Cost consequence analysis of Apathy in Dementia Methylphenidate Trial 2 (ADMET 2).

BACKGROUND: This paper used data from the Apathy in Dementia Methylphenidate Trial 2 (NCT02346201) to conduct a planned cost consequence analysis to investigate whether treatment of apathy with methylphenidate is economically attractive. METHODS: A total of 167 patients with clinically significant apathy randomized to either methylphenidate or placebo were included. The Resource Utilization in Dementia Lite instrument assessed resource utilization for the past 30 days and the EuroQol five dimension five level questionnaire assessed health utility at baseline, 3 months, and 6 months. Resources were converted to costs using standard sources and reported in 2021 USD. A repeated measures analysis of variance compared change in costs and utility over time between the treatment and placebo groups. A binary logistic regression was used to assess cost predictors. RESULTS: Costs were not significantly different between groups whether the cost of methylphenidate was excluded (F(2,330) = 0.626, ηp2 = 0.004, p = 0.535) or included (F(2,330) = 0.629, ηp2 = 0.004, p = 0.534). Utility improved with methylphenidate treatment as there was a group by time interaction (F(2,330) = 7.525, ηp2 = 0.044, p < 0.001). DISCUSSION: Results from this study indicated that there was no evidence for a difference in resource utilization costs between methylphenidate and placebo treatment. However, utility improved significantly over the 6-month follow-up period. These results can aid in decision-making to improve quality of life in patients with Alzheimer's disease while considering the burden on the healthcare system.

Glyphosate and neurological outcomes: A systematic literature review of animal studies.

Studies of nervous system effects of glyphosate, a widely used herbicide, have not been critically examined. The aim of this paper was to systematically review glyphosate-induced neurotoxicity literature to determine its usefulness in regulatory decision-making. The review was restricted to mammalian studies of behavior, neuropathology, and neuropharmacology; in vitro and other biochemical studies were considered supplementary information. Glyphosate formulation studies were also considered, despite uncertainties regarding toxicities of the formulated products; no studies used a formulation vehicle as the control. Inclusion criteria were developed a priori to ensure consistent evaluation of studies, and in vivo investigations were also ranked using ToxRTool software to determine reliability. There were 27 in vivo studies (open literature and available regulatory reports), but 11 studies were considered unreliable (mostly due to critical methodological deficiencies). There were only seven acceptable investigations on glyphosate alone. Studies differed in terms of dosing scenarios, experimental designs, test species, and commercial product. Limitations included using only one dose and/or one test time, small sample sizes, limited data presentation, and/or overtly toxic doses. While motor activity was the most consistently affected endpoint (10 of 12 studies), there were considerable differences in outcomes. In six investigations, there were no marked neuropathological changes in the central or peripheral nervous system. Other neurological effects were less consistent, and some outcomes were less convincing due to influences including high variability and small effect sizes. Taken together, these studies do not demonstrate a consistent impact of glyphosate on the structure or function of the mammalian nervous system.

Blood-based biomarkers of agitation in Alzheimer's disease: Advances and future prospects.

Agitation is a common neuropsychiatric symptom that becomes more prevalent as Alzheimer's disease (AD) increases in severity. The treatment of agitation is an urgent and unmet need due to the poor outcomes associated with it, its disruptive impact on patients and caregivers, and the lack of efficacious and safe treatments. Recent research on agitation in AD with blood-based biomarkers has advanced the search for its biomarkers beyond the brain and provides new insights to understand its mechanisms and improve treatments. Here, we reviewed studies of blood-based biomarkers of agitation in AD, which show that inflammatory biomarkers are increased in patients with agitation, may predict the development of agitation, and are associated with symptom severity. In addition, they may also track symptom severity and response to treatment. Other biomarkers associated with agitation include markers of oxidative stress, brain cholesterol metabolism, motor activity, and clusterin, a chaperone protein. These results are promising and need to be replicated. Preliminary evidence suggests a role for these biomarkers in interventional studies for agitation to predict and monitor treatment response, which may eventually help enrich study samples and deliver therapy likely to benefit individual patients. Advances in blood-based biomarkers of AD including those identified in "-omic" studies and high sensitivity assays provide opportunities to identify new biomarkers of agitation. Future studies of agitation and its treatment should investigate blood-based biomarkers to yield novel insights into the neurobiological mechanisms of agitation, monitoring symptoms and response to treatment, and to identify patients likely to respond to treatments.

Respiratory Syncytial Virus Immunoprophylaxis with Palivizumab: 12-Year Observational Study of Usage and Outcomes in Canada.

OBJECTIVE: This study aimed to evaluate palivizumab (PVZ) use, trends in indications, and outcomes of respiratory illness hospitalizations (RIH) and respiratory syncytial virus hospitalizations (RSVH). STUDY DESIGN: It involves a large, Canadian prospective (2005-2017) observational multicenter study of children at high risk for RSV infection. RESULTS: A total of 25,003 infants (56.3% male) were enrolled at 32 sites; 109,579 PVZ injections were administered. Indications included: prematurity (63.3%); "miscellaneous" (17.8%); hemodynamically significant congenital heart disease (10.5%); bronchopulmonary dysplasia/chronic lung disease (8.4%). The "miscellaneous" group increased over time (4.4% in 2005-2006 to 22.5% in 2016-2017) and included: trisomy 21, airway anomalies, pulmonary disorders, cystic fibrosis, neurological impairments, immunocompromised, cardiac aged >2 years, multiple conditions, and a residual "unclassified" group. Adherence measured by expected versus actual doses plus correct interdose interval was 64.7%. A total of 2,054 RIH occurred (6.9%); 198 (9.6%) required intubation. Three hundred thirty-seven hospitalized children were RSV-positive (overall RSVH 1.6%). Risk factors for RSVH included having siblings, attending daycare, family history of atopy, smoking exposure, and crowded household. Infants with 5 risk factors were 9.0 times (95% CI or confidence interval 4.4-18.2; p < 0.0005) more likely to have RSVH than infants without risk factors. Three adverse events occurred; none were fatal. CONCLUSION: Results are relevant to both clinicians and decision-makers. We confirmed the safety of PVZ. Use of PVZ increased steadily for children with miscellaneous conditions and medical complexity. Medical and social factors pose a risk for severe RIH and RSVH with accompanying burden of illness. A vaccine that protects against RSV is urgently required. KEY POINTS: · Main indications were prematurity (63.3%); "miscellaneous" (17.8%); hemodynamically significant congenital heart disease (10.5%); bronchopulmonary dysplasia/chronic lung disease (8.4%).. · The proportion of children in the "miscellaneous" group, comprised of those with trisomy 21, airway anomalies, pulmonary disorders, cystic fibrosis, neurological impairments, immunocompromised, cardiac aged >2 years, multiple conditions, and a residual "unclassified" group, increased over time (4.4% in 2005-2006 to 22.5% in 2016-2017).. · Respiratory illness-related hospitalization occurred in 2,054 children (6.9%); 198 (9.6%) required intubation. Three hundred thirty-seven hospitalized children were RSV-positive (overall RSVH: 1.6%)..

Medical Cannabis Use Among Older Adults in Canada: Self-Reported Data on Types and Amount Used, and Perceived Effects.

BACKGROUND: Medical cannabis use is growing among older adults. In this retrospective study, we aimed to assess the characteristics of older medical cannabis users including the indications, type and amount of cannabis used, perceived changes in symptoms after cannabis use, change in dose of concurrent medications, and adverse effects. METHODS: Data were collected between October 2014 and October 2020 from patients who were consulting the Canada-wide network of clinics of a medical cannabis provider and who were willing to answer questionnaires based on their medical status. The current study included older adults (≥ 65 years) who completed questionnaires at intake and first follow-up visits. Data were summarized with descriptive statistics, which were compared between men and women with t tests or chi-squared tests. Tests of proportions assessed categorical responses for perceived effects after cannabis use. Logistic regression was used to assess trends in cannabis usage. RESULTS: Data included that from 9766 older adult users at intake (mean ± SD age = 73.2 ± 6.8 years, females = 60.0%), among whom 4673 (females = 61.4%) returned for follow-up after 90.6 ± 58 days. The most common primary indication for which medical cannabis was sought was pain (67.7%), which was more common in women, whereas oncological and neurological conditions were more common in men. At follow-up, cannabis oil was used by 81.0% of older adults, among whom compositions containing only or mostly cannabidiol (CBD) had been used by 83.6%. Adverse effects reported by older adults at the follow-up visit included dry mouth (12.8%), drowsiness (8.6%), and dizziness (4.0%). The majority of older adults reported improvements in pain (72.7%, z = 1482.6, p < 0.0001, compared to worsening or no change), sleep (64.5%, z = 549.4, p < 0.0001), and mood (52.8%, z = 16.4, p < 0.0001), with 35.6% reporting use of a reduced dose of opioids and 19.9% a reduced dose of benzodiazepines. INTERPRETATION: Among older adults, medical cannabis is used more often by women, with CBD-containing cannabis oils being the most commonly used. Users reported improved pain, sleep, and mood symptoms at follow-up after cannabis use. This study describes the patterns of use of medical cannabis by older adults and highlights the need for research to determine appropriate indications, precise doses of active ingredients, and short- and long-term outcomes among older adults.

What risk factors for sudden infant death syndrome are preterm and term medically complex infants exposed to at home?

OBJECTIVES: Risk factors for sudden infant death syndrome include premature birth, maternal smoking, prone or side sleeping position, sleeping with blankets, sharing a sleeping surface with an adult, and sleeping without an adult in the room. In this study, we compare parents' responses on sleep patterns in premature and term infants with medical complexity. METHODS: Parents of children enrolled in the Canadian Respiratory Syncytial Virus Evaluation Study of Palivizumab were phoned monthly regarding their child's health status until the end of each respiratory syncytial virus season. Baseline data were obtained on patient demographics, medical history, and neonatal course. Responses on adherence to safe sleep recommendations were recorded as part of the assessment. RESULTS: A total of 2,526 preterms and 670 term infants with medical complexity were enrolled. Statistically significant differences were found in maternal smoking rates between the two groups: 13.3% (preterm); 9.3% (term) infants (χ 2=8.1, df=1, P=0.004) and with respect to toys in the crib: 12.3% (term) versus 5.8% preterms (χ 2=24.5, df=1, P<0.0005). Preterm infants were also significantly more likely to be placed prone to sleep (8.8%), compared with term infants (3.3%), (χ 2=18.1, df=1, P<0.0005). CONCLUSION: All the infants in this study had frequent medical contacts. There is a greater prevalence of some risk factors for sudden infant death syndrome in preterm infants compared to term infants with medical complexity. Specific educational interventions for vulnerable infants may be necessary.

Diagnostic criteria for apathy in neurocognitive disorders.

INTRODUCTION: Apathy is common in neurocognitive disorders (NCD) but NCD-specific diagnostic criteria are needed. METHODS: The International Society for CNS Clinical Trials Methodology Apathy Work Group convened an expert group and sought input from academia, health-care, industry, and regulatory bodies. A modified Delphi methodology was followed, and included an extensive literature review, two surveys, and two meetings at international conferences, culminating in a consensus meeting in 2019. RESULTS: The final criteria reached consensus with more than 80% agreement on all parts and included: limited to people with NCD; symptoms persistent or frequently recurrent over at least 4 weeks, a change from the patient's usual behavior, and including one of the following: diminished initiative, diminished interest, or diminished emotional expression/responsiveness; causing significant functional impairment and not exclusively explained by other etiologies. DISCUSSION: These criteria provide a framework for defining apathy as a unique clinical construct in NCD for diagnosis and further research.

Measuring Apathy in Alzheimer's Disease in the Apathy in Dementia Methylphenidate Trial 2 (ADMET 2): A Comparison of Instruments.

BACKGROUND: Diagnostic criteria for apathy have been published but have yet to be evaluated in the context of clinical trials. The Apathy in Dementia Methylphenidate Trial 2 (ADMET 2) operationalized the diagnostic criteria for apathy (DCA) into a clinician-rated questionnaire informed by interviews with the patient and caregiver. OBJECTIVE: The goal of the present study was to compare the classification of apathy using the DCA with that using the Neuropsychiatric Inventory-apathy (NPI-apathy) subscale in ADMET 2. Comparisons between NPI-Apathy and Dementia Apathy Interview Rating (DAIR) scale, and DCA and DAIR were also explored. METHODS: ADMET 2 is a randomized, double-blind, placebo-controlled phase III trial examining the effects of 20 mg/day methylphenidate on symptoms of apathy over 6 months in patients with mild to moderate Alzheimer's disease (AD). Participants scoring at least 4 on the NPI-Apathy were recruited. This analysis focuses on cross-sectional correlations between baseline apathy scale scores using cross-tabulation. RESULTS: Of 180 participants, the median age was 76.5 years and they were predominantly white (92.8%) and male (66.1%). The mean (±standard deviation) scores were 7.7 ± 2.4 on the NPI-apathy, and 1.9 ± 0.5 on the DAIR. Of those with NPI-defined apathy, 169 (93.9%, 95% confidence interval [CI] 89.3%-96.9%) met DCA diagnostic criteria. The DCA and DAIR overlapped on apathy diagnosis for 169 participants (93.9%, 95% CI 89.3%-96.9%). CONCLUSION: The measurements used for the assessment of apathy in patients with AD had a high degree of overlap with the DCA. The NPI-apathy cut-off used to determine apathy in ADMET 2 selects those likely to meet DCA criteria.

A Comparison of Respiratory Syncytial Viral Prophylaxis in Multiple Births versus Singletons in the Canadian Registry of Palivizumab.

OBJECTIVE: The aim of this study is to compare respiratory illness-related hospitalization (RIH) and respiratory syncytial virus (RSV)-related hospitalization (RSVH) in multiple births versus singletons, who received palivizumab during the RSV season and participated in the Canadian registry of palivizumab (CARESS). STUDY DESIGN: Prospective, observational study of infants aged <2 years recruited across 32 centers over 12 RSV seasons from 2005 to 2017. Demographic data were collected at enrolment and RIH events were recorded monthly. RESULTS: A total of 25,003 infants were enrolled of whom 6,949 (27.8%) were of multiple birth, and 18,054 (72.2%) were singletons. A significantly larger proportion of the multiple births were premature (80.2%) compared with the singleton group (56.8%). Multiples had a lower gestational age (mean ± standard deviation): 31.2 ± 3.2 versus 33.2 ± 5.5 weeks and birth weight (mean: 1,590 ± 606.8 vs. 2,069.4 ± 1068.5 g; both p < 0.0005). They were younger at enrolment (4.5 ± 5.0 vs. 6.1 ± 6.8 months), and fewer attended daycare (1.9 vs. 4.6%), and experienced exposure to smoking (24.5 vs. 29.9%), but more lived in a crowded household (36.7 vs. 19.4%); all p < 0.0005. Multiples had a longer length of neonatal stay (51.1 ± 65.9 vs. 47.9 ± 67.8 days), and more required respiratory support (65.7 vs. 57.7%), but for shorter duration (22.6 ± 32.9 vs. 24.7 ± 40.6 days); all p < 0.001. RIH and RSVH rates (%) in multiples versus singletons were 4.7; 7.7 and 1.4; and 1.6, respectively. Cox regression showed that multiples had a lower risk of RIH compared with singletons (hazard ratio [HR] = 0.616, 95% confidence interval [CI]: 0.543-0.698, p < 0.0005), but not RSVH (HR: 0.77, 95% CI: 0.57-1.02, p = 0.071). CONCLUSION: Multiple birth infants, who are known to be at greater risk for severe RSVH compared with singletons, are well protected by palivizumab, provided adherence to the monthly injection scheme is guaranteed.

Genotoxicity as a toxicologically relevant endpoint to inform risk assessment: A case study with ethylene oxide.

The purpose of the present investigation is to analyze the in vivo genotoxicity dose-response data of ethylene oxide (EO) and the applicability of the derived point-of-departure (PoD) values when estimating permitted daily exposure (PDE) values. A total of 40 data sets were identified from the literature, and benchmark dose analyses were conducted using PROAST software to identify a PoD value. Studies employing the inhalation route of exposure and assessing gene or chromosomal mutations and chromosomal damage in various tissues were considered the most relevant for assessing risk from EO, since these effects are likely to contribute to adverse health consequences in exposed individuals. The PoD estimates were screened for precision and the values were divided by data-derived adjustment factors. For gene mutations, the lowest PDE was 285 parts per trillion (ppt) based on the induction of lacI mutations in the testes of mice following 48 weeks of exposure to EO. The corresponding lowest PDE value for chromosomal mutations was 1,175 ppt for heritable translocations in mice following 8.5 weeks of EO exposure. The lowest PDE for chromosomal aberrations was 238 ppt in the mouse peripheral blood lymphocytes following 48 weeks of inhalation exposure. The diverse dose-response data for EO-induced genotoxicity enabled the derivation of PoDs for various endpoints, tissues, and species and identified 238 ppt as the lowest PDE in this retrospective analysis.

This is your teen brain on drugs: In search of biological factors unique to dependence toxicity in adolescence.

Response variability across the lifespan is an important consideration in toxicology and risk assessment, and the toxic effects of drugs and chemicals during adolescence need more research. This paper summarizes a workshop presented in March 2019, at the Society of Toxicology Annual Meeting in Baltimore, Maryland, that brought together experts in research on drug dependence and toxicity related to nicotine, cannabis, cocaine, and other illicit drugs during adolescence. The goal of the workshop was to address the following issues: (1) Do the effects of adolescent exposure differ from the same exposure in adults? (2) Are there unique biological markers of adolescent brain development? If so, what are they and how reliable are they? (3) Since multiple factors influence substance use disorder, can we disentangle risk factors for abuse and/or toxicity? What are the underlying biological susceptibilities that lead to dependence and neurotoxicity? What are the social, psychosocial and environmental factors that contribute to abuse susceptibilities? This paper reviews drug policy and national trends in adolescent substance use; the public health consequences of e-cigarettes; rat models of adolescent-onset nicotine self-administration and persisting effects of gestational nicotine; sex-dependent effects of delta-9-tetrahydrocannabinol on adolescent brain-behavior relationships; and translational approaches for identifying adolescent risk factors for transition to drug dependence. There is strong evidence that drug exposure prior to adulthood has longer lasting effects on behavior and the underlying neural circuitry. These effects, which are sex-dependent and influenced by stress, may be candidates as predictors of adolescent vulnerability. A major challenge to determining if adolescents have a unique susceptibility to dependence is whether and to what extent the human data allow distinction between the increased risk due to biological immaturity, an underlying biological susceptibility to dependence, or psychosocial and environmental factors for substance dependence. Factors important to consider for development of animal models include the timing and pattern of exposure as it relates to adolescence; age of assessment, and direct comparison with similar effects following exposures to adults to demonstrate that these effects are unique to adolescence. Here we provide a roadmap for further research into what makes adolescent brain development unique.

Cost-analysis of Withdrawing Immunoprophylaxis for Respiratory Syncytial Virus in Infants Born at 33-35 Weeks Gestational Age in Quebec: A Multicenter Retrospective Study.

BACKGROUND: In 2015, the Quebec Ministry of Health limited palivizumab prophylaxis for respiratory syncytial virus (RSV) in premature infants to those born at <33 weeks gestational age (wGA), unless other indications were present. We compared RSV-related costs for 2 seasons before the change (2013-2014, 2014-2015) and 2 seasons after (2015-2016, 2016-2017) in premature infants 33-35 wGA. METHODS: Using payer and societal perspectives, costs associated with hospitalizations for RSV and lower respiratory tract infection (LRTI) in infants born at 33-35 wGA were estimated. Inputs were from a 2013-2017 retrospective cohort study in 25 Quebec hospitals of RSV/LRTI hospitalizations among infants <6 months old at the start of, or born during, the RSV season. Resource utilization data (hospital stay, procedures, visits, transportation, out-of-pocket expenses and work productivity) were collected from charts and parent interviews allowing estimation of direct and indirect costs. Costs, including palivizumab administration, were derived from provincial sources and adjusted to 2018 Canadian dollars. Costs were modeled for preterm infants hospitalized for RSV/LRTI pre- and postrevision of guidelines and with matched term infants hospitalized for RSV/LRTI during 2015-2017 (comparator). RESULTS: Average total direct and indirect costs for 33-35 wGA infants were higher postrevision of guidelines ($29,208/patient, 2015-2017; n = 130) compared with prerevision ($16,976/patient, 2013-2015; n = 105). Total costs were higher in preterm infants compared with term infants (n = 234) postrevision of guidelines ($29,208/patient vs. $10,291/patient). CONCLUSIONS: Immunoprophylaxis for RSV in infants born at 33-35 wGA held a cost advantage for hospitalizations due to RSV/LRTI.

Respiratory Syncytial Virus Prophylaxis in Immunocompromised Children: Outcomes From the Canadian RSV Evaluation Study of Palivizumab Registry Over Twelve Seasons (2005-2017).

BACKGROUND: Immunocompromised children are at increased risk for respiratory syncytial virus (RSV) infection with associated morbidity and mortality. Prophylaxis is usually provided to these children on a case-by-case basis. METHODS: Immunocompromised children who received ≥1 injection of palivizumab were prospectively enrolled across 32 Canadian sites, between 2005 and 2017, during the RSV season. We assessed respiratory illness hospitalization (RIH) and RSV-related hospitalization (RSVH) hazard ratios (HRs) in immunocompromised children versus infants' prophylaxed for standard indications (SI: prematurity ≤35 weeks' gestation, bronchopulmonary dysplasia, and congenital heart disease) and complex medical disorders (CMD). Data were analyzed using t-tests, χ and Cox proportional hazards adjusted for confounders. RESULTS: A total of 25,003 infants were recruited; 214 immunocompromised, 4283 CMD, 20,506 SI. On average, children received 4.4 ± 1.3 injections. A total of 16,231 children were perfectly adherent (58.4% immunodeficiency, 68.9% CMD, 64.2% SI; P < 0.0005). A higher proportion of immunocompromised children were aboriginal and exposed to smoking compared with CMD and SI. Immunocompromised children also had a higher median; gestational and enrollment age and birth weight compared with CMD and SI. Immunodeficient children had a higher RIH risk compared with SI (HR = 2.4, 95% confidence interval, 1.3-4.7, P = 0.009) but were similar to CMD (HR = 1.7, 95% confidence interval, 0.9-3.4, P = 0.118). RSVH in prophylaxed, immunocompromised children was similar to CMD (HR < 0.005, P = 0.955) and SI (HR < 0.005, P = 0.953). CONCLUSIONS: Immunocompromised children who received palivizumab had an increased RIH hazard compared with the SI group. Similar RSVH hazard between the 3 groups suggests that immunocompromised children may benefit from palivizumab during the RSV season.

Antidepressant-placebo differences for specific adverse events in major depressive disorder: A systematic review.

BACKGROUND: Adverse events (AEs) are known to occur while patients are treated with placebos, part of the so-called nocebo effect. Yet evidence is limited regarding the likelihood that specific AEs occurring with antidepressant treatment are or are not due to nocebo effects. METHODS: This study identified 56 placebo-controlled, randomized controlled trials (RCTs) of antidepressant monotherapy for adults with major depressive disorder that reported AE rates in sufficient detail for comparison. Poisson regression analyses compared rates of AEs according to antidepressant class weighted by study population to determine which separated from placebo. A "nocebo index" was also calculated (with 0 defined as the lowest rate and 1 or higher indicating the same or greater rate of an AE in the placebo group). RESULTS: Numerous AEs did not differ statistically between antidepressant classes and placebo including worsening psychiatric symptoms, all forms of pain, weight gain and respiratory symptoms. Nevertheless, a number of AEs were significantly more common in antidepressants than placebos across multiple antidepressant classes. These were predominantly neurological, sexual and anticholinergic effects. Several AEs that separated statistically between antidepressants and placebos nevertheless had moderate nocebo indices (≥0.5). For example, dizziness in SSRIs separated significantly from placebo (OR 1.50, 95%CI 1.13-1.99) but had a nocebo index of 0.67. LIMITATIONS: This study relied on multiple RCTs with subtle design differences. CONCLUSIONS: This study identified several AEs that are likely the physiological result of antidepressants and many that likely represent nocebo effects. These results should inform clinical decision making and discussions with patients.

Reevaluation of Historical Exposures to Ethylene Oxide Among U.S. Sterilization Workers in the National Institute of Occupational Safety and Health (NIOSH) Study Cohort.

The 2016 U.S. Environmental Protection Agency (EPA) Integrated Risk Information System (IRIS) assessment for ethylene oxide (EO) estimated a 10-6 increased inhalation cancer risk of 0.1 parts per trillion, based on National Institute of Occupational Safety and Health (NIOSH) epidemiology studies of sterilization facility workers exposed to EO between 1938 and 1986. The worker exposure estimates were based on a NIOSH statistical regression (NSR) model "validated" with EO levels measured after 1978. Between 1938 and 1978, when EO data was unavailable, the NSR model predicts exposures lowest in 1938 increasing to peak levels in 1978. That increasing EO concentration trend arose, in part, because engineering/industrial-hygiene (E/IH) factors associated with evolving EO-sterilization equipment and operations before 1978 were not properly considered in the NSR model. To test the NSR model trend prediction, a new E/IH-based model was developed using historical data on EO kill concentrations, EO residue levels in sterilized materials, post-wash EO concentrations in a sterilization chamber, and information on facility characteristics and sterilizer operator practices from operators familiar with pre-1978 industry conditions. The E/IH 90th percentile of 8 h time-weighted average EO exposures (C90) for highly exposed sterilizer operators was calibrated to match 1978 C90 values from the NSR model. E/IH model C90 exposures were estimated to decrease over time from levels 16 and were four-fold greater than NSR-estimated exposures for workers during 1938-1954 and 1955-1964. This E/IH modeled trend is opposite to that of NSR model predictions of exposures before 1978, suggesting that EPA's exclusive reliance on the NIOSH cohort to estimate EO cancer risk should be re-examined.

Respiratory Syncytial Virus Prophylaxis in Neurologic and Muscular Disorders in the Canadian Respiratory Syncytial Virus Evaluation Study of Palivizumab.

BACKGROUND: This study aimed to examine the risk of respiratory-related hospitalization in children with neurologic and muscular disorders (NMDs) who received respiratory syncytial virus (RSV) prophylaxis in the Canadian RSV Evaluation Study of Palivizumab. METHODS: Canadian RSV Evaluation Study of Palivizumab is a prospective registry of children who received ≥1 palivizumab injection among 32 Canadian sites. Demographic data were collected at enrollment, and respiratory events were documented monthly. Cox proportional hazard analyses were conducted to compare respiratory illness-related hospitalization (RIH) and RSV-related hospitalization (RSVH) among children with NMD and those prophylaxed for standard indications (SI) and complex medical disorders. RESULTS: Group differences were found in enrollment age and weight, birth weight, household crowding, neonatal stay and supplemental oxygen requirement (all P < 0.05). RIH and RSVH incidences were 19.2%, 3.3% (NMD, n = 605); 6.0%, 1.5% (SI, n = 20,335), 9.4%, 1.6% (complex medical disorders, n = 4063), respectively. Children with NMD had a higher risk of RIH (hazard ratio [HR]: 1.90; 95% confidence interval (CI): 1.41-2.56; P < 0.0005) than those with SI. RSVH risk was greater in children with NMD compared with both the SI (HR: 2.26; 95% CI: 1.38-3.72; P = 0.001) and complex medical disorders groups (HR: 2.74; 95% CI: 1.55-4.84; P = 0.001). Children with more severe infantile onset NMD had a higher risk of RIH than those with general hypotonic disorders (HR: 1.69; 95% CI: 1.06-2.68; P = 0.027) but not RSVH. CONCLUSIONS: Children with NMD who received palivizumab had a higher risk of both RIH and RSVH. Our results imply that all children with NMD, regardless of disease severity, are at risk for respiratory-related illness and RSV infection.

Practical considerations for developmental thyroid toxicity assessments: What's working, what's not, and how can we do better?

Thyroid hormones (THs; T3 and T4) play a role in development of cardiovascular, reproductive, immune and nervous systems. Thus, interpretation of TH changes from rodent studies (during pregnancy, in fetuses, neonates, and adults) is critical in hazard characterization and risk assessment. A roundtable session at the 2017 Society of Toxicology (SOT) meeting brought together academic, industry and government scientists to share knowledge and different perspectives on technical and data interpretation issues. Data from a limited group of laboratories were compiled for technical discussions on TH measurements, including good practices for reliable serum TH data. Inter-laboratory historical control data, derived from immunoassays or mass spectrometry methods, revealed: 1) assay sensitivities vary within and across methodologies; 2) TH variability is similar across animal ages; 3) laboratories generally achieve sufficiently sensitive TH quantitation levels, although issues remain for lower levels of serum TH and TSH in fetuses and postnatal day 4 pups; thus, assay sensitivity is critical at these life stages. Best practices require detailed validation of rat serum TH measurements across ages to establish assay sensitivity and precision, and identify potential matrix effects. Finally, issues related to data interpretation for biological understanding and risk assessment were discussed, but their resolution remains elusive.

Rates of Screening for Breast, Colorectal, and Cervical Cancers in Older People With Cognitive Impairment or Dementia: A Meta-Analysis.

Purpose: Cancer screening may not be appropriate for some older people. We compare the likelihood of screening for colorectal, breast, and cervical cancers in older people with versus without cognitive impairment or dementia. Method: Systematic search of MEDLINE, Embase, and PsycINFO (to March 9, 2018) for articles reporting screening for colon, breast, and cervical cancers in patients with and without cognitive impairment or dementia. Studies were summarized quantitatively (random effects meta-analysis), according to Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. Results: Studies reported data 1989-2008. The rate of screening for breast cancer by mammography was lower in women with cognitive impairment or dementia compared with those without (pooled odds ratio [OR] = 0.81, 95% confidence interval [CI] = [0.71, 0.91], p = .0007, six studies, N = 18,562). The rates of screening for cervical cancer by Pap smear (pooled OR = 0.88, 95% CI = [0.71, 1.08], p = 0.22, five studies, N = 409,131) and colorectal cancer by fecal occult blood test (pooled OR = 0.87, 95% CI = [0.55, 1.38], p = .55, two studies, N = 2,718) were not significantly lower in people with cognitive impairment or dementia. Conclusion: These historical rates provide a baseline for discussions around the need for more specific guidance to assist with decisions to discontinue screening. The study also identifies a gap in reported knowledge with respect to screening under current guidelines.

Palivizumab prophylaxis for respiratory syncytial virus in infants with cystic fibrosis: is there a need?

Respiratory syncytial virus (RSV) infection in cystic fibrosis (CF) infants is associated with significant morbidities. This study's objective is to evaluate the effectiveness and adverse events related to palivizumab (PVZ) in CF infants. Data on respiratory-related illness (RIH) and RSV hospitalizations (RSVH) were collected retrospectively in CF infants aged < 2 years in Alberta, Canada, from 2000 to 2017. Logistic regression models were used to compare the odds of RSVH or RIH in PVZ infants from the Canadian registry of palivizumab (CARESS) versus untreated (UPVZ) infants from Alberta, after adjusting for potential confounders. Illness severity was compared between cohorts using χ2 and t tests. A total of 267 CF infants were included: 183 (PVZ) and 84 (UPVZ). A total of 53.3% were tested for RSV. Fifty-five infants experienced a RIH and 10 had a RSVH. The PVZ cohort experienced similar odds of RSVH but decreased odds of RIH versus UPVZ, adjusting for gestational age, birth weight, birth during RSV peak months, and presence of siblings (Exp(B) = 0.23 [0.11-0.49], p < 0.0005). In RSVH-related subjects, PVZ subjects experienced shorter length of overall stay (LOS; t = 2.39 [df = 7], p = 0.048). In those with a RIH, the PVZ group had shorter overall intensive care unit (t = 3.52 [df = 15], p = 0.003) and hospital LOS (t = 2.11 [df = 52], p = 0.04). No serious adverse events were related to PVZ. The odds of RSVH were similar between groups, but PVZ subjects had decreased odds of RIH. The low number of RSV tests performed may explain the similarity in RSVH rates. Significant differences in LOS may indicate decreased RSVH and RIH illness severity in the PVZ versus UPVZ groups.

Adherence and outcomes: a systematic review of palivizumab utilization.

INTRODUCTION: Palivizumab is a humanized monoclonal antibody used for respiratory syncytial virus (RSV) prophylaxis. RSV is the primary cause of lower respiratory tract infection in children aged <2 years, and can give rise to high-burden hospitalization and respiratory complications in later life. Adherence to a monthly dosing regimen, both in timing and injection number, is essential to sustain therapeutic levels of palivizumab and maintain protective status. Deviation from the approved dosing schedule may reduce the efficacy of palivizumab and increase the risk of breakthrough RSV infection and hospitalization. Areas covered: There is no standardized definition of adherence to palivizumab treatment. This review addresses the wide variability in defining and reporting adherence to palivizumab prophylaxis across different studies. The review assesses whether a relationship exists in the outcomes reported in studies relative to the monthly adherence protocol as defined in published randomized controlled trials of the efficacy and safety of palivizumab. Expert commentary: Standardized detailed reporting of adherence to palivizumab prophylaxis using consistent definitions will help provide a more robust level of evidence. This information may be important when considering variations in effectiveness, alterations to recommendations and guidelines, and cost-effectiveness of treatment.