Nutritional compensation of the circadian clock is a conserved process influenced by gene expression regulation and mRNA stability.

Compensation is a defining principle of a true circadian clock, where its approximately 24-hour period length is relatively unchanged across environmental conditions. Known compensation effectors directly regulate core clock factors to buffer the oscillator's period length from variables in the environment. Temperature Compensation mechanisms have been experimentally addressed across circadian model systems, but much less is known about the related process of Nutritional Compensation, where circadian period length is maintained across physiologically relevant nutrient levels. Using the filamentous fungus Neurospora crassa, we performed a genetic screen under glucose and amino acid starvation conditions to identify new regulators of Nutritional Compensation. Our screen uncovered 16 novel mutants, and together with 4 mutants characterized in prior work, a model emerges where Nutritional Compensation of the fungal clock is achieved at the levels of transcription, chromatin regulation, and mRNA stability. However, eukaryotic circadian Nutritional Compensation is completely unstudied outside of Neurospora. To test for conservation in cultured human cells, we selected top hits from our fungal genetic screen, performed siRNA knockdown experiments of the mammalian orthologs, and characterized the cell lines with respect to compensation. We find that the wild-type mammalian clock is also compensated across a large range of external glucose concentrations, as observed in Neurospora, and that knocking down the mammalian orthologs of the Neurospora compensation-associated genes CPSF6 or SETD2 in human cells also results in nutrient-dependent period length changes. We conclude that, like Temperature Compensation, Nutritional Compensation is a conserved circadian process in fungal and mammalian clocks and that it may share common molecular determinants.

Telehealth Support for Dementia Caregivers During the COVID-19 Pandemic: Lessons Learned From the NYU Family Support Program.

OBJECTIVES: In response to the needs of dementia caregivers during the COVID-19 pandemic, the NYU Langone Alzheimer's Disease and Related Disorders Family Support Program (FSP) quickly transitioned to providing most services online. To understand how dementia caregivers experienced FSP services after the switch to video telehealth, we conducted qualitative interviews of spouse or partner dementia caregivers. PARTICIPANTS: Ten participants were recruited from a convenience sample of dementia spouse or partner caregivers who used one or more online FSP services offered during the pandemic. DESIGN: Caregivers engaged in semi-structured interviews held via videoconference between May and June 2020. Qualitative analysis of interviews was conducted according to the principles of framework analysis. RESULTS: Caregivers reported high satisfaction with the FSP pre-pandemic and continued to feel supported when services were provided online. They transitioned to video telehealth services with little difficulty. CONCLUSIONS: While video telehealth is frequently cited as beneficial for those in rural communities, socioeconomically disadvantaged groups, or homebound individuals, our findings suggest that video telehealth is also advantageous for dementia caregivers, given their unique barriers, including lack of time due to caregiving responsibilities, lack of respite care for the person with dementia, and the additional burdens of travel time to access in-person services.

Association between early care and education centres policies and practices and children's healthy behaviours.

OBJECTIVE: To examine the impact of nutritional and physical activity (PA) policies and practices at early care and education centres on behavioural changes among children ages 2-5. METHODS: The study population included 586 children from 25 education centres throughout the state of Georgia. Policies and practices were measured using the Georgia Nutrition and PA Assessment at the start of school year in Fall 2017. Survey data were collected at the beginning of school year September/October 2017 and at the end of school year April/May 2018 to measure changes in children's nutritional and PA behaviour over the school year. We used generalised estimating equations to estimate odds ratios and 95% confidence intervals. RESULTS: Children at centres with a high nutrition assessment score had higher odds of increasing vegetable consumption (OR = 2.1; 95% CI: 1.1, 4.0) while the odds of increasing fruit (OR = 1.4; 95% CI: 0.8, 2.4) and water (OR = 1.2; 95% CI: 0.5, 2.7) consumption increased non-significantly. The odds of improving PA were similar between children at centres with a high versus a low PA assessment score. CONCLUSION: The results, though insignificant, indicate that policies and practices could influence children's health behaviours. Further research is warranted to examine whether improvements in policies and practices could explain changes in children's health behaviours, the impact of educator's knowledge on children's health behaviours and the implementation of and adherence to policy and practice improvement plans.

Schools and Wastewater Surveillance: Practical Implications for an Emerging Technology to Impact Child Health.

Since the start of the COVID-19 pandemic, wastewater surveillance has emerged as a public health tool that supplements traditional surveillance methods used to detect the prevalence of the SARS-CoV-2 virus in communities. In May 2020, the Houston Health Department (HHD) partnered with a coalition of municipal and academic partners to develop a wastewater monitoring and reporting system for the city of Houston, Texas. The HHD subsequently launched a program to conduct targeted wastewater sampling at 52 school sites located in a large, urban school district in Houston. Data generated by this program are shared with school district officials and nurses from participating schools. Although initial feedback from these stakeholders indicated that they considered the wastewater data valuable, the emergency nature of the pandemic prevented a systematic evaluation of the program. To address this gap in knowledge, the HHD and Rice University conducted a study to determine how wastewater data are used to make decisions about COVID-19 prevention and mitigation practices in schools. Our findings indicate that maximizing the utility of wastewater data in the school context will require the development of communication strategies and education efforts tailored to the needs of specific audiences and improving collaboration between local health departments, school districts, and school nurses.

Longitudinal study: understanding the lived experience of couples across the trajectory of dementia.

BACKGROUND: The longitudinal study, "Couples Lived Experiences," focuses on whether and how relationship characteristics of older couples change with the cognitive decline of one member of the couple, and how these changes affect each individual's emotional and physical health outcomes. Until now, most psychosocial research in dementia has focused either on the person with dementia (PWD) or the caregiver separately. The previous literature examining relationship characteristics and their role in outcomes for the caregiver and PWD is scant and suffers from methodological issues that limit the understanding of which relationship characteristics most influence outcomes for caregivers and care-receivers and what other factors may mitigate or exacerbate their effects. METHODS: We will enroll 300 dyads and collect information via online interviews of each member of the couple, every 6 months for 3 years. Relationship characteristics will be measured with a set of short, well-validated, and reliable self-report measures, plus the newly developed "Partnership Approach Questionnaire." Outcomes include global quality of life, subjective physical health, mental health (depression and anxiety), and status change (transitions in levels of care; i.e., placement in a nursing home). Longitudinal data will be used to investigate how relationship characteristics are affected by cognitive, functional, and behavioral changes, and the impact of these changes on health outcomes. Qualitative data will also be collected to enrich the interpretation of results of quantitative analyses. DISCUSSION: Psychosocial interventions have demonstrated effectiveness in promoting the wellbeing of PWD and their caregivers. The knowledge gained from this study can lead to the development or enhancement of targeted interventions for older couples that consider the impact of cognitive and functional decline on the relationship between members of a couple and thereby improve their wellbeing. TRIAL REGISTRATION: This study has been registered with ClinicalTrials.gov. ClinicalTrials.gov Identifier is: NCT04863495 .

Obesity and the Risk of Intubation or Death in Patients With Coronavirus Disease 2019.

OBJECTIVES: To characterize the impact of obesity on disease severity in patients with coronavirus disease 2019. DESIGN: This was a retrospective cohort study designed to evaluate the association between body mass index and risk of severe disease in patients with coronavirus disease 2019. Data were abstracted from the electronic health record. The primary endpoint was a composite of intubation or death. SETTING: Two hospitals in Massachusetts (one quaternary referral center and one affiliated community hospital). PATIENTS: Consecutive patients hospitalized with confirmed coronavirus disease 2019 admitted between March 13, 2020, and April 3, 2020. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: A total of 305 patients were included in this study. We stratified patients by body mass index category: < 25 kg/m (54 patients, 18%), ≥ 25 kg/m to < 30 kg/m (124 patients, 41%), ≥ 30 kg/m to < 35 kg/m (58 patients, 19%), and ≥ 35 kg/m (69 patients, 23%). In total, 128 patients (42%) had a primary endpoint (119 patients [39%] were intubated and nine died [3%] without intubation). Sixty-five patients (51%) with body mass index greater than or equal to 30 kg/m were intubated or died. Adjusted Cox models demonstrated that body mass index greater than or equal to 30 kg/m was associated with a 2.3-fold increased risk of intubation or death (95% CI, 1.2-4.3) compared with individuals with body mass index less than 25 kg/m. Diabetes was also independently associated with risk of intubation or death (hazard ratio, 1.8; 95% CI, 1.2-2.7). Fifty-six out of 127 patients (44%) with body mass index greater than or equal to 30 kg/m had diabetes, and the combination of both diabetes and body mass index greater than or equal to 30 kg/m was associated with a 4.5-fold increased risk of intubation or death (95% CI, 2.0-10.2) compared with patients without diabetes and body mass index less than 25 kg/m. CONCLUSIONS: Among consecutive patients hospitalized with coronavirus disease 2019, obesity was an independent risk factor for intubation or death.

Equipoise in Appropriate Initial Volume Resuscitation for Patients in Septic Shock With Heart Failure: Results of a Multicenter Clinician Survey.

PURPOSE: International clinical practice guidelines call for initial volume resuscitation of at least 30 mL/kg body weight for patients with sepsis-induced hypotension or shock. Although not considered in the guidelines, preexisting cardiac dysfunction may be an important factor clinicians weigh in deciding the quantity of volume resuscitation for patients with septic shock. METHODS: We conducted a multicenter survey of clinicians who routinely treat patients with sepsis to evaluate their beliefs, behaviors, knowledge, and perceived structural barriers regarding initial volume resuscitation for patients with sepsis and concomitant heart failure with reduced ejection fraction (HFrEF) <40%. Initial volume resuscitation preferences were captured as ordinal values, and additional testing for volume resuscitation preferences was performed using McNemar and Wilcoxon signed rank tests as indicated. Univariable logistic regression models were used to identify significant predictors of ≥30 mL/kg fluid administration. RESULTS: A total of 317 clinicians at 9 US hospitals completed the survey (response rate 47.3%). Most respondents were specialists in either internal medicine or emergency medicine. Substantial heterogeneity was found regarding sepsis resuscitation preferences for patients with concomitant HFrEF. The belief that patients with septic shock and HFrEF should be exempt from current sepsis bundle initiatives was shared by 39.4% of respondents. A minimum fluid challenge of ∼30 mL/kg or more was deemed appropriate in septic shock by only 56.4% of respondents for patients with concomitant HFrEF, compared to 89.1% of respondents for patients without HFrEF (P < .01). Emergency medicine physicians were most likely to feel that <30 mL/kg was most appropriate in patients with septic shock and HFrEF. CONCLUSIONS: Clinical equipoise exists regarding initial volume resuscitation for patients with sepsis-induced hypotension or shock and concomitant HFrEF. Future studies and clinical practice guidelines should explicitly address resuscitation in this subpopulation.

Association Between Do Not Resuscitate/Do Not Intubate Orders and Emergency Medicine Residents' Decision Making.

BACKGROUND: Research has shown that do not resuscitate (DNR) and do not intubate (DNI) orders may be construed by physicians to be more restrictive than intended by patients. Previous studies of physicians found that DNR/DNI orders are associated with being less willing to provide invasive care. OBJECTIVES: The purpose of this study was to assess the influence of code status on emergency residents' decision-making regarding offering invasive procedures for those patients with DNR/DNI compared with their full code counterparts. METHODS: We conducted a nationwide survey of emergency medicine residents using an instrument of 4 clinical vignettes involving patients with serious illnesses. Two versions of the survey, survey A and survey B, alternated the DNR/DNI and full code status for the vignettes. Residency leaders were contacted in August 2018 to distribute the survey to their residents. RESULTS: Three hundred and three residents responded from across the country. The code status was strongly associated with decisions to intubate or perform CPR and influenced the willingness to offer other invasive procedures. DNR/DNI status was associated with less frequent willingness to place central venous catheters (88.2% for DNR/DNI vs. 97.2% for full code, p < 0.001), admit patients to the intensive care unit (89.9% vs. 99.0%, p < 0.001), offer dialysis (79.3% vs. 98.0%, p < 0.001), and surgical consultation (78.7% vs. 94.2%, p < 0.001). CONCLUSIONS: In a nationwide survey, emergency medicine residents were less willing to provide invasive procedures for patients with DNR/DNI status, including the placement of central venous catheters, admission to the intensive care unit, and consultation for dialysis and surgery.

Two decades of mortality trends among patients with severe sepsis: a comparative meta-analysis*.

OBJECTIVES: Trends in severe sepsis mortality derived from administrative data may be biased by changing International Classification of Diseases, 9th Revision, Clinical Modification, coding practices. We sought to determine temporal trends in severe sepsis mortality using clinical trial data that does not rely on International Classification of Diseases, 9th Revision, Clinical Modifications coding and compare mortality trends in trial data with those observed from administrative data. DESIGN: We searched MEDLINE for multicenter randomized trials that enrolled patients with severe sepsis from 1991 to 2009. We calculated standardized mortality ratios for each trial from observed 28-day mortality of usual care participants and predicted mortality from severity-of-illness scores. To compare mortality trends from clinical trials to administrative data, we identified adult severe sepsis hospitalizations in the Nationwide Inpatient Sample, 1993-2009, using two previously validated algorithms. SETTING: In-patient. PATIENTS: Patients with severe sepsis or septic shock. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Of 3,244 potentially eligible articles, we included 36 multicenter severe sepsis trials, with a total of 14,418 participants in a usual care arm. Participants with severe sepsis receiving usual care had a 28-day mortality of 33.2%. Observed mortality decreased 3.0% annually (95% CI, 0.8%-5.0%; p = 0.009), decreasing from 46.9% (standardized mortality ratio 0.94; 95% CI, 0.86-1.03) during years 1991-1995 to 29% (standardized mortality ratio 0.53; 95% CI, 0.50-0.57) during years 2006-2009 (3.0% annual change). Trends in hospital mortality among patients with severe sepsis identified from administrative data (Angus definition, 4.7% annual change; 95% CI, 4.1%-5.3%; p = 0.69 and Martin definition, 3.5% annual change; 95% CI, 3.0%-4.1%; p = 0.97) were similar to trends identified from clinical trials. CONCLUSION: Since 1991, patients with severe sepsis enrolled in usual care arms of multicenter randomized trials have experienced decreasing mortality. The mortality trends identified in clinical trial participants appear similar to those identified using administrative data and support the use of administrative data to monitor mortality trends in patients with severe sepsis.

Functional analysis of 110 phosphorylation sites on the circadian clock protein FRQ identifies clusters determining period length and temperature compensation.

In the negative feedback loop driving the Neurospora circadian oscillator, the negative element, FREQUENCY (FRQ), inhibits its own expression by promoting phosphorylation of its heterodimeric transcriptional activators, White Collar-1 (WC-1) and WC-2. FRQ itself also undergoes extensive time-of-day-specific phosphorylation with over 100 phosphosites previously documented. Although disrupting individual or certain clusters of phosphorylation sites has been shown to alter circadian period lengths to some extent, it is still elusive how all the phosphorylations on FRQ control its activity. In this study, we systematically investigated the role in period determination of all 110 reported FRQ phosphorylation sites, using mutagenesis and luciferase reporter assays. Surprisingly, robust FRQ phosphorylation is still detected even when 84 phosphosites were eliminated altogether; further mutating another 26 phosphoresidues completely abolished FRQ phosphorylation. To identify phosphoresidue(s) on FRQ impacting circadian period length, a series of clustered frq phosphomutants covering all the 110 phosphosites were generated and examined for period changes. When phosphosites in the N-terminal and middle regions of FRQ were eliminated, longer periods were typically seen while removal of phosphorylation in the C-terminal tail resulted in extremely short periods, among the shortest reported. Interestingly, abolishing the 11 phosphosites in the C-terminal tail of FRQ not only results in an extremely short period, but also impacts temperature compensation (TC), yielding an overcompensated circadian oscillator. In addition, the few phosphosites in the middle of FRQ are also found to be crucial for TC. When different groups of FRQ phosphomutations were combined intramolecularly, expected additive effects were generally observed except for one novel case of intramolecular epistasis, where arrhythmicity resulting from one cluster of phosphorylation site mutants was restored by eliminating phosphorylation at another group of sites.

Medical students' experience of studying while working part-time and the effects of COVID-19.

AIMS: The costs of being a medical student are large and increasing, and many students need to work part-time to meet financial pressures. This study explores the impact that part-time extracurricular paid work during the academic year has on medical student wellbeing, their interactions with the curriculum, and the effect of COVID-19 on work in 2020. METHODS: An online survey in 2020 gathered demographic, quantitative and qualitative information from medical students and their work experiences. Descriptive statistics analysed quantitative data; qualitative data were analysed using qualitative content analysis. RESULTS: Of the 36% (n=530) of students who responded, 255 (49%) reported undertaking paid part-time work, with 59 (24%) reporting they would not be able to remain studying if they did not work. When interacting with the medical programme, 43% of students reported their work conflicted with scheduled medical school commitments, and 70% reported conflicts between work and individual study. COVID-19 disrupted 57% of paid work during the year. Impacts on students' wellbeing were both positive and negative. Positive aspects included developing new skills, self-confidence and resilience. Working also provided an escape from the study demands of the medical programme. Negative aspects were predominantly about the increased stress working had on students, specifically on the impact of paid work on their own health. CONCLUSIONS: Almost half of medical students work part-time while studying. Understanding the perceived implications that part-time work has on student education and wellbeing could help medical schools provide appropriate advice and pastoral support for their students.

White-Nose Syndrome Pathogen Pseudogymnoascus destructans Detected in Migratory Tree-Roosting Bats.

White-nose syndrome (WNS) is an emerging fungal epizootic disease that has caused large-scale mortality in several species of North American bats. The fungus that causes WNS, Pseudogymnoascus destructans (Pd), has also been detected in bat species without diagnostic signs of WNS. Although these species could play a role in WNS spread, understanding of the spatial and temporal extents of Pd occurrence on WNS-resistant species is limited. This study evaluated the presence of Pd on 272 individuals of three species of migratory tree-roosting bats: hoary (Lasiurus cinereus), eastern red (Lasiurus borealis), and silver-haired (Lasionycteris noctivagans) bats, obtained opportunistically during summer and autumn from throughout much of their ranges in North America. We also compared tissue sampling protocols (i.e., tissue swabbing, fur swabbing, and DNA extraction of excised wing tissue). We detected Pd on three eastern red bats from Illinois and Ohio, US, one silver-haired bat from West Virginia, US, and one hoary bat from New York, US, all via DNA extracted from wing tissue of carcasses. These results document the first publicly reported detections of Pd on a hoary bat and on migratory bats during the autumn migratory period, and demonstrate the potential for using carcasses salvaged at wind-energy facilities to monitor for Pd.

Sedative load of medications prescribed for older people with dementia in care homes.

BACKGROUND: The objective of this study was to determine the sedative load and use of sedative and psychotropic medications among older people with dementia living in (residential) care homes. METHODS: Medication data were collected at baseline and at two further time-points for eligible residents of six care homes participating in the EVIDEM-End Of Life (EOL) study for whom medication administration records were available. Regular medications were classified using the Anatomical Therapeutic Chemical classification system and individual sedative loads were calculated using a previously published model. RESULTS: At baseline, medication administration records were reviewed for 115 residents; medication records were reviewed for 112 and 105 residents at time-points 2 and 3 respectively. Approximately one-third of residents were not taking any medications with sedative properties at each time-point, while a significant proportion of residents had a low sedative load score of 1 or 2 (54.8%, 59.0% and 57.1% at baseline and time-points 2 and 3 respectively). More than 10% of residents had a high sedative load score (≥ 3) at baseline (12.2%), and this increased to 14.3% at time-points 2 and 3. Approximately two-thirds of residents (66.9%) regularly used one or more psychotropic medication(s). Antidepressants, predominantly selective serotonin re-uptake inhibitors (SSRIs), were most frequently used, while antipsychotics, hypnotics and anxiolytics were less routinely administered. The prevalence of antipsychotic use among residents was 19.0%, lower than has been previously reported for nursing home residents. Throughout the duration of the study, administration of medications recognised as having prominent sedative adverse effects and/or containing sedative components outweighed the regular use of primary sedatives. CONCLUSIONS: Sedative load scores were similar throughout the study period for residents with dementia in each of the care homes. Scores were lower than previously reported in studies conducted in long-term care wards which have on-site clinical support. Nevertheless, strategies to optimise drug therapy for care home residents with dementia which rely on clinicians external to the care home for support and medication review are required.

Culture, consent, costs and care homes: enabling older people with dementia to participate in research.

OBJECTIVES: To describe factors that support and inhibit recruitment and participation of people with dementia living in care homes. METHOD: This article focuses on the methods used to recruit people with dementia to a longitudinal study that employed a mixed-method design to track events and care that older people with dementia experienced over two years in six care homes. A staged approach to recruitment was adopted involving separate meetings with staff, residents and relatives. Individual consent was secured with residents with dementia who could consent in the moment and for those without capacity, through mail and follow-up telephone contact with consultees. Data were collected on the frequency of meetings, issues raised by staff, consultees and people with dementia as well as the overall time taken to complete recruitment. RESULTS: Over five months, 133 older people with dementia were recruited (62% of sampling frame). The recruitment process was supported or hindered by the number of individuals and organisations that needed to be consulted, the care home culture, staff's understanding of how people with dementia can be involved in research, and how they interpreted their role as mediators, protectors and gatekeepers. CONCLUSIONS: Care homes are isolated communities of care. To achieve the research objectives, researchers in the initial stages need to consider the philosophical underpinnings of individual care homes, and the politics of hierarchy both within the care home and between it, and health professionals. There is a need to develop credible infrastructures of support that enable people with dementia to participate in research.

Effect of Palliative Care Curriculum on Serious Illness Conversation Preparedness.

BACKGROUND: A shortage of palliative pare (PC) specialists underscores the necessity that all clinicians feel comfortable with serious illness conversations (SICs). OBJECTIVE: To assess the effect of an intensive PC curriculum with multiple teaching modalities on Internal Medicine residents' confidence with SICs and advance care planning documentation. METHODS: Twelve PC modules consisting of didactic lectures, role-playing, and online interactive modules were integrated as continuing education during academic year 2018-2019. Surveys were administered precurriculum and at 3 and 6 months postcurriculum to measure the primary outcome of increasing resident preparedness for SICs. A retrospective chart review was used to analyze secondary outcomes of advance care planning documentation for patients cared for by residents exposed to the curriculum versus residents from the previous year who received monthly didactic PC lectures. RESULTS: Postintervention surveys demonstrated statistically significant improvement in resident confidence. An increase in patient code status confirmation rates (odds ratio, 1.81; 95% confidence interval, 1.12-2.94; P = 0.02) and a decrease in PC consultation (odds ratio, 0.56; 95% confidence interval, 0.33-0.97; P = 0.04) was observed when compared with the previous year. CONCLUSION: Among residents, the incorporation of an intensive PC curriculum that uses multiple teaching modalities improves confidence in SICs, which we believe is integral to the practice of goal-concordant patient care.

The effect of patient code status on surgical resident decision making: A national survey of general surgery residents.

BACKGROUND: Multiple studies have demonstrated that, compared with their full code counterparts, patients with do-not-resuscitate or do-not-intubate status have higher in-hospital and postdischarge mortality than predicted by clinical characteristics alone. We sought to determine whether patient code status affects surgical resident decision making. METHODS: We created an online survey that consisted of 4 vignettes, followed by 10 questions regarding decisions on possible diagnostic and therapeutic interventions. All program directors of Accreditation Council for Graduate Medical Education-accredited general surgery residencies were randomized to receive 1 of 2 survey versions that differed only in the code status of the patients described, with requests to distribute the survey to their residents. Responses to each question were based on a Likert scale. RESULTS: A total of 194 residents completed the survey, 51% of whom were women, and all years of surgical residency were represented. In all vignettes, patient code status influenced perioperative medical decisions, ranging from initiation of dialysis to intensive care unit transfer. In 2 vignettes, it affected decisions to proceed with indicated emergency operations. CONCLUSION: When presented with patient scenarios pertaining to clinical decision making, surgical residents tend to assume that patients with a do-not-resuscitate or do-not-intubate code status would prefer to receive less aggressive care overall. As a result, the delivery of appropriate surgical care may be improperly limited unless a patient's goals of care are explicitly stated. It is important for surgical residents to understand that a do-not-resuscitate or do-not-intubate code status should not be interpreted as a "do-not-treat" status.

Pandemic influenza planning: addressing the needs of children.

Children represent one quarter of the US population. Because of its enormous size and special needs, it is critically important to address this population group in pandemic influenza planning. Here we describe the ways in which children are vulnerable in a pandemic, provide an overview of existing plans, summarize the resources available, and, given our experience with influenza A(H1N1), outline the evolving lessons we have learned with respect to planning for a severe influenza pandemic. We focus on a number of issues affecting children-vaccinations, medication availability, hospital capacity, and mental health concerns-and emphasize strategies that will protect children from exposure to the influenza virus, including infection control practices and activities in schools and child care programs.

Oxidative stress and matrix metalloproteinase-9 in acute ischemic stroke: the Biomarker Evaluation for Antioxidant Therapies in Stroke (BEAT-Stroke) study.

BACKGROUND AND PURPOSE: Experimental stroke studies indicate that oxidative stress is a major contributing factor to ischemic cerebral injury. Oxidative stress is also implicated in activation of matrix metalloproteinases (MMPs) and blood-brain barrier injury after ischemia-reperfusion. Plasma biomarkers of oxidative stress may have utility as early indicators of efficacy in Phase 2 trials of antioxidant therapies in human stroke. To date, a valid biomarker has been unavailable. We measured F2-isoprostanes (F2IPs), free-radical induced products of neuronal arachadonic acid peroxidation, in acute ischemic stroke. We aimed to determine the change in plasma F2IP levels over time and relationship with plasma MMP-9 in tPA-treated and tPA-untreated stroke patients. METHODS: We performed a case-control study of consecutive ischemic stroke patients (25 tPA-treated and 27 tPA-untreated) presenting within 8 hours of stroke onset. Controls were individuals without prior stroke from a primary care clinic network serving the source population from which cases were derived. Infarct volume was determined on acute diffusion-weighted MRI (DWI) performed within 48 hours using a semi-automated computerized segmentation algorithm. Phlebotomy was performed at <8 hours, 24 hours, 2 to 5 days, and 4 to 6 weeks. F2IPs were measured by gas chromatography/mass spectrometry and MMP-9 by ELISA. Prestroke antioxidant dietary intake was measured by the 24-hour recall method. RESULTS: In 52 cases and 27 controls, early (median 6 hours postonset) F2IPs were elevated in stroke cases compared with controls (medians 0. 041 versus 0.0295 pg/mL, P=0.012). No difference in F2IPSs was present at later time points. Early plasma F2IPs correlated with MMP-9 in all patients (P=0.01) and the tPA-treated subgroup (P=0.02). No correlation was found with NIHSS, DWI infarct volume, 90-day Rankin score, or C-reactive protein (P>0.05 for all). CONCLUSIONS: In early human stroke we found evidence of increased oxidative stress and a relationship with MMP-9 expression, supporting findings from experimental studies.