Spatiotemporal analysis of out-of-hospital cardiac arrest in the City of Los Angeles, 2011-2019.

OBJECTIVE: The goal of this analysis is to spatiotemporally identify and categorize areas in a large urban city according to Out-of-Hospital Cardiac Arrest (OHCA) rates and No Bystander CPR (NBCPR) risk levels. STUDY AREA AND PARTICIPANTS: The study comprised all cardiac arrests within the administrative geographic boundary of the City of Los Angeles. The final sample included 15,904 cases that were geolocated within 985 census tracts. MAIN OUTCOMES AND MEASURES: The primary outcome was stratification of census tracts into risk levels of OHCA and NBCPR by observed spatiotemporal patterns. RESULTS: Of 985 census tracts in the analytical sample, 182 census tracts (18.5%) were identified as having higher risk of OHCA and NBCPR. This assessment resulted in 129 census tracts in Tier 3 (moderate risk), 36 in Tier 2 (moderate-high risk), and 17 in Tier 1 (highest risk). Census tracts in Tiers 2 and 3 had higher amounts incident OHCA, while those in tier 1 had more OHCA events with NBCPR. These areas were largely contiguous and located in the Central and South areas of Los Angeles. CONCLUSIONS: Using a novel three-tiered neighborhood risk classification tool, specific neighborhoods have been identified in the second largest city in the U.S. with consistently high or accelerating rates of OHCA and low bystander CPR. Further study of bystander response and community-based public health campaigns are needed in these communities.

Safety of Abatacept Versus Placebo in Rheumatoid Arthritis: Integrated Data Analysis of Nine Clinical Trials.

OBJECTIVE: To assess the safety of abatacept treatment in rheumatoid arthritis (RA) using integrated data from multiple clinical trials. METHODS: Data from nine double-blind, placebo-controlled studies of abatacept treatment (seven intravenous, two subcutaneous) in patients with RA were pooled, focusing on safety events in the double-blind treatment period of each study. Incidence rates (IRs) of adverse events (AEs) per 100 patient-years of exposure were calculated for abatacept- and placebo-treated patients. AEs in abatacept-treated patients were combined regardless of dose and formulation. RESULTS: In total, 2653 patients received abatacept and 1485 received placebo, with 2357 and 1254 patient-years of exposure, respectively. The mean (SD) durations of exposure in the abatacept and placebo groups were 10.8 (3.3) and 10.3 (3.5) months, respectively. The IRs (95% confidence interval [CI]) for serious AEs were 14.8 (13.3, 16.5) and 14.6 (12.5, 17.0) in the abatacept and placebo groups, respectively. Death occurred in 12 (0.5%) and 12 (0.8%) patients in the abatacept and placebo groups, respectively, and was most commonly caused by cardiac disorders. Malignancies were observed in 31 patients (1.2%) treated with abatacept (IR: 1.32 [95% CI: 0.90, 1.87]) versus 14 (0.9%; IR: 1.12 [0.61, 1.88]) who received placebo. Solid organ tumor was the most frequent malignancy reported in both groups (abatacept: 1.0%; IR: 1.11 [95% CI: 0.72, 1.62]; placebo: 0.8%; 0.96 [0.50, 1.67]). CONCLUSION: In this integrated analysis, the IRs of safety events in the abatacept and placebo groups were similar with no new safety concerns identified.

Nicotine replacement therapy sampling via primary care: Methods from a pragmatic cluster randomized clinical trial.

BACKGROUND: Primary care is the most important point of healthcare contact for smokers. Brief physician advice to quit, based on the 5As/AAR model, offers some efficacy but is inconsistently administered and has limited population impact. Nicotine replacement therapy (NRT) sampling, defined as provision of a brief NRT starter kit, when added to the 5As/AAR, is well-suited to primary care because it is simple, brief, and can be provided to all smokers. This article describes the design and methods of an ongoing comparative effectiveness trial testing standard care vs. standard care + NRT sampling within primary care. METHODS: Smokers were recruited directly from primary care practices between July 2014 and December 2017 within an established network of South Carolina clinics. Interventions were delivered randomly by clinic personnel, and phone-based follow-ups were centrally coordinated by research staff to track outcomes through six months post-intervention. Primary study aims are to examine the impact of NRT sampling on smoking, inclusive of cessation, quit attempts, and uptake of evidence-based treatment. RESULTS: Twenty-two clinics were recruited. Across clinics, patient census ranged from 985 to 10,957 and number of providers ranged from 1 to 63. Average patient age across clinics was 52.9 years and smoking prevalence across ranged from 10.6% to 28.5%. CONCLUSION: Improving the effectiveness and reach of brief interventions within primary care could have a considerable impact on population quit rates. We consider the advantages and disadvantages of key methodological decisions relevant to the design of future primary care-based cessation trials.

Telotristat ethyl in carcinoid syndrome: safety and efficacy in the TELECAST phase 3 trial.

Telotristat ethyl, a tryptophan hydroxylase inhibitor, was efficacious and well tolerated in the phase 3 TELESTAR study in patients with carcinoid syndrome (CS) experiencing ≥4 bowel movements per day (BMs/day) while on somatostatin analogs (SSAs). TELECAST, a phase 3 companion study, assessed the safety and efficacy of telotristat ethyl in patients with CS (diarrhea, flushing, abdominal pain, nausea or elevated urinary 5-hydroxyindoleacetic acid (u5-HIAA)) with <4 BMs/day on SSAs (or ≥1 symptom or ≥4 BMs/day if not on SSAs) during a 12-week double-blind treatment period followed by a 36-week open-label extension (OLE). The primary safety and efficacy endpoints were incidence of treatment-emergent adverse events (TEAEs) and percent change from baseline in 24-h u5-HIAA at week 12. Patients (N = 76) were randomly assigned (1:1:1) to receive placebo or telotristat ethyl 250 mg or 500 mg 3 times per day (tid); 67 continued receiving telotristat ethyl 500 mg tid during the OLE. Through week 12, TEAEs were generally mild to moderate in severity; 5 (placebo), 1 (telotristat ethyl 250 mg) and 3 (telotristat ethyl 500 mg) patients experienced serious events, and the rate of TEAEs in the OLE was comparable. At week 12, significant reductions in u5-HIAA from baseline were observed, with Hodges-Lehmann estimators of median treatment differences from placebo of -54.0% (95% confidence limits, -85.0%, -25.1%, P < 0.001) and -89.7% (95% confidence limits, -113.1%, -63.9%, P < 0.001) for telotristat ethyl 250 mg and 500 mg. These results support the safety and efficacy of telotristat ethyl when added to SSAs in patients with CS diarrhea (ClinicalTrials.gov identifier: Nbib2063659).

A standardized methodology for the surveillance of antimicrobial prescribing linked to clinical indications in primary care.

Background: A key component of strategies to reduce antimicrobial resistance is better antimicrobial prescribing. The majority of antibiotics are prescribed in primary care. While many existing surveillance systems can monitor trends in the quantities of antibiotics prescribed in this setting, it can be difficult to monitor the quality of prescribing as data on the condition for which prescriptions are issued are often not available. We devised a standardized methodology to facilitate the monitoring of condition-specific antibiotic prescribing in primary care. Methods: We used a large computerized general practitioner database to develop a standardized methodology for routine monitoring of antimicrobial prescribing linked to clinical indications in primary care in the UK. Outputs included prescribing rate by syndrome and percentages of consultations with antibiotic prescription, for recommended antibiotic, and of recommended treatment length. Results: The standardized methodology can monitor trends in proportions of common infections for which antibiotics were prescribed, the specific drugs prescribed and duration of treatment. These data can be used to help assess the appropriateness of antibiotic prescribing and to assess the impact of prescribing guidelines. Conclusions: We present a standardized methodology that could be applied to any suitable national or local database and adapted for use in other countries.

Telotristat Ethyl, a Tryptophan Hydroxylase Inhibitor for the Treatment of Carcinoid Syndrome.

Purpose Preliminary studies suggested that telotristat ethyl, a tryptophan hydroxylase inhibitor, reduces bowel movement (BM) frequency in patients with carcinoid syndrome. This placebo-controlled phase III study evaluated telotristat ethyl in this setting. Patients and Methods Patients (N = 135) experiencing four or more BMs per day despite stable-dose somatostatin analog therapy received (1:1:1) placebo, telotristat ethyl 250 mg, or telotristat ethyl 500 mg three times per day orally during a 12-week double-blind treatment period. The primary end point was change from baseline in BM frequency. In an open-label extension, 115 patients subsequently received telotristat ethyl 500 mg. Results Estimated differences in BM frequency per day versus placebo averaged over 12 weeks were -0.81 for telotristat ethyl 250 mg ( P < .001) and ‒0.69 for telotristat ethyl 500 mg ( P < .001). At week 12, mean BM frequency reductions per day for placebo, telotristat ethyl 250 mg, and telotristat ethyl 500 mg were -0.9, -1.7, and -2.1, respectively. Responses, predefined as a BM frequency reduction ≥ 30% from baseline for ≥ 50% of the double-blind treatment period, were observed in 20%, 44%, and 42% of patients given placebo, telotristat ethyl 250 mg, and telotristat ethyl 500 mg, respectively. Both telotristat ethyl dosages significantly reduced mean urinary 5-hydroxyindole acetic acid versus placebo at week 12 ( P < .001). Mild nausea and asymptomatic increases in gamma-glutamyl transferase were observed in some patients receiving telotristat ethyl. Follow-up of patients during the open-label extension revealed no new safety signals and suggested sustained BM responses to treatment. Conclusion Among patients with carcinoid syndrome not adequately controlled by somatostatin analogs, treatment with telotristat ethyl was generally safe and well tolerated and resulted in significant reductions in BM frequency and urinary 5-hydroxyindole acetic acid.

Low Blood Pressure Is Associated With Greater Risk for Cardiovascular Events in Treated Adults With and Without Apparent Treatment-Resistant Hypertension.

Apparent treatment-resistant hypertension (aTRH) may confound the reported relationship between low blood pressure (BP) and increased cardiovascular disease (CVD) in treated hypertensive patients. Incident CVD was assessed in treated hypertensive patients with and without aTRH (BP ≥140 and/or ≥90 mm Hg on ≥3 medications or <140/<90 mm Hg on ≥4 BP medications) at three BP levels: 1: <120 and/or <70 mm Hg and <140/<90 mm Hg; 2: 120-139/70-89 mm Hg; and 3: ≥140 and/or ≥90 mm Hg. Electronic health data were matched to emergency and hospital claims for incident CVD in 118 356 treated hypertensive patients. In adults with and without aTRH, respectively, CVD was greater in level 1 versus level 2 (multivariable hazard ratio, 1.88 [95% confidence interval [CI], 1.70-2.07]; 1.71 [95% CI, 1.59-1.84]), intermediate in level 1 versus level 3 (hazard ratio, 1.32 [95% CI, 1.21-1.44]; 0.99, [95% CI, 0.92-1.07]), and lowest in level 2 versus level 3 (hazard ratio, 0.70 [95% CI, 0.65-0.76]; 0.58, [95% CI, 0.54-0.62]). Low treated BP was associated with more CVD than less stringent BP control irrespective of aTRH.

2013 ACC/AHA Cholesterol Guideline and Implications for Healthy People 2020 Cardiovascular Disease Prevention Goals.

BACKGROUND: Healthy People 2020 aim to reduce fatal atherosclerotic cardiovascular disease (ASCVD) by 20%, which translates into 310 000 fewer events annually assuming proportional reduction in fatal and nonfatal ASCVD. We estimated preventable ASCVD events by implementing the American College of Cardiology/American Heart Association (ACC/AHA) 2013 Cholesterol Guideline in all statin-eligible adults. Absolute risk reduction (ARR) and number needed-to-treat (NNT) were calculated. METHODS AND RESULTS: National Health and Nutrition Examination Survey data for 2007-2012 were analyzed for adults aged 21 to 79 years and extrapolated to the US population. Literature-guided assumptions were used including (1) low-density lipoprotein cholesterol falls 33% with moderate-intensity statins and 51% with high-intensity statins; (2) for each 39 mg/dL decline in low-density lipoprotein cholesterol, 10-year ASCVD10 risk would fall 21% when ASCVD10 risk was ≥20% and 33% when ASCVD10 risk was <20%; and (3) either all statin-eligible untreated adults or all with ASCVD10 risk ≥7.5% would receive statins. Of 175.9 million adults aged 21 to 79 years not taking statins, 44.8 million (25.5%) were statin eligible. Treating all statin-eligible adults would prevent an estimated 243 589 ASCVD events annually (ARR 5.4%, 10-year NNT 18). Treating all statin-eligible adults with ASCVD10 risk ≥7.5% reduces the number treated to 32.2 million (28.2% fewer), whereas ASCVD events prevented annually fall only 10.5% to 217 974 (6.8% ARR, NNT 15). CONCLUSIONS: Implementing the ACC/AHA 2013 Cholesterol Guideline in all untreated, statin-eligible adults could achieve ≈78% of the Healthy People 2020 ASCVD prevention goal. Most of the benefit is attained by individuals with 10-year ASCVD risk ≥7.5%.

Modelling estimates of the burden of respiratory syncytial virus infection in children in the UK.

OBJECTIVE: The burden of respiratory syncytial virus (RSV) illness is not well characterised in primary care. We estimated the burden of disease attributable to RSV in children in the UK between 1995 and 2009. DESIGN: Time-series regression modelling. SETTING: A multiple linear regression model based on weekly viral surveillance (RSV and influenza, Public Health England), and controlled for non-specific seasonal drivers of disease, estimated the proportion of general practitioner (GP) episodes of care (counted as first visit in a series within 28 days; Clinical Practice Research Datalink, CPRD), hospitalisations (Hospital Episode Statistics, HES) and deaths (Office of National Statistics, ONS) attributable to RSV each season. PARTICIPANTS: Children 0-17 years registered with a GP in CPRD, or with a respiratory disease outcome in the HES or ONS databases. PRIMARY OUTCOME MEASURES: RSV-attributable burden of GP episodes, hospitalisations and deaths due to respiratory disease by age. RSV-attributable burden associated with selected antibiotic prescriptions. RESULTS: RSV-attributable respiratory disease in the UK resulted in an estimated 450 158 GP episodes, 29 160 hospitalisations and 83 deaths per average season in children and adolescents, with the highest proportions in children <6 months of age (14 441/100 000 population, 4184/100 000 and 6/100 000, respectively). In an average season, there were an estimated 125 478 GP episodes for otitis media and 416 133 prescriptions for antibiotics attributable to RSV. More GP episodes, hospitalisations and deaths from respiratory disease were attributable to RSV than to influenza in children under 5 years. CONCLUSIONS: The burden of RSV in children in the UK exceeds that of influenza. RSV in children and adolescents contributes substantially to GP office visits for a diverse range of illnesses, and was associated with an average 416 133 prescribed antibiotic courses per season. Effective antiviral treatments and preventive vaccines are urgently needed for the management of RSV infection in children. TRIAL REGISTRATION NUMBER: NCT01706302.

Modelling estimates of age-specific influenza-related hospitalisation and mortality in the United Kingdom.

BACKGROUND: Influenza is rarely confirmed with laboratory testing and accurate assessment of the overall burden of influenza is difficult. We used statistical modelling methods to generate updated, granular estimates of the number/rate of influenza-attributable hospitalisations and deaths in the United Kingdom. Such data are needed on a continuing basis to inform on cost-benefit analyses of treatment interventions, including vaccination. METHODS: Weekly age specific data on hospital admissions (1997-2009) and on deaths (1997-2009) were obtained from national databases. Virology reports (1996-2009) of influenza and respiratory syncytial virus detections were provided by Public Health England. We used an expanded set of ICD-codes to estimate the burden of illness attributable to influenza which we refer to as 'respiratory disease broadly defined'. These codes were chosen to optimise the balance between sensitivity and specificity. A multiple linear regression model controlled for respiratory syncytial virus circulation, with stratification by age and the presence of comorbid risk status (conditions associated with severe influenza outcomes). RESULTS: In the United Kingdom there were 28,516 hospitalisations and 7163 deaths estimated to be attributable to influenza respiratory disease in a mean season, with marked variability between seasons. The highest incidence rates of influenza-attributable hospitalisations and deaths were observed in adults aged 75+ years (252/100,000 and 131/100,000 population, respectively). Influenza B hospitalisations were highest among 5-17 year olds (12/100,000 population). Of all estimated influenza respiratory deaths in 75+ year olds, 50 % occurred out of hospital, and 25 % in 50-64 year olds. Rates of hospitalisations and death due to influenza-attributable respiratory disease were increased in adults identified as at-risk. CONCLUSIONS: Our study points to a substantial but highly variable seasonal influenza burden in all age groups, particularly affecting 75+ year olds. Effective influenza prevention or early intervention with anti-viral treatment in this age group may substantially impact the disease burden and associated healthcare costs. The high burden of influenza B hospitalisation among 5-17 year olds supports current United Kingdom vaccine policy to extend quadrivalent seasonal influenza vaccination to this age group. TRIAL REGISTRATION: ClinicalTrial.gov, NCT01520935.

Aldosterone Antagonists or Renin-Guided Therapy for Treatment-Resistant Hypertension: A Comparative Effectiveness Pilot Study in Primary Care.

BACKGROUND: Uncontrolled treatment-resistant hypertension (TRH), i.e., blood pressure (BP, mm Hg) ≥140/≥90mm Hg in and out of office on ≥3 different BP medications at optimal doses, is common and has a poor prognosis. Aldosterone antagonist (AA) and renin-guided therapy (RGT) are effective strategies for improving BP control in TRH but have not been compared. METHODS: A comparative effectiveness TRH pilot study of AA vs. RGT was conducted in 4 primary care clinics with 2 each randomized to AA or RGT. The primary outcome was change in clinic BP defined by means of 5 automated office BP values. Eighty-nine patients with apparent TRH were screened and 44 met criteria for true TRH. RESULTS: Baseline characteristics of 20 patients in the AA (70% Black, 45% female, mean age: 57.4 years) and 24 patients in RGT (79% Black, 50% female, 57.8 years) arms were similar with baseline BP 162±5/90±3 vs. 153±3/84±3, respectively, P = 0.11/0.20. BP declined to 144±5/86±4 in AA vs. 132±4/75±3 in RGT, P = 0.07/0.01; BP was controlled to JNC7 (Seventh Joint National Committee Report) goal in 25% vs. 62.5%, respectively, P < 0.01. Although BP changes from baseline, the primary outcome, were not different (-17.6±5.1/-4.0±3.0 AA vs. -20.4±3.8/-9.7±2.0 RGT, P = 0.65/0.10.), more BP medications were added with AA than RGT (+0.9±0.1 vs. +0.4±0.1 per patient, P < 0.01). CONCLUSIONS: In this TRH pilot study, AA and RGT lowered BP similarly, although fewer additional medications were required with RGT. A larger comparative effectiveness study could establish the utility of these treatment strategies for lowering BP of uncontrolled TRH patients in primary care.

Impact of Implementing the 2013 ACC/AHA Cholesterol Guidelines on Vascular Events in a Statewide Community-Based Practice Registry.

Electronic health record data were analyzed to estimate the number of statin-eligible adults with the 2013 American College of Cardiology/American Heart Association cholesterol guidelines not taking statin therapy and the impact of recommended statin therapy on 10-year atherosclerotic cardiovascular disease (ASCVD10 ) events. Adults aged 21 to 80 years in an outpatient network with ≥1 clinic visit(s) from January 2011 to June 2014 with data to calculate ASCVD10 were eligible. Moderate-intensity statin therapy was assumed to lower low-density lipoprotein cholesterol by 30% and high-intensity therapy was assumed to reduce low-density lipoprotein cholesterol by 50%. ASCVD events were assumed to decline 22% for each 39 mg/dL decline in low-density lipoprotein cholesterol. Among 411,768 adults, 260,434 (63.2%) were not taking statins and 103,478 (39.7%) were eligible for a statin, including 79,069 (76.4%) patients with hypertension. Estimated ASCVD10 events were 18,781 without and 13,328 with statin therapy, a 29.0% relative and 5.3% absolute risk reduction with a number needed to treat of 19. The 2013 cholesterol guidelines are a relatively efficient approach to reducing ASCVD in untreated, statin-eligible adults who often have concomitant hypertension.

Modelling estimates of the burden of Respiratory Syncytial virus infection in adults and the elderly in the United Kingdom.

BACKGROUND: Growing evidence suggests respiratory syncytial virus (RSV) is an important cause of respiratory disease in adults. However, the adult burden remains largely uncharacterized as most RSV studies focus on children, and population-based studies with laboratory-confirmation of infection are difficult to implement. Indirect modelling methods, long used for influenza, can further our understanding of RSV burden by circumventing some limitations of traditional surveillance studies that rely on direct linkage of individual-level exposure and outcome data. METHODS: Multiple linear time-series regression was used to estimate RSV burden in the United Kingdom (UK) between 1995 and 2009 among the total population and adults in terms of general practice (GP) episodes (counted as first consultation ≥28 days following any previous consultation for same diagnosis/diagnostic group), hospitalisations, and deaths for respiratory disease, using data from Public Health England weekly influenza/RSV surveillance, Clinical Practice Research Datalink, Hospital Episode Statistics, and Office of National Statistics. The main outcome considered all ICD-listed respiratory diseases and, for GP episodes, related symptoms. Estimates were adjusted for non-specific seasonal drivers of disease using secular cyclical terms and stratified by age and risk group (according to chronic conditions indicating severe influenza risk as per UK recommendations for influenza vaccination). Trial registration NCT01706302 . Registered 11 October 2012. RESULTS: Among adults aged 18+ years an estimated 487,247 GP episodes, 17,799 hospitalisations, and 8,482 deaths were attributable to RSV per average season. Of these, 175,070 GP episodes (36 %), 14,039 hospitalisations (79 %) and 7,915 deaths (93 %) were in persons aged 65+ years. High- versus low-risk elderly were two-fold more likely to have a RSV-related GP episode or death and four-fold more likely be hospitalised for RSV. In most seasons since 2001, more GP episodes, hospitalisations and deaths were attributable to RSV in adults than to influenza. CONCLUSION: RSV is associated with a substantial disease burden in adults comparable to influenza, with most of the hospitalisation and mortality burden in the elderly. Treatment options and measures to prevent RSV could have a major impact on the burden of RSV respiratory disease in adults, especially the elderly.

Striking Similarities in the Presentation and Duration of Illness of Influenza A and B in the Community: A Study Based on Sentinel Surveillance Networks in France and Turkey, 2010-2012.

Influenza B represents a high proportion of influenza cases in some seasons (even over 50%). The Influenza B study in General Practice (IBGP) is a multicenter study providing information about the clinical, demographic and socio-economic characteristics of patients affected by lab-confirmed influenza A or B. Influenza B patients and age-matched influenza A patients were recruited within the sentinel surveillance networks of France and Turkey in 2010-11 and 2011-12 seasons. Data were collected for each patient at the swab test day, after 9±2 days and, if not recovered, after 28±5 days. It was related to patient's characteristics, symptoms at presentation, vaccination status, prescriptions of antibiotics and antivirals, duration of illness, follow-up consultations in general practice or emergency room. We performed descriptive analyses and developed a multiple regression model to investigate the effect of patients and disease characteristics on the duration of illness. Overall, 774 influenza cases were included in the study: 419 influenza B cases (209 in France and 210 in Turkey) and 355 influenza A cases (205 in France and 150 in Turkey). There were no differences between influenza A and B patients in terms of clinical presentation and number of consultations with a practitioner; however, the use of antivirals was higher among influenza B patients in both countries. The average (median) reported duration of illness in the age groups 0-14 years, 15-64 years and 65+ years was 7.4 (6), 8.7 (8) and 10.5 (9) days in France, and 6.3 (6), 8.2 (7) and 9.2 (6) days in Turkey; it increased with age but did not differ by virus type; increased duration of illness was associated with antibiotics prescription. In conclusion, our findings show that influenza B infection appears not to be milder disease than influenza A infection.

An internet-delivered handwashing intervention to modify influenza-like illness and respiratory infection transmission (PRIMIT): a primary care randomised trial.

BACKGROUND: Handwashing to prevent transmission of respiratory tract infections (RTIs) has been widely advocated, especially during the H1N1 pandemic. However, the role of handwashing is debated, and no good randomised evidence exists among adults in non-deprived settings. We aimed to assess whether an internet-delivered intervention to modify handwashing would reduce the number of RTIs among adults and their household members. METHODS: We recruited individuals sharing a household by mailed invitation through general practices in England. After consent, participants were randomised online by an automated computer-generated random number programme to receive either no access or access to a bespoke automated web-based intervention that maximised handwashing intention, monitored handwashing behaviour, provided tailored feedback, reinforced helpful attitudes and norms, and addressed negative beliefs. We enrolled participants into an additional cohort (randomised to receive intervention or no intervention) to assess whether the baseline questionnaire on handwashing would affect handwashing behaviour. Participants were not masked to intervention allocation, but statistical analysis commands were constructed masked to group. The primary outcome was number of episodes of RTIs in index participants in a modified intention-to-treat population of randomly assigned participants who completed follow-up at 16 weeks. This trial is registered with the ISRCTN registry, number ISRCTN75058295. FINDINGS: Across three winters between Jan 17, 2011, and March 31, 2013, we enrolled 20,066 participants and randomly assigned them to receive intervention (n=10,040) or no intervention (n=10,026). 16,908 (84%) participants were followed up with the 16 week questionnaire (8241 index participants in intervention group and 8667 in control group). After 16 weeks, 4242 individuals (51%) in the intervention group reported one or more episodes of RTI compared with 5135 (59%) in the control group (multivariate risk ratio 0·86, 95% CI 0·83-0·89; p<0·0001). The intervention reduced transmission of RTIs (reported within 1 week of another household member) both to and from the index person. We noted a slight increase in minor self-reported skin irritation (231 [4%] of 5429 in intervention group vs 79 [1%] of 6087 in control group) and no reported serious adverse events. INTERPRETATION: In non-pandemic years, an effective internet intervention designed to increase handwashing could have an important effect in reduction of infection transmission. In view of the heightened concern during a pandemic and the likely role of the internet in access to advice, the intervention also has potential for effective implementation during a pandemic. FUNDING: Medical Research Council.

Telotristat etiprate for carcinoid syndrome: a single-arm, multicenter trial.

CONTEXT: Carcinoid syndrome (CS) is associated with elevated serotonin, diarrhea, flushing, and increased risk of valvular heart disease. Many patients respond to somatostatin analogs initially, but response diminishes in most patients. Additional options are needed. OBJECTIVE: To assess whether telotristat etiprate (TE) can reduce gastrointestinal symptoms in CS and reduce urinary 5-hydroxyindoleacetic acid (u5-HIAA; a biomarker of serotonin). DESIGN: A prospective, exploratory, dose-escalating 12-week, open-label, multicenter study of TE with efficacy and safety analyses. SETTING: A multicenter study. PATIENTS: Eligible patients had metastatic, well-differentiated, neuroendocrine tumors and CS with ≥ four bowel movements (BMs) per day. Somatostatin analog use was allowed. INTERVENTIONS: TE, a novel oral inhibitor of peripheral serotonin synthesis. MAIN OUTCOME MEASURES: Primary: safety. Secondary: daily BMs, stool form, and u5-HIAA. RESULTS: Fifteen patients were enrolled, and 14 completed the treatment period. All patients experienced reductions in BMs per day (mean decrease, 43.5%). A 74.2% mean reduction in u5-HIAA, the main metabolite of serotonin, was observed, with generally greater reductions in patients with greater reductions in BMs per day. Nine patients (75%) reported "adequate relief" of gastrointestinal symptoms at 12 weeks, compared with two (17%) at baseline. Stool form and flushing also improved. Adverse events were mostly gastrointestinal (n = 10; 67%), consistent with underlying illness; three adverse events were serious (abdominal pain, diarrhea, and gastroenteritis) but were judged unrelated. CONCLUSION: TE was generally safe and well tolerated. Patients experienced substantial improvement in CS and reductions in u5-HIAA, consistent with the mechanism of action of TE. These results support further evaluation in phase 3 studies.

Trends in antibiotic prescribing in primary care for clinical syndromes subject to national recommendations to reduce antibiotic resistance, UK 1995-2011: analysis of a large database of primary care consultations.

OBJECTIVES: To measure trends in antibiotic prescribing in UK primary care in relation to nationally recommended best practice. PATIENTS AND METHODS: A descriptive study linking individual patient data on diagnosis and prescription in a large primary care database, covering 537 UK general practices during 1995-2011. RESULTS: The proportion of cough/cold episodes for which antibiotics were prescribed decreased from 47% in 1995 to 36% in 1999, before increasing to 51% in 2011. There was marked variation by primary care practice in 2011 [10th-90th percentile range (TNPR) 32%-65%]. Antibiotic prescribing for sore throats fell from 77% in 1995 to 62% in 1999 and then stayed broadly stable (TNPR 45%-78%). Where antibiotics were prescribed for sore throat, recommended antibiotics were used in 69% of cases in 2011 (64% in 1995). The use of recommended short-course trimethoprim for urinary tract infection (UTI) in women aged 16-74 years increased from 8% in 1995 to 50% in 2011; however, a quarter of practices prescribed short courses in ≤16% of episodes in 2011. For otitis media, 85% of prescriptions were for recommended antibiotics in 2011, increasing from 77% in 1995. All these changes in annual prescribing were highly statistically significant (P < 0.001). CONCLUSIONS: The implementation of national guidelines in UK primary care has had mixed success, with prescribing for coughs/colds, both in total and as a proportion of consultations, now being greater than before recommendations were made to reduce it. Extensive variation by practice suggests that there is significant scope to improve prescribing, particularly for coughs/colds and for UTIs.

Telotristat etiprate, a novel serotonin synthesis inhibitor, in patients with carcinoid syndrome and diarrhea not adequately controlled by octreotide.

Serotonin produced by neuroendocrine tumors is believed to be a principal cause of the diarrhea in carcinoid syndrome. We assessed the safety and efficacy of telotristat etiprate, an oral serotonin synthesis inhibitor, in patients with diarrhea associated with carcinoid syndrome. In this prospective, randomized study, patients with evidence of carcinoid tumor and ≥4 bowel movements (BMs)/day despite stable-dose octreotide LAR depot therapy were enrolled in sequential, escalating, cohorts of four patients per cohort. In each cohort, one patient was randomly assigned to placebo and three patients to telotristat etiprate, at 150, 250, 350, or 500 mg three times a day (tid). In a subsequent cohort, one patient was assigned to placebo and six patients to telotristat etiprate 500 mg tid. Patients were assessed for safety, BM frequency (daily diary), 24 h urinary 5-hydroxyindoleacetic acid (u5-HIAA), and adequate relief of carcinoid gastrointestinal symptoms (using a weekly questionnaire). Twenty-three patients were treated: 18 received telotristat etiprate and five received placebo. Adverse events were generally mild. Among evaluable telotristat etiprate-treated patients, 5/18 (28%) experienced a ≥30% reduction in BM frequency for ≥2 weeks, 9/16 (56%) experienced biochemical response (≥50% reduction or normalization in 24-h u5-HIAA) at week 2 or 4, and 10/18 (56%) reported adequate relief during at least 1 of the first 4 weeks of treatment. Similar activity was not observed in placebo-treated patients. Telotristat etiprate was well tolerated. Our observations suggest that telotristat etiprate has activity in controlling diarrhea associated with carcinoid syndrome. Further studies confirming these findings are warranted.

The burden of influenza in England by age and clinical risk group: a statistical analysis to inform vaccine policy.

OBJECTIVES: To assess the burden of influenza by age and clinical status and use this to inform evaluations of the age and risk-based influenza vaccination policy in the United Kingdom. METHODS: Weekly laboratory reports for influenza and 7 other respiratory pathogens were extracted from the national database and used in a regression model to estimate the proportion of acute respiratory illness outcomes attributable to each pathogen. RESULTS: Influenza accounted for ∼10% of the attributed respiratory admissions and deaths in hospital. Healthy children under five had the highest influenza admission rate (1.9/1000). The presence of co-morbidities increased the admission rate by 5.7 fold for 5-14 year olds (from 0.1 to 0.56/1000), the relative risk declining to 1.8 fold in 65+ year olds (from 0.46 to 0.84/1000). The majority (72%) of influenza-attributable deaths in hospital occurred in 65+ year olds with co-morbidities. Mortality in children under 15 years was low with around 12 influenza-attributable deaths in hospital per year in England; the case fatality rate was substantially higher in risk than non-risk children. Infants under 6 months had the highest consultation and admission rates, around 70/1000 and 3/1000 respectively. CONCLUSIONS: Additional strategies are needed to reduce the remaining morbidity and mortality in the high-risk and elderly populations, and to protect healthy children currently not offered the benefits of vaccination.