Estimation of vaccine efficacy in a repeated measures study under heterogeneity of exposure or susceptibility to infection

Vaccine efficacy (VE) is commonly estimated through proportional hazards modelling of the time to first infection or disease, even when the event of interest can recur. These methods can result in biased estimates when VE is heterogeneous across levels of exposure and susceptibility in subjects. These two factors are important sources of unmeasured heterogeneity, since they vary within and across areas, and often cannot be individually quantified. We propose an estimator of VE per exposure that accounts for heterogeneous susceptibility and exposure for a repeated measures study with binary recurrent outcomes. The estimator requires only information about the probability distribution of environmental exposures. Through simulation studies, we compare the properties of this estimator with proportional hazards estimation under the heterogeneity of exposure. The methods are applied to a reanalysis of a malaria vaccine trial in Brazil

Relationship between Funding Source and Conclusion among Nutrition-Related Scientific Articles

BACKGROUND: Industrial support of biomedical research may bias scientific conclusions, as demonstrated by recent analyses of pharmaceutical studies. However, this issue has not been systematically examined in the area of nutrition research. The purpose of this study is to characterize financial sponsorship of scientific articles addressing the health effects of three commonly consumed beverages, and to determine how sponsorship affects published conclusions. METHODS AND FINDINGS: Medline searches of worldwide literature were used to identify three article types (interventional studies, observational studies, and scientific reviews) about soft drinks, juice, and milk published between 1 January, 1999 and 31 December, 2003. Financial sponsorship and article conclusions were classified by independent groups of coinvestigators. The relationship between sponsorship and conclusions was explored by exact tests and regression analyses, controlling for covariates. 206 articles were included in the study, of which 111 declared financial sponsorship. Of these, 22% had all industry funding, 47% had no industry funding, and 32% had mixed funding. Funding source was significantly related to conclusions when considering all article types (p = 0.037). For interventional studies, the proportion with unfavorable conclusions was 0% for all industry funding versus 37% for no industry funding (p = 0.009). The odds ratio of a favorable versus unfavorable conclusion was 7.61 (95% confidence interval 1.27 to 45.73), comparing articles with all industry funding to no industry funding. CONCLUSIONS: Industry funding of nutrition-related scientific articles may bias conclusions in favor of sponsors' products, with potentially significant implications for public health

Pamidronate Disodium for Palliative Therapy of Feline Bone-Invasive Tumors

This study sought to quantify in vitro antiproliferative effects of pamidronate in feline cancer cells and assess feasibility of use of pamidronate in cats by assessing short-term toxicity and dosing schedule in cats with bone-invasive cancer. A retrospective pilot study included eight cats with bone invasive cancer treated with intravenous pamidronate. In vitro, pamidronate reduced proliferation in feline cancer cells (P<0.05). One cat treated with pamidronate in combination with chemotherapy and two cats treated with pamidronate as a single agent after failing prior therapy had subjective clinically stable disease; median progression free interval in these cats from initial pamidronate treatment was 81 days. Three cats developed azotemia while undergoing various treatment modalities including nonsteroidal anti-inflammatory drugs and pamidronate. Median overall survival was 116.5 days for all cats and 170 days for cats with oral squamous cell carcinoma. Median progression free survival was 55 days for all cats and 71 days for cats with oral squamous cell carcinoma. Pamidronate therapy appears feasible for administration in cancer bearing cats with aggressive bone lesions in the dose range of 1-2 mg/kg every 21–28 days for multiple treatments. No acute or short-term toxicity was directly attributable to pamidronate

Stability and Change in Self-Reported Sexual Orientation Identity in Young People: Application of Mobility Metrics

This study investigated stability and change in self-reported sexual orientation identity over time in youth. We describe gender- and age-related changes in sexual orientation identity from early adolescence through emerging adulthood in 13,840 youth ages 12–25 employing mobility measure M, a measure we modified from its original application for econometrics. Using prospective data from a large, ongoing cohort of U.S. adolescents, we examined mobility in sexual orientation identity in youth with up to four waves of data. Ten percent of males and 20% of females at some point described themselves as a sexual minority, while 2% of both males and females reported ever being “unsure” of their orientation. Two novel findings emerged regarding gender and mobility: (1) Although mobility scores were quite low for the full cohort, females reported significantly higher mobility than did males. (2) As expected, for sexual minorities, mobility scores were appreciably higher than for the full cohort; however, the gender difference appeared to be eliminated, indicating that changing reported sexual orientation identity throughout adolescence occurred at a similar rate in female and male sexual minorities. In addition, we found that, of those who described themselves as “unsure” of their orientation identity at any point, 66% identified as completely heterosexual at other reports and never went on to describe themselves as a sexual minority. Age was positively associated with endorsing a sexual-minority orientation identity. We discuss substantive and methodological implications of our findings for understanding development of sexual orientation identity in young people

Early Neuromuscular Blockade in Moderate-to-Severe Pediatric Acute Respiratory Distress Syndrome

Objectives: The use of neuromuscular blocking agents (NMBAs) in pediatric acute respiratory distress syndrome (PARDS) is common but unsupported by efficacy data. We sought to compare the outcomes between patients with moderate-to-severe PARDS receiving continuous NMBA during the first 48 hours of endotracheal intubation (early NMBA) and those without. Design: Secondary analysis of data from the Randomized Evaluation of Sedation Titration for Respiratory Failure (RESTORE) clinical trial, a pediatric multicenter cluster randomized trial of sedation. Setting: Thirty-one PICUs in the United States. Patients: Children 2 weeks to 17 years receiving invasive mechanical ventilation (MV) for moderate-to-severe PARDS (i.e., oxygenation index >= 8 and bilateral infiltrates on chest radiograph on days 0-1 of endotracheal intubation). Interventions: NMBA for the entire duration of days 1 and 2 after intubation. Measurements and Main Results: Among 1,182 RESTORE patients with moderate-to-severe PARDS, 196 (17%) received early NMBA for a median of 50.0% ventilator days (interquartile range, 33.3-60.7%). The propensity score model predicting the probability of receiving early NMBA included high-frequency oscillatory ventilation on days 0-2 (odds ratio [OR], 7.61; 95% CI, 4.75-12.21) and severe PARDS on days 0-1 (OR, 2.16; 95% CI, 1.50-3.12). After adjusting for risk category, early use of NMBA was associated with a longer duration of MV (hazard ratio, 0.57; 95% CI, 0.48-0.68; p < 0.0001), but not with mortality (OR, 1.62; 95% CI, 0.92-2.85; p = 0.096) compared with no early use of NMBA. Other outcomes including cognitive, functional, and physical impairment at 6 months post-PICU discharge were similar. Outcomes did not differ when comparing high versus low NMBA usage sites or when patients were stratified by baseline PaO2/FIO2 less than 150. Conclusions: Early NMBA use was associated with a longer duration of MV. This propensity score analysis underscores the need for a randomized controlled trial in pediatrics

Repeated Changes in Reported Sexual Orientation Identity Linked to Substance Use Behaviors in Youth

Purpose—Previous studies have found that sexual minority (e.g., lesbian, gay, bisexual) adolescents are at higher risk of substance use than heterosexuals, but few have examined how changes in sexual orientation over time may relate to substance use. We examined the associations between change in sexual orientation identity and marijuana use, tobacco use, and binge drinking in U.S. youth. Methods—Prospective data from 10,515 U.S. youth ages 12-27 years in a longitudinal cohort study were analyzed using sexual orientation identity mobility measure M (frequency of change from 0 [no change] to 1 [change at every wave]) in up to five waves of data. Generalized estimating equations were used to estimate substance use risk ratios and 95% confidence intervals; interactions by sex and age group were assessed. Results—All substance use behaviors varied significantly by sexual orientation. Sexual minorities were at higher risk for all outcomes, excluding binge drinking in males, and mobility score was positively associated with substance use in most cases (p\u3c.05). The association between mobility and substance use remained significant after adjusting for current sexual orientation and varied by sex and age for selected substance use behaviors. This association had a higher positive magnitude in females than males and in adolescents than young adults. Conclusions—In both clinical and research settings it is important to assess history of sexual orientation changes. Changes in reported sexual orientation over time may be as important as current sexual orientation for understanding adolescent substance use risk

Tight Glycemic Control After Pediatric Cardiac Surgery in High-Risk Patient Populations

Background—Our previous randomized, clinical trial showed that postoperative tight glycemic control (TGC) for children undergoing cardiac surgery did not reduce the rate of health care–associated infections compared with standard care (STD). Heterogeneity of treatment effect may exist within this population. Methods and Results—We performed a post hoc exploratory analysis of 980 children from birth to 36 months of age at the time of cardiac surgery who were randomized to postoperative TGC or STD in the intensive care unit. Significant interactions were observed between treatment group and both neonate (age ≤30 days; P=0.03) and intraoperative glucocorticoid exposure (P=0.03) on the risk of infection. The rate and incidence of infections in subjects ≤60 days old were significantly increased in the TGC compared with the STD group (rate: 13.5 versus 3.7 infections per 1000 cardiac intensive care unit days, P=0.01; incidence: 13% versus 4%, P=0.02), whereas infections among those \u3e60 days of age were significantly reduced in the TGC compared with the STD group (rate: 5.0 versus 14.1 infections per 1000 cardiac intensive care unit days, P=0.02; incidence: 2% versus 5%, P=0.03); the interaction of treatment group by age subgroup was highly significant (P=0.001). Multivariable logistic regression controlling for the main effects revealed that previous cardiac surgery, chromosomal anomaly, and delayed sternal closure were independently associated with increased risk of infection. Conclusions—This exploratory analysis demonstrated that TGC may lower the risk of infection in children \u3e60 days of age at the time of cardiac surgery compared with children receiving STD. Meta-analyses of past and ongoing clinical trials are necessary to confirm these findings before clinical practice is altered

Sexual Orientation and Functional Pain in U.S. Young Adults: The Mediating Role of Childhood Abuse

Objective: Pain without known pathology, termed ‘‘functional pain,’’ causes much school absenteeism, medication usage, and medical visits. Yet which adolescents are at risk is not well understood. Functional pain has been linked to childhood abuse, and sexual orientation minority youth (gay, lesbian, bisexual, ‘‘mostly heterosexual,’’ and heterosexual with same-sex sexual contact) are more likely to be victims of childhood abuse than heterosexuals, thus may be at greater risk of functional pain. Methods: We examined sexual orientation differences in past-year prevalence of functional headache, pelvic, and abdominal pain and multiple sites of pain in 9,864 young adults (mean age = 23 years) from a large U.S. cohort. We examined whether childhood abuse accounted for possible increased risk of functional pain in sexual minority youth. Results: Sexual minority youth, except for gays and lesbians, were at higher risk of functional pelvic and abdominal pain and multiple sites of pain than heterosexuals. Gay and lesbian youth had elevated prevalence only of abdominal pain. Childhood abuse accounted for 14% to 33% of increased experience of multiple sites of pain in minority youth. Conclusions: Youth who identify as ‘‘mostly heterosexual’’ or bisexual or who identify as heterosexual and have had samesex partners comprised 18% of our sample. Clinicians should be aware that patients with these orientations are at elevated risk of functional pain and may be in need of treatment for sequelae of childhood abuse. Conventional categorization of sexual orientation as heterosexual or homosexual may fail to distinguish a large number of youth who do not wholly identify with either group and may be at elevated risk of health problems

Design and Rationale of Safe Pediatric Euglycemia After Cardiac Surgery (SPECS): A Randomized Controlled Trial of Tight Glycemic Control After Pediatric Cardiac Surgery

Objectives: To describe the design of a clinical trial testing the hypothesis that children randomized to tight glycemic control with intensive insulin therapy after cardiac surgery will have improved clinical outcomes compared to children randomized to conventional blood glucose management. Design: Two-center, randomized controlled trial. Setting: Cardiac ICUs at two large academic pediatric centers. Patients: Children from birth to those aged 36 months recovering in the cardiac ICU after surgery with cardiopulmonary bypass. Interventions: Subjects in the tight glycemic control (intervention) group receive an intravenous insulin infusion titrated to achieve normoglycemia (target blood glucose range of 80–110 mg/dL; 4.4–6.1 mmol/L). The intervention begins at admission to the cardiac ICU from the operating room and terminates when the patient is ready for discharge from the ICU. Continuous glucose monitoring is performed during insulin infusion to minimize the risks of hypoglycemia. The standard care group has no target blood glucose range. Measurements and Main Results: The primary outcome is the development of any nosocomial infection (bloodstream, urinary tract, and surgical site infection or nosocomial pneumonia). Secondary outcomes include mortality, measures of cardiorespiratory function and recovery, laboratory indices of nutritional balance, immunologic, endocrinologic, and neurologic function, cardiac ICU and hospital length of stay, and neurodevelopmental outcome at 1 and 3 yrs of age. A total of 980 subjects will be enrolled (490 in each treatment arm) for sufficient power to show a 50% reduction in the prevalence of the primary outcome. Conclusions: Pediatric cardiac surgery patients may recognize great benefit from tight glycemic control in the postoperative period, particularly with regard to reduction of nosocomial infections. The Safe Pediatric Euglycemia after Cardiac Surgery trial is designed to provide an unbiased answer to the question of whether this therapy is indeed beneficial and to define the associated risks of therapy

Non-invasive Assessment of Cerebral Blood Flow and Oxygen Metabolism in Neonates during Hypothermic Cardiopulmonary Bypass: Feasibility and Clinical Implications

The neonatal brain is extremely vulnerable to injury during periods of hypoxia and/or ischemia. Risk of brain injury is increased during neonatal cardiac surgery, where pre-existing hemodynamic instability and metabolic abnormalities are combined with long periods of low cerebral blood flow and/or circulatory arrest. Our understanding of events associated with cerebral hypoxia-ischemia during cardiopulmonary bypass (CPB) remains limited, largely due to inadequate tools to quantify cerebral oxygen delivery and consumption non-invasively and in real-time. This pilot study aims to evaluate cerebral blood flow (CBF) and oxygen metabolism (CMRO2) intraoperatively in neonates by combining two novel non-invasive optical techniques: frequency-domain near-infrared spectroscopy (FD-NIRS) and diffuse correlation spectroscopy (DCS). CBF and CMRO2 were quantified before, during and after deep hypothermic cardiopulmonary bypass (CPB) in nine neonates. Our results show significantly decreased CBF and CMRO2 during hypothermic CPB. More interestingly, a change of coupling between both variables is observed during deep hypothermic CPB in all subjects. Our results are consistent with previous studies using invasive techniques, supporting the concept of FD-NIRS/DCS as a promising technology to monitor cerebral physiology in neonates providing the potential for individual optimization of surgical management