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Clinical trials disruption has always represented a non negligible part of the ending of interventional studies. While the SARS-CoV-2 (COVID-19) pandemic has led to an impressive and unprecedented initiation of clinical research, it has also led to considerable disruption of clinical trials in other disease areas, with around 80% of non-COVID-19 trials stopped or interrupted during the pandemic. In many cases the disrupted trials will not have the planned statistical power necessary to yield interpretable results. This paper describes methods to compensate for the information loss arising from trial disruptions by incorporating additional information available from auxiliary data sources. The methods described include the use of auxiliary data on baseline and early outcome data available from the trial itself and frequentist and Bayesian approaches for the incorporation of information from external data sources. The methods are illustrated by application to the analysis of artificial data based on the Primary care pediatrics Learning Activity Nutrition (PLAN) study, a clinical trial assessing a diet and exercise intervention for overweight children, that was affected by the COVID-19 pandemic. We show how all of the methods proposed lead to an increase in precision relative to use of complete case data only.

A product’s life cycle hinges on its sales. Product sales are determined by a combination of market demand, industrial production, logistics, supply chains, labor hours, and countless other factors. Business-specific questions about sales are often formalized into questions relating to specific quantities in sales data. Statistical estimation of these quantities of interest is crucial but restricted availability of empirical data reduces the accuracy of such estimation. For example, under certain regularity conditions the variance of maximum likelihood estimators cannot be asymptotically lower than the Cramer-Rao lower bound. The presence of additional information from external sources therefore allows the improvement of statistical estimation. Two types of additional information are considered in this work: unbiased and possibly biased. In order to incorporate these two types of additional information in statistical estimation, this manuscript minimizes mean squared error and variance. Publicly available Walmart sales data from 45 stores across 2010-2012 is used to illustrate how these statistical methods can be applied to use additional information for estimating weekly sales. The holiday effect (sales spikes during holiday weeks) adjusted for overtime trends is estimated with the use of relevant external information.

Sequential likelihood ratio testing is found to be most powerful in sequential studies with early stopping rules when grouped data come from the one-parameter exponential family. First, to obtain this elusive 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 stage specific components. These components are sub-densities of interim test statistics first described by Armitage, McPherson and Rowe (1969) that are commonly used to create stopping boundaries given an $\alpha$-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 the 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 are mixtures of truncated distributions. In contrast to the classical result on local asymptotic normality (Le Cam 1960), statistics that are asymptotically normal without stopping options have asymptotic distributions that are mixtures of truncated normal distributions under local alternatives with stopping options; under fixed alternatives, asymptotic distributions of test statistics are degenerate., Comment: 23 pages

Background Antiprogestins, including selective progesterone receptor (PgR) modulators (SPRMs) that act as PgR antagonists, are a promising class of therapeutics for overcoming endocrine resistance including in patients who develop activating estrogen receptor 1 (ESR1) mutations after prior endocrine therapy (ET). The SMILE study (NCT04738292) is a multi-institutional phase II clinical trial to determine the efficacy and safety of an antiprogestin, onapristone in combination with fulvestrant as second-line therapy for patients with ER+,PgR+, HER2 -metastatic breast cancer (MBC). Methods Patients with locally advanced or MBC who progress on ≥2 lines of prior therapy with ET as a single agent or in combination with CDK4/6 inhibitors, mTOR inhibitors and one line of chemotherapy in the metastatic setting are eligible. Other criteria include ECOG performance status ≤ 2, measurable disease per RECIST 1.1 criteria, adequate organ function, availability of an archived tumor biopsy block confirming the diagnosis of MBC, optional biopsy at disease progression on trial, and optional 18F-fluorofuranylnorprogesterone (18F-FFNP) PET/CT imaging. Ovarian suppression is allowed. Prior ET with tamoxifen or aromatase inhibitor therapy in the adjuvant or metastatic setting is allowed. Patients with prior exposure to fulvestrant, antiprogestins, or CDK inhibitors in the adjuvant setting are ineligible. Following consent, all subjects will receive fulvestrant at the recommended dosing schedule plus onapristone 50 mg orally, twice daily, until disease progression, unacceptable toxicity, or discontinuation for any other reason. Using the Simon Two-Stage design, a total of 39 patients will be enrolled over two years from 6-8 sites within Wisconsin Oncology Network (WON). In the first stage of the trial, 21 subjects will be enrolled; if ≥2 responses are observed, then 18 additional subjects will be enrolled in the second stage. This design yields a one-sided type I error rate of 5% if the ORR is 7% and power of 80% when the combination's true response rate is 20%. The primary objective is to evaluate the objective response rate; secondary objectives include safety and tolerability, progression-free survival, disease control rate, and duration of response. Other correlates include optional functional imaging of PgR binding with 18F-FFNP PET/CT and biomarker analysis (ER, total PgR, HER2, Ki67, CD24, CD44, LDH1, KLF4, CK 5/6, PhosphoSer294-PgR on tissue samples, ESR1 mutations, and circulating tumor DNA analysis). The study was approved in January 2021, and enrollment is active at the time of this submission. Citation Format: Sailaja Kamaraju, Amy Fowler, Chung Yee Cheng, Lubna N Chaudhary, John Burfeind, Janet Retseck, Amye J Tevaarwerk, Mark Burkard, Elisavet Paplomata, Amanda M Parkes, Julie M Jorns, Sergey Tarima, Douglas Yee, Hallgeir Rui, Carol Lange, Tarek Sahmoud, Kari B Wisinski. The SMILE study: A phase 2 trial of onapristone in combination with fulvestrant for patients with ER+ and HER2- metastatic breast cancer after progression on endocrine therapy and CDK4/6 inhibitors [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr OT2-16-01.

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.

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.

The present study evaluates a combination prevention intervention for crack users in San Salvador, El Salvador that included social network HIV testing, community events and small group interventions. We examined the cumulative effects of the social network HIV testing and small group interventions on rates of HIV testing, beyond the increase that we saw with the introduction of the social network HIV testing intervention alone. HIV test data was converted into the number of daily tests and analyzed the immediate and overtime impact of small group interventions during and in the twelve weeks after the small group intervention. The addition of the small group interventions to the baseline of monthly HIV tests resulted in increased rates of testing lasting 7 days after the small group interventions suggesting a reinforcing effect of small group interventions on testing rates.

Background Previous studies have shown varying results between lumbosacral transforaminal epidural steroid injections (TFESIs) performed with particulate versus non-particulate corticosteroids. The purpose of this study was to investigate the difference in pain relief and functional improvement between particulate and non-particulate lumbosacral TFESIs in patients who had undergone both injections, sequentially. Methods This was a self-controlled, retrospective study of 20 patients who underwent both a methylprednisolone and a dexamethasone TFESI to the same vertebral level and side. Primary outcomes included pain relief according to the visual analogue scale (VAS) and functional improvement determined by a yes/no answer to questions regarding mobility and the activities of daily living. Post-injection data was recorded at 2, 3, and 6 months. Results A decrease in VAS scores of -3.4 ± 3.0 (mean ± standard deviation), -3.1 ± 3.1, and -2.8 ± 3.4 was seen for the methylprednisolone group at 2, 3, and 6 months, respectively. Similar decreases of -3.9 ± 3.5, -3.4 ± 2.8, and -2.3 ± 3.4 were seen in the dexamethasone group. There was no significant difference in pain relief at any point between the two medications. The percentage of subjects who reported improved function at 2, 3, and 6 months was 65%, 51%, and 41%, respectively, for the methylprednisolone group and 75%, 53%, and 42% for the dexamethasone group. Conclusions These findings support the use of non-particulate corticosteroids for lumbosacral TFESIs in the context of documented safety concerns with particulate corticosteroids.

Half of HIV-positive persons in Russia are on antiretroviral therapy (ART), and only 27% are virally suppressed. A feasibility pilot intervention to mobilize social capital resources for HIV care s...

The COVID-19 pandemic continues to affect the conduct of clinical trials globally. Complications may arise from pandemic-related operational challenges such as site closures, travel limitations and interruptions to the supply chain for the investigational product, or from health-related challenges such as COVID-19 infections. Some of these complications lead to unforeseen intercurrent events in the sense that they affect either the interpretation or the existence of the measurements associated with the clinical question of interest. In this article, we demonstrate how the ICH E9(R1) Addendum on estimands and sensitivity analyses provides a rigorous basis to discuss potential pandemic-related trial disruptions and to embed these disruptions in the context of study objectives and design elements. We introduce several hypothetical estimand strategies and review various causal inference and missing data methods, as well as a statistical method that combines unbiased and possibly biased estimators for estimation. To illustrate, we describe the features of a stylized trial, and how it may have been impacted by the pandemic. This stylized trial will then be re-visited by discussing the changes to the estimand and the estimator to account for pandemic disruptions. Finally, we outline considerations for designing future trials in the context of unforeseen disruptions.

Background Antiprogestins, including selective progesterone receptor (PgR) modulators (SPRMs) that act as PgR antagonists, are a promising class of therapeutics for overcoming endocrine resistance including in patients who develop activating estrogen receptor alpha (ESR1) mutations after prior endocrine therapy (ET). The SMILE study is a multi-institutional phase II clinical trial to determine the efficacy and safety of an antiprogestin, onapristone in combination with fulvestrant as second-line therapy for patients with ER+,PgR+/-, HER2 -metastatic breast cancer (MBC). Methods Patients with locally advanced or MBC who progress on ≥2 lines of prior therapy with ET as a single agent or in combination with CDK4/6 inhibitors, mTOR inhibitors and one line of chemotherapy in the metastatic setting are eligible. Other criteria include ECOG performance status ≤ 2, measurable disease per RECIST 1.1 criteria, adequate organ function, availability of an archived tumor biopsy block confirming the diagnosis of MBC, optional biopsy at disease progression on trial, and optional 18F-fluorofuranylnorprogesterone (18F-FFNP) PET/CT imaging. Ovarian suppression is allowed. Prior ET with tamoxifen or aromatase inhibitor therapy in the adjuvant or metastatic setting is allowed. Patients with prior exposure to fulvestrant, antiprogestins, or CDK inhibitors in the adjuvant setting are ineligible. Following consent, all subjects will receive fulvestrant at the recommended dosing schedule plus onapristone 50 mg orally, twice daily, until disease progression, unacceptable toxicity, or discontinuation for any other reason. Using the Simon Two-Stage design, a total of 39 patients will be enrolled over two years from 6-8 sites within Wisconsin Oncology Network (WON); study enrollment began in November 2021. In the first stage of the trial, thus far, nine patients were accrued who are tolerating the trial regimen well with no reported toxicities or serious events. The safety monitoring is planned when the cohort size reaches eleven patients, and interim analysis at 21 patients; if ≥2 responses are observed, then 18 additional subjects will be enrolled in the second stage. This design yields a one-sided type I error rate of 5% if the ORR is 7% and power of 80% when the combination’s true response rate is 20%. The primary objective is to evaluate the objective response rate; secondary objectives include safety and tolerability, progression-free survival, disease control rate, and duration of response. Other correlates include optional functional imaging of PgR binding with 18F-FFNP PET/CT and biomarker analysis (ER, total PgR, HER2, Ki67, CD24, CD44, LDH1, KLF4, CK 5/6, PhosphoSer294-PgR on tissue samples, ESR1 mutations, and circulating tumor DNA analysis). Citation Format: Sailaja Kamaraju, Amy Fowler, Lubna N. Chaudhary, Mark Burkard, Thomas Giever, Robert N Hegeman, Michele Pipp-Dahm, Yee Chung Cheng, Carol Lange, Julie M. Jorns, Amy Stella, Nauman Siddiqui, Luke Zurbriggen, Saurabh Rajguru, Sergey Tarima, Deepika Sriram, Janet Retseck, Hallgeir Rui, Tarek Sahmoud, Kari B. Wisinski. The SMILE Study: A phase II trial of onapristone in combination with fulvestrant for patients with ER-positive and HER2-negative metastatic breast cancer after progression on endocrine therapy and CDK 4/6 inhibitors [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr OT2-01-02.

Purpose To assess the impact of two TYR hypomorphic alleles (R402Q and S192Y) on foveal pit and FAZ morphology. Design Prospective cross-sectional study Participants One hundred sixty-four participants with normal vision (67 males and 97 females; mean ± SD age = 30.5 ± 12.8 years) were recruited. Methods Sequencing of over 100 pigmentation-related genes was performed, and results were reviewed for the presence or absence of the TYR polymorphisms R402Q (rs1126809) and S192Y (rs1042602). Volumetric scans of the macula were obtained for each participant using optical coherence tomography (OCT) and retinal thickness maps were analyzed using custom software. OCT angiography (OCT-A) was used to image the foveal avascular zone (FAZ) which was manually segmented and measured. Linear mixed model analysis was used to assess associations between genotype and foveal pit morphology Main Outcome Measures Foveal pit depth, diameter, volume and FAZ area in relation to the presence of hypomorphic alleles R402Q and S192Y on the TYR gene. Results Heterozygosity for the TYR R402Q allele was associated with decreased pit diameter (p = 0.0094) and decreased FAZ area (p = 0.025). Homozygosity for the TYR R402Q allele was associated with reduced pit volume (p = 0.0005), decreased pit depth (p = 0.007), reduced pit diameter (p = 0.0052) and reduced FAZ area (p = 0.0012). Homozygosity for TYR S192Y was associated with reduced FAZ area (p = 0.016). Heterozygosity for the TYR S192Y allele was not associated with differences in foveal pit depth, diameter, volume or FAZ area (p > 0.05). Conclusion While the role of the TYR R402Q and S192Y hypomorphic alleles in albinism remains controversial, our data suggest that these variants contribute to the extensive inter-individual variability in foveal morphology in the normal population. Our results contribute to the evolving picture of the relationship between ocular pigmentation and foveal morphology.

Background Age has been implicated as the main risk factor for COVID-19-related mortality. Our objective was to utilize administrative data to build an explanatory model accounting for geriatrics-focused indicators to predict mortality in hospitalized older adults with COVID-19. Methods Retrospective cohort study of adults age 65 and older (N = 4783) hospitalized with COVID-19 in the greater New York metropolitan area between 3/1/20-4/20/20. Data included patient demographics and clinical presentation. Stepwise logistic regression with Akaike Information Criterion minimization was used. Results The average age was 77.4 (SD = 8.4), 55.9% were male, 20.3% were African American, and 15.0% were Hispanic. In multivariable analysis, male sex (adjusted odds ration (adjOR) = 1.06, 95% CI:1.03-1.09); Asian race (adjOR = 1.08, CI:1.03-1.13); history of chronic kidney disease (adjOR = 1.05, CI:1.01-1.09) and interstitial lung disease (adjOR = 1.35, CI:1.28-1.42); low or normal body mass index (adjOR:1.03, CI:1.00-1.07); higher comorbidity index (adjOR = 1.01, CI:1.01-1.02); admission from a facility (adjOR = 1.14, CI:1.09-1.20); and mechanical ventilation (adjOR = 1.52, CI:1.43-1.62) were associated with mortality. While age was not an independent predictor of mortality, increasing age (centered at 65) interacted with hypertension (adjOR = 1.02, CI:0.98-1.07, reducing by a factor of 0.96 every 10 years); early Do-Not-Resuscitate (DNR, life-sustaining treatment preferences) (adjOR = 1.38, CI:1.22-1.57, reducing by a factor of 0.92 every 10 years); and severe illness on admission (at 65, adjOR = 1.47, CI:1.40-1.54, reducing by a factor of 0.96 every 10 years). Conclusion Our findings highlight that residence prior to admission, early DNR, and acute illness severity are important predictors of mortality in hospitalized older adults with COVID-19. Readily available administrative geriatrics-focused indicators that go beyond age can be utilized when considering prognosis.

Many studies have explored the benefits of physical activity (PA) in mitigating risk for and symptoms of dementia. However, there are challenges to implementing PA with dementia patients. We conducted an acceptability/feasibility study of PA in patients with Dementia and their caregivers. A semi-structured telephone interview was conducted. Questions piloted with 2 independent faculty for content validity. A random sample of 10 participants was recruited from patient-caregiver dyads enrolled in an Alzheimer’s Dementia Care program (ADCP) at an academic geriatrics practice. Responses manually recorded and personal health information omitted. Descriptive statistics generated using SPSS and response themes categorized by the authors. Major themes included lack of time for caregivers; time requirement would increase caregiver burden (50%). Caregivers of patients with home health aides were less likely to consider time a barrier. Other themes included functional status as a challenge (40%), difficulty motivating patient (40%), unsteady gait (20%), difficulty using devices for video-based exercise (20%). Caregivers expressed preference for asynchronous, in-home PA that could be adapted to their schedules and patient capabilities. Although PA is beneficial for patients with dementia, multiple challenges to PA implementation exist. Main barriers are time requirements and greater caregiver burden. Time would be required to motivate patients, assist with managing technology, and functional impairment that poses potential risk of injury (e.g., gait instability). Engaging Home Health Aides in PA programs could address some of these barriers. Alternative PA (i.e.: chair exercises) could be a solution. Responses will be utilized to modify a future PA intervention.

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 Npm1(cAflox/+) and core cohesin subunit Smc3(flox/+) mice to examine AML development. While Npm1(cA/+);Smc3(Δ/+) mice developed AML with a similar latency and penetrance as Npm1(cA/+) mice, RNA-seq suggests that the Npm1(cA/+); Smc3(Δ/+) mutational combination uniquely alters the transcriptome. We found that the Rac1/2 nucleotide exchange factor Dock1 was specifically upregulated in Npm1(cA/+);Smc3(Δ/+) HSPCs. Knockdown of Dock1 resulted in decreased growth and adhesion and increased apoptosis only in Npm1(cA/+);Smc3(Δ/+) AML. Higher Rac activity was also observed in Npm1(cA/+);Smc3(Δ/+) vs. Npm1(cA/+) AMLs. Importantly, the Dock1/Rac pathway is targetable in Npm1(cA/+);Smc3(Δ/+) 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.

Introduction: Prior data suggest associations between hearing loss, cardiovascular (CV) risk factors, and CV disease. Whether specific hearing loss patterns, including a strial pattern associated with inner ear vascular disease, are associated with systemic endothelial dysfunction and carotid intima–media thickness (IMT) remains unclear. Methods: We evaluated participants without prevalent CVD in the Framingham Offspring Study who underwent formal audiogram testing and brachial and carotid artery ultrasounds. Audiograms were categorized as normal or as belonging to one of four abnormal patterns: cochlear-conductive, low-sloping, sensorineural, or strial. Endothelial function as measured by brachial artery flow-mediated dilation (FMDmm and FMD%). Internal and common intima–media thicknesses (icIMT and ccIMT, respectively) were compared between audiogram patterns. Results: We studied 1672 participants (mean age 59 years, 57.6% women). The prevalence of each hearing pattern was as follows: 43.7% normal; 20.3% cochlear-conductive; 20.3% sensorineural; 7.7% low-sloping; and 8.0% strial. Strial pattern hearing loss was nearly twice as prevalent ( p = 0.001) in those in the highest quartile of ccIMT and nearly 50% higher in those in the highest icIMT quartile ( p = 0.04). There were no statistically significant differences between the prevalence of the strial pattern comparing the lowest quartiles of FMDmm and FMD% with the upper three quartiles. Age- and sex-adjusted linear regression models did not show significant associations between the vascular measures and hearing patterns. Conclusion: Abnormal hearing patterns were not significantly associated with impaired brachial FMD and increased carotid IMT after adjusting for age and sex effects, which may reflect age and sex-related distributional differences based on hearing loss pattern.

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 [Formula: see text] 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.

Russia has over 1.2 million HIV infections and Europe's highest HIV incidence. Although its HIV epidemic is intertwined with high alcohol consumption rates, the interaction between alcohol use and HIV care in Russia is understudied. Five hundred eighty-six HIV-positive persons were recruited using social network methods in St. Petersburg. Fifty-nine percent of males, and 45% of females, drank regularly. Thirty percent of alcohol users reported binge drinking (males: ≥ 5 drinks; females ≥ 4 drinks) in the past week. Alcohol use was associated with lower HIV care engagement and having a detectable viral load. Multivariate analyses showed that any alcohol consumption, number of alcohol drinks consumed, and having a binge drinking day in the past week were associated with male gender, use of illicit drugs, drug injection, smaller social network size, lower social supports, being unmarried, and reporting condomless intercourse with non-main partners. Interventions to improve HIV care in Russia must comprehensively address the use of alcohol and substances that interfere with care engagement.

Aim: To investigate the effect of knee osteoarthritis (OA) compartment location on pain relief following genicular radiofrequency ablation. Materials & methods: A retrospective chart review was performed on 62 patients. Visual analog scale scores at 3 and 6 months post procedure were compared with baseline and between compartment groups. Results: Pain significantly improved for all patients at 3 and 6 months (p

This manuscript investigates sample sizes for interim analyses in group sequential designs. Traditional group sequential designs (GSD) define interim sample sizes in terms of “information fractions”. Then, interim maximum likelihood estimators (MLEs) are used to decide whether to stop [for full text, please go to the a.m. URL], 65th Annual Meeting of the German Association for Medical Informatics, Biometry and Epidemiology (GMDS), Meeting of the Central European Network (CEN: German Region, Austro-Swiss Region and Polish Region) of the International Biometric Society (IBS)

Purpose To examine the foveal avascular zone (FAZ) in patients with congenital achromatopsia (ACHM). Methods Forty-two patients with genetically confirmed ACHM were imaged either with Optovue's AngioVue system or Zeiss's Plex Elite 9000, and the presence or absence of a FAZ was determined. For images where a FAZ was present and could be confidently segmented, FAZ area, circularity index, and roundness were measured and compared with previously published normative values. Structural optical coherence tomography images were acquired to assess the degree of foveal hypoplasia (number and thickness of inner retinal layers present at the fovea). Results A FAZ was present in 31 of 42 patients imaged (74%), although no determination could be made for 11 patients due to poor image quality (26%). The mean ± SD FAZ area for the ACHM retina was 0.281 ± 0.112 mm2, which was not significantly different from the previously published normative values (P = 0.94). However, their FAZs had decreased circularity (P < 0.0001) and decreased roundness (P < 0.0001) compared to the normative cohort. In the patients with ACHM examined here, the FAZ area decreased as the number and thickness of the retained inner retinal layers increased. Conclusions Our data demonstrate that despite the presence of foveal hypoplasia, patients with ACHM can have a FAZ. This is distinct from other conditions associated with foveal hypoplasia, which generally show an absence of the FAZ. In ACHM, FAZ formation does not appear to be sufficient for complete pit formation, contrary to some models of foveal development.

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

The goal of this study is to understand and mitigate the effects of wounds on acute radiation syndrome (ARS) and delayed effects of acute radiation exposure (DEARE), for preparedness against a radiological attack or accident. Combined injuries from concomitant trauma and radiation are likely in these scenarios. Either exacerbation or mitigation of radiation damage by wound trauma has been previously reported in preclinical studies. Female WAG/RijCmcr rats received 13 Gy X-rays, with partial-body shielding of one leg. Within 2 h, irradiated rats and non-irradiated controls were given full-thickness skin wounds with or without lisinopril, started orally 7 days after irradiation. Morbidity, skin wound area, breathing interval and blood urea nitrogen were measured up to 160 days post-irradiation to independently evaluate wound trauma and DEARE. Wounding exacerbated morbidity in irradiated rats between 5 and 14 days post-irradiation (during the ARS phase), and irradiation delayed wound healing. Wounding did not alter delayed morbidities from radiation pneumonitis or nephropathy after 30 days post-irradiation. Lisinopril did not mitigate wound healing, but markedly decreased morbidity during DEARE from 31 through 160 days. The results derived from this unique model of combined injuries suggest different molecular mechanisms of injury and healing of ARS and DEARE after radiation exposure.

Background: Cardiac rehabilitation (CR) is recommended in clinical practice guidelines, but dose prescribed varies highly by country. This study characterized the dose offered in supervised CR programs and alternative models worldwide and their potential correlates. Methods and Results: In this cross-sectional study, an online survey was administered to CR programs globally. Cardiac associations and local champions facilitated program identification. Countries were classified based on region and income categories. Dose was operationalized as program duration×sessions per week. Generalized linear mixed models were performed to assess correlates. Of 203 countries in the world, 111 (54.7%) offered CR; data were collected in 93 (83.8% country response rate; n=1082 surveys, 32.1% program response rate). Globally, supervised CR programs were a median of 24 sessions (n=619, 57.3% programs ≥12 sessions); home-based and community-based programs offered 6 and 20 sessions, respectively. There was significant variation in supervised CR dose by region ( P ≤0.001), with the Americas (median, 36 sessions) offering a significantly greater dose than several other regions; there was also a trend for variation by country income classification. There was no difference in home-based dose by region ( P =0.43) but there was for community-based programs ( P P =0.002 and P P =0.026), proximity to other programs ( P =0.002), and accepting patients with noncardiac indications ( P =0.037). Conclusions: CR programs in many countries may need to increase their dose, which could be supported through physician champions.

The newsvendor problem is a popular inventory management problem in supply chain management and logistics. Solutions to the newsvendor problem determine optimal inventory levels. This model is typically fully determined by a purchase and sale prices and a distribution of random market demand. From a statistical point of view, this problem is often considered as a quantile estimation of a critical fractile which maximizes anticipated profit. The distribution of demand is a random variable and is often estimated on historic data. In an ideal situation, when the probability distribution of the demand is known, one can determine the quantile of a critical fractile minimizing a particular loss function. Since maximum likelihood estimation is asymptotically efficient, under certain regularity assumptions, the maximum likelihood estimators are used for the quantile estimation problem. Then, the Cramer-Rao lower bound determines the lowest possible asymptotic variance. Can one find a quantile estimate with a smaller variance then the Cramer-Rao lower bound? If a relevant additional information is available then the answer is yes. Additional information may be available in different forms. This manuscript considers minimum variance and minimum mean squared error estimation for incorporating additional information for estimating optimal inventory levels. By a more precise assessment of optimal inventory levels, we maximize expected profit, Comment: 6 pages

Because of the complexity of hematopoietic cell transplant trial treatments, informed consent forms are often long and difficult to read. We evaluated a 2-column easy-to-read informed consent (ETRIC) form that incorporates elements of health literacy and readability in participants and centers participating in Blood and Marrow Transplant Clinical Trials Network (BMT CTN) clinical trials. In a randomized study 198 adult patients from 25 centers potentially eligible to participate in 4 BMT CTN interventional trials were randomized to the ETRIC form or a standard consent form for that trial. Both forms were written at no more than an eighth-grade reading level. The primary endpoint was objective comprehension score on the Quality of Informed Consent, part A (QuIC-A) instrument. In a parallel evaluation study, 2 moderators conducted semistructured interviews of 49 investigators, research staff, and institutional review board (IRB) members at 9 BMT CTN trial sites. The mean QuIC-A scores were comparable in 152 patients (77%) assessable for the primary endpoint (ETRIC form, 80.5; standard form, 81.8; P = .37). In regression analysis there was no significant association between the consent type and QuIC-A score. In the evaluation study dominant themes identified on qualitative analyses included general comfort and willingness to use the ETRIC template and that its formatting and layout enhancements would offer additional value to research participants, investigators, and IRBs. IRB language preferences and requirements, length, and prior experience with alternative consent formats were perceived as barriers. Among patients considering participation in BMT CTN clinical trials, the formatting enhancements of the ETRIC form did not alter comprehension of the trial. Despite local challenges to implementation, trial sites generally viewed the ETRIC form favorably and expressed willingness to use it over standard consent form.

Study Design Prospective. Objectives The purpose of this study was to compare gait among patients with scoliosis undergoing posterior spinal fusion and instrumentation (PSFI) to typically developing subjects and determine if the location of the lowest instrumented vertebra impacted results. Summary of Background Data PSFI is the standard of care for correcting spine deformities, allowing the preservation of body equilibrium while maintaining as many mobile spinal segments as possible. The effect of surgery on joint motion distal to the spine must also be considered. Very few studies have addressed the effect of PSFI on activities such as walking and even fewer address how surgical choice of the lowest instrumented vertebra (LIV) influences possible motion reduction. Methods Individuals with scoliosis undergoing PSFI (n = 38) completed gait analysis preoperatively and at postoperative years 1 and 2 along with a control group (n = 24). Comparisons were made with the control group at each time point and between patients fused at L2 and above (L2+) versus L3 and below (L3–). Results The kinematic results of the AIS group showed some differences when compared to the Control Group, most notably decreased range of motion (ROM) in pelvic tilt and trunk lateral bending. When comparing the LIV groups, only minor differences were observed, and the results showed decreased coronal trunk and pelvis ROM at the one-year visit and decreased hip rotation ROM at the two-year visit in the L3– group. Conclusions Patients with AIS showed decreased ROM preoperatively with further decreases postoperatively. These changes remained relatively consistent following the two-year visit, indicating that most kinematic changes occurred in the first year following surgery. Limited functional differences between the two LIV groups may be due to the lack of full ROM used during normal gait, and future work could address tasks that use greater ROM. Level of Evidence Level II.

Context: Patellofemoral pain (PFP) is a common injury that interferes with quality of life and physical activity. Clinical subgroups of patients may exist, one of which is caused by proximal muscle dysfunction. Objectives: To develop clinical prediction rules that predict a positive outcome after either a hip and core- or knee-focused strengthening program for individuals with PFP. Design: Secondary analysis of data from a randomized control trial. Setting: Four university laboratories. Patients or Other Participants: A total of 199 participants with PFP. Intervention(s): Participants were randomly allocated to either a hip and core-focused (n = 111) or knee-focused (n = 88) rehabilitation group for a 6-week program. Main Outcome Measure(s): Demographics, self-reported knee pain (visual analog scale) and function (Anterior Knee Pain Scale), hip strength, abdominal muscle endurance, and hip range of motion were evaluated at baseline. Treatment success was defined as a decrease in visual analog scale score by ≥2 cm or an increase in the Anterior Knee Pain Scale score by ≥8 points or both. Bivariate relationships between the outcome (treatment success) and the predictor variables were explored, followed by a forward stepwise logistic regression to predict a successful outcome. Results: Patients with more pain, better function, greater lateral core endurance, and less anterior core endurance were more likely to have a successful outcome after hip and core strengthening (88% sensitivity and 54% specificity). Patients with lower weight, weaker hip internal rotation, stronger hip extension, and greater trunk-extension endurance were more likely to have success after knee strengthening (82% sensitivity and 58% specificity). Conclusion: The patients with PFP who have more baseline pain and yet maintain a high level of function may experience additional benefit from hip and core strengthening. The clinical prediction rules from this study remain in the developmental phase and should be applied with caution until externally validated.

Acute myeloid leukemia (AML) is an aggressive malignancy of the blood and bone marrow resulting from the accumulation of multiple serially acquired mutations. The mutational complexity of the disease makes AML difficult to treat, contributing to a low 5-year survival rate. A better understanding of how different mutations interact with one another to influence disease characteristics is critical and may result in the development of targeted therapies to improve patient outcome. The most common recurrent somatic mutation in AML affects the gene NPM1 and occurs in 25-30% of patients. This mutation results in the aberrant cytoplasmic localization of the protein and is termed NPM1cA (Falini et al. 2005, Cancer Genome Atlas Research Network 2013). NPM1cA is considered to be a driver of AML, however Npm1 cA/+ mice only develop disease after a long latency (median 18 months), suggesting that other cooperating mutations are required for AML development (Vassiliou et al. 2011). Approximately 50% of patients with an NPM1cA mutation also harbor a mutation in one of four members of the cohesin complex (STAG2, SMC3, SMC1A, and RAD21). Mutations in cohesin genes are mutually exclusive and result in haploinsufficiency of the complex. As cohesin is known to regulate gene expression by facilitating promoter-enhancer interactions and three-dimensional genome organization, we wished to determine how cohesin mutation influences AML biology and gene expression in the presence of NPM1cA. We utilized the inducible Npm1 cAflox/+ and Smc3 flox/+ mouse models to examine this genetic interaction. We and others have shown that cohesin mutations result in enhanced hematopoietic stem and progenitor cell (HSPC) self-renewal (Mazumdar et al. 2015, Viny et al. 2015, Mullenders et al. 2015, Galeev et al. 2016, Fisher et al. 2017). Consistent with this, Npm1 cA/+;Smc3 Δ/+ HSPCs show enhanced self-renewal in vitro over HSPCs harboring either single mutation. Despite a shared role in self-renewal, Npm1 cA/+;Smc3 Δ/+mice developed AML with similar latency as Npm1 cA/+ mice. Interestingly, however, Npm1 cA/+;Smc3 Δ/+ HSPCs exhibited dysregulation of a unique set of genes compared to cells from either single mutant, suggesting that the Npm1 cA;cohesin mutational combination uniquely alters the transcriptional environment. Further, Npm1 cA/+;Smc3 Δ/+ leukemias had a completely unique spectrum of acquired mutations compared to Npm1 cA/+ leukemias, suggesting that the addition of Smc3 haploinsufficiency to Npm1 cA/+alters AML evolution and that different driver mutations result in the accumulation of very different somatic mutations. Among the uniquely upregulated genes in Npm1 cA/+;Smc3 Δ/+ HSPCs is Dock1, a guanine nucleotide exchange factor (GEF) for Rac1/2. As high Dock1 expression has been associated with low overall and disease-free survival in multiple cohorts of AML patients (Lee et al. 2017, Zhang et al. 2019), we hypothesized that Dock1 would be a novel target for the treatment of Npm1cA; cohesin mut leukemias. Consistent with this hypothesis, We found that knockdown of Dock1 resulted in decreased growth and adhesion and increased apoptosis in an Npm1 cA/+;Smc3 Δ/+leukemic line, but not in an Npm1 cAsingle mutant line. Higher Rac activity was also observed in Npm1 cA/+;Smc3 Δ/+ vs. Npm1 cA/+ leukemic lines. We found that DN Rac2 specifically impacted both the growth and apoptosis of an Npm1 cA/+;Smc3 Δ/+line, suggesting that Dock1 functions primarily through Rac2 to regulate survival. Importantly, the Dock1/Rac pathway is specifically targetable in Npm1 cA/+;Smc3 Δ/+ AMLs in vitro and in vivo, as knockdown of Dock1 resulted in prolonged latency in a Npm1 cA/+;Smc3 Δ/+ transplant model and slowed the growth and enhanced apoptosis of an Npm1 cA/+;Smc3 Δ/+, but not an Npm1 cA/+, leukemic line. Further, small molecule inhibitors of Dock and Rac had similar effects. Our results suggest that Dock1/Rac2 represent unique targets for the treatment of patients harboring the NPM1cA;cohesin mutational combination and provide validity to the concept that combinatorial genetics can uncover novel precision oncology targets. Disclosures Vassiliou: Kymab Ltd: Divested equity in a private or publicly-traded company in the past 24 months; STRM.BIO: Consultancy; Astrazeneca: Consultancy.

Degenerative joint disease (DJD) of the ankle is a debilitating chronic disease associated with severe pain and dysfunction resulting in antalgic gait alteration. Little information is available about segmental foot and ankle motion distribution during gait in ankle osteoarthritis. The aim of the current study was to dynamically characterize segmental foot and ankle kinematics of patients with severe ankle arthrosis requiring total ankle replacement. This was a prospective study involving 36 (19 M, 17 F) adult patients with a clinical diagnosis of ankle arthrosis ("DJD" group) and 36 (23 M, 13 F) healthy subjects ("Control" group). Motion data were collected at 120 Hz using a 3-D motion camera system at self-selected speed along a 6-m walkway and processed using the Milwaukee Foot Model (MFM). The SF-36 Health Survey and Orthopaedic Foot and Ankle Society (AOFAS) ankle-hindfoot scale were administered to evaluate functional levels. Findings include decreases in walking speed, cadence, stride length and swing phase, and reduced outcomes scores (SF-36 and AOFAS). Multisegemental motion in patients with ankle DJD demonstrates significant changes in foot mechanics characterized by altered segment kinematics and significant reduction in dynamic ROM at the tibia, hindfoot, forefoot, and hallux when compared to controls. The results demonstrate decreased temporal-spatial parameters and low outcomes scores indicative of functional limitations. Statement of clinical significance: Altered segment kinematics and reduced overall range of motion demonstrate how a single joint pathology affects kinematic distribution in the other segments of the foot and ankle and alters patients' overall gait. © 2017 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 36:1739-1746, 2018.

Children with severe osteogenesis imperfecta (OI) typically experience numerous fractures and progressive skeletal deformities over their lifetime. Recent studies proposed finite element models to assess fracture risk and guide clinicians in determining appropriate intervention in children with OI, but lack of appropriate material property inputs remains a challenge. This study aimed to characterize macroscopic anisotropic cortical bone material properties and investigate relationships with bone density measures in children with severe OI. Specimens were obtained from tibial or femoral shafts of nine children with severe OI and five controls. The specimens were cut into beams, characterized in bending, and imaged by synchrotron radiation X-ray micro-computed tomography. Longitudinal modulus of elasticity, yield strength, and bending strength were 32-65% lower in the OI group (p

Background Despite significant advances in the prevention and treatment of pediatric trauma, preventable injuries continue to burden the lives of millions of children. To target prevention strategies, it is critical to identify areas with high burdens of pediatric trauma. Therefore, this study analyzed statewide data from the Ohio Trauma Registry from 2007 to 2012 to identify geographical patterns in pediatric injury. Methods Data from the first hospital of care for 16,330 pediatric trauma patients younger than 16 years were analyzed using the disease mapping method adaptive spatial filtering to estimate a series of maps that display age- and sex-adjusted rates of pediatric trauma, severe trauma, and standardized mortality ratios while controlling for population size to create stable estimates throughout the study area. The locations of all trauma centers were mapped to highlight access to trauma care. Results Areas with significantly higher than expected rates of severe injury were identified in nonurban areas, where children lacked timely access to a pediatric trauma center or Level I adult trauma center. Although highest standardized mortality ratios were in urban areas, nonurban areas experienced elevated mortality with rates over four times higher than expected. Conclusion Areas with higher than expected age- and sex-adjusted rates of severe injury and mortality should be further explored to identify opportunities for injury prevention and appropriate access to timely care. Level of evidence Epidemiologic study, level III.

This study examined the association between Latino acculturation indicators (language and citizenship/nativity status) and periodontitis using data from the National Health and Nutrition Examination Survey (NHANES) 2009-2012. Descriptive statistics and logistic regression analyses were performed and all analyses were adjusted for the complex survey design. Results showed that 63.2% of participants had periodontitis: 9.4% mild, 37.9% moderate, and 16% severe. Language was significantly associated with periodontitis after adjusting for age, educational level, gender, usual source of care, flossing, smoking, and glycohemoglobin level (P = .02). Dental public and private health efforts should implement culturally tailored oral health promotion education efforts for this population.

Introduction: ES after autoHCT encompasses a continuum of peri-engraftment complications characterized by non-infectious fever, rash, diarrhea, and capillary leak features. ES is an increasingly recognized complication after autoHCT in MM, with the varying incidence reported, based on the diagnostic criteria used. ES is typically mild and self-limited in most patients, while a subset can develop severe complications. In this study, we explored whether the use of budesonide prophylaxis reduces ES rates in MM patients undergoing autoHCT. Methods: All patients who underwent autoHCT for MM from 12/2017 to 11/2019 were included after IRB approval at our institution. Beginning on 12/15/2018, as a quality improvement institutional initiative to reduce ES, budesonide 3 mg orally three times a day was initiated at day +5 post autoHCT and continued until the time of discharge. In patients developing ES, systemic steroids were started, and budesonide was discontinued. The efficacy of the intervention was compared with patients who did not receive prophylaxis prior to the study period. ES was defined according to the previously published criteria [T R Spitzer BMT 50, 469-475(2015)]. Patient demographics, disease, and treatment outcomes between the 2 groups were compared using Mann-Whitney and Chi-squared tests when appropriate. The primary outcome was the ES rates between the 2 groups. Multiple logistic regression was used to model ES rates with other predictors, including budesonide prophylaxis as the main effect. Length of stay (LOS) and 30-day readmission were the secondary endpoints. Results: Table 1 shows the patient-, disease- and treatment characteristics between no prophylaxis (N=148) and prophylaxis (N=109) groups. The two groups were well matched overall except for induction therapy and Karnofsky performance status (KPS). The rates of ES were significantly higher in the no prophylaxis group vs. prophylaxis group [69 (75%) vs. 23 (25%); p On adjusted analysis, budesonide prophylaxis was associated with a significantly lower risk of developing ES compared to no prophylaxis groups [Odds ratio, OR 0.30 (95%CI: 0.17-0.53); p Conclusion: Our study concludes that the use of budesonide prophylaxis significantly reduces the risk of ES in MM patients undergoing autoHCT. Future large-scale randomized studies are needed to confirm these findings in patients undergoing autoHCT for MM and other diseases. Disclosures Dhakal: Celgene: Consultancy, Honoraria; Takeda: Consultancy, Other: Advisory Board; Sanofi: Research Funding; Amgen: Consultancy, Other: AdvIsory Board, Research Funding; Janssen: Consultancy, Other: Advisory Board, Research Funding; GSK: Consultancy, Research Funding, Speakers Bureau.

Consider an experiment in which the primary objective is to determine the significance of a treatment effect at a predetermined type I error and statistical power. Assume that the sample size required to maintain these type I error and power will be re-estimated at an interim analysis. A secondary objective is to estimate the treatment effect. Our main finding is that the asymptotic distributions of standardized statistics are random mixtures of distributions, which are non-normal except under certain model choices for sample size re-estimation (SSR). Monte-Carlo simulation studies and an illustrative example highlight the fact that asymptotic distributions of estimators with SSR may differ from the asymptotic distribution of the same estimators without SSR.

OBJECTIVEThis study aimed to assess the safety and efficacy of MR-guided stereotactic laser ablation (SLA) therapy in the treatment of pediatric brain tumors.METHODSData from 17 North American centers were retrospectively reviewed. Clinical, technical, and radiographic data for pediatric patients treated with SLA for a diagnosis of brain tumor from 2008 to 2016 were collected and analyzed.RESULTSA total of 86 patients (mean age 12.2 ± 4.5 years) with 76 low-grade (I or II) and 10 high-grade (III or IV) tumors were included. Tumor location included lobar (38.4%), deep (45.3%), and cerebellar (16.3%) compartments. The mean follow-up time was 24 months (median 18 months, range 3–72 months). At the last follow-up, the volume of SLA-treated tumors had decreased in 80.6% of patients with follow-up data. Patients with high-grade tumors were more likely to have an unchanged or larger tumor size after SLA treatment than those with low-grade tumors (OR 7.49, p = 0.0364). Subsequent surgery and adjuvant treatment were not required after SLA treatment in 90.4% and 86.7% of patients, respectively. Patients with high-grade tumors were more likely to receive subsequent surgery (OR 2.25, p = 0.4957) and adjuvant treatment (OR 3.77, p = 0.1711) after SLA therapy, without reaching significance. A total of 29 acute complications in 23 patients were reported and included malpositioned catheters (n = 3), intracranial hemorrhages (n = 2), transient neurological deficits (n = 11), permanent neurological deficits (n = 5), symptomatic perilesional edema (n = 2), hydrocephalus (n = 4), and death (n = 2). On long-term follow-up, 3 patients were reported to have worsened neuropsychological test results. Pre-SLA tumor volume, tumor location, number of laser trajectories, and number of lesions created did not result in a significantly increased risk of complications; however, the odds of complications increased by 14% (OR 1.14, p = 0.0159) with every 1-cm3 increase in the volume of the lesion created.CONCLUSIONSSLA is an effective, minimally invasive treatment option for pediatric brain tumors, although it is not without risks. Limiting the volume of the generated thermal lesion may help decrease the incidence of complications.

INTRODUCTION AND OBJECTIVES:Urinary retention is a significant adverse event after surgery which predisposes patients to increased hospital stay and avoidable returns to the Emergency Department. T...

Objective: The retina is an extension of the central nervous system (CNS), and ocular symptoms can precede manifestations of CNS disorders. Given that several neurodegenerative conditions that affect the brain exhibit ocular symptoms, the retina may be an accessible biomarker to monitor disease progression. Dopamine, the key neurotransmitter related to Parkinson’s disease (PD), is contained in amacrine and interplexiform cells, which reside in specific retinal layers. Understanding how loss of dopaminergic cells affects retinal anatomy could be relevant for monitoring disease progression. Here, our objective is to evaluate retinal structure (foveal pit morphology and thickness) in patients with PD. Methods: Thirty-three Caucasian subjects diagnosed with PD and 40 age-matched Caucasian control subjects underwent retinal imaging with spectral-domain optical coherence tomography (SD-OCT). Axial length measurements were used to correct the lateral scale of each macular volume scan. From these corrected volumes, foveal morphology was quantified with previously described algorithms, and Early Treatment Diabetic Retinopathy Study (ETDRS) grids of retinal thickness were generated and incorporated into a logistic regression model to predict PD. Results: Interocular foveal morphology measurements were highly symmetrical in PD patients and control subjects. There were no significant differences in foveal pit morphology between PD patients and control subjects. Using a model incorporating gender and axial-length corrected ETDRS regions; we generated a receiver operating characteristic curve with a c-statistic of 0.80. Conclusion: Our study, which to our knowledge is the first to properly scale OCT measurements when quantifying retinal thickness, demonstrates that PD patients retain foveal symmetry between eyes. When constructing a model to predict PD, gender, along with the center 1mm and temporal outer ETDRS regions, were significant predictors of PD. In addition to proper scaling of OCT measures, gender and racial differences in retinal anatomy should be considered in building future predictive PD models when using OCT.

Purpose To evaluate how metrics used to describe the cone mosaic change in response to simulated photoreceptor undersampling (i.e., cell loss or misidentification). Methods Using an adaptive optics ophthalmoscope, we acquired images of the cone mosaic from the center of fixation to 10° along the temporal, superior, inferior, and nasal meridians in 20 healthy subjects. Regions of interest (n = 1780) were extracted at regular intervals along each meridian. Cone mosaic geometry was assessed using a variety of metrics - density, density recovery profile distance (DRPD), nearest neighbor distance (NND), intercell distance (ICD), farthest neighbor distance (FND), percentage of six-sided Voronoi cells, nearest neighbor regularity (NNR), number of neighbors regularity (NoNR), and Voronoi cell area regularity (VCAR). The "performance" of each metric was evaluated by determining the level of simulated loss necessary to obtain 80% statistical power. Results Of the metrics assessed, NND and DRPD were the least sensitive to undersampling, classifying mosaics that lost 50% of their coordinates as indistinguishable from normal. The NoNR was the most sensitive, detecting a significant deviation from normal with only a 10% cell loss. Conclusions The robustness of cone spacing metrics makes them unsuitable for reliably detecting small deviations from normal or for tracking small changes in the mosaic over time. In contrast, regularity metrics are more sensitive to diffuse loss and, therefore, better suited for detecting such changes, provided the fraction of misidentified cells is minimal. Combining metrics with a variety of sensitivities may provide a more complete picture of the integrity of the photoreceptor mosaic.

Elucidating quantitative associations between antibiotic exposure and antibiotic resistance development is important. In the absence of randomized trials, observational studies are the next best alternative to derive such estimates. Yet, as antibiotics are prescribed for varying time periods, antibiotics constitute time-dependent exposures. Cox regression models are suited for determining such associations. After explaining the concepts of hazard, hazard ratio, and proportional hazards, the effects of treating antibiotic exposure as fixed or time-dependent variables are illustrated and discussed. Wider acceptance of these techniques will improve quantification of the effects of antibiotics on antibiotic resistance development and provide better evidence for guideline recommendations.

Directional optical coherence tomography (D-OCT) allows the visualization of the Henle fiber layer (HFL) in vivo. Here, we used D-OCT to characterize the HFL and outer nuclear layer (ONL) in albinism and examine the relationship between true foveal ONL and peak cone density.Horizontal D-OCT B-scans were acquired, registered, and averaged for 12 subjects with oculocutaneous albinism and 26 control subjects. Averaged images were manually segmented to extract HFL and ONL thickness. Adaptive optics scanning light ophthalmoscopy was used to acquire images of the foveal cone mosaic in 10 subjects with albinism, from which peak cone density was assessed.Across the foveal region, the HFL topography was different between subjects with albinism and normal controls. In particular, foveal HFL thickness was thicker in albinism than in normal controls (P0.0001), whereas foveal ONL thickness was thinner in albinism than in normal controls (P0.0001). The total HFL and ONL thickness was not significantly different between albinism and controls (P = 0.3169). Foveal ONL thickness was positively correlated with peak cone density in subjects with albinism (r = 0.8061, P = 0.0072).Foveal HFL and ONL topography are significantly altered in albinism relative to normal controls. Our data suggest that increased foveal cone packing drives the formation of Henle fibers, more so than the lateral displacement of inner retinal neurons (which is reduced in albinism). The ability to quantify foveal ONL and HFL may help further stratify grading schemes used to assess foveal hypoplasia.

This article examines the effects of a multi-level, community-based HIV prevention intervention for crack users residing in low-income neighborhoods in San Salvador, El Salvador conducted between August 2011 and June 2016. The intervention consisted of three components introduced sequentially: 1) rapid HIV testing in community settings; 2) a Social Network HIV testing intervention; and 3) Small Group interventions with crack users who were members of the same social network. The intervention was evaluated with an interrupted time series design in which we used respondent-driven sampling to conduct 7 cross-sectional surveys with crack users along a 3–4 month period for each assessment (total n=1597). Results revealed a significant increase in exposure to the intervention over time with 50% of the participants reporting exposure to one or more of the three components. Getting an HIV test at the community site was associated with reductions in total times each individual had sex without a condom (p