Outcomes of Total Knee Arthroplasty in Patients Who Have Ehlers-Danlos syndrome: A Matched Cohort Study.

INTRODUCTION: Total knee arthroplasty is an excellent surgical option for patients who have end-stage knee osteoarthritis. While rates of major postoperative complications have steadily decreased with modern implants and operative techniques, contemporary outcome data for patients who have Ehlers-Danlos syndrome is scarce. The goal of this study was to compare complication rates after primary total knee arthroplasty in patients who have Ehlers-Danlos syndrome versus matched controls. METHODS: A large administrative database was used to identify patients who underwent primary total knee arthroplasty from 2009 to 2020. Patients who had a diagnosis of Ehlers-Danlos syndrome were identified by International Classification of Disease Coding. Propensity scores were utilized to match these patients with controls at a 1:4 ratio based on age, sex, and various comorbidities. Multivariable logistic regression analysis was used to compare the rates of medical and surgical complications at 90 days and 2 years. A total of 188 patients who had Ehlers-Danlos syndrome and 752 controls were included in this study. RESULTS: After univariate analysis, Ehlers-Danlos patients exhibited significantly higher rates of wound complications (4.8 versus 0.9%, P = 0.001) at 90 days. When adjusted for comorbidities, Ehlers-Danlos patients still exhibited significantly increased odds of developing wound complications (OR [odds ratio] 7.06, P < 0.001). CONCLUSIONS: Patients who have Ehlers-Danlos syndrome undergoing total knee arthroplasty exhibited significantly higher rates of wound complications within 90 days postoperatively, compared to matched controls. Rates of instability, manipulation under anesthesia, periprosthetic joint infection, aseptic loosening, and aseptic revision arthroplasty did not significantly differ between the cohorts. This study found generally favorable short-term outcomes of total knee arthroplasty in this population; however, the inability to control for implant type and other confounding variables may have influenced the lack of difference in complication rates at 2 years. Surgeons should monitor for the potentially increased risk of wound complications and consider the possible need for increased constraint in this population during preoperative planning.

Early Versus Late Periprosthetic Joint Infection After Total Knee Arthroplasty: Do Patient Differences Exist?

BACKGROUND: Periprosthetic joint infection (PJI) is a devastating complication following total knee arthroplasty (TKA). Little evidence exists comparing those with early versus late PJI. The purpose of the study was to determine comorbidity profile differences between patients developing early and late PJI. METHODS: There were 72,659 patients undergoing primary TKA from 2009 to 2021, who were identified from a commercial claims and encounters database. Subjects diagnosed with PJI were categorized as either 'early' (within 90 days of index procedure) or 'late' (> 2 years after index arthroplasty). Non-infected patients within these periods served as control groups following 4:1 propensity score matching on other extraneous variables. Logistic regression analyses were performed comparing comorbidities between groups. RESULTS: Patients were significantly younger in the late compared to the early infection group (58.1 versus 62.4 years, P < .001). When compared to those with early PJI, patients who had chronic kidney disease (13.3 versus 4.1%; OR [odds ratio] 5.17, P = .002), malignancy (20.4 versus 10.5%; OR 2.53, P = .009), uncomplicated diabetes (40.8 versus 30.6%; OR 2.00, P = .01), rheumatoid arthritis (9.2 versus 3.3%; OR 2.66, P = .046), and hypertension (88.8 versus 81.6%; OR 2.17, P = .04), were all significant predictors of developing a late PJI. CONCLUSIONS: When compared to patients diagnosed with early PJI following primary TKA, the presence of chronic kidney disease, malignancy, uncomplicated diabetes, rheumatoid arthritis, and hypertension, were independent risk factors for the development of late PJI. Younger patients who have these comorbidities may be targets for preoperative optimization interventions that minimize the risk of PJI.

Complications Rates Among Revision Total Knee Arthroplasty Patients Diagnosed With COVID-19 Postoperatively.

BACKGROUND: The COVID-19 pandemic introduced a new set of challenges for the arthroplasty community, including the management of patients diagnosed with COVID-19 following revision total knee arthroplasty (rTKA) and its potential impact on postoperative recovery. This study sought to characterize the risks of postoperative COVID-19 infection among rTKA patients. METHODS: A large national database was utilized to query 8,022 total patients who underwent rTKA between 2018 and 2021, of which 60 had a COVID diagnosis within 90 days after surgery (rTKA/COVID positive). These patients were 1:10 propensity-score matched to 600 rTKA patients who did not have a 90-day postoperative COVID diagnosis (rTKA/COVID negative) and 600 COVID positive patients who did not undergo rTKA. Controlling for potential confounders, multivariate logistic regressions were utilized to compare 90-day postoperative complications between groups. RESULTS: Compared to rTKA/COVID negativepatients, the rTKA/COVID positive cohort had significantly higher rates of pneumonia (odds ratio [OR] = 6.1, P < .001), pulmonary embolism (PE) (OR = 32.4, P < .001), deep venous thrombosis (DVT) (OR = 32.4, P < .001), and 90-day readmissions (OR = 2.1, P = .02). Similarly, the rTKA/COVID positive cohort had significantly higher rates of pneumonia (OR = 4.3, P = .001), PE (OR = 36.8, P < .001), and DVT (OR = 36.8, P < .001) compared to COVID positive patients who did not undergo rTKA. CONCLUSIONS: Revision total knee arthroplasty patients diagnosed with COVID-19 postoperatively had increased rates of thromboembolic events, pneumoniae, and 90-day readmissions. Risk mitigation efforts would suggest extending the prophylactic anticoagulation period for rTKA patients diagnosed with postoperative COVID-19.

What Is the Quality of Surgical Care for Patients with Hip Fractures at Critical Access Hospitals?

BACKGROUND: Critical access hospitals (CAHs) play an important role in providing access to care for many patients in rural communities. Prior studies have shown that these facilities are able to provide timely and quality care for patients who undergo various elective and emergency general surgical procedures. However, little is known about the quality and reimbursement of surgical care for patients undergoing surgery for hip fractures at CAHs compared with non-CAH facilities. QUESTIONS/PURPOSES: Are there any differences in 90-day complications, readmissions, mortality, and Medicare payments between patients undergoing surgery for hip fractures at CAHs and those undergoing surgery at non-CAHs? METHODS: The 2005 to 2014 Medicare 100% Standard Analytical Files were queried using ICD-9 procedure codes to identify Medicare-eligible beneficiaries undergoing open reduction and internal fixation (79.15, 79.35, and 78.55), hemiarthroplasty (81.52), and THA (81.51) for isolated closed hip fractures. This database was selected because the claims capture inpatient diagnoses, procedures, charged amounts and paid claims, as well as hospital-level information of the care, of Medicare patients across the nation. Patients with concurrent fixation of an upper extremity, lower extremity, and/or polytrauma were excluded from the study to ensure an isolated cohort of hip fractures was captured. The study cohort was divided into two groups based on where the surgery took place: CAHs and non-CAHs. A 1:1 propensity score match, adjusting for baseline demographics (age, gender, Census Bureau-designated region, and Elixhauser comorbidity index), clinical characteristics (fixation type and time to surgery), and hospital characteristics (whether the hospital was located in a rural ZIP code, the average annual procedure volume of the operating facility, hospital bed size, hospital ownership and teaching status), was used to control for the presence of baseline differences in patients presenting at CAHs and those presenting at non-CAHs. A total of 1,467,482 patients with hip fractures were included, 29,058 of whom underwent surgery in a CAH. After propensity score matching, each cohort (CAH and non-CAH) contained 29,058 patients. Multivariate logistic regression analyses were used to assess for differences in 90-day complications, readmissions, and mortality between the two matched cohorts. As funding policies of CAHs are regulated by Medicare, an evaluation of costs-of-care (by using Medicare payments as a proxy) was conducted. Generalized linear regression modeling was used to assess the 90-day Medicare payments among patients undergoing surgery in a CAH, while controlling for differences in baseline demographics and clinical characteristics. RESULTS: Patients undergoing surgery for hip fractures were less likely to experience many serious complications at a critical access hospital (CAH) than at a non-CAH. In particular, after controlling for patient demographics, hospital-level factors and procedural characteristics, patients treated at a CAH were less likely to experience: myocardial infarction (3% (916 of 29,058) versus 4% (1126 of 29,058); OR 0.80 [95% CI 0.74 to 0.88]; p < 0.001), sepsis (3% (765 of 29,058) versus 4% (1084 of 29,058); OR 0.69 [95% CI 0.63 to 0.78]; p < 0.001), acute renal failure (6% (1605 of 29,058) versus 8% (2353 of 29,058); OR 0.65 [95% CI 0.61 to 0.69]; p < 0.001), and Clostridium difficile infections (1% (367 of 29,058) versus 2% (473 of 29,058); OR 0.77 [95% CI 0.67 to 0.88]; p < 0.001) than undergoing surgery in a non-CAH. CAHs also had lower rates of all-cause 90-day readmissions (18% (5133 of 29,058) versus 20% (5931 of 29,058); OR 0.83 [95% CI 0.79 to 0.86]; p < 0.001) and 90-day mortality (4% (1273 of 29,058) versus 5% (1437 of 29,058); OR 0.88 [95% CI 0.82 to 0.95]; p = 0.001) than non-CAHs. Further, CAHs also had risk-adjusted lower 90-day Medicare payments than non-CAHs (USD 800, standard error 89; p < 0.001). CONCLUSION: Patients who received hip fracture surgical care at CAHs had a lower risk of major medical and surgical complications than those who had surgery at non-CAHs, even though Medicare reimbursements were lower as well. Although there may be some degree of patient selection at CAHs, these facilities appear to provide high-value care to rural communities. These findings provide evidence for policymakers evaluating the impact of the CAH program and allocating funding resources, as well as for community members seeking emergent care at local CAH facilities. LEVEL OF EVIDENCE: Level III, therapeutic study.

Behind the Wheel: Specialized Driving Instructors' Experiences and Strategies for Teaching Autistic Adolescents to Drive.

IMPORTANCE: In the transition to adulthood, driving supports independence. For autistic adolescents, training provided by specialized driving instructors, including occupational therapists, may establish fitness to drive and continued independence. OBJECTIVE: To examine specialized driving instructors' experiences providing behind-the-wheel instruction to autistic adolescents. DESIGN: We recruited participants through purposive and snowball sampling of members of ADED, the Association for Driver Rehabilitation Specialists. Interviews investigated experiences providing instruction, autistic students' strengths and challenges, strategies used, and recommendations to improve the learning-to-drive process. We coded transcripts using a directed content analysis approach. SETTING: Telephone interviews. PARTICIPANTS: Specialized driving instructors (N = 17) trained as occupational therapists, driver rehabilitation specialists, or licensed driving instructors with recent experience providing behind-the-wheel training for autistic adolescents participated. RESULTS: Behind-the-wheel challenges included mental inflexibility, distractibility, and difficulties with social cues and motor coordination. Instructors acknowledged students' strengths, including adherence to rules of the road, limited risk taking, and careful observations. Instructors scaffolded learning to help students develop skills. Although licensure and driving outcomes were sometimes unknown to instructors, students who became licensed frequently drove with supervision or restrictions. CONCLUSIONS AND RELEVANCE: Licensure is possible for autistic adolescents, although developing fitness to drive requires individualization and rigorous specialized instruction, which may culminate in delayed or restricted driving. What This Article Adds: This article highlights challenges and strengths encountered by specialized driving instructors teaching autistic adolescents. Despite requiring prolonged training, autistic adolescents can achieve licensure when supported by specialized instruction that is individualized to their needs and strengths.

The subventricular zone is able to respond to a demyelinating lesion after localized radiation.

Radiation is a common tool in the treatment of brain tumors that induces neurological deficits as a side effect. Some of these deficits appear to be related to the impact of radiation on the neurogenic niches, producing a drastic decrease in the proliferative capacity of these regions. In the adult mammalian brain, the subventricular zone (SVZ) of the lateral ventricles is the main neurogenic niche. Neural stem/precursor cells (NSCs) within the SVZ play an important role in brain repair following injuries. However, the irradiated NSCs' ability to respond to damage has not been previously elucidated. In this study, we evaluated the effects of localized radiation on the SVZ ability to respond to a lysolecithin-induced demyelination of the striatum. We demonstrated that the proliferation rate of the irradiated SVZ was increased after brain damage and that residual NSCs were reactivated. The irradiated SVZ had an expansion of doublecortin positive cells that appeared to migrate from the lateral ventricles toward the demyelinated striatum, where newly generated oligodendrocytes were found. In addition, in the absence of demyelinating damage, remaining cells in the irradiated SVZ appeared to repopulate the neurogenic niche a year post-radiation. These findings support the hypothesis that NSCs are radioresistant and can respond to a brain injury, recovering the neurogenic niche. A more complete understanding of the effects that localized radiation has on the SVZ may lead to improvement of the current protocols used in the radiotherapy of cancer.

General surgery textbooks and surgical disparities.

INTRODUCTION: Some academic textbooks have previously disseminated simplistic or even incorrect conceptions of race. Propagation of such ideas in General Surgery could contribute to gaps in quality of care received by minority patients. This study aims to determine whether General Surgery textbooks provide a thorough understanding of racial disparities. METHODS: General Surgery texts were drawn from Doody's list, an industry-standard list of textbooks for medical education. Technical guides, atlases, and books for non-General Surgery professionals were excluded. Passages mentioning medical differences amongst racial and ethnic groups were extracted. Six binary classifications were made, based on whether passages (a) described interventions to alleviate difference; (b) addressed environmental mediators of difference; (c) described the contribution of racism or discrimination; (d) used causal language to connect race to difference; (e) referred to known, heritable genetic mechanisms; and (f) directly provided a reference. Types of intervention were also extracted. A heuristic scale was calculated granting one point each for classifications a-c and losing one point for classification d. Three authors performed classifications, and raw agreement and Cohen's kappa were used to assess inter-rater reliability. RESULTS: Thirteen textbooks from Doody's list contained 511 passages discussing medical differences among racial/ethnic groups. Among passages, 25% discussed white people, 22% Black people/African Americans, 19% Asians, 9% Latinos, 4% Jewish/Ashkenazi people, 3% Native Americans, and 18% other. Fifteen passages (2.9%) used language indicating race was the cause of medical difference, and only two explicitly discussed racism or discrimination. Most passages (370, 72.3%) received a scale of 0. 120 (23.5%) received a scale of 1, eight (1.2%) received a scale of 2, and zero received a scale of 3. The mean passage scale was 0.24 and is not changing with time (regression coefficient -0.006/year, p = 0.538). Agreement was 91.2% across all categories and overall Kappa was 0.62. CONCLUSIONS: General Surgery textbooks do not provide readers with scientifically thorough understanding of health disparities. Teaching more comprehensive conceptions, including systemic causes and the role of racism, may prevent reflexive association of minority patients with poor outcomes. Future editions should include these details where disparities are discussed in an independent, comprehensive section.

Database analysis comparing incidence and complication rates between inpatient and outpatient laminotomies for lumbar disc herniation.

Background: Lumbar disc herniation (LDH) is a common condition that can be characterized with disabling pain. While most patients recover without surgery, some still require operative intervention. The epidemiology and trends of laminotomy for LDH have not been recently studied, and current practice patterns might be different from historical norms. This study aimed to investigate the trends of inpatient and outpatient laminotomies for LDH and compare complication rates between these two sites of service. Methods: A large, national database was utilized to identify patients > 8 years old who underwent a laminotomy for LDH between 2009 and 2019. Two cohorts were created based on site of surgery: inpatient versus outpatient. The outpatient cohort was defined as patients who had a length of stay less than 1 day without any associated hospitalization. Epidemiologic analyses for these cohorts were performed by demographics. Patients in both groups were then 1:1 propensity-score matched based on age, sex, insurance type, geographic region, and comorbidities. Ninety-day postoperative complications were compared between cohorts utilizing multivariate logistic regressions. Results: The average incidence of laminotomy for LDH was 13.0 per 10,000 persons-years. Although the national trend in incidence had not changed from 2009 to 2019, the proportion of outpatient laminotomies significantly increased in this time period (p=.02). Outpatient laminotomies were more common among younger and healthier patients. Patients with inpatient laminotomies had significantly higher rates of surgical site infections (odds ratio [OR] 1.61, p<.001), venous thromboembolism (VTE) (OR 1.96, p<.001), hematoma (OR 1.71, p<.001), urinary tract infections (OR 1.41, p<.001), and acute kidney injuries (OR 1.75, p=.001), even when controlling for selected confounders. Conclusions: Our study demonstrated an increasing trend in the performance of laminotomy for LDH toward the outpatient setting. Even when controlling for certain confounders, patients requiring inpatient procedures had higher rates of postoperative complications. This study highlights the importance of carefully evaluating the advantages and disadvantages of performing these procedures in an outpatient versus inpatient setting.

The Impact of Increased Time to Surgery in Geriatric Patients With Acetabular Fractures.

OBJECTIVES: To explore the association between time to surgery (TTS) and postoperative complications in geriatric patients with acetabular fractures. DESIGN: Retrospective cohort study. SETTING: Level I trauma center. PATIENTS/PARTICIPANTS: 51 consecutive geriatric patients (60 years of age or older) who presented to a Level 1 trauma center for surgical fixation of an acetabular fracture between 2013 and 2020. MAIN OUTCOME MEASUREMENT: The primary and secondary outcomes were 30-day postoperative complications and length of hospital stay (LOS), respectively. TTS was determined by time between arrival to ED and time of surgery, with a threshold of 48 hours (early vs. delayed TTS group). RESULTS: Nineteen patients (37.3%) had ≥1 postoperative complications. Patients in the delayed TTS group had 5× higher odds of developing ≥1 complications (odds ratio: 4.86, confidence interval: 1.48-15.96). There were no 30-day mortalities in either group. Patients in the delayed TTS group had an average LOS of 19 days compared with early TTS patients who had an average LOS of 12 days ( P = 0.040). CONCLUSION: Geriatric patients with acetabular fractures with delayed TTS had increased postoperative complications and LOS. These data suggest that expedited care may have a similar protective effect in geriatric patients with acetabular fractures, as it does in the acute hip fracture population. LEVEL OF EVIDENCE: Therapeutic Level III. See Instructions for Authors for a complete description of levels of evidence.

What do Trauma Surgery Textbooks Teach About Racial Disparities and the Roots of Violence?

This study presents a formal text analysis of trauma surgery textbooks. We examine passages that describe disparities or mechanisms of injury, and we report types of underlying causes and preventative interventions discussed. Trauma textbooks were drawn from an industry-standard list used by medical libraries. Chi-square testing was used to determine whether different types of underlying causes or preventative interventions were discussed by disparity type (those affecting racial minorities vs rural populations) and injury mechanism (accidental injuries vs intentional interpersonal injury). 146 passages were extracted from 7 textbooks, totaling 5576 pages of text. Passages discussing rural disadvantages or unintentional injury were substantially more likely to describe structural risk factors or governmental interventions than those discussing racial disadvantages or intentional injury, respectively. Textbook authors should consider enriching discussion of violence prevention or racial disparities to emphasize structural causes and interventions.

Increases in adolescent firearm injuries were associated with school closures during COVID-19.

BACKGROUND: Mitigation measures, including school closures, were enacted to protect the public during the COVID-19 pandemic. However, the negative effects of mitigation measures are not fully known. Adolescents are uniquely vulnerable to policy changes since many depend on schools for physical, mental, and/or nutritional support.  This study explores the statistical relationships between school closures and adolescent firearm injuries (AFI) during the pandemic. METHODS: Data were drawn from a collaborative registry of 4 trauma centers in Atlanta, GA (2 adult and 2 pediatric). Firearm injuries affecting adolescents aged 11-21 years from 1/1/2016 to 6/30/2021 were evaluated. Local economic and COVID data were obtained from the Bureau of Labor Statistics and the Georgia Department of Health. Linear models of AFI were created based on COVID cases, school closure, unemployment, and wage changes. RESULTS: There were 1,330 AFI at Atlanta trauma centers during the study period, 1,130 of whom resided in the 10 metro counties. A significant spike in injuries was observed during Spring 2020. A season-adjusted time series of AFI was found to be non- stationary (p = 0.60). After adjustment for unemployment, seasonal variation, wage changes, county baseline injury rate, and county-level COVID incidence, each additional day of unplanned school closure in Atlanta was associated with 0.69 (95% CI 0.34- 1.04, p < 0.001) additional AFIs across the city. CONCLUSION: AFI increased during the COVID pandemic. This rise in violence is statistically attributable in part to school closures after adjustment for COVID cases, unemployment, and seasonal variation. These findings reinforce the need to consider the direct implications on public health and adolescent safety when implementing public policy.

Cardiovascular Magnetic Resonance Imaging in Patients With Ibrutinib-Associated Cardiotoxicity.

Importance: Ibrutinib has been associated with serious cardiotoxic arrhythmias. In preclinical models, these events are paralleled or proceeded by diffuse myocardial injury (inflammation and fibrosis). Yet whether this is seen in patients or has implications for future cardiotoxic risk is unknown. Objective: To assess the incidence and outcomes of myocardial injury among patients with ibrutinib-related cardiotoxicity. Design, Setting, and Participants: This cohort study included consecutive patients treated with ibrutinib from 2012 to 2019, phenotyped using cardiovascular magnetic resonance (CMR) from a large US Comprehensive Cancer Center registry. Exposures: Ibrutinib treatment for cancer control. Main Outcomes and Measures: The primary outcome was the presence of late gadolinium enhancement (LGE) fibrosis. The secondary outcome was the occurrence of major adverse cardiac events (MACE), defined as atrial fibrillation, heart failure, symptomatic ventricular arrhythmias, and sudden death of probable or definite ibrutinib association after CMR. We also assessed parametric-mapping subclinical fibrosis (native-T1, extracellular volume fraction) and inflammation/edema (max-T2) measures. Cardiovascular magnetic resonance measures were compared with those obtained in similar consecutive patients with cancer without ibrutinib treatment (pretreatment controls). Observed measures were also compared with similar-aged broad population rates (general-population controls) and a broader pool of cardiovascular disease (CVD) risk-matched cancer controls. Multivariable regression was used to assess the association between CMR measures and MACE. Results: Overall, 49 patients treated with ibrutinib were identified, including 33 imaged after treatment initiation (mean [SD] age, 65 [10] years, 9 [27%] with hypertension, and 23 [69.7%] with index-arrhythmias); median duration of ibrutinib-use was 14 months. The mean (SD) pretreatment native T1 was 977.0 (73.0) ms, max-T2 56.5 (4.0) ms, and 4 (13.3%) had LGE. Posttreatment initiation, mean (SD) native T1 was 1033.7 (48.2) ms, max-T2 61.5 (4.8) ms, and 17 (54.8%) had LGE (P < .001, P = .01, and P < .001, respectively, pre- vs post-ibrutinib treatment). Native T12SDs was elevated in 9 (28.6%), and max-T22SDs in 21 (63.0%), respectively. Cardiovascular magnetic resonance measures were highest in those with suspected toxic effects (P = .01 and P = .01, respectively). There was no association between traditional CVD-risk or cancer-treatment status and abnormal CMR measures. Among those without traditional CVD, 16 (58.6%) had LGE vs 38 (13.3%) in matched-controls (relative-risk, 4.8; P < .001). Over a median follow-up of 19 months, 13 (39.4%) experienced MACE. In multivariable models inclusive of traditional CVD risk factors, LGE (hazard ratio [HR], 4.9; P = .04), and native-T12SDs (HR, 3.3; P = .05) associated with higher risks of MACE. Conclusions and Relevance: In this cohort study, myocardial injury was common in ibrutinib users, and its presence was associated with higher cardiotoxic risk.

Optimising the management of childhood acute diarrhoeal disease using a rapid test-and- treat strategy and/or Lactobacillus reuteri DSM 17938: a multicentre, randomised, controlled, factorial trial in Botswana.

INTRODUCTION: The study aim was to determine if rapid enteric diagnostics followed by the provision of targeted antibiotic therapy ('test-and-treat') and/or Lactobacillus reuteri DSM 17938 would improve outcomes in children hospitalised in Botswana with acute gastroenteritis. METHODS: This was a multicentre, randomised, factorial, controlled, trial. Children aged 2-60 months admitted for acute non-bloody diarrhoea to four hospitals in southern Botswana were eligible. Participants were assigned to treatment groups by web-based block randomisation. Test-and-treat results were not blinded, but participants and research staff were blinded to L. reuteri/placebo assignment; this was dosed as 1×108 cfu/mL by mouth daily and continued for 60 days. The primary outcome was 60-day age-standardised height (HAZ) adjusted for baseline HAZ. All analyses were by intention to treat. The trial was registered at Clinicaltrials.gov. RESULTS: Recruitment began on 12 June 2016 and continued until 24 October 2018. There were 66 participants randomised to the test-and-treat plus L. reuteri group, 68 randomised to the test-and-treat plus placebo group, 69 to the standard care plus L. reuteri group and 69 to the standard care plus placebo group. There was no demonstrable impact of the test-and-treat intervention (mean increase of 0.01 SD, 95% CI -0.14 to 0.16 SD) or the L. reuteri intervention (mean decrease of 0.07 SD, 95% CI -0.22 to 0.08 SD) on adjusted HAZ at 60 days. CONCLUSIONS: In children hospitalised for acute gastroenteritis in Botswana, neither a test-and-treat algorithm targeting enteropathogens, nor a 60-day course of L. reuteri DSM 17938, were found to markedly impact linear growth or other important outcomes. We cannot exclude the possibility that test-and-treat will improve the care of children with significant enteropathogens (such as Shigella) in their stool. TRIAL REGISTRATION NUMBER: NCT02803827.

Reporting of Cardiovascular Events in Clinical Trials Supporting FDA Approval of Contemporary Cancer Therapies.

BACKGROUND: Cardiovascular disease (CVD) has become an increasingly common limitation to effective anticancer therapy. Yet, whether CVD events were consistently reported in pivotal trials supporting contemporary anticancer drugs is unknown. OBJECTIVES: The authors sought to evaluate the incidence, consistency, and nature of CVD event reporting in cancer drug trials. METHODS: From the Drugs@FDA, clinicaltrials.gov, MEDLINE, and publicly available U.S. Food and Drug Administration (FDA) drug reviews, all reported CVD events across latter-phase (II and III) trials supporting FDA approval of anticancer drugs from 1998 to 2018 were evaluated. The primary outcome was the report of major adverse cardiovascular events (MACE), defined as incident myocardial infarction, stroke, heart failure, coronary revascularization, atrial fibrillation, or CVD death, irrespective of treatment arm. The secondary outcome was report of any CVD event. Pooled reported annualized incidence rates of MACE in those without baseline CVD were compared with reported large contemporary population rates using relative risks. Population risk differences for MACE were estimated. Differences in drug efficacy using pooled binary endpoint hazard ratios on the basis of the presence or absence of reported CVD were also assessed. RESULTS: Overall, there were 189 trials, evaluating 123 drugs, enrolling 97,365 participants (58.5 ± 5 years, 46.0% female, 72.5% on biologic, targeted, or immune-based therapies) with 148,138 person-years of follow-up. Over a median follow-up of 30 months, 1,148 incidents of MACE (375 heart failure, 253 myocardial infarction, 180 strokes, 65 atrial fibrillation, 29 revascularizations, and 246 CVD deaths; 792 in the intervention vs. 356 in the control arm; p < 0.01) were reported from the 62.4% of trials noting any CVD. The overall weighted-average incidence was 542 events per 100,000 person-years (716 per 100,000 in the intervention arm), compared with 1,408 among similar-aged non-cancer trial subjects (relative risk: 0.38; p < 0.01), translating into a risk difference of 866. There was no association between reporting CVD events and drug efficacy (hazard ratio: 0.68 vs. 0.67; p = 0.22). CONCLUSIONS: Among pivotal clinical trials linked to contemporary FDA-approved cancer drugs, reported CVD event rates trail expected population rates.

Teaching Autistic Adolescents and Young Adults to Drive: Perspectives of Specialized Driving Instructors.

Background: Limited transportation access may curtail education, occupational training, social, and community engagement opportunities for autistic adolescents. Nearly one-third of autistic adolescents obtain a driver's license by age 21 years, which may increase mobility and improve autistic adolescents' transition to independent adulthood. This study examined driving instructors' perspectives and experiences of teaching autistic adolescents to drive to facilitate a safe learning-to-drive process. Methods: We conducted interviews with driving instructors with specialized training to teach autistic adolescents to drive. Participants were recruited through purposive and snowball sampling. Semistructured interviews investigated family engagement; instructor observations; instructors' teaching strategies; and recommendations for improving the learning-to-drive process. A directed content analysis approach informed the development of a coding scheme. Coded transcripts were reviewed to identify themes. Results: We interviewed 17 driving instructors who primarily identified as occupational therapists. Key themes included importance of parent engagement; fostering independence; individualization of instructional strategies; and enhancements to the learning-to-drive process. Parent engagement prepared autistic students to undertake on-road instruction and supported skill development. While some families paradoxically limited adolescents' independence (e.g., heavy supervision while cooking, limiting participation in bicycling or lawn mowing) despite wanting them to pursue licensure, instructors believed that demonstrating independence in such life skills was necessary for safely undertaking on-road instruction. Instructors shared how they individualized assessments and tailored lessons over a prolonged period of time to promote safety and skill acquisition. Specific recommendations for enhancing the learning-to-drive process included standardizing instructional approaches and refining clinical assessment tools to determine driver readiness. Conclusions: Our findings highlight the need for parental engagement to support the learning-to-drive process and to foster the independence necessary to undertake highly individualized driving instruction. Efforts to increase families' access to tools to promote driving readiness and establishing best practices for instructors may enhance the efficiency and standardization of the learning-to-drive process. LAY SUMMARY: Why was this study done? Becoming licensed to drive increases the independence and mobility of adolescents, potentially improving access to educational, occupational training, social, and community engagement opportunities. Driving instructors are a critical resource for families, particularly for autistic adolescents who may receive training from specialized instructors, such as occupational therapists (OTs). However, little is known about the process and experience of teaching autistic adolescents to drive, which limits the ability to provide adolescents and families with guidance to prepare for and support the learning-to-drive process. What was the purpose of this study? The goal of this study was to examine the experiences and perspectives of driving instructors who provide behind-the-wheel training for autistic adolescents and young adults. What did the researchers do? We conducted semistructured interviews with specialized driving instructors who had experience working with autistic youth. Team members transcribed the interviews, coded them, and summarized common themes. What were the results of the study? We interviewed 17 driving instructors who primarily identified as OTs. Key themes included the importance of parents as partners, the need to encourage independence in daily living skills before driving, and the individualized approach used when working with autistic adolescents. Instructors provided suggestions for enhancing the learning-to-drive process and supporting nonspecialized instructors who also provide training to adolescents. Suggestions included enhancing the use of state-level Vocational Rehabilitation Services to provide financial support for instruction, use of a life skills checklist to identify and promote prerequisite driving skills, parent-supervised practice driving (including commentary driving where adolescents narrate driving instructions to a driver), and individualization of instruction tailored to adolescents' particular needs. What do these findings add to what was already known? These results inform efforts to prepare parents, nonspecialized instructors, and autistic adolescents themselves for undertaking on-road instruction and licensure. Instructors recommended that parents help adolescents develop independence, including skills to use alternative forms of transportation and practice predriving skills, such as navigation. Furthermore, these results highlight the need to establish best practices for instruction and refinement of tools and strategies used by both specialized and general driving instructors. What are potential weaknesses in the study? Our recruitment approach may have led instructors with similar training or opinions to participate, so important aspects of teaching autistic drivers may have not been elicited. We did not interview general driving instructors who may have different perspectives and needs that were not discussed. We were unable to determine how characteristics such as work location, race/ethnicity, or years in practice may have influenced participants' responses. How will these findings help autistic adults now or in the future? Results from this study identify tools, such as a life skills checklist, and practice activities, such as commentary driving, that can be used by families to support autistic adolescents who are learning to drive. This study highlights the need to examine experiences with the learning-to-drive process from autistic adolescents and parents themselves to understand their needs and recommendations for enhancing the process of safely learning to drive.

Lessons from the field: the conduct of randomized controlled trials in Botswana.

BACKGROUND: The conduct of randomized controlled trials (RCTs) in low-resource settings may present unique financial, logistic, and process-related challenges. Middle-income countries that have comparable disease burdens to low-income countries, but greater availability of resources, may be conducive settings for RCTs. Indeed, the country of Botswana is experiencing a rapid increase in the conduct of RCTs. Our objective was to explore the experiences of individuals conducting RCTs in Botswana to gain an understanding of the challenges and adaptive strategies to their work. METHODS: We conducted in-depth interviews with 14 national and international individuals working on RCTs in Botswana. Participants included principal investigators, research coordinators, lab technicians, research assistants, and other healthcare professionals. Interviews were audiotaped, transcribed verbatim, and coded for thematic analysis. RESULTS: Five primary themes were identified: ethics board relationships (including delays in the process); research staff management (including staff attrition and career development); study recruitment and retention (including the use of reimbursements); resource availability (including challenges accessing laboratory equipment); and capacity-building (including issues of exporting locally sourced samples). These themes were explored to discuss key challenges and adaptive strategies. CONCLUSIONS: This study offers a first-hand account of individuals engaged in conducting RCTs in Botswana, a nation that is experiencing a rapid increase in research activities. Findings provide a foundational understanding for researchers in Botswana and trial managers in similar settings when planning RCTs so that the conduct of research does not outpace the ability to manage, support, and regulate it.

Implications of irradiating the subventricular zone stem cell niche.

Radiation therapy is a standard treatment for brain tumor patients. However, it comes with side effects, such as neurological deficits. While likely multi-factorial, the effect may in part be associated with the impact of radiation on the neurogenic niches. In the adult mammalian brain, the neurogenic niches are localized in the subventricular zone (SVZ) of the lateral ventricles and the dentate gyrus of the hippocampus, where the neural stem cells (NSCs) reside. Several reports showed that radiation produces a drastic decrease in the proliferative capacity of these regions, which is related to functional decline. In particular, radiation to the SVZ led to a reduced long-term olfactory memory and a reduced capacity to respond to brain damage in animal models, as well as compromised tumor outcomes in patients. By contrast, other studies in humans suggested that increased radiation dose to the SVZ may be associated with longer progression-free survival in patients with high-grade glioma. In this review, we summarize the cellular and functional effects of irradiating the SVZ niche. In particular, we review the pros and cons of using radiation during brain tumor treatment, discussing the complex relationship between radiation dose to the SVZ and both tumor control and toxicity.