Social determinants of health and obstetric outcomes: A report and recommendations of the workshop of the Society for Maternal-Fetal Medicine.

This article is a report of a 2-day workshop, entitled "Social determinants of health and obstetric outcomes," held during the Society for Maternal-Fetal Medicine 2022 Annual Pregnancy Meeting. Participants' fields of expertise included obstetrics, pediatrics, epidemiology, health services, health equity, community-based research, and systems biology. The Commonwealth Foundation and the Alliance of Innovation on Maternal Health cosponsored the workshop and the Society for Women's Health Research provided additional support. The workshop included presentations and small group discussions, and its goals were to accomplish the following.

Understanding racial disparities in childhood asthma using individual- and neighborhood-level risk factors.

BACKGROUND: Racial disparities in childhood asthma outcomes result from a complex interplay of individual- and neighborhood-level factors. OBJECTIVES: We sought to examine racial disparities in asthma-related emergency department (ED) visits between African American (AA) and European American (EA) children. METHODS: This is a retrospective study of patients younger than 18 years who visited the ED at Cincinnati Children's for asthma from 2009 to 2018. The outcome was number of ED visits during a year. We assessed 11 social, economic, and environmental variables. Mediation and mixed-effects analyses were used to assess relationships between race, mediators, and number of ED visits. RESULTS: A total of 31,114 children (46.1% AA, 53.9% EA) had 186,779 asthma-related ED visits. AA children had more visits per year than EA children (2.23 vs 2.15; P < .001). Medicaid insurance was associated with a 7% increase in rate of ED visits compared with commercial insurance (1.07; 95% CI, 1.03-1.1). Neighborhood socioeconomic deprivation was associated with an increased rate of ED visits in AA but not in EA children. Area-level particulate matter with diameter less than 2.5 µm, pollen, and outdoor mold were associated with an increased rate of ED visits for both AA and EA children (all P < .001). Associations between race and number of ED visits were mediated by insurance, area-level deprivation, particulate matter with diameter less than 2.5 µm, and outdoor mold (all P < .001), altogether accounting for 55% of the effect of race on ED visits. Race was not associated with number of ED visits (P = .796) after accounting for mediators. CONCLUSIONS: Racial disparities in asthma-related ED visits are mediated by social, economic, and environmental factors, which may be amenable to interventions aimed at improving outcomes and eliminating inequities.

Inequality and child health: dynamic population health interventions.

PURPOSE OF REVIEW: Established social gradients across a wide range of child health issues including obesity, anxiety, infectious diseases, injuries, prematurity and low birth weight suggest that much illness is avoidable and there is an imperative to intervene in this whole of society issue. This review examines recent advances in understanding of the pathways to health and health inequalities and their application to interventions to improve health equity. RECENT FINDINGS: Children's health develops over the life course in ways that are profoundly influenced by their entire developmental ecosystem including individual, family, community and system-level factors. Interventions to address child health inequalities must include action on the structural determinants of health, a greater focus on family and community health development, and attention to the acquisition of developmental capabilities. Nascent dynamic population health initiatives that address whole developmental ecosystems such as All Children Thrive, Better Start Bradford and Generation V, hold real promise for achieving child health equity. SUMMARY: Pathways to health inequalities are driven by social and structural determinants of health. Interventions to address inequalities need to be driven less by older biomedical models, and more by prevailing ecological and complex systems models incorporating a life course health development approach.

A Successful Collaboration Between an Urban School District, a Health System, and a Public Health Department to Address COVID-19 While Returning Children to the Classroom.

We sought to create and implement a set of COVID-19 mitigation processes including reliable testing to minimize in-school transmission of SARS-CoV-2. A large urban school district (> 33,000 students), a city health department, and a free-standing children's hospital partnered to implement multi-layered mitigation procedures which included access to polymerase chain reaction (PCR) testing with same day or next morning results. We tracked COVID-19 cases as well as probable/confirmed transmissions and identified needed mitigations through frequent huddles. During the 2020-2021 school year, there were 13 weeks of hybrid in person learning and 9 weeks of 5 day a week learning. Of the 1936 cases documented, only 3.2% resulted in subsequent school-related transmission. When children felt ill in the classroom, they were isolated within 10 min of reporting ill symptoms (> 90% of the time). PCR test results were routinely available to the school district by 6AM the following morning (79-99% of the time, depending on the learning model). An adaptive, fast-learning partnership across school district, public health, and a children's hospital minimized school-related transmission of COVID-19 and allowed children to safely return to the classroom.

Genetic ancestry differences in pediatric asthma readmission are mediated by socioenvironmental factors.

BACKGROUND: Social and financial hardships, combined with disease managment and environmental factors explain approximately 80% of the observed disparity in asthma-related readmissions between Black and White children. OBJECTIVE: We sought to determine whether asthma-related readmissions differed by degree of African ancestry and the extent to which such an association would also be explained by socioenvironmental risk factors. METHODS: This study used data from a prospective cohort study of 695 Black and White children aged 1 to 16 years with an asthma-related admission. The primary outcome was a similar readmission within 12 months. Each subject's African ancestry was determined by single nucleotide polymorphisms on a continuous scale ranging from 0 to 1 (0 = no African ancestry; 1 = 100% African ancestry). We also assessed 37 social, environmental, and clinical variables that we clustered into 6 domains (for example, hardship, disease management). Survival and mediation analyses were conducted. RESULTS: A total of 134 children (19.3%) were readmitted within 12 months. Higher African ancestry was associated with asthma readmission (odds ratio 1.11, 95% confidence interval 1.05-1.18 for every 10% increase in African ancestry) with adjustment for age and gender. The association between African ancestry and readmission was mediated by hardship (sß = 3.42, P < .001) and disease management (sß = 0.046, P = .001), accounting for >50% of African ancestry's effect on readmission. African ancestry was no longer significantly associated with readmission (sß = 0.035, P = .388) after accounting for these mediators. CONCLUSIONS: African ancestry was strongly associated with readmission, and the association was mediated by family hardship and disease management. These results are consistent with the notion that asthma-related racial disparities are driven by factors like structural racism and social adversity.

Voter Participation is Associated with Child Health Outcomes at the Population Level.

Civic engagement, including voting, has been linked to health outcomes for adults. Here, we found that census tract-level voter participation rates are significantly associated with pediatric inpatient bed-day rates even after adjustment for socioeconomic deprivation. Such links suggest that promotion of voting participation could be warranted in healthcare settings.

Community Socioeconomic Deprivation and Nonalcoholic Fatty Liver Disease Severity.

BACKGROUND AND OBJECTIVES: Nonalcoholic fatty liver disease (NAFLD) is linked to obesity. Obesity is associated with lower socioeconomic status (SES). An independent link between pediatric NAFLD and SES has not been elucidated. The objective of this study was to evaluate the distribution of socioeconomic deprivation, measured using an area-level proxy, in pediatric patients with known NAFLD and to determine whether deprivation is associated with liver disease severity. METHODS: Retrospective study of patients <21 years with NAFLD, followed from 2009 to 2018. The patients' addresses were mapped to census tracts, which were then linked to the community deprivation index (CDI; range 0--1, higher values indicating higher deprivation, calculated from six SES-related variables available publicly in US Census databases). RESULTS: Two cohorts were evaluated; 1 with MRI (magnetic resonance imaging) and/or MRE (magnetic resonance elastography) findings indicative of NAFLD (n = 334), and another with biopsy-confirmed NAFLD (n = 245). In the MRI and histology cohorts, the majority were boys (66%), non-Hispanic (77%-78%), severely obese (79%-80%), and publicly insured (55%-56%, respectively). The median CDI for both groups was 0.36 (range 0.15-0.85). In both cohorts, patients living above the median CDI were more likely to be younger at initial presentation, time of MRI, and time of liver biopsy. MRI-measured fat fraction and liver stiffness, as well as histologic characteristics were not different between the high- and low-deprivation groups. CONCLUSIONS: Children with NAFLD were found across the spectrum of deprivation. Although children from more deprived neighborhoods present at a younger age, they exhibit the same degree of NAFLD severity as their peers from less deprived areas.

Perspectives from the Society for Pediatric Research: interventions targeting social needs in pediatric clinical care.

The social determinants of health (SDoH) are defined by the World Health Organization as the "conditions in which people are born, grow, live, work, and age." Within pediatrics, studies have highlighted links between these underlying social, economic, and environmental conditions, and a range of health outcomes related to both acute and chronic disease. Additionally, within the adult literature, multiple studies have shown significant links between social problems experienced during childhood and "adult diseases" such as diabetes mellitus and hypertension. A variety of potential mechanisms for such links have been explored including differential access to care, exposure to carcinogens and pathogens, health-affecting behaviors, and physiologic responses to allostatic load (i.e., toxic stress). This robust literature supports the importance of the SDoH and the development and evaluation of social needs interventions. These interventions are also driven by evolving economic realities, most importantly, the shift from fee-for-service to value-based payment models. This article reviews existing evidence regarding pediatric-focused clinical interventions that address the SDoH, those that target basic needs such as food insecurity, housing insecurity, and diminished access to care. The paper summarizes common challenges encountered in the evaluation of such interventions. Finally, the paper concludes by introducing key opportunities for future inquiry.

Transformation of a Pediatric Primary Care Waiting Room: Creating a Bridge to Community Resources.

Introduction Children and families living in poverty frequently encounter social risks that significantly affect their health and well-being. Physicians' near universal access to at-risk children and their parents presents opportunities to address social risks, but time constraints frequently interfere. We sought to redesign our waiting room to create a clinic-to-community bridge and evaluate the impact of that redesign on family-centered outcomes. Methods We conducted a pre-post study of a waiting room redesign at a large, academic pediatric primary care center. Design experts sought input about an optimal waiting room from families, community partners and medical providers. Family caregivers were surveyed before and after redesign regarding perceived availability of help with social needs and access to community resources, and hospitality and feelings of stress. Pre-post differences were assessed using the Chi square or Wilcoxon rank sum test. Results The key redesign concepts that emerged included linkages to community organizations, a welcoming environment, and positive distractions for children. A total of 313 caregiver surveys were completed (pre-160; post-153). Compared to pre-redesign, caregivers surveyed post-redesign were significantly more likely to perceive the waiting room as a place to obtain help connecting to community resources and find information about clinical and educational resources (both p < 0.05). Families were also significantly more likely to report the waiting room as more welcoming and relaxing, with sufficient privacy and space (all p < 0.05). Discussion Waiting rooms, typically a place of wasted time and space, can be redesigned to enhance families' engagement and connection to community resources.

The Child Opportunity Index and Disparities in Pediatric Asthma Hospitalizations Across One Ohio Metropolitan Area, 2011-2013.

OBJECTIVES: To determine whether the Child Opportunity Index (COI), a nationally available measure of relative educational, health/environmental, and social/economic opportunity across census tracts within metropolitan areas, is associated with population- and patient-level asthma morbidity. STUDY DESIGN: This population-based retrospective cohort study was conducted between 2011 and 2013 in a southwest Ohio county. Participants included all children aged 1-16 years with hospitalizations or emergency department visits for asthma or wheezing at a major pediatric hospital. Patients were identified using discharge diagnosis codes and geocoded to their home census tract. The primary population-level outcome was census tract asthma hospitalization rate. The primary patient-level outcome was rehospitalization within 12 months of the index hospitalization. Census tract opportunity was characterized using the COI and its educational, health/environmental, and social/economic domains. RESULTS: Across 222 in-county census tracts, there were 2539 geocoded hospitalizations. The median asthma-related hospitalization rate was 5.0 per 1000 children per year (IQR, 1.9-8.9). Median hospitalization rates in very low, low, moderate, high, and very high opportunity tracts were 9.1, 7.6, 4.6, 2.1, and 1.8 per 1000, respectively (P < .0001). The social/economic domain had the most variables significantly associated with the outcome at the population level. The adjusted patient-level analyses showed that the COI was not significantly associated with a patient's risk of rehospitalization within 12 months. CONCLUSIONS: The COI was associated with population-level asthma morbidity. The details provided by the COI may inform interventions aimed at increasing opportunity and reducing morbidity across regions.

Characteristics of Pediatric Emergency Revisits After an Asthma-Related Hospitalization.

STUDY OBJECTIVE: We identify and characterize factors related to subsequent emergency revisits among children hospitalized for asthma. METHODS: This population-based, prospective, observational cohort included children aged 2 to 16 years, hospitalized for asthma at an urban pediatric facility and followed for greater than or equal to 12 months. The primary outcome was asthma-related emergency revisit within 12 months of discharge. Revisits were identified by billing codes, respiratory chief complaints, and medications administered (eg, albuterol, systemic corticosteroids), dispensed, or prescribed. Predictors and covariates include demographic, socioeconomic, access, and environmental exposure variables collected during index admission. Multivariable logistic regression was used to evaluate the association between predictors and odds of asthma-related revisit. RESULTS: A total of 671 children were enrolled; the majority were boys (65%), aged 4 to 11 years (59%), black (59%), and publicly insured (73%). There were 274 patients (41%) who were treated for asthma-related emergency revisits within 12 months of the index admission. In adjusted models, younger children, black children, children with excellent reported access to primary care, and children with a history of inhaled steroids were more likely to experience emergency revisits. Low income, detectable cotinine levels, and traffic exposure did not independently predict revisit. CONCLUSION: Asthma-related emergency revisit is common after hospitalization, with more than 40% of children returning within 12 months. Socioeconomic and exposure-related risk factors typically predictive of asthma morbidity were not independently associated with emergency revisit among children in this cohort.

Areas with High Rates of Police-Reported Violent Crime Have Higher Rates of Childhood Asthma Morbidity.

OBJECTIVES: To assess whether population-level violent (and all) crime rates were associated with population-level child asthma utilization rates and predictive of patient-level risk of asthma reutilization after a hospitalization. STUDY DESIGN: A retrospective cohort study of 4638 pediatric asthma-related emergency department visits and hospitalizations between 2011 and 2013 was completed. For population-level analyses, census tract asthma utilization rates were calculated by dividing the number of utilization events within a tract by the child population. For patient-level analyses, hospitalized patients (n = 981) were followed until time of first asthma-related reutilization. The primary predictor was the census tract rate of violent crime as recorded by the police; the all crime (violent plus nonviolent) rate was also assessed. RESULTS: Census tract-level violent and all crime rates were significantly correlated with asthma utilization rates (both P < .0001). The violent crime rate explained 35% of the population-level asthma utilization variance and remained associated with increased utilization after adjustment for census tract poverty, unemployment, substandard housing, and traffic exposure (P = .002). The all crime rate explained 28% of the variance and was similarly associated with increased utilization after adjustment (P = .02). Hospitalized children trended toward being more likely to reutilize if they lived in higher violent (P = .1) and all crime areas (P = .01). After adjustment, neither relationship was significant. CONCLUSIONS: Crime data could help facilitate early identification of potentially toxic stressors relevant to the control of asthma for populations and patients.

Financial and Social Hardships in Families of Children with Medical Complexity.

OBJECTIVE: To describe hardships experienced by families of children with medical complexity (CMC) and compare them with those experienced by families of children with asthma. STUDY DESIGN: We assessed hardships in a cohort of 167 families of CMC. Surveys assessed sociodemographics and hardships (eg, financial: inability to pay bills; social: limited help from family/friends). CMC cohort hardships were compared with those of an established cohort of children hospitalized with asthma using multivariable logistic regression. RESULTS: CMC had diagnoses in a median of 5 different complex chronic condition categories (most common neurologic/neuromuscular), and the majority (74%) were dependent on technology. Over 80% of families of CMC reported experiencing ≥1 hardship; 68% with financial and 46% with social hardship. Despite higher socioeconomic status than families with asthma, families of CMC often experienced more hardships. For example, families of CMC were significantly more likely to report failure to pay rent/mortgage (aOR 2.6, 95% CI 1.6, 4.3) and the expectation of little to no help from family/friends (aOR 2.9, 95% CI 1.9, 4.7). CONCLUSIONS: Families of CMC frequently report financial and social hardships, often at rates higher than families with asthma who were generally of lower socioeconomic status. Identifying and acting upon hardships may be an important addition to the care of CMC.

Care Coordination Associated with Improved Timing of Newborn Primary Care Visits.

Objective Despite practice recommendations that all newborns be examined within 3-5 days after discharge, many are not seen within this timeframe. Our objective was to determine the association between care coordination and timing of newborn follow-up. Methods This retrospective study evaluated 6251 newborns from eight maternity hospitals who scheduled a primary care appointment at one of two academic pediatric practices over 3.5 years. Two programs were sequentially implemented: (1) newborn discharge coordination, and (2) primary care intake coordination. Primary outcome was days between discharge and follow-up, dichotomized as ≤ or >5 days. Number of rescheduled appointments and loss to follow-up were also assessed. Adjusted relative risks (RR) and odds ratios (OR) were determined by piecewise generalized linear and logistic regression. Results Among 5943 newborns with a completed visit, 52.9 % were seen within 5 days of discharge (mean 6.7 days). After multivariable adjustment, the pre-exposure period (8 months) demonstrated a downward monthly trend in completing early follow-up (RR 0.93, p < 0.001). After initial program implementation, we observed a 3 % monthly increase (RR 1.03, p < 0.001 for test of slope change from pre-exposure to post-exposure), such that likelihood of recommended follow-up increased by roughly 72 % after discharge coordinator implementation and roughly 33 % after primary care coordinator implementation. The latter was also associated with a 13 % monthly decrease in odds of loss to follow-up (OR 0.87, p < 0.001). Conclusions for Practice Care coordination increases adherence among low income families to recommended newborn follow-up after birth hospitalization.

Pediatric asthma medication therapy management through community pharmacy and primary care collaboration.

OBJECTIVES: To design and implement a collaborative medication therapy management (MTM) program targeting pediatric patients with high-risk asthma in a community pharmacy. SETTING: Underserved inner city of Cincinnati, OH. PRACTICE DESCRIPTION: A large national grocery store chain pharmacy and an academic hospital developed a partnership aimed at improving asthma care for shared patients. An interdisciplinary project team was formed, including 2 clinical pharmacists, 1 pharmacy district clinical coordinator, 1 pharmacy division clinical coordinator, 1 associate professor at a college of pharmacy, 1 pharmacy resident, and 3 pediatric physicians. This pilot project involved 2 Kroger Pharmacy sites and Cincinnati Children's Hospital Medical Center's (CCHMC) 3 pediatric primary care centers. PRACTICE INNOVATION: Kroger and CCHMC staff identified shared high-risk asthma patients (those cared for at the included primary care centers who used Kroger for their medication fills) with the use of information from validated symptom assessments (Asthma Control Test), refill history, and recent health care utilization. Community pharmacists recruited jointly identified patients and provided a targeted MTM intervention. Education focused on asthma diagnosis, types of asthma medications, appropriate medication administration, and environmental triggers. Pharmacists suggested medication changes to prescribers via facsimile. Pharmacists followed up with patients in 30 days to assess asthma control, provide additional education, and propose further recommendations. EVALUATION: Outcomes evaluated included the average number of recommendations made to patients and prescribers and acceptance rates for each of those measures. RESULTS: Six patients completed the project. Pharmacists provided an average of 3.7 recommendations to each patient and 1.5 to prescribers for each patient; 77.3% and 100% recommendations were accepted, respectively. CONCLUSION: This pilot project describes the design and implementation of a pharmacist-physician collaborative program for high-risk pediatric asthma patients. The greatest outcome of this project was the formation of a collaborative team between pharmacists and physicians that continues to work together on additional family-centered initiatives.

Safety and activity of the anti-CD79B antibody-drug conjugate polatuzumab vedotin in relapsed or refractory B-cell non-Hodgkin lymphoma and chronic lymphocytic leukaemia: a phase 1 study.

BACKGROUND: Patients with relapsed or refractory B-cell non-Hodgkin lymphoma (NHL) have an unfavourable prognosis with few treatment options. Polatuzumab vedotin is an antibody-drug conjugate containing an anti-CD79B monoclonal antibody conjugated to the microtubule-disrupting agent monomethyl auristatin E. We aimed to assess the safety and clinical activity of polatuzumab vedotin in relapsed or refractory B-cell NHL and chronic lymphocytic leukaemia (CLL). METHODS: In this phase 1, multicentre, open-label study, we enrolled patients with documented NHL or CLL expected to express CD79B (confirmation of CD79B expression was not required) and for whom no suitable therapy of curative intent or higher priority existed from 13 centres. The primary endpoints of the study were to assess safety and tolerability, determine the maximum tolerated dose, and identify the recommended phase 2 dose of polatuzumab vedotin as a single agent and in combination with rituximab. A 3 + 3 dose-escalation design was used in which we treated patients with polatuzumab vedotin (0·1-2·4 mg/kg every 21 days) in separate dose-escalation cohorts for NHL and CLL. After determination of the recommended phase 2 dose, we enrolled patients with relapsed or refractory diffuse large B-cell lymphoma and relapsed or refractory indolent NHL into indication-specific cohorts. We also enrolled patients with relapsed or refractory NHL into an additional cohort to assess the feasibility of the combination of polatuzumab vedotin and rituximab 375 mg/m(2). Patients who received any dose of polatuzumab vedotin were available for safety analyses. This study is registered with ClinicalTrials.gov, number NCT01290549. FINDINGS: Between March 21, 2011, and Nov 30, 2012, we enrolled 95 patients (34 to the NHL dose-escalation cohort, 18 to the CLL dose-escalation cohort, 34 with NHL to the expansion cohort at the recommended phase 2 dose, and nine with NHL to the rituximab combination cohort; no expansion cohort of CLL was started due to lack of activity in the dose-escalation cohort). The recommended phase 2 dose in NHL was 2·4 mg/kg as a single agent and in combination with rituximab; the maximum tolerated dose in CLL was 1·0 mg/kg as a result of dose-limiting toxic effects reported in two of five patients given 1·8 mg/kg. Grade 3-4 adverse events were reported in 26 (58%) of 45 patients with NHL treated at the single-agent recommended phase 2 dose, and the most common grade 3-4 adverse events were neutropenia (18 [40%] of 45), anaemia (five [11%]), and peripheral sensory neuropathy (four [9%]). Serious adverse events were reported in 17 (38%) of 45 patients, and included diarrhoea (two patients), lung infection (two patients), disease progression (two patients), and lung disorder (two patients). Seven (77%) of nine patients in the rituximab combination cohort had a grade 3-4 adverse event, with neutropenia (five [56%]), anaemia (two [22%]), and febrile neutropenia (two [22%]) reported in more than one patient. 11 (12%) of 95 patients died during the study: eight with relapsed or refractory diffuse large B-cell lymphoma (due to progressive disease in four patients, infections in three patients [two treatment related], and treatment-related worsening ascites in one patient) and three with relapsed or refractory CLL (due to progressive disease, pulmonary infection, and pneumonia; none thought to be treatment-related). At the recommended phase 2 dose, objective responses were noted in 23 of 42 activity-evaluable patients with NHL given single-agent polatuzumab vedotin (14 of 25 with diffuse large B-cell lymphoma, seven of 15 with indolent NHL, and two with mantle-cell lymphoma) and seven of nine patients treated with polatuzumab vedotin combined with rituximab. No objective responses were observed in patients with CLL. INTERPRETATION: Polatuzumab vedotin has an acceptable safety and tolerability profile in patients with NHL but not in those with CLL. Its clinical activity should be further assessed in NHL. FUNDING: Genentech.

Pediatric asthma readmission: asthma knowledge is not enough?

OBJECTIVE: To characterize factors associated with readmission for acute asthma exacerbation, particularly around caregiver asthma knowledge, beliefs, and reported adherence to prescribed medication regimens. STUDY DESIGN: We enrolled 601 children (aged 1-16 years) who had been hospitalized for asthma. Caregivers completed a face-to-face survey regarding their asthma knowledge, beliefs, and medication adherence. Caregivers also reported demographic data, child's asthma severity, exposure to triggers, access to primary care, and financial strains. We prospectively identified asthma readmission events via billing data over a 1-year minimum follow-up period. We examined time to readmission with Cox proportional hazards. RESULTS: The study cohort's median age was 5 years, 53% were African American, and 57% were covered by Medicaid. At 1 year, 22% had been readmitted for asthma. In the multivariate analysis, a caregiver's demonstration of increased asthma knowledge was associated with increased readmission risk. In addition, children whose caregivers reported less-than-perfect adherence to daily medication regimens had increased readmission risk. Likewise, having previously been admitted for asthma, decreased medical home access, and black race were associated with increased readmission risk. CONCLUSION: In a multifactorial assessment of risk factors for asthma readmission, greater asthma knowledge and decreased medication adherence were associated with readmission. Inpatient efforts to prevent readmission might best target medication adherence rather than continuing to primarily provide asthma education.

Swine and influenza: a challenge to one health research.

The challenge of increasing swine production and a rising number of novel and known swine influenza viruses has prompted a considerable boost in research into how and why pigs have become such significant hosts for influenza viruses. The ecology of influenza A viruses is rather complicated, involving multiple host species and a segmented genome. Wild aquatic birds are the reservoir for the majority of influenza A viruses, but novel influenza viruses were recently identified in bats. Occasionally, influenza A viruses can be transmitted to mammals from avian species and this event could lead to the generation of human pandemic strains. Swine are thought to be "mixing vessels" because they are susceptible to infection with both avian and mammalian influenza viruses; and novel influenza viruses can be generated in pigs by reassortment. At present, it is difficult to predict which viruses might cause a human pandemic. Therefore, both human and veterinary research needs to give more attention to the potential cross-species transmission capacity of influenza A viruses.

A thorough QT study of guanfacine.

OBJECTIVES: Guanfacine extended- release (GXR) is approved for the treatment of attention-deficit/hyperactivity disorder in children and adolescents. As part of the clinical development of GXR, and to further explore the effect of guanfacine on QT intervals, a thorough QT study of guanfacine was conducted (ClinicalTrials. gov identifier: NCT00672984). METHODS: In this double-blind, 3-period, crossover trial, healthy adults (n = 83) received immediaterelease guanfacine (at therapeutic (4 mg) and supra-therapeutic (8 mg) doses), placebo, and 400 mg moxifloxacin (positive control) in 1 of 6 randomly assigned sequences. Continuous 12-lead electrocardiograms were extracted, and guanfacine plasma concentrations were assessed pre-dose and at intervals up to 24 hours post-dose. QT intervals were corrected using 2 methods: subject-specific (QTcNi) and Fridericia (QTcF). Time-matched analyses examined the largest, baseline-adjusted, drug-placebo difference in QTc intervals. RESULTS: In the QTcNi analysis, the largest 1-sided 95% upper confidence bound (UCB) through hour 12 was 1.94 ms (12 hours postdose). For the 12-hour QTcF analysis, the largest 1-sided 95% UCB was 10.34 ms (12 hours post-supratherapeutic dose), representing the only 1-sided 95% UCB > 10 ms. Following the supra-therapeutic dose, maximum guanfacine plasma concentration was attained at 5.0 hours (median) post-dose. Assay sensitivity was confirmed by moxifloxacin results. Among guanfacine-treated subjects, most treatment-emergent adverse events were mild (78.9%); dry mouth (65.8%) and dizziness (61.8%) were most common. CONCLUSIONS: Neither therapeutic nor supra-therapeutic doses of guanfacine prolonged QT interval after adjusting for heart rate using individualized correction, QTcNi, through 12 hours postdose. Guanfacine does not appear to interfere with cardiac repolarization of the form associated with pro-arrhythmic drugs.