Conclusions: Our study identified three cognitive subtypes of ET patients presenting for DBS. Future work should examine the subgroups for progression to dementia, particularly the Low Memory Multi-Domain subgroup which may be at highest risk.

Objective To assess facilitators and barriers to participation in the Child and Adult Care Food Program (CACFP) and estimate foregone federal funds because of CACFP underuse. Methods An online survey of food service practices and experiences with CACFP among Connecticut-based licensed child care centers (n = 231). Results Serving meals and the center's nonprofit status predicted CACFP participation. The most common challenge among participants was collecting family income eligibility. Streamlining paperwork (mentioned by 44% of respondents) and funding for nonfood, administrative costs (40%) were recommended facilitators to increase CACFP uptake. Nonparticipating centers had limited knowledge about the program and its eligibility. Foregone federal funding due to CACFP underuse among eligible Connecticut centers was estimated at $30.7 million in 2019, suggesting that 20,300 young children from low-income areas missed out on CACFP-subsidized food. Conclusions and Implications Improving knowledge about CACFP and reducing participation burdens through additional funding and technical assistance can help expand the program to support child nutrition.

Calcaneus fractures can be devastating injuries, and operative treatment is fraught with complications. We are unaware of any studies evaluating all calcaneus fractures, both open and closed, treated operatively in the military. The purpose of this study is to evaluate all calcaneus fractures that required open reduction internal fixation to determine soldiers' ability to return to work and the need for additional surgeries.All active-duty patients undergoing open reduction internal fixation of calcaneus fractures from 2010-2016 were identified utilizing the Military Health System Management Analysis and Reporting Tool (M2). Armed Forces Health Longitudinal Technology Application (AHLTA) was utilized to determine comorbid medical conditions, subsequent procedures, surgical outcomes, and duty status within the military.Three hundred seventy-five active-duty service members who met our inclusion/exclusion criteria were identified. One hundred fifty-one patients (55.1%) sustained their calcaneus fracture as a result of a blast injury. One hundred sixty (59.3%) patients required separation from the military as a result of their injury. Among patients who required a subsequent procedure, thirty-four patients (9.1%) required a subtalar arthrodesis, and thirty-two patients (8.5%) eventually required a below knee amputation. Blast as mechanism of injury was the single most predictive variable for patients requiring separation from the military (Odds Ratio 16.2, p.001), requiring a subsequent procedure (Odds Ratio 8.4, p.001), and for requiring a below knee amputation (Odds Ratio 47.3, p.001).Calcaneus fractures treated operatively in the military are often caused by blast injuries, and have a high rate of requiring subsequent procedures, amputation, and separation from the military.

Introduction:Private equity firms have recently acquired several large urology practices in the United States. As little is known about these acquisitions, we sought to characterize trends ...

Thalassaemia is caused by genetic globin defects leading to anaemia, transfusion-dependence and comorbidities. Reduced survival and systemic organ disease affect transfusion-dependent thalassaemia major and thalassaemia intermedia. Recent improvements in clinical management have reduced thalassaemia mortality. The therapeutic landscape of thalassaemia may soon include gene therapies as functional cures. An analysis of the adult US thalassaemia population has not been performed since the Thalassemia Clinical Research Network cohort study from 2000 to 2006. The Centers for Disease Control and Prevention supported US thalassaemia treatment centres (TTCs) to compile longitudinal information on individuals with thalassaemia. This dataset provided an opportunity to evaluate iron balance, chelation, comorbidities and demographics of adults with thalassaemia receiving care at TTCs. Two adult cohorts were compared: those over 40 years old (n = 75) and younger adults ages 18-39 (n = 201). The older adult cohort was characterized by higher numbers of iron-related comorbidities and transfusion-related complications. By contrast, younger adults had excess hepatic and cardiac iron and were receiving combination chelation therapy. The ethnic composition of the younger cohort was predominantly of Asian origin, reflecting the demographics of immigration. These findings demonstrate that comprehensive care and periodic surveys are needed to ensure optimal health and access to emerging therapies.

Purpose of review The purpose of this review is to describe the causes, management, and clinical outcomes associated with cachexia and related components including sarcopenia, among patients with bladder cancer (BCa). Recent findings Cachexia in patients with BCa is associated with poorer outcomes after radical cystectomy (RC), radiation, and chemotherapy. Nutritional supplements and novel pharmaceutical agents including magnolol, flucoidan and Anamorelin are currently undergoing investigation for their potential use in BCa patients with cachexia. Summary Cachexia is a hypercatabolic state thought to be caused by an immune-regulated release of cytokines and disruptions of molecular pathways within the tumor microenvironment and systemically. Nutritional deficiencies in patients with BCa also contribute to cachexia and sarcopenia. Patients with BCa -related cachexia and sarcopenia experience worse survival and therapeutic outcomes after RC, chemotherapy, and radiation therapy. Patients with cachexia also experience more postoperative complications after RC. The management of cachexia in patients with BCa remains challenging and requires timely identification, and multidisciplinary management including nutritional supplementation, physical therapy, palliative care, and pharmacological agents. Clinical trials and human studies are still required to determine which pharmacological agents are optimal for BCa cachexia.

To explore the use of wearable sensors for objective measurement of motor impairment in spinocerebellar ataxia (SCA) patients during clinical assessments of gait and balance. In total, 14 patients with genetically confirmed SCA (mean age 61.6 ± 8.6 years) and 4 healthy controls (mean age 49.0 ± 16.4 years) were recruited through the Massachusetts General Hospital (MGH) Ataxia Center. Participants donned seven inertial sensors while performing two independent trials of gait and balance assessments from the Scale for the Assessment and Rating of Ataxia (SARA) and Brief Ataxia Rating Scale (BARS2). Univariate analysis was used to identify sensor-derived metrics from wearable sensors that discriminate motor function between the SCA and control groups. Multivariate linear regression models were used to estimate the subjective in-person SARA/BARS2 ratings. Spearman correlation coefficients were used to evaluate the performance of the model. Stride length variability, stride duration, cadence, stance phase, pelvis sway, and turn duration were different between SCA and controls (p

Objective:To determine the impact of clinical decision support on guideline-concordant Clostridioides difficile infection (CDI) treatment.Design:Quasi-experimental study in >50 ambulatory clinics.Setting:Primary, specialty, and urgent-care clinics.Patients:Adult patients were eligible for inclusion if they were diagnosed with and treated for a first episode of symptomatic CDI at an ambulatory clinic between November 1, 2019, and November 30, 2020.Interventions:An outpatient best practice advisory (BPA) was implemented to notify prescribers that “vancomycin or fidaxomicin are preferred over metronidazole for C.difficile infection” when metronidazole was prescribed to a patient with CDI.Results:In total, 189 patients were included in the study: 92 before the BPA and 97 after the BPA. Their median age was 59 years; 31% were male; 75% were white; 30% had CDI-related comorbidities; 35% had healthcare exposure; 65% had antibiotic exposure; 44% had gastric acid suppression therapy within 90 days of CDI diagnosis. The BPA was accepted 23 of 26 times and was used to optimize the therapy of 16 patients in 6 months. Guideline-concordant therapy increased after implementation of the BPA (72% vs 91%; P = .001). Vancomycin prescribing increased and metronidazole prescribing decreased after the BPA. There was no difference in clinical response or unplanned encounter within 14 days after treatment initiation. Fewer patients after the BPA had CDI recurrence within 14–56 days of the initial episode (27% vs 7%; P < .001).Conclusions:Clinical decision support increased prescribing of guideline-concordant CDI therapy in the outpatient setting. A targeted BPA is an effective stewardship intervention and may be especially useful in settings with limited antimicrobial stewardship resources.

Objective: To quantify the potential population-wide costs, number of individuals reached, and impact on obesity of five effective interventions to reduce children's television viewing if implemented nationally. Study Design: Utilizing evidence from systematic reviews, the Childhood Obesity Intervention Cost Effectiveness Study (CHOICES) microsimulation model estimated the cost, population reach, and impact on childhood obesity from 2020 to 2030 of five hypothetical policy strategies to reduce the negative impact of children's TV exposure: (1) eliminating the tax deductibility of food and beverage advertising; (2) targeting TV reduction during home visiting programs; (3) motivational interviewing to reduce home television time at Women, Infants, and Children (WIC) clinic visits; (4) adoption of a television-reduction curriculum in child care; and (5) limiting noneducational television in licensed child care settings. Results: Eliminating the tax deductibility of food advertising could reach the most children [106 million, 95% uncertainty interval (UI): 105–107 million], prevent the most cases of obesity (78,700, 95% UI: 30,200–130,000), and save more in health care costs than it costs to implement. Strategies targeting young children in child care and WIC also cost little to implement (between $0.19 and $32.73 per child reached), and, although reaching fewer children because of the restricted age range, were estimated to prevent between 25,500 (95% UI: 4600–59,300) and 35,400 (95% UI: 13,200–62,100) cases of obesity. Home visiting to reduce television viewing had high costs and a low reach. Conclusions: Interventions to reduce television exposure across a range of settings, if implemented widely, could help prevent childhood obesity in the population at relatively low cost.

Summary Background Parkinson's disease is heterogeneous in symptom presentation and progression. Increased understanding of both aspects can enable better patient management and improve clinical trial design. Previous approaches to modelling Parkinson's disease progression assumed static progression trajectories within subgroups and have not adequately accounted for complex medication effects. Our objective was to develop a statistical progression model of Parkinson's disease that accounts for intra-individual and inter-individual variability and medication effects. Methods In this longitudinal data study, data were collected for up to 7-years on 423 patients with early Parkinson's disease and 196 healthy controls from the Parkinson's Progression Markers Initiative (PPMI) longitudinal observational study. A contrastive latent variable model was applied followed by a novel personalised input-output hidden Markov model to define disease states. Clinical significance of the states was assessed using statistical tests on seven key motor or cognitive outcomes (mild cognitive impairment, dementia, dyskinesia, presence of motor fluctuations, functional impairment from motor fluctuations, Hoehn and Yahr score, and death) not used in the learning phase. The results were validated in an independent sample of 610 patients with Parkinson's disease from the National Institute of Neurological Disorders and Stroke Parkinson's Disease Biomarker Program (PDBP). Findings PPMI data were download July 25, 2018, medication information was downloaded on Sept 24, 2018, and PDBP data were downloaded between June 15 and June 24, 2020. The model discovered eight disease states, which are primarily differentiated by functional impairment, tremor, bradykinesia, and neuropsychiatric measures. State 8, the terminal state, had the highest prevalence of key clinical outcomes including 18 (95%) of 19 recorded instances of dementia. At study outset 4 (1%) of 333 patients were in state 8 and 138 (41%) of 333 patients reached stage 8 by year 5. However, the ranking of the starting state did not match the ranking of reaching state 8 within 5 years. Overall, patients starting in state 5 had the shortest time to terminal state (median 2·75 [95% CI 1·75–4·25] years). Interpretation We developed a statistical progression model of early Parkinson's disease that accounts for intra-individual and inter-individual variability and medication effects. Our predictive model discovered non-sequential, overlapping disease progression trajectories, supporting the use of non-deterministic disease progression models, and suggesting static subtype assignment might be ineffective at capturing the full spectrum of Parkinson's disease progression. Funding Michael J Fox Foundation.

Introduction It is unknown whether dental opioid prescriptions are associated with opioid overdose in patients or their family members, who may have access to patients’ opioids. Methods During July–October 2020, the 2011–2018 IBM MarketScan Dental, IBM MarketScan Commercial, and Medicaid Multi-State Databases were analyzed. Two analyses were conducted. In the patient analysis, dental procedures for privately and publicly insured patients aged 13–64 years were identified. The exposure was ≥1 initial prescription (dispensed opioid prescription within 3 days of the procedure). The association between the exposure and ≥1 overdose within 90 days of the procedure was evaluated using logistic regression. In the family analysis, procedures for privately insured patients in family plans were identified. The association between the exposure and ≥1 overdose in a family member within 90 days was evaluated using logistic regression. In both analyses, the average marginal effect of the exposure was calculated, representing the change in the probability of the outcome if all versus if no procedures were associated with ≥1 initial prescription. Results The patient analysis included 8,544,098 procedures. When ≥1 initial prescription did and did not occur, the 90-day risk of overdose was 5.8 versus 2.2 per 10,000 procedures (average marginal effect=1.5, 95% CI=1.2, 1.8). The family analysis included 3,461,469 procedures. When ≥1 initial prescription did and did not occur, the 90-day risk of overdose in a family member was 1.7 versus 1.0 per 10,000 procedures (average marginal effect=0.4, 95% CI=0.1, 0.7). Conclusions Findings further highlight the importance of avoiding unnecessary dental opioid prescribing.

The purpose of this study is to analyze the significance of specific factors in choosing radiology as a specialty compared to switching to/from a different specialty as reported in the Graduation Questionnaire (GQ) and Matriculating Student Questionnaire (MSQ) data provided by Association of American Medical Colleges.The study cohort included students who completed both the MSQ and GQ questionnaires in the span of 3-5 years. The cohort was divided into three groups-"Committed" (students who chose radiology in both the first and final year of medical school), "Switched Away" (students who chose radiology on the MSQ but later switched to a different specialty, and "Switched-To" (students who chose radiology on GQ after initially selecting an alternate specialty on the MSQ).Of 1965 students who chose radiology between the years 2013 and 2016, 281 were Committed, 625 Switched-Away, and 1059 Switched-To. There were significant differences among the groups for salary, length of residency, and work-life balance factors. In the Switched-Away group, more students were influenced by length of residency (18% vs. 5%, p0.001) and fewer were influenced by salary (21% vs. 30%, p=0.004) or work-life balance (54% vs. 66%, p = 0.001) when compared to the Committed group. The Switched-To group did not significantly differ from the Committed group (all p0.05) for length of residency (6% vs. 5%), salary (30% vs. 30%) and work-life balance (69% vs. 66%).The data provide insight into factors that influence medical students to initially commit to, switch away from, and switch to radiology during medical school. Understanding these dynamics can inform mentors to guide medical students who are interested in a radiology career.

Aging is associated with a gradual decline in the sensory systems and noisier sensory information. Some research has found that older adults compensate for this with enhanced multisensory integration. However, less is known about how aging influences visual-vestibular integration, an ability that underlies self-motion perception. We examined how visual-vestibular integration changes in participants from across the lifespan (18-79 years old) with a simple reaction time task. Participants were instructed to respond to visual (optic flow) and vestibular (inertial motion) acceleration cues, presented either alone or at a stimulus onset asynchrony. We measured reaction times and computed the violation area relative to the race model inequality as a measure of visual-vestibular integration. Across all ages, the greatest visual-vestibular integration occurred when the vestibular cue was presented first. Age was associated with longer reaction times and a significantly lower detection rate in the vestibular-only condition, a finding that is consistent with an age-related increase in vestibular noise. Although the relationship between age and visual-vestibular integration was positive, the effect size was very small and did not reach statistical significance. Our results suggest that although age is associated with a significant increase in vestibular perceptual threshold, the relative amount of visual-vestibular integration remains largely intact.

Background Colony-stimulating factor-1 receptor (CSF1R)-related leukoencephalopathy is a rapidly progressive neurodegenerative disease for which there is currently no cure. Hematopoietic stem cell transplantation (HSCT) has been proposed as a disease-modifying treatment. Objective The objective of this study was to determine the effect of HSCT on disease progression. Methods We collected all available clinical data from a cohort of 7 patients with CSF1R-related leukoencephalopathy who underwent HSCT at our institutions. Clinical data included detailed neurological examination by a board-certified neurologist, serial cognitive screens, formal neuropsychological evaluations, and serial brain magnetic resonance imaging (MRI). Results Our patients had an average disease duration of 27.6 months at the time of transplant, and we have 87 months of total posttransplant follow-up time (median, 11; range, 2-27). One patient died in the periprocedural period. The remaining patients showed a variable response to treatment, with 6 of 7 patients trending toward stabilization on motor examination, cognitive scores, and/or MRI abnormalities, especially with white matter lesion burden. Conclusions This is the largest series of patients with CSF1R-related leukoencephalopathy receiving HSCT. We conclude that HSCT can stabilize the disease in some patients. Variability in patient responsiveness suggests that measures of disease heterogeneity and severity need to be considered when evaluating a patient's candidacy for transplant. HSCT appears to be the first disease-modifying therapy for CSF1R-related leukoencephalopathy. This milestone may serve as a foothold toward better understanding the disease's pathomechanism, thus providing new opportunities for better disease-specific therapies. © 2021 International Parkinson and Movement Disorder Society.

Background Identification of therapies to prevent severe COVID-19 remains a priority. We sought to determine whether hydroxychloroquine treatment for outpatients with SARS-CoV-2 infection could prevent hospitalization, mechanical ventilation or death. Methods This randomized controlled trial was conducted in Alberta during the first wave of the COVID-19 pandemic without direct contact with participants. Community-dwelling individuals with confirmed SARS-CoV-2 infection (by reverse transcription polymerase chain reaction [RT-PCR] viral ribonucleic acid test) within the previous 4 days, and symptom onset within the previous 12 days, were randomly assigned to oral hydroxychloroquine or matching placebo for 5 days. Enrolment began Apr. 15, 2020. The primary outcome was the composite of hospitalization, invasive mechanical ventilation or death within 30 days. Secondary outcomes included symptom duration and disposition at 30 days. Safety outcomes, such as serious adverse events and mortality, were also ascertained. Outcomes were determined by telephone follow-up and administrative data. Results Among 4919 individuals with a positive RT-PCR test, 148 (10.2% of a planned 1446 patients) were randomly assigned, 111 to hydroxychloroquine and 37 to placebo. Of the 148 participants, 24 (16.2%) did not start the study drug. Four participants in the hydroxychloroquine group met the primary outcome (4 hospitalizations, 0 mechanical ventilation, 4 survived to 30 days) and none in the placebo group. Hydroxychloroquine did not reduce symptom duration (hazard ratio 0.77, 95% confidence interval 0.49-1.21). Recruitment was paused on May 22, 2020, when a since-retracted publication raised concerns about the safety of hydroxychloroquine for hospitalized patients with COVID-19. Although we had not identified concerns in a safety review, enrolment was slower than expected among those eligible for the study, and cases within the community were decreasing. Recruitment goals were deemed to be unattainable and the trial was not resumed, resulting in a study underpowered to assess the effect of treatment with hydroxychloroquine and safety. Interpretation There was no evidence that hydroxychloroquine reduced symptom duration or prevented severe outcomes among outpatients with proven COVID-19, but the early termination of our study meant that it was underpowered. Trial registration ClinicalTrials.gov, no. NCT04329611.

Prolonged postoperative mechanical ventilation (PPMV) increases length of stay, hospitalization costs, and postoperative complications. Independent risk factors associated with PPMV are not well-known for children.We identified children (18 years) in the ACS NSQIP-P database who underwent a general surgical abdominal operation. We excluded children with preoperative ventilator dependence and mortality within 48 h of surgery. PPMV was defined as cumulative postoperative mechanical ventilation exceeding 72 h. A multivariable logistic regression model identified independent predictors of PPMV.We identified 108,392 children who underwent a general surgical abdominal operation in the ACS NSQIP-P database from 2012 to 2017. We randomly divided the population into a derivation cohort of 75,874(70%) and a validation cohort of 32,518(30%). In the derivation cohort, we identified PPMV in 1,643(2.2%). In the multivariable model, the strongest independent predictor of PPMV was neonatal age (OR:20.66; 95%CI:16.44-25.97). Other independent risk factors for PPMV were preoperative inotropic support (OR:10.56; 95%CI:7.56-14.77), an operative time longer than 150 min (OR:4.30; 95%CI:3.72-4.52), and an American Society of Anesthesiologists classification3 (OR:12.16; 95%CI:10.75-13.75).Independent preoperative risk factors for PPMV in children undergoing a general surgical operation were neonatal age, preoperative ionotropic support, duration of operation, and ASA classification3.

Disclaimer In an effort to expedite the publication of articles related to the COVID-19 pandemic, AJHP is posting these manuscripts online as soon as possible after acceptance. Accepted manuscripts have been peer-reviewed and copyedited, but are posted online before technical formatting and author proofing. These manuscripts are not the final version of record and will be replaced with the final article (formatted per AJHP style and proofed by the authors) at a later time. Purpose Patients with a reported β-lactam allergy (BLA) are often given alternative perioperative antibiotic prophylaxis, increasing risk of surgical site infections (SSIs), acute kidney injury (AKI), and Clostridioides difficile infection (CDI). The purpose of this study was to implement and evaluate a pharmacist-led BLA clarification interview service in the preoperative setting. Methods A pharmacist performed BLA clarification telephone interviews before elective procedures from November 2018 to March 2019. On the basis of allergy history and a decision algorithm, first-line preoperative antibiotics, alternative antibiotics, or allergy testing referral was recommended. The pharmacist intervention (PI) group was compared to a standard of care (SOC) group who underwent surgery from November 2017 to March 2018. Results Eighty-seven patients were included, with 50 (57%) and 37 (43%) in the SOC and PI groups, respectively. The most common surgeries included orthopedic surgery in 41 patients (47%) and neurosurgery in 17 patients (20%). In the PI group, all BLA labels were updated after interview. Twenty-three patients were referred for allergy testing, 12 of the 23 (52%) completed BLA testing, and penicillin allergies were removed for 9 of the 12 patients. Overall, 28 of the 37 (76%) pharmacy antibiotic recommendations were accepted. Cefazolin use significantly increased from 28% to 65% after the intervention (P = 0.001). SSI occurred in 5 (10%) patients in the SOC group and no patients in the PI group (P = 0.051). All of these SSIs were associated with alternative antibiotics. Incidence of AKI and CDI was similar between the groups. No allergic reactions occurred in either group. Conclusion Implementation of a pharmacy-driven BLA reconciliation significantly increased β-lactam preoperative use without negative safety outcomes.

Cigarette smoking is a risk factor for developing nonmuscle invasive bladder cancer, and continued smoking exposure after diagnosis may increase the likelihood of adverse clinical outcomes. We compare self-reported vs biochemically verified nicotine exposure to determine the accuracy of self-report among recently diagnosed nonmuscle invasive bladder cancer patients.This cross-sectional analysis consisted of 517 nonmuscle invasive bladder cancer patients who contributed a urine or saliva specimen the same day as self-reporting their smoking, use of e-cigarettes, nicotine replacement therapy and whether they lived with a smoker. Cotinine, the primary metabolite of nicotine, was used as an objective biomarker of recent nicotine exposure.The prevalence of high, low and no cotinine exposure was 13%, 54% and 33%, respectively. Overall, 7.3% of patients (38/517) reported being a current cigarette smoker, while 13% (65/517) had cotinine levels consistent with active smoking exposure. Of these 65 patients 27 denied current smoking, resulting in a sensitivity of self-reported current smoking of 58%. After considering other sources of nicotine exposure such as e-cigarettes, cigars, nicotine replacement therapy and living with a smoker, the sensitivity was higher, at 82%. Nearly all patients with low cotinine denied any smoking-related exposure.Our findings suggest either biochemical verification with cotinine or additional questions about other sources of nicotine are needed to accurately identify nonmuscle invasive bladder cancer patients who have smoking-related exposures. Accurate classification of active and passive smoking exposure is essential to allow clinicians to advise cessation and help researchers estimate the association between post-diagnosis smoking-related exposure and nonmuscle invasive bladder cancer recurrence risk.

Surgery is a common gateway to opioid-related morbidity. Ambulatory anorectal cases are common, with opioids widely prescribed, but there is limited data on their role in this crisis. We sought to determine prescribing trends, new persistent opioid use rates, and factors associated with new persistent opioid use after ambulatory anorectal procedures.The Optum Clinformatics claims database was analyzed for opioid-naïve adults undergoing outpatient hemorrhoid, fissure, or fistula procedures from January 1, 2010, to June 30, 2017. The main outcome measure was the rate of new persistent opioid use after anorectal cases. Secondary outcomes were annual rates of perioperative opioid fills and the prescription size over time (oral morphine equivalents).A total of 23,426 cases were evaluated: 69.09% (n = 16,185) hemorrhoids, 24.29% (n = 5,690) fissures, and 6.45% (n = 1,512) fistulas. The annual rate of perioperative opioid fills decreased on average 1.2%/year, from 72% in 2010 to 66% in 2017 (P.001). Prescribing rates were consistently highest for fistulas, followed by hemorrhoids, then fissures (P.001). There was a significant reduction in prescription size (oral morphine equivalents) over the study period, with median oral morphine equivalents (interquartile range) of 280 (250-400) in 2010 and 225 (150-375) in 2017 (P.0001). Overall, 2.1% (n = 499) developed new persistent opioid use. Logistic regression found new persistent opioid use was associated with additional perioperative opioid fills (odds ratio 3.92; 95% confidence interval: 2.92-5.27; P.0001), increased comorbidity (odds ratio 1.15; confidence interval: 1.09-1.20; P.00001), tobacco use (odds ratio 1.79; confidence interval: 1.37-2.36; P.0001), and pain disorders (odds ratio, 1.49; confidence interval, 1.23-1.82); there was no significant association with procedure performed.Over 2% of ambulatory anorectal procedures develop new persistent opioid use. Despite small annual reductions in opioid prescriptions, there has been little change in the amount prescribed. This demonstrates a need to develop and disseminate best practices for anorectal surgery, focusing on eliminating unnecessary opioid prescribing.

Patients with childhood, adolescent, and young adult cancer who will be treated with gonadotoxic therapies are at increased risk for infertility. Many patients and their families desire biological children but effective communication about treatment-related infertility risk and procedures for fertility preservation does not always happen. The PanCareLIFE Consortium and the International Late Effects of Childhood Cancer Guideline Harmonization Group reviewed the literature and developed a clinical practice guideline that provides recommendations for ongoing communication methods for fertility preservation for patients who were diagnosed with childhood, adolescent, and young adult cancer at age 25 years or younger and their families. Moreover, the guideline panel formulated considerations of the ethical implications that are associated with these procedures. Grading of Recommendations Assessment, Development and Evaluation methodology was used to grade the evidence and recommendations. In this clinical practice guideline, existing evidence and international expertise are combined to develop transparent recommendations that are easy to use to facilitate ongoing communication between health-care providers and patients with childhood, adolescent, and young adult cancer who might be at high risk for fertility impairment and their families.

BACKGROUND For over 20 years, the United States has suffered the detrimental effects of an opioid epidemic. Extended-release opioid products are particularly prone to abuse due to the high amount of opioid present. By bypassing the controlled-release mechanisms and nonoral administration, individuals experience intense and dangerous "highs." Abuse-deterrent opioid formulations have been recommended as a potential solution to the crisis, but widespread utilization has been stunted and their role in therapy remains unclear owing to limited real-world efficacy data and affordability issues. This review discusses abuse-deterrent opioid formulations, the mechanisms and data underlying available products, and a pharmacist's perspective of their role in the opioid crisis. METHODS The authors reviewed PubMed, MEDLINE, and Google Scholar electronic databases for premarketing and postmarketing studies on OxyContin, Xtampza ER, and Hysingla ER. RESULTS Studies showed lower rates of abuse (19% reduction), opioid use disorder (27%), overdose (34%), and fatalities (85%) with the reformulated OxyContin when compared with the original product and comparator opioids. However, these studies revealed the potential for bypassing abuse-deterrent mechanisms and diverting abuse to other drugs. Postmarketing studies are unavailable for Xtampza ER or Hysingla ER, although premarketing studies suggested that some controlled-release properties persist when the product is manipulated, indicating that abuse may be more difficult and less rewarding. CONCLUSIONS Abuse-deterrent opioid products may lead to reductions in abuse, overdose, and overdose fatalities. However, cost, loopholes in deterrence mechanism, and possible diversion to other substances hinder their role in the opioid crisis. Multiple approaches must be used to improve opioid safety, and further postmarketing and real-world analyses should be performed on available opioid formulations to assess their impact on abuse-related adverse events.

Aortic aneurysms occur concomitantly with malignancy in approximately 1.0-17.0% of patients. There is little published information regarding the effects of subsequent oncological therapies on aortic aneurysm growth. The aim of this study was to determine the effects of chemoradiation therapies on the natural progression of small abdominal aortic aneurysm (AAA), thoracic aortic aneurysm, and thoracoabdominal aortic aneurysm.Patients with aortic aneurysms with and without malignancy between 2005 and 2017 were identified within institutional databases using Current Procedural Terminology and International Classification of Disease codes. Inclusion criteria included complete chemotherapy documentation, a minimum of 3 multiplanar axial/coronal imaging or ultrasonography before, during, and after receiving therapy or 2 studies for patients without malignancy. Propensity matching, Cox and linear regression, and Kaplan-Meier survival analyses were performed.A total of 159 (172 aneurysms) patients with malignancy and 127 (149 aneurysms) patients without malignancy were included. Average patient demographics were 74.4 ± 9.8-years-old, Caucasian (66.8%), male (70.3%), with hypertension (71.1%), current smoking (24.5%), coronary atherosclerotic disease (26.2%), and AAA (71.0%). The most common malignancy was lung cancer (48.4%) with most chemotherapy regimens including a platinum-based alkylating agent and concurrent antimetabolite (56.0%). The overall median follow-up time was 28.2 (range 3.1-174.4) months. Aortic aneurysms in patients without malignancy grew to larger sizes (4.43 ± 0.96 vs. 4.14 ± 1.00, P = 0.008) with similar median growth rates (0.12 vs. 0.12 cm/year, P = 0.090), had more atypical morphologic features (14.1% vs. 0.6%, P 0.001), more frequently underwent repair (22.1% vs. 8.7%, P = 0.001), and more frequently required emergency repair for rupture (5.4% vs. 0.0%, P = 0.087). Cox regression identified initial aortic size ≥4.0 cm (hazard ratio [HR] 3.028), AAA (HR 2.146), chronic aortic findings (3.589), and the use of topoisomerase inhibitors (HR 2.694). Linear regression demonstrated increased growth rates predicted by antimetabolite chemotherapy (β 0.170), initial aortic size (β 0.086), and abdominal aortic location (β 0.139, all P 0.002).Small aortic aneurysms with concomitant malignancies are discovered at smaller initial sizes, grow at similar rates, require fewer interventions, and have fewer ruptures and acute dissections than patients without malignancy. Antimetabolite therapies modestly accelerate aneurysmal growth, and patients receiving topoisomerase inhibitors may require earlier repair. Patients with concomitant disease can be confidently treated according to standard institutional aneurysm surveillance protocols. Overall, we recommend treatment of the malignancy before small aortic aneurysm repair as these aneurysms behave similarly to those in patients without malignancy.

Purpose To assess the incidence, risk factors, and clinical outcomes associated with (Clostridioides difficile infection) CDI following urological surgery, which is the leading cause of nosocomial diarrhea and a growing public health burden. Methods We queried the National Surgical Quality Improvement Program (NSQIP) to identify patients undergoing urological surgery in 2015–2016. We evaluated the 30-day incidence and factors associated with postoperative CDI and 30-day hospital readmission and length of stay as secondary outcomes. Among the subset of patients undergoing radical cystectomy with urinary diversion (surgery with highest CDI incidence) we used multivariable logistic regression analysis to evaluate independent clinical and demographic factors associated with postoperative CDI. Results We identified 98,463 patients during the study period. The overall 30-day incidence of CDI was 0.31%, but varied considerably across surgery type. The risk of CDI was greatest following radical cystectomy with urinary diversion (2.72%) compared to all other urologic procedures (0.19%) and was associated with increased risk of hospital readmission (p

Greater trochanter (GT) fractures affect 0.6–29% of patients after direct anterior approach (DAA) total hip arthroplasty (THA). Given the growing popularity of this approach, this study aimed to assess the evolution of the GT fractures during the learning curve, their risk factors and their consequences. 537 total hip arthroplasties were retrospectively included from May 2013 to December 2017 in a single academic centre. Patient characteristics, perioperative management, clinical consequences and postoperative radiographs were analysed. GT fractures represented 2.4% (n = 13) of the THA, and there was not a decrease with experience. The GT fracture patients did not require any additional support during the surgery, and full weight bearing was always allowed without any restriction. This complication only happened in females, with the risk significantly increased in those > 70 years old (OR = 4.9). There was no specific consequence during the follow-up, mean HHS score was 98.5 and all of the patients were satisfied or very satisfied postoperatively. Older osteoporotic women are known to be at risk for GT fracture during DAA THA. Those results reinforce the argument in favour of proper patient selection in DAA to lower the complications since it does not improve with surgeon’s experience. Retrospective, consecutive case series; Level IV.

Aging is associated with heart and vascular dysfunction that contributes to cardiovascular disease (CVD) risk. Clinical data support a sexual dimorphism in the time course of aging-associated CVD. However, the mechanisms driving sex differences in cardiovascular aging and whether they can be modeled in mice have not been explored. Mineralocorticoid receptors (MRs) regulate blood pressure, and we previously demonstrated in male mice that MR expression increases in aging mouse vessels and smooth muscle cell-specific MR deletion (SMC-MR-KO) protects from cardiovascular aging. This study characterizes sex differences in murine cardiovascular aging and the associated sex-specific role of SMC-MR. Aortic stiffness, measured by pulse wave velocity, increased from 3 to 12 mo of age in males but not until 18 mo in females. The timing of the rise in aortic stiffening correlated with the timing of increased aortic MR expression, and aortic stiffness did not increase with age in SMC-MR-KO mice of both sexes. Vascular fibrosis increased at 12 mo in males and later at 18 mo in females; however, fibrosis was attenuated by SMC-MR-KO in males only. In resistance vessels, angiotensin type 1 receptor (AT(1)R)-mediated vasoconstriction also increased at 12 mo in males and 18 mo in females. ANG II-induced vasoconstriction was decreased in SMC-MR-KO specifically in males in association with decreased AT(1)R expression. Cardiac systolic function declined in males and females by 18 mo of age, which was prevented by SMC-MR-KO specifically in females. Cardiac perivascular fibrosis increased with age in both sexes accompanied by sex-specific changes in the expression levels of MR-regulated profibrotic genes. NEW & NOTEWORTHY These data demonstrate that the delayed and steeper decline in cardiovascular function observed in aging females can be modeled in aging mice. Moreover, the mechanisms driving vascular and cardiac aging phenotypes are distinct between males and females. Mineralocorticoid receptors in smooth muscle cells play a significant role in cardiovascular aging in both sexes; however, they do so by distinct mechanisms. Overall, these findings suggest that sex-specific therapies may be necessary to retard the aging process and improve cardiovascular disease outcomes in the aging population.

Summary Background Among asymptomatic patients with severe carotid artery stenosis but no recent stroke or transient cerebral ischaemia, either carotid artery stenting (CAS) or carotid endarterectomy (CEA) can restore patency and reduce long-term stroke risks. However, from recent national registry data, each option causes about 1% procedural risk of disabling stroke or death. Comparison of their long-term protective effects requires large-scale randomised evidence. Methods ACST-2 is an international multicentre randomised trial of CAS versus CEA among asymptomatic patients with severe stenosis thought to require intervention, interpreted with all other relevant trials. Patients were eligible if they had severe unilateral or bilateral carotid artery stenosis and both doctor and patient agreed that a carotid procedure should be undertaken, but they were substantially uncertain which one to choose. Patients were randomly allocated to CAS or CEA and followed up at 1 month and then annually, for a mean 5 years. Procedural events were those within 30 days of the intervention. Intention-to-treat analyses are provided. Analyses including procedural hazards use tabular methods. Analyses and meta-analyses of non-procedural strokes use Kaplan-Meier and log-rank methods. The trial is registered with the ISRCTN registry, ISRCTN21144362. Findings Between Jan 15, 2008, and Dec 31, 2020, 3625 patients in 130 centres were randomly allocated, 1811 to CAS and 1814 to CEA, with good compliance, good medical therapy and a mean 5 years of follow-up. Overall, 1% had disabling stroke or death procedurally (15 allocated to CAS and 18 to CEA) and 2% had non-disabling procedural stroke (48 allocated to CAS and 29 to CEA). Kaplan-Meier estimates of 5-year non-procedural stroke were 2·5% in each group for fatal or disabling stroke, and 5·3% with CAS versus 4·5% with CEA for any stroke (rate ratio [RR] 1·16, 95% CI 0·86–1·57; p=0·33). Combining RRs for any non-procedural stroke in all CAS versus CEA trials, the RR was similar in symptomatic and asymptomatic patients (overall RR 1·11, 95% CI 0·91–1·32; p=0·21). Interpretation Serious complications are similarly uncommon after competent CAS and CEA, and the long-term effects of these two carotid artery procedures on fatal or disabling stroke are comparable. Funding UK Medical Research Council and Health Technology Assessment Programme.

ObjectiveTo update the consensus recommendations for reporting of quantitative optical coherence tomography (OCT) study results, thus revising the previously published Advised Protocol for OCT Study Terminology and Elements (APOSTEL) recommendations.MethodsTo identify studies reporting quantitative OCT results, we performed a PubMed search for the terms “quantitative” and “optical coherence tomography” from 2015 to 2017. Corresponding authors of the identified publications were invited to provide feedback on the initial APOSTEL recommendations via online surveys following the principle of a modified Delphi method. The results were evaluated and discussed by a panel of experts and changes to the initial recommendations were proposed. A final survey was recirculated among the corresponding authors to obtain a majority vote on the proposed changes.ResultsA total of 116 authors participated in the surveys, resulting in 15 suggestions, of which 12 were finally accepted and incorporated into an updated 9-point checklist. We harmonized the nomenclature of the outer retinal layers, added the exact area of measurement to the description of volume scans, and suggested reporting device-specific features. We advised to address potential bias in manual segmentation or manual correction of segmentation errors. References to specific reporting guidelines and room light conditions were removed. The participants' consensus with the recommendations increased from 80% for the previous APOSTEL version to greater than 90%.ConclusionsThe modified Delphi method resulted in an expert-led guideline (evidence Class III; Grading of Recommendations, Assessment, Development and Evaluations [GRADE] criteria) concerning study protocol, acquisition device, acquisition settings, scanning protocol, funduscopic imaging, postacquisition data selection, postacquisition analysis, nomenclature and abbreviations, and statistical approach. It will be essential to update these recommendations to new research and practices regularly.

The opioid epidemic continues to affect pregnant women with opioid use disorder adversely in unique and enduring ways. The onset of the coronavirus disease 2019 (COVID-19) pandemic and the necessary public health measures implemented to slow the transmission have increased barriers to care for these same women. This commentary explores the implications of these measures and discusses strategies we have developed to manage these challenges based on our work in a clinical trial providing patient navigation to pregnant mothers with OUD. We believe these solutions can be applied in medical, behavioral health, and research settings through the pandemic and beyond to increase the quality of care and resources to this vulnerable population.

NEW FINDINGS What is the central question of this study? Are ultraviolet radiation (UVR)-induced increases in skin blood flow independent of skin erythema? Does broad-spectrum UVR exposure attenuate NO-mediated cutaneous vasodilatation, and does sunscreen or sweat modulate this response? What are the main findings and their importance? Erythema and vascular responses to UVR are temporally distinct, and sunscreen prevents both responses. Exposure to UVR attenuates NO-mediated vasodilatation in the cutaneous microvasculature; sunscreen or simulated sweat on the skin attenuates this response. Sun over-exposure may elicit deleterious effects on human skin that are separate from sunburn, and sunscreen or sweat on the skin may provide protection. ABSTRACT Exposure to ultraviolet radiation (UVR) may result in cutaneous vascular dysfunction independent of erythema (skin reddening). Two studies were designed to differentiate changes in erythema from skin vasodilatation throughout the 8 h after acute broad-spectrum UVR exposure with (+SS) or without SPF-50 sunscreen (study 1) and to examine NO-mediated cutaneous vasodilatation after acute broad-spectrum UVR exposure with or without +SS or simulated sweat (+SW) on the skin (study 2). In both studies, laser-Doppler flowmetry was used to measure red cell flux, and cutaneous vascular conductance (CVC) was calculated (CVC = flux/mean arterial pressure). In study 1, in 14 healthy adults (24 ± 4 years old; seven men and seven women), the skin erythema index and CVC were measured over two forearm sites (UVR only and UVR+SS) before, immediately after and every 2 h for 8 h post-exposure (750 mJ cm-2 ). The erythema index began to increase immediately post-UVR (P

Objective To determine the optimal thresholds for intereye differences in retinal nerve fiber and ganglion cell + inner plexiform layer thicknesses for identifying unilateral optic nerve lesions in multiple sclerosis. Current international diagnostic criteria for multiple sclerosis do not include the optic nerve as a lesion site despite frequent involvement. Optical coherence tomography detects retinal thinning associated with optic nerve lesions. Methods In this multicenter international study at 11 sites, optical coherence tomography was measured for patients and healthy controls as part of the International Multiple Sclerosis Visual System Consortium. High- and low-contrast acuity were also collected in a subset of participants. Presence of an optic nerve lesion for this study was defined as history of acute unilateral optic neuritis. Results Among patients (n = 1,530), receiver operating characteristic curve analysis demonstrated an optimal peripapillary retinal nerve fiber layer intereye difference threshold of 5μm and ganglion cell + inner plexiform layer threshold of 4μm for identifying unilateral optic neuritis (n = 477). Greater intereye differences in acuities were associated with greater intereye retinal layer thickness differences (p ≤ 0.001). Interpretation Intereye differences of 5μm for retinal nerve fiber layer and 4μm for macular ganglion cell + inner plexiform layer are robust thresholds for identifying unilateral optic nerve lesions. These thresholds may be useful in establishing the presence of asymptomatic and symptomatic optic nerve lesions in multiple sclerosis and could be useful in a new version of the diagnostic criteria. Our findings lend further validation for utilizing the visual system in a multiple sclerosis clinical trial setting. Ann Neurol 2019;85:618-629.

Phosphaturic mesenchymal tumors (PMT) are rare neoplasms characterized by secretion of FGF23, resulting in renal phosphate wasting and osteomalacia. This tumor-induced osteomalacia (TIO) is cured by complete resection; thus, diagnosis is important, particularly on biopsy. Although PMT have a classic histologic appearance of bland spindled cells with conspicuous vascular network and characteristic smudgy basophilic matrix, there is a broad histologic spectrum and variant histologic patterns can make recognition difficult. Recent studies have demonstrated FN1-FGFR1 and FN1-FGF1 gene fusions in PMT; however, approximately 50% of cases are negative for these fusions. We sought to characterize 6 cases of PMT in-depth, compare fusion detection methods, and determine whether alternative fusions could be uncovered by targeted RNA sequencing. Of the 6 cases of PMT in our institutional archive, 3 were not given diagnoses of PMT at the time of initial pathologic examination. We characterized the immunoprofile (SMA, D2-40, CD56, S100 protein, desmin, SATB2, and ERG) and gene fusion status (FN1 and FGFR1 rearrangements by fluorescent in situ hybridization (FISH) and two targeted RNA sequencing approaches) in these cases. Tumors were consistently positive for SATB2 and negative for desmin, with 5/6 cases expressing ERG and CD56. One specimen was acid-decalcified and failed FISH and RNA sequencing. We found FN1 gene rearrangements by FISH in 2/5 cases, and a FN1-FGFR1 fusion by targeted RNA sequencing. No alternative gene fusions were identified by RNA sequencing. Our findings suggest that IHC and molecular analysis can aid in the diagnosis of PMT, guiding excision of the tumor and resolution of osteomalacia.

Background A recent article provided compelling evidence for a cardioprotective effect of afternoon compared with morning operation in patients undergoing aortic valve replacement. The present study sought to investigate any daytime-dependent effect on perioperative myocardial injury or clinical outcomes in a large cohort of patients undergoing elective cardiac surgery. Methods The study identified all patients who underwent nonemergency aortic valve replacement and/or on-pump coronary artery bypass grafting at the Department of Cardiothoracic and Vascular Surgery of Aarhus University Hospital, Aarhus, Denmark between 1999 and 2018. Propensity-score matching was used to create adjusted cohorts for morning and afternoon operation. The primary end point was a composite of 30-day mortality and in-hospital acute myocardial infarction (major adverse cardiac events). Secondary end points were new-onset in-hospital atrial fibrillation, peak creatine kinase-MB levels, and up to 19 years of follow-up for all-cause mortality. Results The study identified 7148 patients who underwent either aortic valve replacement with or without coronary artery bypass grafting (n = 2806) or isolated coronary artery bypass grafting (n = 4342). Propensity-score matching resulted in comparable cohorts of morning and afternoon operation. The morning and afternoon operation cohorts had no differences in the rates of major adverse cardiac events after both procedures. Similarly, no daytime-dependent variation in the rate of new-onset in-hospital atrial fibrillation, long-term all-cause mortality, or peak creatine kinase-MB levels could be identified. Conclusions In this large cohort study of Danish patients, who underwent either aortic valve replacement and/or coronary artery bypass grafting, the study identified no clinically relevant biorhythm for myocardial ischemia-reperfusion tolerance.

The location, extent and progression of longitudinal morphometric changes after first-episode of psychosis (FEP) remains unclear. We investigated ventricular and cortico-subcortical regions over a 3-year period in FEP patients compared with healthy controls. High resolution 1.5T T1-weighted MR images were obtained at baseline from 28 FEP patients at presentation and 28 controls, and again after 3-years. The longitudinal FreeSurfer pipeline (v.5.3.0) was used for regional volumetric and cortical reconstruction image analyses. Repeated-measures ANCOVA and vertex-wise linear regression analyses compared progressive changes between groups in subcortical structures and cortical thickness respectively. Compared with controls, patients displayed progressively reduced volume of the caudate [F (1,51)=5.86, p=0.02, Hedges’ g=0.66], putamen [F (1,51)=6.06, p=0.02, g=0.67], thalamus [F (1,51)=6.99, p=0.01, g=0.72] and increased right lateral ventricular volume [F (1, 51)=4.03, p=0.05], and significantly increased rate of cortical thinning [F (1,52)=5.11, p=0.028)] at a mean difference of 0.84% [95% CI (0.10, 1.59)] in the left lateral orbitofrontal region over the 3-year period. In patients, greater reduction in putamen volume over time was associated with lower cumulative antipsychotic medication dose (r=0.49, p=0.01), and increasing lateral ventricular volume over time was associated with worsening negative symptoms (r=0.41, p=0.04) and poorer global functioning (r= −0.41, p=0.04). This study demonstrates localised progressive structural abnormalities in the cortico-striato-thalamo-cortical circuit after the onset of psychosis, with increasing ventricular volume noted as a neuroanatomical marker of poorer clinical and functional outcome.

Background Opioid use disorder (OUD) among women delivering at a hospital has increased 400% from 1999–2014 in the United States. From the years 2007 to 2016, opioid-related mortality during pregnancy increased over 200%, and drug-overdose deaths made up nearly 10% of all pregnancy-associated mortality in 2016 in the US. Disproportionately higher rates of neonatal opioid withdrawal syndrome (NOWS) have been reported in rural areas of the country, suggesting that perinatal OUD is a pressing issue among these communities. There is an urgent need for comprehensive, evidence-based treatment services for pregnant women experiencing OUD. The purpose of this article is to describe a study protocol aimed at developing and evaluating a perinatal OUD curriculum, enhancing evidence-based perinatal OUD treatment in a rural setting, and evaluating the implementation of such collaborative care for perinatal OUD. Methods This two-year study employed a one group, repeated measures, hybrid type-1 effectiveness-implementation design. This study delivered interventions at 2 levels, both targeting improvement of care for pregnant women with OUD. The first area of focus was at the community healthcare provider-level, which aimed to evaluate the acceptability and feasibility of perinatal OUD education across time and to improve provider education by increasing knowledge specific to: MOUD provision; screening, brief intervention, and referral to treatment (SBIRT) utilization; and NOWS treatment. The second area of intervention focus was at the patient-level, which assessed the preliminary effect of perinatal OUD provider education in promoting illicit opioid abstinence and treatment engagement among pregnant women with OUD. We adopted constructs from the Consolidated Framework for Implementation Research (CFIR) to assess contextual factors that may influence implementation, and the Reach, Effectiveness, Adoption, Implementation, and Maintenance (RE-AIM) model to comprehensively evaluate implementation outcomes. Discussion This article presents the protocol of an implementation study that is employing the CFIR and RE-AIM frameworks to implement and evaluate a perinatal OUD education and service coordination program in two rural counties. This protocol could serve as a model for clinicians and researchers seeking to implement improvements in perinatal care for women with OUD in other rural communities. Trial registration NCT04448015 clinicaltrials.gov.

Background There is a paucity of literature that examines how patient-reported outcomes correspond to early radiographic progression of thumb carpometacarpal (CMC) osteoarthritis (OA). This study examines how Australian/Canadian Osteoarthritis Hand Index (AUSCAN) and Patient-Rated Hand and Wrist Evaluation (PRWHE) scores change over 36 months in subjects with early CMC OA. Methods Ninety-one subjects with symptomatic early thumb CMC OA were enrolled. Differences in AUSCAN and PRWHE scores were measured between subjects at baseline and at 18-month follow-up, and between the subjects at baseline and at 36-month follow-up. Radiographic progression was defined as an increase in modified Eaton Stage. Differences in AUSCAN and PRWHE scores were compared between these 2 groups in order to determine if radiographic progression was associated with a greater change in AUSCAN and PRWHE at 18- and 36-month follow-up. Results At 18- and 36-month follow-up visits, there were no significant differences in AUSCAN or PRWHE compared to baseline. Multivariable logistic regression analysis did not reveal any significant differences between subjects with radiographic progression to subjects without radiographic progression at 18-month follow-up. At 36-month follow-up, this analysis did demonstrate that subjects with evidence of radiographic progression had a significant increase in the PRWHE pain subscale. Conclusion AUSCAN and PRWHE scores were not found to significantly progress at 18-month and 36-month follow-up. However, when comparing the subset of subjects with and without radiographic OA, subjects with early CMC OA who had 1 stage of radiographic progression were found to have a significantly higher intensity of pain on the PRWHE pain subscale at 36-month follow-up.

OBJECTIVE To assess differences between lymphatic function in the affected hands of rheumatoid arthritis (RA) patients with active synovitis and that of healthy controls, using indocyanine green (ICG) dye and near-infrared (NIR) imaging. METHODS NIR imaging of the hands of 8 patients with active RA and 13 healthy controls was performed following web space injection of 0.1 ml of 100 μM ICG. The percentage of ICG retention in the web spaces was determined by NIR imaging at baseline and at 7 days (±1 day) after the initial injections; image analysis provided contraction frequency. ICG+ lymphatic vessel (LV) length and branching architecture were assessed. RESULTS Retention of ICG in RA hands was higher compared to controls (P < 0.01). The average contraction frequency of ICG+ LVs in RA patients and in controls did not differ (mean ± SD 0.53 ± 0.39 contractions/minute versus 0.51 ± 0.35 contractions/minute). Total ICG+ LV length in RA hands was lower compared to healthy controls (58.3 ± 15.0 cm versus 71.4 ± 16.1 cm; P < 0.001), concomitant with a decrease in the number of ICG+ basilic LVs in the hands of RA patients (P < 0.05). CONCLUSION Lymphatic drainage in the hands of RA patients with active disease was reduced compared to controls. This reduction was associated with a decrease in total length of ICG+ LVs on the dorsal surface of the hands, which continued to contract at a similar rate to that observed in controls. These findings provide a plausible mechanism for exacerbation of synovitis and joint damage, specifically the accumulation and retention of inflammatory cells and catabolic factors in RA joints due to impaired efferent lymphatic flow. NIR/ICG imaging of RA hands is feasible and warrants formal investigation as a primary outcome measure for arthritis disease severity and/or persistence in future clinical trials.

BACKGROUND Despite current neurological guidelines that a single brain death examination (SBDE) is sufficient to determine brain death, a vast majority of hospitals still use a two brain death examination (TBDE) policy based on historical practice. The purpose of this study was to analyze the outcomes and implications of an SBDE policy compared with a TBDE policy with respect to organ donation outcomes. METHODS We retrospectively reviewed all adult patients declared dead by neurological criteria between 2010 and 2018 at a high-volume trauma center. The study population was divided into SBDE and TBDE cohorts. Primary outcomes included time to organ donation, terminal donor creatinine and bilirubin, and number of procured and transplanted organs. RESULTS A total of 327 patients comprised the study population: 66.7% SBDE (n = 218 of 327 patients) and 33.3% TBDE (n = 109 of 327 patients). The SBDE group had a shorter median time from examination to procurement (38 vs. 44 hours, p = 0.02) as well as lower terminal donor creatinine (1.1 vs. 1.35 mg/dL, p = 0.004) and bilirubin (0.8 vs. 1.1 mg/dL, p = 0.04). Furthermore, the SBDE group had a significantly greater proportion of kidneys (90.6% vs. 81.6%, p = 0.02), lungs (11.8% vs. 4.6%, p = 0.02), and total organs (58.2% vs. 46.6%; p = 0.0001) procured with intent to transplant and a greater proportion of total organs transplanted (53.1% vs. 42.4%, p = 0.0004). Multivariable regression analysis confirmed that SBDE was independently associated with a shorter time to procurement, lower terminal creatinine, and increased number of procured organs. CONCLUSION These data highlight the potential benefit of an SBDE policy with regards to organ donation outcomes at a high-volume trauma center and should facilitate future randomized prospective studies to more rigorously test this hypothesis. LEVEL OF EVIDENCE Therapeutic/Care Management, level IV.

Background The type of total knee arthroplasty (TKA) fixation (cemented or uncemented) is still subject to debate. The aim of this study is to assess the survival rate, clinical outcomes, and radiological results of TKA according to the fixation type. Methods A total of 130 patients were randomly assigned to either the cement group (cemented femoral and tibial implants) or the hybrid group (cemented tibial implant, uncemented femoral implant). The inclusion criteria were patients between 50 and 90 years old who underwent primary TKA for osteoarthritis between 2004 and 2005 without a history of open knee surgery. Revisions and complications were reported, as well as clinical scores and radiological signs of loosening. Results One hundred eighteen patients had complete data at 10 years of minimum follow-up (59 in each group). The mean age was 72 years old. The mean follow-up was 13 years. The survival rate was 98% at 13 years in both groups (1 aseptic loosening at 2 years in the cement group, 1 septic loosening in the hybrid group). The complication rate in the cement group was 8.5% (n = 5) vs 12.1% (n = 7) in the hybrid group (P = .8). The clinical results were not significantly different. In the cement group, 25% of patients (n = 15) had radiolucent lines at 10 years. In the hybrid group, 33% of patients had bone transparencies, not evolving or symptomatic. Conclusion At a minimum follow-up of 10 years, there were no significant differences between cemented TKA and hybrid TKA for the survivorship, the complication rate, the clinical scores, or the radiological signs of loosening. Level of Evidence I.

Background: Case reports and pharmacokinetic data suggest off-label echinocandin dosing may be needed to reach adequate serum concentrations in obese patients. Few outcome studies exist evaluating this population. Objectives: Of this study were to (1) determine the association of body mass index (BMI) with clinical outcomes of candidemia patients on standard doses of anidulafungin and (2) characterize fungal infections by body weight. Methods: A retrospective cohort was conducted to evaluate hospitalized patients treated for candidemia with anidulafungin at Food and Drug Administration–labeled dosing for at least 72 hours from January 1, 2014, through January 31, 2018. Candidemia was diagnosed by blood culture or T2 magnetic resonance (T2MR). Patients were compared according to BMI category. Results: One hundred seventy-three patients were included. Candida albicans and Candida glabrata were identified in 58 (33%) and 57 (33%) patients, respectively. Mortality was comparable according to BMI category: 4 (36.4%) underweight, 8 (25.8%) normal weight, 16 (32.0%) overweight, 20 (33.9%) obese, and 7 (31.8%) morbidly obese, P = .976. Variables associated with mortality included: severe sepsis (adjusted odds ratio [OR] = 5.1, 95% CI: 1.7-14.8) and liver disease (adjusted OR = 3.2, 95% CI: 1.1-9.4). Variables that were protective of mortality included: line removal (adjusted OR = 0.05, 95% CI: 0.02-0.2) and receipt of anidulafungin for at least 5 days (adjusted OR = 0.35, 95% CI: 0.15-0.8). Conclusion: There was no difference detected in mortality among patients with candidemia across BMI category. Larger studies are needed to confirm whether standard doses of anidulafungin are sufficient for candidemia in obese patients.

ObjectiveTo quantify benchmark treatment outcomes that may be enabled by newborn screening surveillance for X-linked adrenoleukodystrophy (ALD), we report neurocognitive, neuropsychiatric, and MRI change for boys who underwent hematopoietic stem cell transplant (HSCT) at initial stages of demyelination, prior to neurocognitive signs of disease.MethodsRetrospective chart review identified 36 patients whose cerebral ALD was detected and treated early, with lesion severity less than 5 on the ALD-specific MRI scoring system. Median age at transplant was 7.3 years (range, 4.0–16.1). Progression of radiologic disease on MRI in the 2 years following HSCT was examined relative to the severity of the initial lesion for 33 patients, and longitudinal neurocognitive and neuropsychiatric outcomes were studied for 30 patients.ResultsPatients whose pretransplant lesion extended beyond the splenium of the corpus callosum and adjacent periventricular white matter (MRI severity score >2) demonstrated lower posttransplant neurocognitive scores, more neuropsychiatric symptoms, and more disease progression on MRI than patients with a less severe lesion. Changes from baseline neurocognitive functioning were greater at 2 years posttransplant as compared to 1 year. There was greater variance and risk of lesion progression as pretransplant MRI severity increased.ConclusionTo realize the full benefits of newborn screening, clinicians must detect very small demyelinating lesions during surveillance and intervene quickly. Novel interventions that reduce risks inherent in allogeneic transplantation are needed. Trial endpoints should include direct neurocognitive assessment and extend at least 2 years posttreatment to provide the greatest sensitivity to detect neurocognitive morbidity.

Diabetes mellitus, commonly known as diabetes, is a chronic disease that often results in multiple complications. Risk prediction of diabetes complications is critical for healthcare professionals to design personalized treatment plans for patients in diabetes care for improved outcomes. In this paper, focusing on Type 2 diabetes mellitus (T2DM), we study the risk of developing complications after the initial T2DM diagnosis from longitudinal patient records. We propose a novel multi-task learning approach to simultaneously model multiple complications where each task corresponds to the risk modeling of one complication. Specifically, the proposed method strategically captures the relationships (1) between the risks of multiple T2DM complications, (2) between different risk factors, and (3) between the risk factor selection patterns, which assumes similar complications have similar contributing risk factors. The method uses coefficient shrinkage to identify an informative subset of risk factors from high-dimensional data, and uses a hierarchical Bayesian framework to allow domain knowledge to be incorporated as priors. The proposed method is favorable for healthcare applications because in addition to improved prediction performance, relationships among the different risks and among risk factors are also identified. Extensive experimental results on a large electronic medical claims database show that the proposed method outperforms state-of-the-art models by a significant margin. Furthermore, we show that the risk associations learned and the risk factors identified lead to meaningful clinical insights.

OBJECTIVECranial neurosurgical procedures can cause changes in brain function. There are many potential explanations, but the effect of simply opening the skull has not been addressed, except for research into syndrome of the trephined. The glymphatic circulation, by which CSF and interstitial fluid circulate through periarterial spaces, brain parenchyma, and perivenous spaces, depends on arterial pulsations to provide the driving force for bulk flow; opening the cranial cavity could dampen this force. The authors hypothesized that a craniectomy, without any other pathological insult, is sufficient to alter brain function due to reduced arterial pulsatility and decreased glymphatic flow. Furthermore, they postulated that glymphatic impairment would produce activation of astrocytes and microglia; with the reestablishment of a closed cranial compartment, the glymphatic impairment, astrocytic/microglial activation, and neurobehavioral decline caused by opening the cranial compartment might be reversed.METHODSUsing two-photon in vivo microscopy, the pulsatility index of cortical vessels was quantified through a thinned murine skull and then again after craniectomy. Glymphatic influx was determined with ex vivo fluorescence microscopy of mice 0, 14, 28, and 56 days following craniectomy or cranioplasty; brain sections were immunohistochemically labeled for GFAP and CD68. Motor and cognitive performance was quantified with rotarod and novel object recognition tests at baseline and 14, 21, and 28 days following craniectomy or cranioplasty.RESULTSPenetrating arterial pulsatility decreased significantly and bilaterally following unilateral craniectomy, producing immediate and chronic impairment of glymphatic CSF influx in the ipsilateral and contralateral brain parenchyma. Craniectomy-related glymphatic dysfunction was associated with an astrocytic and microglial inflammatory response, as well as with the development of motor and cognitive deficits. Recovery of glymphatic flow preceded reduced gliosis and return of normal neurological function, and cranioplasty accelerated this recovery.CONCLUSIONSCraniectomy causes glymphatic dysfunction, gliosis, and changes in neurological function in this murine model of syndrome of the trephined.

Microvascular endothelial dysfunction, a precursor to atherosclerotic cardiovascular disease, increases with aging. Endothelium-derived hyperpolarizing factors (EDHFs), which act through K+channels, regulate blood flow and are important to vascular health. It is unclear how EDHFs change with healthy aging. To evaluate microvascular endothelial reliance on K+channel-mediated dilation as a function of age in healthy humans. Microvascular function was assessed using intradermal microdialysis in healthy younger (Y; n = 7; 3 M/4 W; 26 ± 1 yr) and older adults (O; n = 12; 5 M/7 W; 64 ± 2 yr) matched for V̇o2peak(Y: 39.0 ± 3.8, O: 37.6 ± 3.1 mL·kg−1·min−1). Participants underwent graded local infusions of: the K+channel activator Na2S (10−6to 10−1M), acetylcholine (ACh, 10−10to 10−1M), ACh + the K+channel inhibitor tetraethylammonium (TEA; 25 or 50 mM), and ACh + the nitric oxide synthase-inhibitor l-NAME (15 mM). Red blood cell flux was measured with laser-Doppler flowmetry and used to calculate cutaneous vascular conductance (CVC; flux/mean arterial pressure) as a percentage of each site-specific maximum (%CVCmax, 43°C+28 mM sodium nitroprusside). The %CVCmaxresponse to Na2S was higher in older adults (mean, O: 51.7 ± 3.9% vs. Y: 36.1 ± 5.3%; P = 0.03). %CVCmaxwas lower in the ACh+TEA vs. the ACh site starting at 10−5M (ACh: 34.0 ± 5.7% vs. ACh+TEA: 19.4 ± 4.5%; P = 0.002) in older and at 10−4M (ACh: 54.5 ± 9.4% vs. ACh+TEA: 31.2 ± 6.7%; P = 0.0002) in younger adults. %CVCmaxwas lower in the ACh+l-NAME vs. the ACh site in both groups starting at 10−4M ACh (Y: P < 0.001; O: P = 0.02). Healthy active older adults have enhanced K+channel-dependent endothelial vasodilatory mechanisms, suggesting increased responsiveness to EDHFs with age.

Objective:Prescribing metrics, cost, and surrogate markers are often used to describe the value of antimicrobial stewardship (AMS) programs. However, process measures are only indirectly related to clinical outcomes and may not represent the total effect of an intervention. We determined the global impact of a multifaceted AMS initiative for hospitalized adults with common infections.Design:Single center, quasi-experimental study.Methods:Hospitalized adults with urinary, skin, and respiratory tract infections discharged from family medicine and internal medicine wards before (January 2017–June 2017) and after (January 2018–June 2018) an AMS initiative on a family medicine ward were included. A series of AMS-focused initiatives comprised the development and dissemination of: handheld prescribing tools, AMS positive feedback cases, and academic modules. We compared the effect on an ordinal end point consisting of clinical resolution, adverse drug events, and antimicrobial optimization between the preintervention and postintervention periods.Results:In total, 256 subjects were included before and after an AMS intervention. Excessive durations of therapy were reduced from 40.3% to 22% (P < .001). Patients without an optimized antimicrobial course were more likely to experience clinical failure (OR, 2.35; 95% CI, 1.17–4.72). The likelihood of a better global outcome was greater in the family medicine intervention arm (62.0%, 95% CI, 59.6–67.1) than in the preintervention family medicine arm.Conclusion:Collaborative, targeted feedback with prescribing metrics, AMS cases, and education improved global outcomes for hospitalized adults on a family medicine ward.

Purpose: Examine the clinical utility of the Fitkids Treadmill Test (FTT) for assessing cardiovascular endurance in youth with chronic pain.Materials and methods: Fifty-five youth with chronic pain...

ObjectiveTo measure exosomal and plasma levels of candidate blood biomarkers in veterans with history of mild traumatic brain injury (mTBI) and test their relationship with chronic symptoms.MethodsExosomal and plasma levels of neurofilament light (NfL) chain, tumor necrosis factor (TNF)–α, interleukin (IL)–6, IL-10, and vascular endothelial growth factor (VEGF) were measured using an ultrasensitive assay in a cohort of 195 veterans, enrolled in the Chronic Effects of Neurotrauma Consortium Longitudinal Study. We examined relationships between candidate biomarkers and symptoms of postconcussive syndrome (PCS), posttraumatic stress disorder (PTSD), and depression. Biomarker levels were compared among those with no traumatic brain injury (TBI) (controls), 1–2 mTBIs, and repetitive (3 or more) mTBIs.ResultsElevated exosomal and plasma levels of NfL were associated with repetitive mTBIs and with chronic PCS, PTSD, and depression symptoms. Plasma TNF-α levels correlated with PCS and PTSD symptoms. The total number of mTBIs correlated with exosomal and plasma NfL levels and plasma IL-6. Increased number of years since the most recent TBI correlated with higher exosomal NfL and lower plasma IL-6 levels, while increased number of years since first TBI correlated with higher levels of exosomal and plasma NfL, as well as plasma TNF-α and VEGF.ConclusionRepetitive mTBIs are associated with elevated exosomal and plasma levels of NfL, even years following these injuries, with the greatest elevations in those with chronic PCS, PTSD, and depression symptoms. Our results suggest a possible neuroinflammatory and axonal disruptive basis for symptoms that persist years after mTBI, especially repetitive.

Introduction:We examined geographic variations in the direct costs of endourological procedures, including percutaneous nephrolithotomy, shock wave lithotripsy and retrograde intrarenal sur...