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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.

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.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.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.

To characterize the degree to which individual coping strategies may influence speech perception after cochlear implantation.Retrospective cohort study.Tertiary referral center.Adult, postlingually deaf cochlear implant recipients.The Coping Orientation to Problems Experience inventory, a validated, multidimensional self-reported coping scale, was administered preoperatively.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.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; p0.01). Denial was associated with a decreased AzBio in quiet score (b = -0.05; 95% CI, -0.09 to -0.01; p0.05), whereas humor was associated with an increased AzBio in quiet score (b = 0.02; 95% CI, 0.01 to 0.04; p0.05). Humor was also associated with an increased Hearing in Noise Test score (b = 0.05; 95% CI, 0.02 to 0.07; p0.05). Denial was associated with decreased CNC word (b = -0.04; 95% CI, -0.06 to -0.02; p0.01) and phoneme (b = -0.04; 95% CI, -0.07 to -0.02; p0.01) scores, whereas substance use was associated with increased CNC word (b = 0.03; 95% CI, 0.01 to 0.05, p0.01) and phoneme (b = 0.04; 95% CI, 0.02 to 0.06; p0.01) scores. Scores on self-reported quality of life measures were not significantly correlated with coping strategies.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.

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.

Engraftment syndrome (ES) after autologous hematopoietic cell transplantation (AHCT) in multiple myeloma (MM) encompasses a continuum of periengraftment complications characterized by noninfectious fever, rash, diarrhea, and capillary leak features.We analyzed the ES outcomes in 257 consecutive patients MM patients who underwent AHCT at our institution from 12/2017 to 11/2019 with budesonide prophylaxis (3 mg PO daily at day +5 post-AHCT till the time of discharge) (N = 109) and no prophylaxis (N = 148).The rates of ES were significantly higher in the no prophylaxis group versus prophylaxis group [69 (46%) vs. 23 (21%); P.001]. There was no significant difference in length of stay (LOS) [mean 15 (±3.2) vs. 16 (±2.8); P = .27] and 30-day readmission [9 (6%) vs. 8 (7%); P = .81] between the no prophylaxis and prophylaxis groups, respectively. On adjusted analysis, budesonide prophylaxis was associated with a significantly lower risk of developing ES [odds ratio (OR) 0.29 (95% confidence interval [CI], 0.16-0.51); P.0001]. There was no difference in the 30-day readmission rates [OR 1.12 (95% CI, 0.41-3.03); P = .81], but a trend for shorter LOS in the prophylaxis group [7.3% reduction in LOS (95% CI, -14.4% to 0%); P = .06].Budesonide prophylaxis significantly reduces the risk of ES in MM patients undergoing AHCT. These promising results suggest the need for a randomized study investigate the role of budesonide for ES prophylaxis.

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

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.

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.

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.

420 Background: Oral Mucositis related pain is one of the most common radiation therapy (RT) related toxicities associated with the treatment of head and neck cancer (HNC). Questionnaire-based assessment of mucositis pain is based on a patient's recall which can be inaccurate sometimes. Therefore, real-time monitoring of patient-reported pain is required for better evaluation of mucositis pain. Methods: We performed a single-arm, observational study (NCT02727062) to investigate the feasibility of a smartphone-based pain app (OMP) in assessing mucositis pain in locally advanced HNC patients(pts) undergoing a course of definitive or adjuvant RT (> 50 Gy), +/- chemotherapy, for oral cavity or oropharynx cancer. The app prompted pts to input pain severity scores using a visual analog (0-10) scale (VAS) at multiple time points during a day throughout the study. OMP software-generated time-weighted average weekly summary measure of pain by integrating multiple serial daily pain assessments. In addition, pts completed weekly Brief pain inventory (BPI) and MD Anderson head & neck symptom inventory (MDASI-HN) questionnaires. Feasibility surveys were also collected to assess the ease of use of OMP and the burden of study participation. Responses to questions on this survey were scored on a scale of 0-3, with 0 standing for not at all and 3 for extremely. Linear mixed models (LMM) controlling for person random effects were used to evaluate association and quantify differences between average weekly pain (AWP) calculated by OMP and AWP recorded using VAS by BPI survey (question 5). LMM was also used to evaluate the association between AWP score from OMP and BPI pain score with MDASI-HN scores. Descriptive statistics, including averages and frequency, were used to analyze feasibility surveys. Results: We report results of 15 pts who have complete data out of 18 registered pts. Using LMM, we compared AWP score curves calculated from BPI and OMP. We observed that both curves followed a parallel trajectory. However, pain scores calculated from OMP were 0.40 units higher than BPI pain. The Bland-Altman plot also confirmed that BPI pain and OMP did not clearly agree. Additionally, AWP scores from OMP had a positive correlation with fatigue (p < 0.001), drowsiness (p < 0.001), decreased activity (p < 0.001), and interference with work (p < 0.001) related scores recorded in MDASI-HN. In terms of feasibility, most surveys indicated that it was extremely easy for subjects to enter responses and not at all difficult for them to use all features of OMP. Furthermore, study participation did not interfere with subjects’ usual activities. Conclusions: Our study showed that pain scores calculated through OMP were, on average higher than those reported by BPI. It also showed the correlation between pain and physical activity. Hence, utilization of OMP in conjunction with questionnaires may improve our understanding of the severity of mucositis-related pain. Clinical trial information: NCT02727062.

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.

OBJECTIVE To examine predictors of prolonged symptom duration from mild traumatic brain injury (mTBI) in a pediatric sports medicine specialty clinic cohort as these predictors may be distinct in this population. DESIGN Retrospective chart review. SETTING Outpatient specialty clinic. PATIENTS Charts of 549 patients (age range: 10-18 years) with concussions were reviewed in an outpatient clinic that predominantly managed sports-related injuries (77.3%). Patients (n = 431) included in the final analysis met the criteria for mTBI and were symptomatic at their first visit. ASSESSMENT OF RISK FACTORS Patient history, injury, and recovery variables were evaluated. MAIN OUTCOME MEASURES Predictors of prolonged time to reach self-reported symptom recovery were evaluated using Cox proportional hazards. RESULTS Median time to symptom recovery of the 431 patients who presented to clinic with symptoms was 40 days (full clinic sample median = 34 days). Analyses identified 3 unique predictors of symptom recovery: loss of consciousness (LOC) [hazard ratio (HR) = 0.56, P < 0.0001], female sex (HR = 0.57, P < 0.0001), and concussion symptom score at first clinic visit (HR = 0.76, P < 0.0001). CONCLUSIONS Prolonged duration of mTBI symptoms in patients who present to a pediatric sports-based concussion clinic is related to initial symptom severity, female sex, and LOC.

Adolescent idiopathic scoliosis (AIS) is a complex condition characterized by a lateral curvature and axial rotational deformity of the spine. Though bracing is effective, a need remains to identify the effect brace type has on spine curvature. To examine differences in patient demographics between the Boston and Providence brace, determine the corrective change in Cobb angle and RVAD and investigate the effect of brace type on curvature over time. A retrospective chart review was conducted of 105 patients diagnosed with AIS from 2013–2016 at CHW. Five spinal parameters were measured: Cobb angle, Risser, RVAD, kyphosis and lordosis. Data was collected before bracing, in-brace and at 24 months. A final treatment outcome of either Cobb angle correction (reduction >5°), stabilization (change ±5°) or progression (deterioration >5°) was then evaluated. Providence brace provided significantly greater in-brace thoracolumbar Cobb angle and RVAD reduction in comparison to the Boston brace (Cobb angle -21.9° vs. -12.5°; RVAD: -1.8° vs. 1.62°). Similarly, Providence users had a significantly smaller increase in Cobb angle and RVAD over time (Cobb angle: thoracic 14.2° vs. 15.0°; thoracolumbar 23.6° vs. 26.0°; RVAD: 5.2° vs. 8.5°). Ultimately, no significant difference in final treatment outcome was established between brace groups. Although the Providence brace provides less of an increase in thoracic and thoracolumbar curvatures over time, both braces are an effective treatment and achieve comparable outcomes. Selection of braces may vary with primary curve angle, curve location, patient compliance and quality of life.

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

Among four sub-patterns of Gleason grade 4 prostate cancer, voluminous evidence supports that the cribriform pattern holds an unfavorable prognostic impact, as compared with poorly-formed, fused, or glomeruloid. The International Society of Urological Pathology (ISUP) recommends specifying whether invasive grade 4 cancer is cribriform. Recently, ISUP experts published a consensus definition of cribriform pattern highlighting criteria that distinguish it from mimickers. The current study aimed to analyze morphologic features separately to identify those that define the essence of the cribriform pattern. Thirty-two selected photomicrographs were classified by 12 urologic pathologists as: definitely cribriform cancer, probably cribriform, unsure, probably not cribriform, or definitely not cribriform. Consensus was defined as 9/12 agree or disagree, with ≤1 strongly supporting the opposite choice. Final consensus was achieved in 21 of 32 cases. Generalized estimating equation (GEE) model with logit link was fitted to estimate effect of multiple morphologic predictors. Fisher exact test was used for categorical findings. Presence of intervening stroma precluded calling cribriform cancer (p = 0.006). Mucin presence detracted (p = 0.003) from willingness to call cribriform cancer (only 3 cases had mucin). Lumen number was associated with cribriform consensus (p = 0.0006), and all consensus cases had ≥9 lumens. Predominant papillary pattern or an irregular outer boundary detracted (p = NS). Invasive cribriform carcinoma should have absence of intervening stroma, and usually neither papillary pattern, irregular outer boundary, nor very few lumens. Setting the criteria for cribriform will help prevent over- or undercalling this important finding.

This manuscript investigates sample sizes for interim analyses in group sequential designs. Traditional group sequential designs (GSD) rely on "information fraction" arguments to define the interim sample sizes. Then, interim maximum likelihood estimators (MLEs) are used to decide whether to stop early or continue the data collection until the next interim analysis. The possibility of early stopping changes the distribution of interim and final MLEs: possible interim decisions on trial stopping excludes some sample space elements. At each interim analysis the distribution of an interim MLE is a mixture of truncated and untruncated distributions. The distributional form of an MLE becomes more and more complicated with each additional interim analysis. Test statistics that are asymptotically normal without a possibly of early stopping, become mixtures of truncated normal distributions under local alternatives. Stage-specific information ratios are equivalent to sample size ratios for independent and identically distributed data. This equivalence is used to justify interim sample sizes in GSDs. Because stage-specific information ratios derived from normally distributed data differ from those derived from non-normally distributed data, the former equivalence is invalid when there is a possibility of early stopping. Tarima and Flournoy [3] have proposed a new GSD where interim sample sizes are determined by a pre-defined sequence of ordered alternative hypotheses, and the calculation of information fractions is not needed. This innovation allows researchers to prescribe interim analyses based on desired power properties. This work compares interim power properties of a classical one-sided three stage Pocock design with a one-sided three stage design driven by three ordered alternatives.

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)

Ankle arthritis is a debilitating disease marked by pain and limited function. Total ankle arthroplasty improves pain while preserving motion and offers an alternative to the traditional treatment of ankle fusion. Gait analysis and functional outcomes tools can provide an objective balanced analysis of ankle replacement for the treatment of ankle arthritis. Twenty-nine patients with end-stage ankle arthritis were evaluated before and after ankle arthroplasty. Multi-segment foot and ankle kinematics were assessed annually following surgery (average 3.5 years, range 1-6 years) using the Milwaukee Foot Model and a Vicon video motion analysis system. Functional outcomes (American Orthopedic Foot and Ankle Society [AOFAS] ankle/hindfoot scale, short form 36 [SF-36] questionnaire) and temporal-spatial parameters were also assessed. Kinematic results were compared to findings from a previously collected group of healthy ambulators. AOFAS and SF-36 mean scores improved postoperatively. Walking speed and stride length increased after surgery. There were significant improvements in tibial sagittal range of motion in terminal stance and hindfoot sagittal range of motion in preswing. Decreased external rotation of the tibia and increased external rotation of the hindfoot were noted throughout the gait cycle. Pain and function improved after ankle replacement as supported by better outcomes scores, increased temporal-spatial parameters, and significant improvement in tibial sagittal range of motion during terminal stance and hindfoot sagittal range of motion during preswing. While multi-segment foot kinematics were improved, they were not restored to control values. Statement of clinical significance: Total ankle arthroplasty does not fully normalize mutli-segment gait kinematics despite improved patient-reported outcomes and gait mechanics.

The International Society of Urological Pathology endorses specifying presence of cribriform architecture in Gleason (G)4 prostate cancer because of cribriform's aggressiveness. The relative effect of cribriform presence versus percentage G4 within grade group (GG)2 or 3 was uncertain. 194 men's biopsies with GG2 with or without cribriform (excluding glomeruloid from cribriform) and GG3 without cribriform (controls) from 4 years were reviewed. 173 cases had follow-up including 147 GG2 (15/147 or 10% had cribriform) and 26 GG3. Effects of total tumor specimen involvement, %Gleason 4, and cribriform were stratified into prostatectomy (n = 90), radiotherapy (n = 61), and watching waiting (n = 22) groups. Median follow-up duration was 3.32 years (range 1.90–6.18). Biochemical failures in the above 3 cohorts numbered 9 (9/90; 10%), 5 (5/61; 8%), and 13 (13/22; 59%) respectively. In all groups, (GG2+ GG3, n = 173), the HR for C pattern was 1.64. In GG2, cribriform presence (considering glomeruloid as non-cribriform) conferred a hazard ratio (HR) of 1.51 (p = 0.48). It was 1.38, excluding glomeruloid. In watchful waiting cohort only, presence of C conferred a HR of 2.62 (p = 0.086). All remaining comparisons including percent G4, remained not significant. Thus, only in WW group did cribriform pattern presence approach significance. Detection of differences otherwise was not feasible, probably because: 1) biochemical failure is too rare in GG2 cancer; 2) cribriform frequency was only 10% in GG2 (in current study), less than in higher-grade cancer. 3) Use of biopsy tissue is subject to sampling variation which may undersample cribriform pattern, though biopsy forms the basis of treatment decisions.

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.