Chemically induced cone degeneration in the 13-lined ground squirrel.

Animal models of retinal degeneration are critical for understanding disease and testing potential therapies. Inducing degeneration commonly involves the administration of chemicals that kill photoreceptors by disrupting metabolic pathways, signaling pathways, or protein synthesis. While chemically induced degeneration has been demonstrated in a variety of animals (mice, rats, rabbits, felines, 13-lined ground squirrels (13-LGS), pigs, chicks), few studies have used noninvasive high-resolution retinal imaging to monitor the in vivo cellular effects. Here, we used longitudinal scanning light ophthalmoscopy (SLO), optical coherence tomography, and adaptive optics SLO imaging in the euthermic, cone-dominant 13-LGS (46 animals, 52 eyes) to examine retinal structure following intravitreal injections of chemicals, which were previously shown to induce photoreceptor degeneration, throughout the active season of 2019 and 2020. We found that iodoacetic acid induced severe pan-retinal damage in all but one eye, which received the lowest concentration. While sodium nitroprusside successfully induced degeneration of the outer retinal layers, the results were variable, and damage was also observed in 50% of contralateral control eyes. Adenosine triphosphate and tunicamycin induced outer retinal specific damage with varying results, while eyes injected with thapsigargin did not show signs of degeneration. Given the variability of damage we observed, follow-up studies examining the possible physiological origins of this variability are critical. These additional studies should further advance the utility of chemically induced photoreceptor degeneration models in the cone-dominant 13-LGS.

Quantitative Foveal Structural Metrics as Predictors of Visual Acuity in Human Albinism.

Purpose: To assess the degree to which quantitative foveal structural measurements account for variation in best-corrected visual acuity (BCVA) in human albinism. Methods: BCVA was measured and spectral domain optical coherence tomography (SD-OCT) images were acquired for 74 individuals with albinism. Categorical foveal hypoplasia grades were assessed using the Leicester Grading System for Foveal Hypoplasia. Foveal anatomical specialization (foveal versus parafoveal value) was quantified for inner retinal layer (IRL) thickness, outer segment (OS) length, and outer nuclear layer (ONL) thickness. These metrics, participant sex, and age were used to build a multiple linear regression of BCVA. This combined linear model's predictive properties were compared to those of categorical foveal hypoplasia grading. Results: The cohort included three participants with type 1a foveal hypoplasia, 23 participants with type 1b, 33 with type 2, ten with type 3, and five with type 4. BCVA ranged from 0.08 to 1.00 logMAR (mean ± SD: 0.53 ± 0.21). IRL ratio, OS ratio, and ONL ratio were measured in all participants and decreased with increasing severity of foveal hypoplasia. The best-fit combined linear model included all three quantitative metrics and participant age expressed as a binary variable (divided into 0-18 years and 19 years or older; adjusted R2 = 0.500). This model predicted BCVA more accurately than a categorical foveal hypoplasia model (adjusted R2 = 0.352). Conclusions: A quantitative model of foveal specialization accounts for more variance in BCVA in albinism than categorical foveal hypoplasia grading. Other factors, such as optical aberrations and eye movements, may account for the remaining unexplained variance.

Child Anxiety and Depression During the COVID-19 Pandemic and Unmet Mental Health Care Needs.

Child anxiety and depression increased in recent years, while access to health care improved in some ways and worsened in others. The purpose of this study was to understand the prevalence of child anxiety and depression during the COVID-19 pandemic, unmet mental health care need among children with these conditions, and whether disparities exist by race/ethnicity and sex. A cross-sectional secondary data analysis was conducted using the 2021 National Survey of Children's Health (ages 3-17 years, unweighted n = 42,175). Parent/caregiver-reported child anxiety and depression prevalence was greater among non-Hispanic White children than those of other racial/ethnic groups and females compared to males, after adjusting for covariates. Unmet mental health care need among children with anxiety and depression was greater among Hispanic children than those of other racial/ethnic groups, after adjusting for covariates. In conclusion, this study identified a disparity in unmet need between Hispanic children and those of other races and ethnicities. Implications for policy and practice are discussed.

Substance Use Overdose Deaths Among Black and Indigenous Women in Wisconsin: A Review of Death Certificate Data From 2018 to 2020.

OBJECTIVES: We are in the midst of an overdose epidemic that has grown during the concurrent COVID-19 pandemic. In Wisconsin, overdose deaths increased 11-fold from 2000 to 2020, with over 1200 deaths in 2020. Because of disparities in substance use initiation, relapse, and treatment success among racially minoritized women, this study's purpose was to investigate overdose death rates among Black and Indigenous women in Wisconsin from 2018 to 2020. METHODS: Overdose death rates were examined under the following parameters: sex, race (Black, Indigenous, White), age, year, and manner of death. Logistic regression analysis was also conducted looking at death count data, with race, age, and year as potential predictor variables. RESULTS: Death rates (per 100,000) in 2018 were 14.1 (12.6-15.5) for White women, 20.8 (14.7-26.9) for Black women, and 26.5 (10.0-42.9) for Indigenous women; these rates increased in 2020 to 16.4 (14.8-17.9), 32.5 (25.0-40.0), and 59.9 (35.8-84.0) for White, Black, and Indigenous women, respectively. Regression findings illustrated that being Black or Indigenous and aged 15 to 44 or 45 to 64 years were significantly more likely to die from most causes of death (any drug, any opioid, prescription opioid, heroin, synthetic opioids, and cocaine; adjusted odds ratios > 1.25, P s < 0.001). CONCLUSIONS: This study confirms that deaths in Wisconsin are disproportionately higher in female minoritized populations. Understanding the complex intricacies between the impacts of the COVID-19 pandemic coupled with barriers to treatment access or acceptability in these populations is urgently needed. It will take a multipronged approach to address the overdose epidemic and better serve these marginalized, vulnerable populations.

Isolation and survival: The impact of local and MSA isolation on survival among non-Hispanic Black women diagnosed with breast cancer in the United States using a SEER-Medicare cohort.

BACKGROUND: Residential segregation is an important factor that negatively impacts cancer disparities, yet studies yield mixed results and complicate clear recommendations for policy change and public health intervention. In this study, we examined the relationship between local and Metropolitan Statistical Area (MSA) measures of Black isolation (segregation) and survival among older non-Hispanic (NH) Black women with breast cancer (BC) in the United States. We hypothesized that the influence of local isolation on mortality varies based on MSA isolation-specifically, that high local isolation may be protective in the context of highly segregated MSAs, as ethnic density may offer opportunities for social support and buffer racialized groups from the harmful influences of racism. METHODS: Local and MSA measures of isolation were linked by Census Tract (CT) with a SEER-Medicare cohort of 5,231 NH Black women aged 66-90 years with an initial diagnosis of stage I-IV BC in 2007-2013 with follow-up through 2018. Proportional and cause-specific hazards models and estimated marginal means were used to examine the relationship between local and MSA isolation and all-cause and BC-specific mortality, accounting for covariates (age, comorbidities, tumor stage, and hormone receptor status). FINDINGS: Of 2,599 NH Black women who died, 40.0% died from BC. Women experienced increased risk for all-cause mortality when living in either high local (HR = 1.20; CI = 1.08-1.33; p < 0.001) or high MSA isolation (HR = 1.40; CI = 1.17-1.67; p < 0.001). A similar trend existed for BC-specific mortality. Pairwise comparisons for all-cause mortality models showed that high local isolation was hazardous in less isolated MSAs but was not significant in more isolated MSAs. INTERPRETATION: Both local and MSA isolation are independently associated with poorer overall and BC-specific survival for older NH Black women. However, the impact of local isolation on survival appears to depend on the metropolitan area's level of segregation. Specifically, in highly segregated MSAs, living in an area with high local isolation is not significantly associated with poorer survival. While the reasons for this are not ascertained in this study, it is possible that the protective qualities of ethnic density (e.g., social support and buffering from experiences of racism) may have a greater role in more segregated MSAs, serving as a counterpart to the hazardous qualities of local isolation. More research is needed to fully understand these complex relationships. FUNDING: National Cancer Institute.

Magnetic resonance imaging-guided stereotactic laser ablation therapy for the treatment of pediatric epilepsy: a retrospective multiinstitutional study.

OBJECTIVE: The authors of this study evaluated the safety and efficacy of stereotactic laser ablation (SLA) for the treatment of drug-resistant epilepsy (DRE) in children. METHODS: Seventeen North American centers were enrolled in the study. Data for pediatric patients with DRE who had been treated with SLA between 2008 and 2018 were retrospectively reviewed. RESULTS: A total of 225 patients, mean age 12.8 ± 5.8 years, were identified. Target-of-interest (TOI) locations included extratemporal (44.4%), temporal neocortical (8.4%), mesiotemporal (23.1%), hypothalamic (14.2%), and callosal (9.8%). Visualase and NeuroBlate SLA systems were used in 199 and 26 cases, respectively. Procedure goals included ablation (149 cases), disconnection (63), or both (13). The mean follow-up was 27 ± 20.4 months. Improvement in targeted seizure type (TST) was seen in 179 (84.0%) patients. Engel classification was reported for 167 (74.2%) patients; excluding the palliative cases, 74 (49.7%), 35 (23.5%), 10 (6.7%), and 30 (20.1%) patients had Engel class I, II, III, and IV outcomes, respectively. For patients with a follow-up ≥ 12 months, 25 (51.0%), 18 (36.7%), 3 (6.1%), and 3 (6.1%) had Engel class I, II, III, and IV outcomes, respectively. Patients with a history of pre-SLA surgery related to the TOI, a pathology of malformation of cortical development, and 2+ trajectories per TOI were more likely to experience no improvement in seizure frequency and/or to have an unfavorable outcome. A greater number of smaller thermal lesions was associated with greater improvement in TST. Thirty (13.3%) patients experienced 51 short-term complications including malpositioned catheter (3 cases), intracranial hemorrhage (2), transient neurological deficit (19), permanent neurological deficit (3), symptomatic perilesional edema (6), hydrocephalus (1), CSF leakage (1), wound infection (2), unplanned ICU stay (5), and unplanned 30-day readmission (9). The relative incidence of complications was higher in the hypothalamic target location. Target volume, number of laser trajectories, number or size of thermal lesions, or use of perioperative steroids did not have a significant effect on short-term complications. CONCLUSIONS: SLA appears to be an effective and well-tolerated treatment option for children with DRE. Large-volume prospective studies are needed to better understand the indications for treatment and demonstrate the long-term efficacy of SLA in this population.

Historical redlining and breast cancer treatment and survival among older women in the United States.

BACKGROUND: Breast cancer (BC) is the most common cancer among US women, and institutional racism is a critical cause of health disparities. We investigated impacts of historical redlining on BC treatment receipt and survival in the United States. METHODS: Home Owners' Loan Corporation (HOLC) boundaries were used to measure historical redlining. Eligible women in the 2010-2017 Surveillance, Epidemiology, and End Results-Medicare BC cohort were assigned a HOLC grade. The independent variable was a dichotomized HOLC grade: A and B (nonredlined) and C and D (redlined). Outcomes of receipt of various cancer treatments, all-cause mortality (ACM), and BC-specific mortality (BCSM) were analyzed using logistic or Cox models. Indirect effects by comorbidity were examined. RESULTS: Among 18 119 women, 65.7% resided in historically redlined areas (HRAs), and 32.6% were deceased at a median follow-up of 58 months. A larger proportion of deceased women resided in HRAs (34.5% vs 30.0%). Of all deceased women, 41.6% died of BC; a larger proportion resided in HRAs (43.4% vs 37.8%). Historical redlining is a statistically significant predictor of poorer survival after BC diagnosis (hazard ratio = 1.09, 95% confidence interval [CI] = 1.03 to 1.15 for ACM, and hazard ratio = 1.26, 95% CI = 1.13 to 1.41 for BCSM). Indirect effects via comorbidity were identified. Historical redlining was associated with a lower likelihood of receiving surgery (odds ratio = 0.74, 95% CI = 0.66 to 0.83, and a higher likelihood of receiving palliative care odds ratio = 1.41, 95% CI = 1.04 to 1.91). CONCLUSION: Historical redlining is associated with differential treatment receipt and poorer survival for ACM and BCSM. Relevant stakeholders should consider historical contexts when designing and implementing equity-focused interventions to reduce BC disparities. Clinicians should advocate for healthier neighborhoods while providing care.

Discussion on "Adaptive enrichment designs with a continuous biomarker" by Nigel Stallard.

We congratulate Dr. Nigel Stallard on his stimulating paper on adaptive enrichment designs with a continuous biomarker. Dr. Stallard details a framework for a large and interesting class of enrichment procedures. His work has motivated us to offer some thoughts in response. Dr. Stallard's strategy is to use the maximum of a test statistic over a set of possible threshold values to define the enriched population to be sampled in a second stage. This reminds us of procedures for identifying a change point, a biomarker value beyond which the effect of treatment is increased. For simplicity we focus our comments on Dr. Stallard's Rule 1 for selecting the second-stage sampling threshold. Using this rule, we present the likelihood ratio approach for adaptive testing and compare it to Dr. Stallard's approach for a few scenarios.

A Pilot Study Examining the Effects of Ischemic Conditioning on Walking Capacity and Lower Extremity Muscle Performance in Patients with Claudication.

INTRODUCTION: This study investigated whether a novel therapy called ischemic conditioning (IC) improves walking capacity and lower extremity muscle performance in patients with peripheral vascular disease who experience intermittent claudication. METHODS: Forty-three patients with claudication were enrolled and received either IC or IC Sham for 2 weeks in this randomized, controlled, double-blinded, prospective study. IC sessions involved five cycles of alternating 5-min inflations of a blood pressure cuff to 225 mm Hg (25 mm Hg for IC Sham) and 5-min deflations, around the thigh of the affected lower extremity. RESULTS: There was no difference in the change in claudication onset time (Δ = 114 ± 212 s IC vs. 104 ± 173 s IC Sham; p = 0.67) or peak walking time (Δ = 42 ± 139 s IC vs. 12 ± 148 s IC Sham; p = 0.35) between the IC and IC Sham groups. At the level of the knee, participants in the IC group performed more work (Δ = 3,029 ± 4,999 J IC vs. 345 ± 2,863 J IC Sham; p = 0.03) and displayed a greater time to muscle fatigue (Δ = 147 ± 221 s IC vs. -27 ± 236 s IC Sham; p = 0.01). DISCUSSION/CONCLUSION: In patients with claudication, IC improved total work performed and time to fatigue at the knee but did not change walking parameters.

IL-12p40 promotes secondary damage and functional impairment after spinal cord contusional injury.

Secondary damage obstructs functional recovery for individuals who have sustained a spinal cord injury (SCI). Two processes significantly contributing to tissue damage after trauma are spinal cord hemorrhage and inflammation: more specifically, the recruitment and activation of immune cells, frequently driven by pro-inflammatory factors. Cytokines are inflammatory mediators capable of modulating the immune response. While cytokines are necessary to elicit inflammation for proper healing, excessive inflammation can result in destructive processes. The pro-inflammatory cytokines IL-12 and IL-23 are pathogenic in multiple autoimmune diseases. The cytokine subunit IL-12p40 is necessary to form bioactive IL-12 and IL-23. In this study, we examined the relationship between spinal cord hemorrhage and IL-12-related factors, as well as the impact of IL-12p40 (IL-12/IL-23) on secondary damage and functional recovery after SCI. Using in vivo magnetic resonance imaging and protein tissue analyses, we demonstrated a positive correlation between IL-12 and tissue hemorrhage. Receptor and ligand subunits of IL-12 were significantly upregulated after injury and colocalized with astrocytes, demonstrating a myriad of opportunities for IL-12 to induce an inflammatory response. IL-12p40-/- mice demonstrated significantly improved functional recovery and reduced lesion sizes compared to wild-type mice. Targeted gene array analysis in wild-type and IL-12p40-/- female mice after SCI revealed an upregulation of genes associated with worsened recovery after SCI. Taken together, our data reveal a pathogenic role of IL-12p40 in the secondary damage after SCI, hindering functional recovery. IL-12p40 (IL-12/IL-23) is thus an enticing neuroinflammatory target for further study as a potential therapeutic target to benefit recovery in acute SCI.

Association of Self-Reported Coping Strategies With Speech Recognition Outcomes in Adult Cochlear Implant Users.

OBJECTIVE: To characterize the degree to which individual coping strategies may influence speech perception after cochlear implantation. STUDY DESIGN: Retrospective cohort study. SETTING: Tertiary referral center. PATIENTS: Adult, postlingually deaf cochlear implant recipients. INTERVENTIONS: The Coping Orientation to Problems Experience inventory, a validated, multidimensional self-reported coping scale, was administered preoperatively. MAIN OUTCOME MEASURES: Speech perception was measured using consonant-nucleus-consonant (CNC) phoneme and word scores, AzBio sentence accuracy in quiet and noise, and Hearing in Noise Test sentences in quiet preoperatively and at 1, 3, and 6 months postoperatively. Quality of life was measured with the Hearing Implant Sound Quality Index and the Nijmegen Cochlear Implant Questionnaire. RESULTS: Thirty-six patients were included in this study. Mean age at surgery was 70.7 ± 11.4 years. Acceptance was associated with a decreased AzBio in noise score in the 6 months after CI (regression coefficient b = -0.05; 95% confidence interval [CI], -0.07 to -0.03; p < 0.01). Denial was associated with a decreased AzBio in quiet score (b = -0.05; 95% CI, -0.09 to -0.01; p < 0.05), whereas humor was associated with an increased AzBio in quiet score (b = 0.02; 95% CI, 0.01 to 0.04; p < 0.05). Humor was also associated with an increased Hearing in Noise Test score (b = 0.05; 95% CI, 0.02 to 0.07; p < 0.05). Denial was associated with decreased CNC word (b = -0.04; 95% CI, -0.06 to -0.02; p < 0.01) and phoneme (b = -0.04; 95% CI, -0.07 to -0.02; p < 0.01) scores, whereas substance use was associated with increased CNC word (b = 0.03; 95% CI, 0.01 to 0.05, p < 0.01) and phoneme (b = 0.04; 95% CI, 0.02 to 0.06; p < 0.01) scores. Scores on self-reported quality of life measures were not significantly correlated with coping strategies. CONCLUSION: A variety of adaptive and maladaptive coping strategies are used by postlingually deaf adult cochlear implant users. Denial and acceptance may be more predictive of poor speech performance, whereas humor and substance use may be more predictive of improved speech performance.

Combinatorial genetics reveals the Dock1-Rac2 axis as a potential target for the treatment of NPM1;Cohesin mutated AML.

Acute myeloid leukemia (AML) is driven by mutations that occur in numerous combinations. A better understanding of how mutations interact with one another to cause disease is critical to developing targeted therapies. Approximately 50% of patients that harbor a common mutation in NPM1 (NPM1cA) also have a mutation in the cohesin complex. As cohesin and Npm1 are known to regulate gene expression, we sought to determine how cohesin mutation alters the transcriptome in the context of NPM1cA. We utilized inducible Npm1cAflox/+ and core cohesin subunit Smc3flox/+ mice to examine AML development. While Npm1cA/+;Smc3Δ/+ mice developed AML with a similar latency and penetrance as Npm1cA/+ mice, RNA-seq suggests that the Npm1cA/+; Smc3Δ/+ mutational combination uniquely alters the transcriptome. We found that the Rac1/2 nucleotide exchange factor Dock1 was specifically upregulated in Npm1cA/+;Smc3Δ/+ HSPCs. Knockdown of Dock1 resulted in decreased growth and adhesion and increased apoptosis only in Npm1cA/+;Smc3Δ/+ AML. Higher Rac activity was also observed in Npm1cA/+;Smc3Δ/+ vs. Npm1cA/+ AMLs. Importantly, the Dock1/Rac pathway is targetable in Npm1cA/+;Smc3Δ/+ AMLs. Our results suggest that Dock1/Rac represents a potential target for the treatment of patients harboring NPM1cA and cohesin mutations and supports the use of combinatorial genetics to identify novel precision oncology targets.

Move more and sit less pilot intervention for individuals with heart failure.

BACKGROUND: Higher physical activity (PA) and lower sedentary behavior (SB) have been independently associated with lower risk of Heart Failure (HF). However, few individuals with HF engage in sufficient PA to confer benefits and many engage in high amounts of SB. This this feasibility study was conducted to examine changes in steps/day and SB in response to a tailored move more and sit less intervention. METHODS: This study used a single group, pre-post study design to assess changes in steps/day, inactive time, and time in moderate- to vigorous-intensity physical activity in individuals with HF stage C and D. Participants completed 1-week baseline assessment and an 11-week intervention. GEE Poisson model was used to evaluate the effect of intervention on change in PA and SB. RESULTS AND TRANSLATIONAL CONCLUSIONS: Thirteen participants with an average age of 69 ± 13 years that had been living with heart failure for 5.5 ± 4.2 years completed this intervention study. Average steps per day increased significantly over the intervention from 4778 steps/day at baseline to 5518 steps/day post-intervention. Time spent sedentary did not change. Move more and sit less interventions that include behavioral change techniques such as immediate feedback on steps can result in changes in walking behavior. Further strategies for reducing SB in this population should be explored.

Practical notes on popular statistical tests in renal physiology.

Competent statistical analysis is essential to maintain rigor and reproducibility in physiological research. Unfortunately, the benefits offered by statistics are often negated by misuse or inadequate reporting of statistical methods. To address the need for improved quality of statistical analysis in papers, the American Physiological Society released guidelines for reporting statistics in journals published by the society. The guidelines reinforce high standards for the presentation of statistical data in physiology but focus on the conceptual challenges and, thus, may be of limited use to an unprepared reader. Experimental scientists working in the renal field may benefit from putting the existing guidelines in a practical context. This paper discusses the application of widespread hypothesis tests in a confirmatory study. We simulated pharmacological experiments assessing intracellular calcium in cultured renal cells and kidney function at the systemic level to review best practices for data analysis, graphical presentation, and reporting. Such experiments are ubiquitously used in renal physiology and could be easily translated to other practical applications to fit the reader's specific needs. We provide step-by-step guidelines for using the most common types of t tests and ANOVA and discuss typical mistakes associated with them. We also briefly consider normality tests, exclusion criteria, and identification of technical and experimental replicates. This review is supposed to help the reader analyze, illustrate, and report the findings correctly and will hopefully serve as a gauge for a level of design complexity when it might be time to consult a biostatistician.

Distribution Theory Following Blinded and Unblinded Sample Size Re-estimation under Parametric Models.

Asymptotic distribution theory for maximum likelihood estimators under fixed alternative hypotheses is reported in the literature even though the power of any realistic test converges to one under fixed alternatives. Under fixed alternatives, authors have established that nuisance parameter estimates are inconsistent when sample size re-estimation (SSR) follows blinded randomization. These results have helped to inhibit the use of SSR. In this paper, we argue for local alternatives to be used instead of fixed alternatives. Motivated by Gould and Shih (1998), we treat unavailable treatment assignments in blinded experiments as missing data and rely on single imputation from marginal distributions to fill in for missing data. With local alternatives, it is sufficient to proceed only with the first step of the EM algorithm mimicking imputation under the null hypothesis. Then, we show that blinded and unblinded estimates of the nuisance parameter σ θ 2 are consistent, and re-estimated sample sizes converge to their locally asymptotically optimal values. This theoretical finding is confirmed through Monte-Carlo simulation studies. Practical utility is illustrated through a multiple logistic regression example. We conclude that, for hypothesis testing with a predetermined minimally clinically relevant local effect size, both blinded and unblinded SSR procedures lead to similar sample sizes and power.

People Living With HIV in St. Petersburg, Russia: Gender and Exposure Group Differences in HIV Care Engagement, Psychosocial Health, Substance Use, and Transmission Risk Behavior.

This study examined psychosocial and health needs of persons living with HIV (PLWH) in Russia. The study combined baseline datasets from two social network samples of PLWH in St. Petersburg (N = 872). Samples were recruited between 2014 and 2018 by enrolling a PLWH seed who was either out-of-care or treatment nonadherent as well as network members surrounding each seed, assessing each participant's HIV care, transmission risk, substance use, and mental health characteristics. Almost one-quarter of participants said they were never offered antiretroviral therapy (ART), and-among those offered ART-one-quarter refused or discontinued therapy and 45% were <95% ART-adherent. Almost half of participants had detectable viral load, and many reported continued condomless intercourse with potentially nonconcordant serostatus partners or needle sharing. Over 46% of participants had elevated scores on measures of depression, hopelessness, state anxiety, or poor social support. Study findings illustrate unmet needs of PLWH in Russia.

Most Powerful Test Sequences with Early Stopping Options.

We extended the application of uniformly most powerful tests to sequential tests with different stage-specific sample sizes and critical regions. In the one parameter exponential family, likelihood ratio sequential tests are shown to be uniformly most powerful for any predetermined α-spending function and stage-specific sample sizes. To obtain this result, the probability measure of a group sequential design is constructed with support for all possible outcome events, as is useful for designing an experiment prior to having data. This construction identifies impossible events that are not part of the support. The overall probability distribution is dissected into components determined by the stopping stage. These components are the sub-densities of interim test statistics first described by Armitage, McPherson and Rowe (1969) that are commonly used to create stopping boundaries given an α-spending function and a set of interim analysis times. Likelihood expressions conditional on reaching a stage are given to connect pieces of the probability anatomy together. The reduction of support caused by the adoption of an early stopping rule induces sequential truncation (not nesting) in the probability distributions of possible events. Multiple testing induces mixtures on the adapted support. Even asymptotic distributions of inferential statistics that are typically normal, are not. Rather they are derived from mixtures of truncated multivariate normal distributions.

Improving Child Development Screening: Implications for Professional Practice and Patient Equity.

INTRODUCTION AND OBJECTIVES: A pediatric group with 25 clinics and 150 providers used multifaceted approaches to implement workflow processes and an electronic health record (EHR) flowsheet to improve child developmental screening. The key outcome was developmental screening done for every patient during 3 periods between ages 8 and 36 months. Identification of developmental concerns was the secondary study outcome. Screening rates and referrals were hypothesized to be optimized for children regardless of demographic backgrounds. METHODS: During preventive visits, developmental screens targeted patients in age groups 8 to 12, 13 to 24, and 25 to 36 months. EHRs were analyzed for screening documentation, results, and referrals by patient demographics. Fifteen pediatric professionals were interviewed about their qualitative experiences. Quality improvement interventions included appointing clinic champions, training staff about the screening process and responsibilities, using a standardized tool, employing plan-do-study-act cycles, posting EHR prompts, providing financial incentives, and monitoring screening rates using control charts. RESULTS: Within 25 months, screening rates improved from 60% to >95% within the 3 preventive visit age groups for a total of more than 30 000 children. Professionals valued the team process improvements. Children enrolled in Medicaid, black children, and those living in lower income zip codes had lower screening rates than privately insured, white children, and those living in higher income areas. Ages and Stages Questionnaire 3rd edition results were significantly different by gender, race/ethnicity, insurance, and income categories across all groups. Referral rates varied by race/ethnicity and zip code of residence. CONCLUSIONS: This project resulted in an effective and efficient process to improve child developmental screening that was valued by pediatric professionals. Analyses of patient demographics revealed disparities in services for the most vulnerable families. Ongoing quality improvement, health services research, and advocacy offer hope to improve health equity.

Prevalence of lateral epicondylosis in veteran manual wheelchair users participating in adaptive sports.

Objective: Determine the prevalence of lateral epicondylosis (LE) of the dominant elbow in manual wheelchair users based on ultrasound assessment and physical exam.Design: Prospective, cross-sectional.Setting: National Veteran Wheelchair Games 2018 and 2019 (event medical services).Participants: Manual wheelchair users who attended the National Veteran Wheelchair Games (n = 87).Interventions: Participants completed a questionnaire then underwent an ultrasound assessment and a physical exam of their dominant arm evaluating for common extensor tendinopathy (CET) or clinically LE.Main Outcome Measure: Prevalence of CET diagnosed by ultrasound criteria was compared with other diagnostic criteria with MaNemar test for paired binary data.Results: Forty-six percent (N = 40) of participants met diagnostic criteria for CET by ultrasound assessment and 17% (N = 15) of participants met criteria for LE based on physical exam. These values are dramatically higher than what has been reported in the able-bodied population where the prevalence is estimated to be <2%. Age and number of years of wheelchair use were significant predictors of ultrasound diagnosis of LE (P = 0.02, 95% confidence interval [CI] 1.01-1.11) and (P = 0.05, 95% CI 1.00-1.09), respectively. Association analysis based on odds ratio and CI found no association between ultrasound findings suggestive of LE with regular adaptive sport participation greater than 1.5 h per week.Conclusion: Compared to able-bodied population, there is an increased prevalence of both CET and LE in manual wheelchair users based on either ultrasound assessment or physical exam. CET is associated with increased age and increased years using a manual wheelchair. There is no association between the diagnosis of LE and participation in adaptive sport.