Handling misclassified stratification variables in the analysis of randomised trials with continuous outcomes

Many trials use stratified randomisation, where participants are randomised within strata defined by one or more baseline covariates. While it is important to adjust for stratification variables in the analysis, the appropriate method of adjustment is unclear when stratification variables are affected by misclassification and hence some participants are randomised in the incorrect stratum. We conducted a simulation study to compare methods of adjusting for stratification variables affected by misclassification in the analysis of continuous outcomes when all or only some stratification errors are discovered, and when the treatment effect or treatment-by-covariate interaction effect is of interest. The data were analysed using linear regression with no adjustment, adjustment for the strata used to perform the randomisation (randomisation strata), adjustment for the strata if all errors are corrected (true strata), and adjustment for the strata after some errors are discovered and corrected (updated strata). The unadjusted model performed poorly in all settings. Adjusting for the true strata was optimal, while the relative performance of adjusting for the randomisation strata or the updated strata varied depending on the setting. As the true strata are unlikely to be known with certainty in practice, we recommend using the updated strata for adjustment and performing subgroup analyses, provided the discovery of errors is unlikely to depend on treatment group, as expected in blinded trials. Greater transparency is needed in the reporting of stratification errors and how they were addressed in the analysis

Market Assessment for Capturing Water Conservation Opportunities in the Federal Sector

The Department of Energy's Federal Energy Management Program (FEMP) is considering the development of a technology-specific Super-Energy Saving Performance Contract (ESPC) for water conservation. Prior to the development however, FEMP requires the completion of a market assessment to better understand the water conservation opportunities and the strategies available for capturing them. Thus, this market assessment has been undertaken to evaluate the water conservation opportunities and answer the key questions necessary for FEMP to make recommendations on whether or not to proceed with strategies for water conservation primarily through the development of a water conservation technology-specific performance contract

Protocol for the Locomotor Experience Applied Post-stroke (LEAPS) trial: a randomized controlled trial

<p>Abstract</p> <p>Background</p> <p>Locomotor training using body weight support and a treadmill as a therapeutic modality for rehabilitation of walking post-stroke is being rapidly adopted into clinical practice. There is an urgent need for a well-designed trial to determine the effectiveness of this intervention.</p> <p>The objective of the Locomotor Experience Applied Post-Stroke (LEAPS) trial is to determine if there is a difference in the proportion of participants who recover walking ability at one year post-stroke when randomized to a specialized locomotor training program (LTP), conducted at 2- or 6-months post-stroke, or those randomized to a home based non-specific, low intensity exercise intervention (HEP) provided 2 months post-stroke. We will determine if the timing of LTP delivery affects gait speed at 1 year and whether initial impairment severity interacts with the timing of LTP. The effect of number of treatment sessions will be determined by changes in gait speed taken pre-treatment and post-12, -24, and -36 sessions.</p> <p>Methods/Design</p> <p>We will recruit 400 adults with moderate or severe walking limitations within 30 days of stroke onset. At two months post stroke, participants are stratified by locomotor impairment severity as determined by overground walking speed and randomly assigned to one of three groups: (a) LTP-Early; (b) LTP-Late or (c) Home Exercise Program -Early. The LTP program includes body weight support on a treadmill and overground training. The LTP and HEP interventions are delivered for 36 sessions over 12 weeks.</p> <p>Primary outcome measure include successful walking recovery defined as the achievement of a 0.4 m/s gait speed or greater by persons with initial severe gait impairment or the achievement of a 0.8 m/s gait speed or greater by persons with initial moderate gait impairment.</p> <p>LEAPS is powered to detect a 20% difference in the proportion of participants achieving successful locomotor recovery between the LTP groups and the HEP group, and a 0.1 m/s mean difference in gait speed change between the two LTP groups.</p> <p>Discussion</p> <p>The goal of this single-blinded, phase III randomized clinical trial is to provide evidence to guide post-stroke walking recovery programs.</p> <p>Trial registration</p> <p>NCT00243919.</p

Pharmacokinetics of Clindamycin in Obese and Nonobese Children

ABSTRACT Although obesity is prevalent among children in the United States, pharmacokinetic (PK) data for obese children are limited. Clindamycin is a commonly used antibiotic that may require dose adjustment in obese children due to its lipophilic properties. We performed a clindamycin population PK analysis using data from three separate trials. A total of 420 samples from 220 children, 76 of whom had a body mass index greater than or equal to the 95th percentile for age, were included in the analysis. Compared to other metrics, total body weight (TBW) was the most robust measure of body size. The final model included TBW and a sigmoidal maturation relationship between postmenstrual age (PMA) and clearance (CL): CL (liters/hour) = 13.8 × (TBW/70) 0.75 × [PMA 2.83 /(39.5 2.83 +PMA 2.83 )]; volume of distribution ( V ) was associated with TBW, albumin (ALB), and alpha-1 acid glycoprotein (AAG): V (liters) = 63.6 × (TBW/70) × (ALB/3.3) −0.83 × (AAG/2.4) −0.25 . After accounting for differences in TBW, obesity status did not explain additional interindividual variability in model parameters. Our findings support TBW-based dosing for obese and nonobese children

The Grizzly, October 13, 1989

Berman Opening Draws Near • Sculptor Chadwick Visits UC • Frats Angered • Letters: Grizzly, Get on the Ball!; Shape up!; Dump Starkist! • Michener Opens Museum • Swarthmore, Hopkins Defeated • V-Ball Wins • Hockey Squad Beats Nationally Ranked Teams • 1989 Candidates for Homecoming Queen • Soccer Looks to Future • Wagner Runs Wild • Athletes of the Week • Control Pledging Power Abuses • The Wismer Beastieshttps://digitalcommons.ursinus.edu/grizzlynews/1243/thumbnail.jp

Association of Maternal Perinatal SARS-CoV-2 Infection With Neonatal Outcomes During the COVID-19 Pandemic in Massachusetts

Importance: The incidence of mother-to-newborn SARS-CoV-2 transmission appears low and may be associated with biological and social factors. However, data are limited on the factors associated with neonatal clinical or viral testing outcomes. Objective: To ascertain the percentage of neonates who were born to mothers with positive SARS-CoV-2 test results during the birth hospitalization, the clinical and sociodemographic factors associated with neonatal test result positivity, and the clinical and virological outcomes for newborns during hospitalization and 30 days after discharge. Design, Setting, and Participants: This multicenter cohort study included 11 academic or community hospitals in Massachusetts and mother-neonate dyads whose delivery and discharge occurred between March 1, 2020, and July 31, 2020. Eligible dyads were identified at each participating hospital through local COVID-19 surveillance and infection control systems. Neonates were born to mothers with positive SARS-CoV-2 test results within 14 days before to 72 hours after delivery, and neonates were followed up for 30 days after birth hospital discharge. Exposures: Hypothesized maternal risk factors in neonatal test result positivity included maternal COVID-19 symptoms, vaginal delivery, rooming-in practice, Black race or Hispanic ethnicity, and zip code-derived social vulnerability index. Delivery indicated by worsening maternal COVID-19 symptoms was hypothesized to increase the risk of adverse neonatal health outcomes. Main Outcomes and Measures: Primary outcomes for neonates were (1) positive SARS-CoV-2 test results, (2) indicators of adverse health, and (3) clinical signs and viral testing. Test result positivity was defined as at least 1 positive result on a specimen obtained by nasopharyngeal swab using a polymerase chain reaction-based method. Clinical and testing data were obtained from electronic medical records of nonroutine health care visits within 30 days after hospital discharge. Results: The cohort included 255 neonates (mean [SD] gestational age at birth, 37.9 [2.6] weeks; 62 [24.3%] with low birth weight or preterm delivery) with 250 mothers (mean [SD] age, 30.4 [6.3] years; 121 [48.4%] were of Hispanic ethnicity). Of the 255 neonates who were born to mothers with SARS-CoV-2 infection, 225 (88.2%) were tested for SARS-CoV-2 and 5 (2.2%) had positive results during the birth hospitalization. High maternal social vulnerability was associated with higher likelihood of neonatal test result positivity (adjusted odds ratio, 4.95; 95% CI, 1.53-16.01; P = .008), adjusted for maternal COVID-19 symptoms, delivery mode, and rooming-in practice. Adverse outcomes during hospitalization were associated with preterm delivery indicated by worsening maternal COVID-19 symptoms. Of the 151 newborns with follow-up data, 28 had nonroutine clinical visits, 7 underwent SARS-CoV-2 testing, and 1 had a positive result. Conclusions and Relevance: The findings emphasize the importance of both biological and social factors in perinatal SARS-CoV-2 infection outcomes. Newborns exposed to SARS-CoV-2 were at risk for both direct and indirect adverse health outcomes, supporting efforts of ongoing surveillance of the virus and long-term follow-up

The Grizzly, September 8, 1989

Hudson Gets $ Flowing • Earth Day Seed Planted • French Studies Papa\u27s Notes • Lopez Lures Listeners • Kruse Spot to Dawleys House • Presidential Candidates • Victory at GB Classic • Captains Lead Attack • Gros Sets Goals • Quest Continues • V-ball: Ichiban! • Coaches Added • Optimistic Lady Bears Start Season • Beaches No Bumshttps://digitalcommons.ursinus.edu/grizzlynews/1239/thumbnail.jp

Trisomy 21 dysregulates T cell lineages toward an autoimmunity-prone state associated with interferon hyperactivity

Trisomy 21 (T21) causes Down syndrome (DS), a condition characterized by high prevalence of autoimmune disorders. However, the molecular and cellular mechanisms driving this phenotype remain unclear. Building upon our previous finding that T cells from people with DS show increased expression of interferon (IFN)stimulated genes, we have completed a comprehensive characterization of the peripheral T cell compartment in adults with DS with and without autoimmune conditions. CD8+ T cells from adults with DS are depleted of naïve subsets and enriched for differentiated subsets, express higher levels of markers of activation and senescence (e.g., IFN-γ, Granzyme B, PD-1, KLRG1), and overproduce cytokines tied to autoimmunity (e.g., TNF-α). Conventional CD4+ T cells display increased differentiation, polarization toward the Th1 and Th1/17 states, and overproduction of the autoimmunity-related cytokines IL-17A and IL-22. Plasma cytokine analysis confirms elevation of multiple autoimmunity-related cytokines (e.g., TNF-α, IL17A–D, IL-22) in people with DS, independent of diagnosis of autoimmunity. Although Tregs are more abundant in DS, functional assays show that CD8+ and CD4+ effector T cells with T21 are resistant to Treg-mediated suppression, regardless of Treg karyotype. Transcriptome analysis of white blood cells and T cells reveals strong signatures of T cell differentiation and activation that correlate positively with IFN hyperactivity. Finally, mass cytometry analysis of 8 IFN-inducible phosphoepitopes demonstrates that T cell subsets with T21 show elevated levels of basal IFN signaling and hypersensitivity to IFN-α stimulation. Therefore, these results point to T cell dysregulation associated with IFN hyperactivity as a contributor to autoimmunity in DS.Fil: Araya, Paula. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Córdoba. Centro de Investigaciones en Bioquímica Clínica e Inmunología; ArgentinaFil: Waugh, Katherine A.. University Of Colorado. School Of Medicine.; Estados UnidosFil: Sullivan, Kelly D.. University Of Colorado. School Of Medicine.; Estados UnidosFil: Núñez, Nicolás. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Córdoba. Centro de Investigaciones en Bioquímica Clínica e Inmunología; ArgentinaFil: Roselli, Emiliano. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Córdoba. Centro de Investigaciones en Bioquímica Clínica e Inmunología; ArgentinaFil: Smith, Keith P.. University Of Colorado. School Of Medicine.; Estados UnidosFil: Granrath, Ross E.. University Of Colorado. School Of Medicine.; Estados UnidosFil: Rachubinski, Angela L.. University of Colorado; Estados UnidosFil: Enriquez Estrada, Belinda. University Of Colorado. School Of Medicine.; Estados UnidosFil: Butcher, Eric T.. University of Colorado; Estados UnidosFil: Minter, Ross. University of Colorado; Estados UnidosFil: Tuttle, Kathryn D.. University of Colorado; Estados UnidosFil: Bruno, Tullia C.. University Of Colorado. School Of Medicine.; Estados UnidosFil: Maccioni, Mariana. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Córdoba. Centro de Investigaciones en Bioquímica Clínica e Inmunología; ArgentinaFil: Espinosa, Joaquín M.. University Of Colorado. School Of Medicine.; Estados Unido

Improving palliative care outcomes for Aboriginal Australians: Service providers' perspectives

Background: Aboriginal Australians have a lower rate of utilisation of palliative care services than the general population. This study aimed to explore care providers’ experiences and concerns in providing palliative care for Aboriginal people, and to identify opportunities for overcoming gaps in understanding between them and their Aboriginal patients and families. Methods: In-depth, qualitative interviews with urban, rural and remote palliative care providers were undertaken in inpatient and community settings in Western Australia. Interviews were audio-recorded, transcribed verbatim and coded independently by two researchers with QSR NVivo 10 software used to help manage data. Data analysis was informed by multiple theoretical standpoints, including the social ecological model, critical cultural theories and the ‘cultural security’ framework. Thematic analysis was carried out that identified patterns within data. Results: Fifteen palliative care providers were interviewed. Overall they reported lack of understanding of Aboriginal culture and being uncertain of the needs and priorities of Aboriginal people during end-of-life care. According to several participants, very few Aboriginal people had an understanding of palliative care. Managing issues such as anger, denial, the need for non-medical support due to socioeconomic disadvantage, and dealing with crises and conflicts over funeral arrangements were reported as some of the tensions between Aboriginal patients and families and the service providers.Conclusion: Early referral to palliative care is important in demonstrating and maintaining a caring therapeutic relationship. Paramount to meeting the needs for Aboriginal patients was access to appropriate information and logistical, psychological and emotional support. These were often seen as essential but additional to standard palliative care services. The broader context of Aboriginal history and historical distrust of mainstream services was seen to impinge on Aboriginal people’s willingness and ability to accept care and support from these services. This context needs to be understood and acknowledged at the system level. More cultural safety training was requested by care providers but it was not seen as replacing the need for an Aboriginal worker in the palliative care team

Cooperation between CYB5R3 and NOX4 via coenzyme Q mitigates endothelial inflammation

NADPH oxidase 4 (NOX4) regulates endothelial inflammation by producing hydrogen peroxide (H2O2) and to a lesser extent O2•-. The ratio of NOX4-derived H2O2 and O2•- can be altered by coenzyme Q (CoQ) mimics. Therefore, we hypothesize that cytochrome b5 reductase 3 (CYB5R3), a CoQ reductase abundant in vascular endothelial cells, regulates inflammatory activation. To examine endothelial CYB5R3 in vivo, we created tamoxifen-inducible endothelium-specific Cyb5r3 knockout mice (R3 KO). Radiotelemetry measurements of systolic blood pressure showed systemic hypotension in lipopolysaccharides (LPS) challenged mice, which was exacerbated in R3 KO mice. Meanwhile, LPS treatment caused greater endothelial dysfunction in R3 KO mice, evaluated by acetylcholine-induced vasodilation in the isolated aorta, accompanied by elevated mRNA expression of vascular adhesion molecule 1 (Vcam-1). Similarly, in cultured human aortic endothelial cells (HAEC), LPS and tumor necrosis factor α (TNF-α) induced VCAM-1 protein expression was enhanced by Cyb5r3 siRNA, which was ablated by silencing the Nox4 gene simultaneously. Moreover, super-resolution confocal microscopy indicated mitochondrial co-localization of CYB5R3 and NOX4 in HAECs. APEX2-based electron microscopy and proximity biotinylation also demonstrated CYB5R3's localization on the mitochondrial outer membrane and its interaction with NOX4, which was further confirmed by the proximity ligation assay. Notably, Cyb5r3 knockdown HAECs showed less total H2O2 but more mitochondrial O2•-. Using inactive or non-membrane bound active CYB5R3, we found that CYB5R3 activity and membrane translocation are needed for optimal generation of H2O2 by NOX4. Lastly, cells lacking the CoQ synthesizing enzyme COQ6 showed decreased NOX4-derived H2O2, indicating a requirement for endogenous CoQ in NOX4 activity. In conclusion, CYB5R3 mitigates endothelial inflammatory activation by assisting in NOX4-dependent H2O2 generation via CoQ.This work was supported by National Institutes of Health (NIH) R01 awards [R01 HL 133864 (A.C.S), R01 HL 128304 (A.C.S), R01 HL 149825 (A.C.S), R01 HL 153532 (A.C.S), R01 GM 125944 (F.J.S.), R01 DK 112854 (F.J.S.), 1S10OD021540-01 (Center for Biologic Imaging, University of Pittsburgh), 1S10RR019003-01 (Simon Watkins (S.W.)), 1S10RR025488-01 (S.W.), 1S10RR016236-01 (S.W)]. American Heart Association (AHA) [Established Investigator Award 19EIA34770095 (A.C.S.)], Post-doctoral Fellowship 19POST34410028 (S.Y.)]. American Society of Hematology (ASH) Minority Hematology Graduate Award (A.M.D-O.). Junta de Andalucía grant BIO-177 (P.N.), the FEDER Funding Program from the European Union and Spanish Ministry of Science, Innovation and Universities grant RED2018-102576-T (P.N.)