Adverse Events Among Young Adults Following a Third Dose of Measles-Mumps-Rubella Vaccine.

BACKGROUND: A third measles-mumps-rubella vaccine (MMR) dose (MMR3) is recommended in the United States for persons at increased risk for mumps during outbreaks. MMR3 is also likely given to persons who might have received 2 doses of MMR but lack documentation. Since MMR3 safety data are limited, we describe adverse events in persons receiving MMR3 in a nonoutbreak setting. METHODS: Young adults with 2 documented MMR doses were administered MMR3. From 2 weeks before until 4 weeks after MMR3 receipt, participants reported daily on 11 solicited, common symptoms potentially associated with MMR. Weekly rate differences in post- vs prevaccination (baseline) were evaluated by Poisson regression. Baseline rates were subtracted from postvaccination rates of significantly different symptoms to estimate the number and percentage of participants with excess risk for symptoms post-MMR3. Descriptive analyses were performed for 3 postvaccination injection-site symptoms. RESULTS: The 662 participants were aged 18-28 years (median = 20 years); 56% were women. Headache, joint problems, diarrhea, and lymphadenopathy rates were significantly higher postvaccination vs baseline. We estimate that 119 participants (18%) reported more symptoms after MMR3 than prevaccination. By symptom, 13%, 10%, 8%, and 6% experienced increased symptoms of headache, joint problems, diarrhea, and lymphadenopathy, respectively, after MMR3. The median onset was Days 3-6 postvaccination; the median duration was 1-2 days. One healthcare visit for a potential vaccination-related symptom (urticaria) was reported. Injection-site symptoms were reported by 163 participants (25%); the median duration was 1-2 days. CONCLUSIONS: Reported systemic and local events were mild and transient. MMR3 is safe and tolerable among young adults.

Upper Airway Cell Transcriptomics Identify a Major New Immunological Phenotype with Strong Clinical Correlates in Young Children with Acute Wheezing.

Asthma exacerbations are triggered by rhinovirus infections. We employed a systems biology approach to delineate upper-airway gene network patterns underlying asthma exacerbation phenotypes in children. Cluster analysis unveiled distinct IRF7hi versus IRF7lo molecular phenotypes, the former exhibiting robust upregulation of Th1/type I IFN responses and the latter an alternative signature marked by upregulation of cytokine and growth factor signaling and downregulation of IFN-γ. The two phenotypes also produced distinct clinical phenotypes. For IRF7lo children, symptom duration prior to hospital presentation was more than twice as long from initial symptoms (p = 0.011) and nearly three times as long for cough (p < 0.001), the odds ratio of admission to hospital was increased more than 4-fold (p = 0.018), and time to recurrence was shorter (p = 0.015). In summary, our findings demonstrate that asthma exacerbations in children can be divided into IRF7hi versus IRF7lo phenotypes with associated differences in clinical phenotypes.

Measles Virus Neutralizing Antibody Response, Cell-Mediated Immunity, and Immunoglobulin G Antibody Avidity Before and After Receipt of a Third Dose of Measles, Mumps, and Rubella Vaccine in Young Adults.

BACKGROUND: Two doses of measles, mumps, and rubella (MMR) vaccine are 97% effective against measles, but waning antibody immunity to measles and failure of the 2-dose vaccine occur. We administered a third MMR dose (MMR3) to young adults and assessed immunogenicity over 1 year. METHODS: Measles virus (MeV) neutralizing antibody concentrations, cell-mediated immunity (CMI), and immunoglobulin G (IgG) antibody avidity were assessed at baseline and 1 month and 1 year after MMR3 receipt. RESULTS: Of 662 subjects at baseline, 1 (0.2%) was seronegative for MeV-neutralizing antibodies (level, <8 mIU/mL), and 23 (3.5%) had low antibody levels (8-120 mIU/mL). One month after MMR3 receipt, 1 subject (0.2%) was seronegative, and 6 (0.9%) had low neutralizing antibodies, with only 21 of 662 (3.2%) showing a ≥ 4-fold rise in neutralizing antibodies. One year after MMR3 receipt, no subject was seronegative, and 10 of 617 (1.6%) had low neutralizing antibody levels. CMI analyses showed low levels of spot-forming cells after stimulation, suggesting the presence of T-cell memory, but the response was minimal after MMR3 receipt. MeV IgG avidity did not correlate with findings of neutralization analyses. CONCLUSIONS: Most subjects were seropositive before MMR3 receipt, and very few had a secondary immune response after MMR3 receipt. Similarly, CMI and avidity analyses showed minimal qualitative improvements in immune response after MMR3 receipt. We did not find compelling data to support a routine third dose of MMR vaccine.

Seasonal Influenza Vaccination of Children Induces Humoral and Cell-Mediated Immunity Beyond the Current Season: Cross-reactivity With Past and Future Strains.

BACKGROUND: Influenza viruses gradually accumulate point mutations, reducing the effectiveness of prior immune protection. METHODS: Children aged 9-14 years received 2010-2011 trivalent inactivated influenza vaccine (TIV). Vaccination history, hemagglutination-inhibition (HI) titers, and cell-mediated immune responses were assessed to investigate the cross-reactivity with past and future influenza virus strains. RESULTS: 2010-2011 TIV induced significant T-cell responses and HI titers of ≥160, with a fold-rise of ≥4 and titers of ≥100 maintained for >7 months in the majority of children. Pre-existing memory B cells in these children differentiated quickly to antibody-secreting cells to the new vaccine antigens. Children vaccinated in the previous year maintained high HI titers well into 2010, demonstrating elevated HI titers against A/Perth/16/2009, the future (in 2010-2011) H3N2 component. Prior vaccination enhanced CD8+ T-cell responses to A/Perth/16/2009. Children vaccinated with the prior 2009-2010 seasonal vaccine also demonstrated higher preexisting levels of interferon γ-secreting CD4+CD69+ T cells to 2009 pandemic influenza A(H1N1). Children previously vaccinated with 2009-2010 seasonal influenza vaccine also showed greater expansion of tumor necrosis factor α-secreting CD8+CD69+ T cells to 2009 pandemic influenza A(H1N1) upon vaccination in the 2010-2011 season than those who were not previously vaccinated. CONCLUSIONS: Seasonal influenza viruses continuously drift, which allows them to circumvent protective immunity, but conserved epitopes provide immunological cross-reactivity in children through either vaccination directly or through prime/boost in the prior influenza season.

Comparison of Interviewer-Administered and Automated Self-Administered 24-Hour Dietary Recalls in 3 Diverse Integrated Health Systems.

Twenty-four-hour dietary recalls provide high-quality intake data but have been prohibitively expensive for large epidemiologic studies. This study's goal was to assess whether the web-based Automated Self-Administered 24-Hour Recall (ASA24) performs similarly enough to the standard interviewer-administered, Automated Multiple-Pass Method (AMPM) 24-hour dietary recall to be considered a viable alternative. In 2010-2011, 1,081 adults from 3 integrated health systems in Detroit, Michigan; Marshfield, Wisconsin; and Kaiser-Permanente Northern California participated in a field trial. A quota design ensured a diverse sample by sex, age, and race/ethnicity. Each participant was asked to complete 2 recalls and was randomly assigned to 1 of 4 protocols differing by type of recall and administration order. For energy, the mean intakes were 2,425 versus 2,374 kcal for men and 1,876 versus 1,906 kcal for women by AMPM and ASA24, respectively. Of 20 nutrients/food groups analyzed and controlling for false discovery rate, 87% were judged equivalent at the 20% bound. ASA24 was preferred over AMPM by 70% of the respondents. Attrition was lower in the ASA24/AMPM study group than in the AMPM/ASA24 group, and it was lower in the ASA24/ASA24 group than in the AMPM/AMPM group. ASA24 offers the potential to collect high-quality dietary intake information at low cost with less attrition.

Factors associated with maintenance of antibody responses to influenza vaccine in older, community-dwelling adults.

BACKGROUND: Little is known about factors associated with maintenance of hemagglutinin inhibition (HAI) antibodies after influenza vaccination in older adults. METHODS: Adults ≥50 years of age were vaccinated prior to the 2009-10 influenza season. Serum was drawn pre-vaccination (S1), 21-28 days post-vaccination (S2), and after the influenza season (S3) for HAI assays. Seroconversion was defined as ≥ 4-fold increase S1 to S2 (or if S1 < 10, by an S2 ≥ 40) and seroprotection was defined as S2 ≥ 40. Maintenance of antibody response was measured in participants with an S2 ≥ 40, and defined as an S3 ≥ 40. RESULTS: We enrolled 510 participants during Fall 2009 at Vanderbilt University Medical Center and Marshfield Clinic Research Foundation. Participants' mean age was 64 years with 62% female and 96% white. Seroconversion and seroprotection rates were lowest for influenza A H1N1 (12% and 26%, respectively), highest for influenza A H3N2 (45% and 82%), and intermediate for influenza B (28% and 72%). Of the participants with an S2 ≥ 40, 36% (46/126), 71% (289/407), and 74% (263/354) maintained an S3 ≥ 40 for H1N1, H3N2, and B influenza vaccine strains, respectively. S1 HAI titer was strongly associated with both post-vaccination seroprotection and maintaining seroprotection at S3 for all three influenza antigens. Age, sex, body mass index, self-reported stress, and vaccination site were not consistently associated with vaccine response or maintenance of response. CONCLUSIONS: Pre-vaccination antibody titer was the only study variable consistently and positively associated with both serologic response to vaccination and maintenance of response. Antibody responses were lowest for the H1N1 vaccine strain. CLINICALTRIALS: gov Identifier: NCT02401893.

GPs have key role in early diagnosis of endometriosis.

Endometriosis is defined as the presence of endometrial-like tissue outside the uterus. Deposits are commonly distributed on the ovaries, uterosacral ligaments, pouch of Douglas, rectum and sigmoid colon, bladder and ureter. Endometriosis is common, affecting 10% of the female adult population and up to 50% of women with infertility. Risk factors include early menarche, late menopause, delayed childbearing, vaginal outflow obstruction and a first-degree relative affected. Women commonly present to their GP with pelvic pain, painful intercourse or subfertility. Classically the pain starts several days before the period which is extremely painful. After the period, symptoms tend to improve until mid-cycle when the pattern repeats again. Patients also complain of fatigue. Abdominal palpation, bimanual and speculum examination are important to identify signs of endometriosis, but also to exclude alternative diagnoses such as fibroid uterus, infection or pregnancy. However, a normal examination does not exclude a diagnosis of endometriosis. Serum CA125 can be raised in endometriosis but is not specific or sensitive for the condition and is therefore not recommended as a screening test. A normal pelvic ultrasound scan does not exclude a diagnosis of endometriosis. The gold standard investigation for endometriosis is laparoscopy and biopsy with histological confirmation. Referral should be considered if pain is not controlled with simple analgesia or the diagnosis is suspected in a woman who is actively trying to conceive. Early referral should be considered in women with abnormal examination findings, or an abnormal ultrasound result.

Effectiveness of seasonal influenza vaccines in the United States during a season with circulation of all three vaccine strains.

BACKGROUND: Influenza vaccines may be reformulated annually because of antigenic drift in influenza viruses. However, the relationship between antigenic characteristics of circulating viruses and vaccine effectiveness (VE) is not well understood. We conducted an assessment of the effectiveness of US influenza vaccines during the 2010-2011 season. METHODS: We performed a case-control study comparing vaccination histories between subjects with acute respiratory illness with positive real-time reverse transcription polymerase chain reaction for influenza and influenza test-negative controls. Subjects with acute respiratory illness of ≤7 days duration were enrolled in hospitals, emergency departments, or outpatient clinics in communities in 4 states. History of immunization with the 2010-2011 vaccine was ascertained from vaccine registries or medical records. Vaccine effectiveness was estimated in logistic regression models adjusted for study community, age, race, insurance status, enrollment site, and presence of a high-risk medical condition. RESULTS: A total of 1040 influenza-positive cases and 3717 influenza-negative controls were included from the influenza season, including 373 cases of influenza A(H1N1), 334 cases of influenza A(H3N2), and 333 cases of influenza B. Overall adjusted VE was 60% (95% confidence interval [CI], 53%-66%). Age-specific VE estimates ranged from 69% (95% CI, 56%-77%) in children aged 6 months-8 years to 38% (95% CI, -16% to 67%) in adults aged ≥65 years. CONCLUSIONS: The US 2010-2011 influenza vaccines were moderately effective in preventing medically attended influenza during a season when all 3 vaccine strains were antigenically similar to circulating viruses. Continued monitoring of influenza vaccines in all age groups is important, particularly as new vaccines are introduced.

Impact of diabetes status on immunogenicity of trivalent inactivated influenza vaccine in older adults.

Individuals with type 2 diabetes mellitus experience high rates of influenza virus infection and complications. We compared the magnitude and duration of serologic response to trivalent influenza vaccine in adults aged 50-80 with and without type 2 diabetes mellitus. Serologic response to influenza vaccination was similar in both groups: greater fold-increases in antibody titer occurred among participants with lower pre-vaccination antibody titers. Waning of antibody titers was not influenced by diabetes status.

Dietary intake in the Personalized Medicine Research Project: a resource for studies of gene-diet interaction.

BACKGROUND: To describe the dietary intake of participants in the Personalized Medicine Research Project (PMRP), and to quantify differences in nutrient intake by smoking status and APOE4-a genetic marker that has been shown to modify the association between risk factors and outcomes. METHODS: The PMRP is a population-based DNA, plasma and serum biobank of more than 20,000 adults aged 18 years and older in central Wisconsin. A questionnaire at enrollment captures demographic information as well as self-reported smoking and alcohol intake. The protocol was amended to include the collection of dietary intake and physical activity via self-reported questionnaires: the National Cancer Institute 124-item Diet History Questionnaire and the Baecke Physical Activity Questionnaire. These questionnaires were mailed out to previously enrolled participants. APOE was genotyped in all subjects. RESULTS: The response rate to the mailed questionnaires was 68.2% for subjects who could still be contacted (alive with known address). Participants ranged in age from 18 to 98 years (mean 54.7) and 61% were female. Dietary intake is variable when comparing gender, age, smoking, and APOE4. Over 50% of females are dietary supplement users; females have higher supplement intake than males, but both have increasing supplement use as age increases. Food energy, total fat, cholesterol, protein, and alcohol intake decreases as both males and females age. Female smokers had higher macronutrient intake, whereas male nonsmokers had higher macronutrient intake. Nonsmokers in both genders use more supplements. In females, nonsmokers and smokers with APOE4 had higher supplement use. In males, nonsmokers with APOE4 had higher supplement use between ages 18-39 only, and lower supplement use at ages above 39. Male smokers with APOE4 had lower supplement use. CONCLUSION: Dietary intake in PMRP subjects is relatively consistent with data from the National Health and Nutrition Examination Survey (NHANES). Findings suggest a possible correlation between the use of supplements and APOE4. The PMRP dietary data can benefit studies of gene-environment interactions and the development of common diseases.

Association between physiological performance and short temporal changes in habitat utilisation modulated by environmental factors.

Temporal environmental variability causes behavioural and physiological responses in organisms that can affect their spatial location in time, and ultimately drive changes in population and community dynamics. Linking ecological changes with underlying environmental drivers is a complex task that can however be facilitated through the integration of physiology. Our overarching aim was to investigate the association between physiological performance and habitat utilisation patterns modulated by short temporal fluctuations in environmental factors. We used in situ monitoring data from a system experiencing extreme environmental fluctuations over a few hours and we selected four fish species with different habitat utilisation patterns across dissolved oxygen (DO) fluctuations: two commonly observed species (Siganus lineatus and Acanthopagrus pacificus), including at low DO (40 and 50% saturation, respectively), and two reef species (Heniochus acuminatus and Chaetodon vagabundus) never recorded below 70% saturation. We hypothesised that these patterns were associated to species' physiological performance in hypoxia. Therefore, we measured different metabolic variables (O2crit, incipient lethal oxygen (ILO), time to ILO, index of cumulative ambient oxygen deficit (O2deficit), maximum oxygen supply capacity (α)) using respirometry. Physiological performance differed among species and was intrinsically associated to habitat use patterns. S. lineatus had a lower O2crit than H. acuminatus, A. pacificus and C. vagabundus (13, 18.7, 20 and 20.2% saturation respectively). Additionally, S. lineatus and A. pacificus displayed better capacity for survival below O2crit than C. vagabundus and H. acuminatus (lower ILO, higher O2deficit and longer time to ILO) and higher α. Field monitoring data revealed that DO temporarily falls below species' O2crit and even ILO on most days, suggesting that short temporal variability in DO likely forces species to temporarily avoid harmful conditions, driving important changes in ecosystem structure over a few hours. Our results support the hypothesis that organismal physiology can provide insights into ecological changes occurring over a few hours as a result of environmental variability. Consequently, integrating physiology with ecological data at relevant temporal scales may help predict temporal shifts in ecosystems structure and functions to account for ecological patterns often overlooked and difficult to identify.

Personal Network Inference Unveils Heterogeneous Immune Response Patterns to Viral Infection in Children with Acute Wheezing.

Human rhinovirus (RV)-induced exacerbations of asthma and wheeze are a major cause of emergency room presentations and hospital admissions among children. Previous studies have shown that immune response patterns during these exacerbations are heterogeneous and are characterized by the presence or absence of robust interferon responses. Molecular phenotypes of asthma are usually identified by cluster analysis of gene expression levels. This approach however is limited, since genes do not exist in isolation, but rather work together in networks. Here, we employed personal network inference to characterize exacerbation response patterns and unveil molecular phenotypes based on variations in network structure. We found that personal gene network patterns were dominated by two major network structures, consisting of interferon-response versus FCER1G-associated networks. Cluster analysis of these structures divided children into subgroups, differing in the prevalence of atopy but not RV species. These network structures were also observed in an independent cohort of children with virus-induced asthma exacerbations sampled over a time course, where we showed that the FCER1G-associated networks were mainly observed at late time points (days four-six) during the acute illness. The ratio of interferon- and FCER1G-associated gene network responses was able to predict recurrence, with low interferon being associated with increased risk of readmission. These findings demonstrate the applicability of personal network inference for biomarker discovery and therapeutic target identification in the context of acute asthma which focuses on variations in network structure.

Effect of Bimagrumab vs Placebo on Body Fat Mass Among Adults With Type 2 Diabetes and Obesity: A Phase 2 Randomized Clinical Trial.

Importance: Antibody blockade of activin type II receptor (ActRII) signaling stimulates skeletal muscle growth. Previous clinical studies suggest that ActRII inhibition with the monoclonal antibody bimagrumab also promotes excess adipose tissue loss and improves insulin resistance. Objective: To evaluate the efficacy and safety of bimagrumab on body composition and glycemic control in adults with type 2 diabetes and overweight and obesity. Design, Setting, and Participants: This double-masked, placebo-controlled, 48-week, phase 2 randomized clinical trial was conducted among adults with type 2 diabetes, body mass index between 28 and 40, and glycated hemoglobin (HbA1c) levels between 6.5% and 10.0% at 9 US and UK sites. The trial was conducted from February 2017 to May 2019. Only participants who completed a full treatment regimen were included in analysis. Interventions: Patients were randomized to intravenous infusion of bimagrumab (10 mg/kg up to 1200 mg in 5% dextrose solution) or placebo (5% dextrose solution) treatment every 4 weeks for 48 weeks; both groups received diet and exercise counseling. Main Outcomes and Measures: The primary end point was least square mean change from baseline to week 48 in total body fat mass (FM); secondary and exploratory end points were lean mass (LM), waist circumference (WC), HbA1c level, and body weight (BW) changes from baseline to week 48. Results: A total of 75 patients were randomized to bimagrumab (n = 37; 23 [62.2%] women) or placebo (n = 38; 12 [31.6%] women); 58 (77.3%) completed the 48-week study. Patients at baseline had a mean (SD) age of 60.4 (7.7) years; mean (SD) BMI of 32.9 (3.4); mean (SD) BW of 93.6 (14.9) kg; mean (SD) FM of 35.4 (7.5) kg; and mean (SD) HbA1c level of 7.8% (1.0%). Changes at week 48 for bimagrumab vs placebo were as follows: FM, -20.5% (-7.5 kg [80% CI, -8.3 to -6.6 kg]) vs -0.5% (-0.18 kg [80% CI, -0.99 to 0.63 kg]) (P < .001); LM, 3.6% (1.70 kg [80% CI, 1.1 to 2.3 kg]) vs -0.8% (-0.4 kg [80% CI, -1.0 to 0.1 kg]) (P < .001); WC, -9.0 cm (80% CI, -10.3 to -7.7 cm) vs 0.5 cm (80% CI, -0.8 to 1.7 cm) (P < .001); HbA1c level, -0.76 percentage points (80% CI, -1.05 to -0.48 percentage points) vs -0.04 percentage points (80% CI, -0.23 to 0.31 percentage points) (P = .005); and BW, -6.5% (-5.9 kg [80% CI, -7.1 to -4.7 kg]) vs -0.8% (-0.8 kg [80% CI, -1.9 to 0.3 kg]) (P < .001). Bimagrumab's safety and tolerability profile was consistent with prior studies. Conclusions and Relevance: In this phase 2 randomized clinical trial, ActRII blockade with bimagrumab led to significant loss of FM, gain in LM, and metabolic improvements during 48 weeks in patients with overweight or obesity who had type 2 diabetes. ActRII pathway inhibition may provide a novel approach for the pharmacologic management of excess adiposity and accompanying metabolic disturbances. Trial Registration: ClinicalTrials.gov number: NCT03005288.

Body mass index measurement and obesity prevalence in ten U.S. health plans.

OBJECTIVE: The objective of this study was to examine the frequency of body mass index (BMI) measurement before the implementation of two new Healthcare Effectiveness Data and Information Set (HEDIS) performance measures for obesity that require U.S. health plans to annually report the frequency of BMI and BMI percentile measurement among all adults and children who had at least one outpatient visit during the past two years. DESIGN: Cross-sectional study. SETTING: A consortium of ten U.S. health plans and care delivery systems from the Health Maintenance Organization Research Network, which together provide care to more than 6.5 million adults and children. PARTICIPANTS: Children and adults, age 2 years and older, who were continuously enrolled in one of ten U.S. health plans for at least one full year from 2005 to 2006. METHODS: We extracted available anthropometric data for 3.7 million adults and 1.2 million children with at least one visit captured from ten electronic medical record databases from 2005 to 2006. RESULTS: We found that the availability of BMI measurements for adults ranged widely across health plans from 28% to 88%, and availability of BMI percentiles for children ranged from 21% to 81%. Among adults and children with BMI measures in these ten health plans, the overall prevalence of overweight and obesity were very similar to those reported in the 2005 to 2006 U.S. national surveys that used measured heights and weights. CONCLUSION: The newly approved HEDIS performance measures likely represent an important step in addressing the quality of obesity care in the United States. The current study demonstrates that these HEDIS measures are achievable, especially among health plans that have implemented electronic medical records. Future research should assess the relationship between BMI assessment, provider counseling and treatment practices, and long-term changes in obesity rates among different population groups.

Clinical characteristics and 30-day outcomes for influenza A 2009 (H1N1), 2008-2009 (H1N1), and 2007-2008 (H3N2) infections.

CONTEXT: The clinical characteristics of pandemic 2009 influenza A(H1N1) infections have not been compared directly with illnesses caused by other influenza A strains. OBJECTIVE: To compare clinical features and outcomes for 2009 H1N1, seasonal H1N1, and H3N2 influenza in a population-based cohort. DESIGN, SETTING, AND PARTICIPANTS: Active surveillance with 30-day follow-up for influenza cases among children and adults living in a 14-zip code area in Wisconsin. Patients with subjective fever, chills, or cough of fewer than 8 days' duration were screened for eligibility during an outpatient or inpatient encounter. Consenting patients were interviewed and tested for influenza A during the 2007-2008 and 2008-2009 influenza seasons and from May to November 2009; 6874 patients (70%-86% of eligible patients) agreed to participate. Medical records were reviewed to assess outcomes. MAIN OUTCOME MEASURES: Hospital admission, radiographically confirmed pneumonia, and clinical characteristics of influenza A by strain. RESULTS: We identified 545 2009 H1N1, 221 seasonal H1N1, and 632 H3N2 infections. The median ages of infected participants were 10, 11, and 25 years, respectively (P < .001). Hospital admission occurred within 30 days for 6 of 395 children with 2009 H1N1 (1.5%; 95% confidence interval [CI], 0.6%-3.1%), 5 of 135 with seasonal H1N1 (3.7%; 95% CI, 1.4%-8.0%), and 8 of 255 with H3N2 (3.1%; 95% CI, 1.5%-5.9%). Among adults, hospital admission occurred in 6 of 150 with 2009 H1N1 (4.0%; 95% CI, 1.6%-8.1%), 2 of 86 with seasonal H1N1 (2.3%; 95% CI, 0.3%-8.1%), and 17 of 377 with H3N2 (4.5%; 95% CI, 2.7%-7.0%). Pneumonia occurred in 10 children with 2009 H1N1 (2.5%; 95% CI, 1.3%-4.5%), 2 with seasonal H1N1 (1.5%; 95% CI, 0.2%-5.2%), and 5 with H3N2 (2.0%; 95% CI, 0.7%-4.3%). Among adults, pneumonia occurred in 6 with 2009 H1N1 (4.0%; 95% CI, 1.6%-8.1%), 2 with seasonal H1N1 (2.3%; 95% CI, 0.3%-8.1%), and 4 with H3N2 (1.1%; 95% CI, 0.3%-2.7%). CONCLUSIONS: In this population, individuals with 2009 H1N1 infection were younger than those with H3N2. The risk of most serious complications was not elevated in adults or children with 2009 H1N1 compared with recent seasonal strains.

Patient initiated follow up after gynaecological malignancy: National survey of current UK practice.

OBJECTIVE: To establish the prevalence of follow up regimes following treatment for gynaecological malignancies in the UK. STUDY DESIGN: Online questionnaire Survey of gynaecological cancer centres across the UK. All members of the British Gynaecological Cancer Society (BGCS) and the National Forum of Gynaecological Oncology Nurses (NFGON) were invited to complete the survey between 12/07/2018 and 12/04/2019. Responses were grouped into cancer centres for analysis. RESULTS: 90 % (44/49) of cancer centres from across the UK responded. All centres offer consultant follow up, most commonly for 5 years (77 %). Routine CA125 surveillance was performed for ovarian cancer in 27 % and cervical or vault cytology for cervical cancer in 9 %. Cancer centres also utilised patient initiated follow up (PIFU) (42 %), telephone follow up (36 %) and nurse led follow up (45 %). PIFU was most commonly offered in endometrial cancer (100 %) but also in vulval (26 %), cervical (32 %) and ovarian (26 %) cancer. Timing of PIFU initiation following completion of treatment varied by cancer stage and grade in endometrial cancer. For patients with grade 1 stage 1a endometrial cancer, PIFU was initiated within 3 months in 82 % of centres that use PIFU. CONCLUSION: Non hospital based follow up regimes are increasingly prevalent in the UK following gynaecological malignancy. The appointment and cost savings in secondary care may be significant however there is likely to be a substantial impact on the primary care sector. There is no evidence regarding the impact of PIFU on overall survival and a randomised controlled trial is strongly recommended.

Vitamin D receptor polymorphisms are associated with severity of wheezing illnesses and asthma exacerbations in children.

Single nucleotide polymorphisms (SNPs) of the vitamin D receptor (VDR) gene have shown linkage and association with asthma development in multiple cohort studies. However, the majority of investigations have focused on asthma phenotypes in cohorts with stable disease. We investigated the relationship between VDR SNPs and the frequency and severity of acute episodes of wheeze/asthma in a cohort of Australian children, as the ability to identify children at risk of more severe exacerbations could lead to personalized and improved genotype-specific treatment pathways. We successfully genotyped five SNPs of the VDR gene (rs2525046, rs9729, rs1544410 (BsmI), rs22239179, and rs2228570 (FokI)) in 657 children presenting to a tertiary children's hospital with acute asthma, bronchiolitis, or a wheezing illness. The relationships between VDR SNPs and exacerbation severity scores, ß2-agonist use, and frequency of respiratory exacerbations were analysed using multiple regression. The rs2525046 (FokI) CT genotype was associated with higher VDR mRNA intensity levels (p = 0.007) compared to the CC genotype. A trend towards significance (p=0.056) was identified between the rs2525046 TT genotype and higher VDR mRNA intensity levels compared to the CC genotype. Children with rs2228570 AA genotype had higher exacerbation severity scores (p=0.001) and poorer ß2-agonist treatment response (doses at 6 h: p = 0.009 and 12 h: p=0.033) compared to those with the GG genotype. Children with rs1544410 (BsmI) TT genotype had lower exacerbation severity scores (p = 0.005) compared to those with the CC genotype. Children with rs2228570 GA genotype presented to and/or were admitted to hospital more times since birth with respiratory (p = 0.011) and wheezing (p = 0.021) illnesses than children with the GG genotype. No associations were identified between rs9729, rs2525046 and r2239179 polymorphisms and acute wheezing/asthma variables. These findings suggest that genetic variants at the VDR locus may play a role in acute wheeze/asthma severity in children.

Bimagrumab vs Optimized Standard of Care for Treatment of Sarcopenia in Community-Dwelling Older Adults: A Randomized Clinical Trial.

Importance: The potential benefit of novel skeletal muscle anabolic agents to improve physical function in people with sarcopenia and other muscle wasting diseases is unknown. Objective: To confirm the safety and efficacy of bimagrumab plus the new standard of care on skeletal muscle mass, strength, and physical function compared with standard of care alone in community-dwelling older adults with sarcopenia. Design, Setting, and Participants: This double-blind, placebo-controlled, randomized clinical trial was conducted at 38 sites in 13 countries among community-dwelling men and women aged 70 years and older meeting gait speed and skeletal muscle criteria for sarcopenia. The study was conducted from December 2014 to June 2018, and analyses were conducted from August to November 2018. Interventions: Bimagrumab 700 mg or placebo monthly for 6 months with adequate diet and home-based exercise. Main Outcomes and Measures: The primary outcome was the change in Short Physical Performance Battery (SPPB) score after 24 weeks of treatment. Secondary outcomes included 6-minute walk distance, usual gait speed, handgrip strength, lean body mass, fat body mass, and standard safety parameters. Results: A total of 180 participants were recruited, with 113 randomized to bimagrumab and 67 randomized to placebo. Among these, 159 participants (88.3%; mean [SD] age, 79.1 [5.3] years; 109 [60.6%] women) completed the study. The mean SPPB score increased by a mean of 1.34 (95% CI, 0.90 to 1.77) with bimagrumab vs 1.03 (95% CI, 0.53 to 1.52) with placebo (P = .13); 6-minute walk distance increased by a mean of 24.60 (95% CI, 7.65 to 41.56) m with bimagrumab vs 14.30 (95% CI, -4.64 to 33.23) m with placebo (P = .16); and gait speed increased by a mean of 0.14 (95% CI, 0.09 to 0.18) m/s with bimagrumab vs 0.11 (95% CI, 0.05 to 0.16) m/s with placebo (P = .16). Bimagrumab was safe and well-tolerated and increased lean body mass by 7% (95% CI, 6% to 8%) vs 1% (95% CI, 0% to 2%) with placebo, resulting in difference of 6% (95% CI, 4% to 7%) (P < .001). Conclusions and Relevance: This randomized clinical trial found no significant difference between participants treated with bimagrumab vs placebo among older adults with sarcopenia who had 6 months of adequate nutrition and light exercise, with physical function improving in both groups. Bimagrumab treatment was safe, well-tolerated, increased lean body mass, and decreased fat body mass. The effects of sarcopenia, an increasing cause of disability in older adults, can be reduced with proper diet and exercise. Trial Registration: ClinicalTrials.gov Identifier: NCT02333331; EudraCT number: 2014-003482-25.

Aberrant cell migration contributes to defective airway epithelial repair in childhood wheeze.

Abnormal wound repair has been observed in the airway epithelium of patients with chronic respiratory diseases, including asthma. Therapies focusing on repairing vulnerable airways, particularly in early life, present a potentially novel treatment strategy. We report defective lower airway epithelial cell repair to strongly associate with common pre-school-aged and school-aged wheezing phenotypes, characterized by aberrant migration patterns and reduced integrin α5ß1 expression. Next generation sequencing identified the PI3K/Akt pathway as the top upstream transcriptional regulator of integrin α5ß1, where Akt activation enhanced repair and integrin α5ß1 expression in primary cultures from children with wheeze. Conversely, inhibition of PI3K/Akt signaling in primary cultures from children without wheeze reduced α5ß1 expression and attenuated repair. Importantly, the FDA-approved drug celecoxib - and its non-COX2-inhibiting analogue, dimethyl-celecoxib - stimulated the PI3K/Akt-integrin α5ß1 axis and restored airway epithelial repair in cells from children with wheeze. When compared with published clinical data sets, the identified transcriptomic signature was also associated with viral-induced wheeze exacerbations highlighting the clinical potential of such therapy. Collectively, these results identify airway epithelial restitution via targeting the PI3K-integrin α5ß1 axis as a potentially novel therapeutic avenue for childhood wheeze and asthma. We propose that the next step in the therapeutic development process should be a proof-of-concept clinical trial, since relevant animal models to test the crucial underlying premise are unavailable.