Risk of hospitalisation or death in households with a case of COVID-19 in England: an analysis using the HOSTED data set.

OBJECTIVE: To determine whether household contacts of confirmed cases of COVID-19 have an increased risk of hospitalisation or death. METHODS: We used the HOSTED data set of index cases of COVID-19 in England between June and November 2020, linked to Secondary Uses Service data on hospital episodes and Office for National Statistics' mortality data. Multivariable logistic regression models of the odds of household contacts being hospitalised or dying within six weeks of an index case, adjusted for case type, age, sex and calendar month were calculated. Excess risk was determined by comparing the first six weeks after the index case with 6-12 weeks after the index case in a survival analysis framework. RESULTS: Index cases were more likely to be hospitalised or die than either secondary cases or non-cases, having adjusted for age and sex. There was an increased risk of hospitalisation for non-cases (adjusted hazard ratio (aHR) 1.10; 95% confidence interval (CI) 1.04, 1.16) and of death (aHR 1.57; 95% CI 1.14, 2.16) in the first six weeks after an index case, compared to 6-12 weeks after. CONCLUSION: Risks of hospitalisation and mortality are predictably higher in cases compared to non-cases. The short-term increase in risks for non-case contacts following diagnosis of the index case may suggest incomplete case ascertainment among contacts, although this was relatively small.

Associations of components of sarcopenia with risk of fracture in the Osteoporotic Fractures in Men (MrOS) study.

Our aim was to evaluate the associations between the individual components of sarcopenia and fracture types. In this cohort, the risk of experiencing any clinical, hip, or major osteoporotic fracture is greater in men with slow walking speed in comparison to normal walking speed. INTRODUCTION: The association between the components of sarcopenia and fractures has not been clearly elucidated and has hindered the development of appropriate therapeutic interventions. Our aim was to evaluate the associations between the individual components of sarcopenia, specifically lean mass, strength, and physical performance and fracture (any fracture, hip fracture, major osteoporotic fracture) in the Osteoporotic Fractures in Men (MrOS) study. METHODS: The Osteoporotic Fractures in Men study (MrOS) recruited 5995 men ≥ 65 years of age. We measured appendicular lean mass (ALM) by dual-energy X-ray absorptiometry (low as residual value < 20th percentile for the cohort), walking speed (fastest trial of usual pace, values < 0.8 m/s were low), and grip strength (max score of 2 trials, values < 30 kg were low). Information on fractures was assessed tri-annually over an average follow-up of 12 years and centrally adjudicated. Cox proportional hazard models estimated the hazard ratio (HR) (95% confidence intervals) for slow walking speed, low grip strength, and low lean mass. RESULTS: Overall, 1413 men had a fracture during follow-up. Slow walking speed was associated with an increased risk for any HR = 1.39, 1.05-1.84; hip HR = 2.37, 1.54-3.63; and major osteoporotic, HR = 1.89, 1.34-2.67 in multi-variate-adjusted models. Low lean mass and low grip strength were not significantly associated with fracture. CONCLUSIONS: In this cohort of older adult men, the risk of experiencing any, hip, or major osteoporotic fracture is greater in men with slow walking speed in comparison to men with normal walking speed, but low grip strength and low lean mass were not associated with fracture.

HOSTED-England's Household Transmission Evaluation Dataset: preliminary findings from a novel passive surveillance system of COVID-19.

BACKGROUND: Household transmission of SARS-CoV-2 is an important component of the community spread of the pandemic. Little is known about the factors associated with household transmission, at the level of the case, contact or household, or how these have varied over the course of the pandemic. METHODS: The Household Transmission Evaluation Dataset (HOSTED) is a passive surveillance system linking laboratory-confirmed COVID-19 cases to individuals living in the same household in England. We explored the risk of household transmission according to: age of case and contact, sex, region, deprivation, month and household composition between April and September 2020, building a multivariate model. RESULTS: In the period studied, on average, 5.5% of household contacts in England were diagnosed as cases. Household transmission was most common between adult cases and contacts of a similar age. There was some evidence of lower transmission rates to under-16s [adjusted odds ratios (aOR) 0.70, 95% confidence interval (CI) 0.66-0.74). There were clear regional differences, with higher rates of household transmission in the north of England and the Midlands. Less deprived areas had a lower risk of household transmission. After controlling for region, there was no effect of deprivation, but houses of multiple occupancy had lower rates of household transmission [aOR 0.74 (0.66-0.83)]. CONCLUSIONS: Children are less likely to acquire SARS-CoV-2 via household transmission, and consequently there was no difference in the risk of transmission in households with children. Households in which cases could isolate effectively, such as houses of multiple occupancy, had lower rates of household transmission. Policies to support the effective isolation of cases from their household contacts could lower the level of household transmission.

Broadband, millimeter-wave antireflection coatings for large-format, cryogenic aluminum oxide optics.

We present two prescriptions for broadband ($ {\sim} 77 - 252\;{\rm GHz} $), millimeter-wave antireflection coatings for cryogenic, sintered polycrystalline aluminum oxide optics: one for large-format (700 mm diameter) planar and plano-convex elements, the other for densely packed arrays of quasi-optical elements-in our case, 5 mm diameter half-spheres (called "lenslets"). The coatings comprise three layers of commercially available, polytetrafluoroethylene-based, dielectric sheet material. The lenslet coating is molded to fit the 150 mm diameter arrays directly, while the large-diameter lenses are coated using a tiled approach. We review the fabrication processes for both prescriptions, then discuss laboratory measurements of their transmittance and reflectance. In addition, we present the inferred refractive indices and loss tangents for the coating materials and the aluminum oxide substrate. We find that at 150 GHz and 300 K the large-format coating sample achieves $ (97 \pm 2)\% $ transmittance, and the lenslet coating sample achieves $ (94 \pm 3)\% $ transmittance.

Proliferation of microalgae and enterococci in the Lake Okeechobee, St. Lucie, and Loxahatchee watersheds.

This study is an analysis of relationships between microalgae (measured as chlorophyll a) and the fecal indicator bacteria enterococci. Microalgae blooms and enterococci exceedances have been occurring in Florida's recreational waterways for years. More recently, this has become a management concern as microalgae blooms have been attributed to potentially toxic cyanobacteria, and enterococci exceedances link to human infection/illness. Since both the microalgal blooms and bacterial exceedances occur in regions that receive managed freshwater releases from Lake Okeechobee, we hypothesized that both the blooms and exceedances are related to excess nutrients from the lake. Two experimental sites, on Lake Okeechobee and the St. Lucie River (downstream of the lake), plus a control site on the Loxahatchee River (which does not receive lake flow) were evaluated. The hypothesis was evaluated through three study components: 1) analysis of available long-term data from local environmental databases, 2) a year-long monthly sampling and analysis of chlorophyll a, enterococci, nutrients, and physical-chemical data, and 3) microcosm experiments with altered water/sediment conditions. Results support the hypothesis that excess nutrients play a role in both chlorophyll a and enterococci levels. For the St. Lucie River, analyses indicate that chlorophyll a correlated significantly with total Kjeldahl nitrogen (TKN) (R2 = 0.30, p = 0.008) and the strongest model for enterococci included nitrate-nitrite, TKN, total phosphorus, orthophosphorus, and turbidity in our long-term analysis (n = 39, R2 = 0.83, p ≤ 0.001). The microcosm results indicated that chlorophyll a and enterococci only persisted for 36 h in water from all sources, and that sediments from Lake Okeechobee may have allowed for sustained levels of chlorophyll a and enterococci levels. Overall similarities were observed in chlorophyll a and enterococci relationships with nutrient concentrations regardless of a Lake Okeechobee connection, as underscored by a study of flow out of the lake and downstream areas. This suggests that both nutrient-rich lake water and untreated surface water runoff contribute to microalgae blooms and enterococci exceedances in southeast Florida.

HIV care cost in England: a cross-sectional analysis of antiretroviral treatment and the impact of generic introduction.

OBJECTIVES: Reliable and timely HIV care cost estimates are important for policy option appraisals of HIV treatment and prevention strategies. As HIV clinical management and outcomes have changed, we aimed to update profiles of antiretroviral (ARV) usage pattern, patent/market exclusivity details and management costs in adults (≥ 18 years old) accessing HIV specialist care in England. METHODS: The data reported quarterly to the HIV and AIDS Reporting System in England was used to identify ARV usage pattern, and were combined with British National Formulary (BNF) prices, non-ARV care costs and patent/market exclusivity information to generate average survival-adjusted lifetime care costs. The cumulative budget impact from 2018 to the year in which all current ARVs were expected to lose market exclusivity was calculated for a hypothetical 85 000 (± 5000) person cohort, which provided an illustration of potential financial savings afforded by bioequivalent generic switches. Price scenarios explored BNF70 (September 2015) prices and generics at 10/20/30/50% of proprietary prices. The analyses took National Health Service (NHS) England's perspective (as the payer), and results are presented in 2016/2017 British pounds. RESULTS: By 2033, most currently available ARVs would lose market exclusivity; that is, generics could be available. Average per person lifetime HIV cost was ~£200 000 (3.5% annual discount) or ~£400 000 (undiscounted), reducing to ~£70 000 (3.5% annual discount; ~£120 000 undiscounted) with the use of generics (assuming that generics cost 10% of proprietary prices). The cumulative budget to cover 85 000 (± 5000) persons for 16 years (2018-2033) was £10.5 (± 0.6) billion, reducing to £3.6 (± 0.2) billion with the use of generics. CONCLUSIONS: HIV management costs are high but financial efficiency could be improved by optimizing generic use for treatment and prevention to mitigate the high cost of lifelong HIV treatment. Earlier implementation of generics as they become available offers the potential to maximize the scale of the financial savings.

Epidemiology of parainfluenza infection in England and Wales, 1998-2013: any evidence of change?

Human parainfluenza virus (HPIV) infections are one of the commonest causes of upper and lower respiratory tract infections. In order to determine if there have been any recent changes in HPIV epidemiology in England and Wales, laboratory surveillance data between 1998 and 2013 were analysed. The UK national laboratory surveillance database, LabBase, and the newly established laboratory-based virological surveillance system, the Respiratory DataMart System (RDMS), were used. Descriptive analysis was performed to examine the distribution of cases by year, age, sex and serotype, and to examine the overall temporal trend using the χ 2 test. A random-effects model was also employed to model the number of cases. Sixty-eight per cent of all HPIV detections were due to HPIV type 3 (HPIV-3). HPIV-3 infections were detected all year round but peaked annually between March and June. HPIV-1 and HPIV-2 circulated at lower levels accounting for 20% and 8%, respectively, peaking during the last quarter of the year with a biennial cycle. HPIV-4 was detected in smaller numbers, accounting for only 4% and also mainly observed in the last quarter of the year. However, in recent years, HPIV-4 detection has been reported much more commonly with an increase from 0% in 1998 to 3·7% in 2013. Although an overall higher proportion of HPIV infection was reported in infants (43·0%), a long-term decreasing trend in proportion in infants was observed. An increase was also observed in older age groups. Continuous surveillance will be important in tracking any future changes.

Treatment regimens for rifampicin-resistant tuberculosis: highlighting a research gap.

Treatment guidance for non-multidrug-resistant (MDR) rifampicin-resistant (RMP-R) tuberculosis (TB) is variable. We aimed to undertake a systematic review and meta-analysis of the randomised controlled trial (RCT) data behind such guidelines to identify the most efficacious treatment regimens. Ovid MEDLINE, the Web of Science and EMBASE were mined using search terms for TB, drug therapy and RCTs. Despite 12 604 records being retrieved, only three studies reported treatment outcomes by regimen for patients with non-MDR RMP-R disease, preventing meta-analysis. Our systematic review highlights a substantial gap in the literature regarding evidence-based treatment regimens for RMP-R TB.

What are the most efficacious treatment regimens for isoniazid-resistant tuberculosis? A systematic review and network meta-analysis.

INTRODUCTION: Consensus on the best treatment regimens for patients with isoniazid-resistant TB is limited; global treatment guidelines differ. We undertook a systematic review and meta-analysis using mixed-treatment comparisons methodology to provide an up-to-date summary of randomised controlled trials (RCTs) and relative regimen efficacy. METHODS: Ovid MEDLINE, the Web of Science and EMBASE were mined using search terms for TB, drug therapy and RCTs. Extracted data were inputted into fixed-effects and random-effects models. ORs for all possible network comparisons and hierarchical rankings for different regimens were obtained. RESULTS: 12 604 records were retrieved and 118 remained postextraction, representing 59 studies-27 standalone and 32 with multiple papers. In comparison to a baseline category that included the WHO-recommended regimen for countries with high levels of isoniazid resistance (rifampicin-containing regimens using fewer than three effective drugs at 4 months, in which rifampicin was protected by another effective drug at 6 months, and rifampicin was taken for 6 months), extending the duration of rifampicin and increasing the number of effective drugs at 4 months lowered the odds of unfavourable outcomes (treatment failure or the lack of microbiological cure; relapse post-treatment; death due to TB) in a fixed-effects model (OR 0.31 (95% credible interval 0.12-0.81)). In a random-effects model all estimates crossed the null. CONCLUSIONS: Our systematic review and network meta-analysis highlight a regimen category that may be more efficacious than the WHO population level recommendation, and identify knowledge gaps where data are sparse. SYSTEMATIC REVIEW REGISTRATION NUMBER: PROSPERO CRD42014015025.

Gold carbenes, gold-stabilized carbocations, and cationic intermediates relevant to gold-catalysed enyne cycloaddition.

Cationic gold complexes in which gold is bound to a formally divalent carbon atom, typically formulated as gold carbenes or α-metallocarbenium ions, have been widely invoked in a range of gold-catalyzed transformations, most notably in the gold-catalyzed cycloisomerization of 1,n-enynes. Although the existence of gold carbene complexes as intermediates in gold-catalyzed transformations is supported by a wealth of indirect experimental data and by computation, until recently no examples of cationic gold carbenes/α-metallocarbenium ions had been synthesized nor had any cationic intermediates generated via gold-catalyzed enyne cycloaddition been directly observed. Largely for this reason, there has been considerable debate regarding the electronic structure of these cationic complexes, in particular the relative contributions of the carbene (LAu(+)[double bond, length as m-dash]CR2) and α-metallocarbenium (LAu-CR2(+)) forms, which is intimately related to the extent of d → p backbonding from gold to the C1 carbon atom. However, over the past ∼ seven years, a number of cationic gold carbene complexes have been synthesized in solution and generated in the gas phase and cationic intermediates have been directly observed in the gold-catalyzed cycloaddition of enynes. Together, these advances provide insight into the nature and electronic structure of gold carbene/α-metallocarbenium complexes and the cationic intermediates generated via gold-catalyzed enyne cycloaddition. Herein we review recent advances in this area.

New treatments for hepatitis C virus (HCV): scope for preventing liver disease and HCV transmission in England.

New direct-acting antivirals have the potential to transform the hepatitis C (HCV) treatment landscape, with rates of sustained viral response in excess of 90%. As these new agents are expensive, an important question is whether to focus on minimizing the consequences of severe liver disease, or reducing transmission via 'treatment as prevention'. A back-calculation model was used to estimate the impact of treatment of mild, moderate and compensated cirrhosis on incident cases of HCV-related end-stage liver disease/hepatocellular carcinoma (ESLD/HCC). In addition, a dynamic model was used to determine the impact on incidence and prevalence of chronic infection in people who inject drugs (PWID), the main risk group in England. Treating 3500 cirrhotics per year was predicted to reduce ESLD/HCC incidence from 1100 (95% CrI 970-1240) cases per year in 2015 to 630 (95% CrI 530-770) in 2020, around half that currently expected, although treating moderate-stage disease will also be needed to sustain this reduction. Treating mild-stage PWID was required to make a substantial impact on transmission: with 2500 treated per year, chronic prevalence/annual incidence in PWID was reduced from 34%/4.8% in 2015 to 11%/1.4% in 2030. There was little overlap between the two goals: treating mild stage had virtually no impact on ESLD/HCC within 15 years, but the long timescale of liver disease means relatively few PWID reach cirrhosis before cessation of injecting. Strategies focussing on treating advanced disease have the potential for dramatic reductions in severe morbidity, but virtually no preventative impact.

Ethnicity, deprivation and mortality due to 2009 pandemic influenza A(H1N1) in England during the 2009/2010 pandemic and the first post-pandemic season.

The relationship between risk of death following influenza A(H1N1)pdm09 infection and ethnicity and deprivation during the 2009/2010 pandemic period and the first post-pandemic season of 2010/2011 in England was examined. Poisson regression models were used to estimate the mortality risk, adjusted for age, gender, and place of residence. Those of non-White ethnicity experienced an increased mortality risk compared to White populations during the 2009/2010 pandemic [10·5/1000 vs. 6·0/1000 general population; adjusted risk ratio (RR) 1·84, 95% confidence interval (CI) 1·39-2·54] with the highest risk in those of Pakistani ethnicity. However, no significant difference between ethnicities was observed during the following 2010/2011 season. Persons living in areas with the highest level of deprivation had a significantly higher risk of death (RR 2·08, 95% CI 1·49-2·91) compared to the lowest level for both periods. These results highlight the importance of rapid identification of groups at higher risk of severe disease in the early stages of future pandemics to enable the implementation of optimal prevention and control measures for vulnerable populations.

Second generation tyrosine kinase inhibitors prevent disease progression in high-risk (high CIP2A) chronic myeloid leukaemia patients.

High cancerous inhibitor of PP2A (CIP2A) protein levels at diagnosis of chronic myeloid leukaemia (CML) are predictive of disease progression in imatinib-treated patients. It is not known whether this is true in patients treated with second generation tyrosine kinase inhibitors (2G TKI) from diagnosis, and whether 2G TKIs modulate the CIP2A pathway. Here, we show that patients with high diagnostic CIP2A levels who receive a 2G TKI do not progress, unlike those treated with imatinib (P=<0.0001). 2G TKIs induce more potent suppression of CIP2A and c-Myc than imatinib. The transcription factor E2F1 is elevated in high CIP2A patients and following 1 month of in vivo treatment 2G TKIs suppress E2F1 and reduce CIP2A; these effects are not seen with imatinib. Silencing of CIP2A, c-Myc or E2F1 in K562 cells or CML CD34+ cells reactivates PP2A leading to BCR-ABL suppression. CIP2A increases proliferation and this is only reduced by 2G TKIs. Patients with high CIP2A levels should be offered 2G TKI treatment in preference to imatinib. 2G TKIs disrupt the CIP2A/c-Myc/E2F1 positive feedback loop, leading to lower disease progression risk. The data supports the view that CIP2A inhibits PP2Ac, stabilising E2F1, creating a CIP2A/c-Myc/E2F1 positive feedback loop, which imatinib cannot overcome.

Effect of BCG vaccination against Mycobacterium tuberculosis infection in children: systematic review and meta-analysis.

OBJECTIVES: To determine whether BCG vaccination protects against Mycobacterium tuberculosis infection as assessed by interferon γ release assays (IGRA) in children. DESIGN: Systematic review and meta-analysis. Searches of electronic databases 1950 to November 2013, checking of reference lists, hand searching of journals, and contact with experts. SETTING: Community congregate settings and households. INCLUSION CRITERIA: Vaccinated and unvaccinated children aged under 16 with known recent exposure to patients with pulmonary tuberculosis. Children were screened for infection with M tuberculosis with interferon γ release assays. DATA EXTRACTION: Study results relating to diagnostic accuracy were extracted and risk estimates were combined with random effects meta-analysis. RESULTS: The primary analysis included 14 studies and 3855 participants. The estimated overall risk ratio was 0.81 (95% confidence interval 0.71 to 0.92), indicating a protective efficacy of 19% against infection among vaccinated children after exposure compared with unvaccinated children. The observed protection was similar when estimated with the two types of interferon γ release assays (ELISpot or QuantiFERON). Restriction of the analysis to the six studies (n=1745) with information on progression to active tuberculosis at the time of screening showed protection against infection of 27% (risk ratio 0.73, 0.61 to 0.87) compared with 71% (0.29, 0.15 to 0.58) against active tuberculosis. Among those infected, protection against progression to disease was 58% (0.42, 0.23 to 0.77). CONCLUSIONS: BCG protects against M tuberculosis infection as well as progression from infection to disease.Trial registration PROSPERO registration No CRD42011001698 (www.crd.york.ac.uk/prospero/).

Two decades of successes and failures in controlling the transmission of HIV through injecting drug use in England and Wales, 1990 to 2011.

Responses to injecting drug use have changed focus over the last 20 years. Prevalence and incidence of human immunodeficiency virus (HIV) among people who inject drugs (PWID) in England and Wales were examined in relation to these changes. A voluntary unlinked-anonymous surveillance study obtained a biological sample and questionnaire data from PWID through annual surveys since 1990. Prevalence and incidence trends were estimated via generalised linear models, and compared with a policy time-line. Overall HIV prevalence among 38,539 participations was 1.15%. Prevalence was highest among those who started injecting before 1985; throughout the 1990s, prevalence fell in this group and was stable among those who started injecting later. Prevalence was higher in 2005 than 2000 (odds ratio: 3.56 (95% confidence interval (CI) 1.40­9.03) in London, 3.40 (95% CI 2.31­5.02) elsewhere). Estimated HIV incidence peaked twice, around 1983 and 2005. HIV was an important focus of policy concerning PWID from 1984 until 1998. This focus shifted at a time when drug use and risk were changing. The increased incidence in 2005 cannot be ascribed to the policy changes, but these appeared to be temporally aligned. Policy related to PWID should be continually reviewed to ensure rapid responses to increased risk.

Estimating tuberculosis burden and case detection in Pakistan.

BACKGROUND: The National Tuberculosis Control Programme (NTP) in Pakistan has officially achieved a tuberculosis (TB) case detection rate of 64% in 2011, with an estimated incidence rate of 230 per 100 000 population, but is likely to be missing an unknown number of patients, particularly in the private sector. SETTING: All public and private sector providers in 12 randomly selected districts of Pakistan were included. OBJECTIVE: To estimate TB incidence and TB notification rates in Pakistan in 2012. DESIGN: A surveillance system was established among all eligible non-NTP providers in selected districts from January to March 2012. Record linkage and capture-recapture analysis was conducted. RESULTS: Of 8346 TB cases identified after record linkage, 6061 were registered with the NTP. The estimated number of unobserved TB cases was 10 030 (95%CI 7800-12 910), which meant that the proportion of notified cases was 32% (95%CI 17-49). The calculated annual incidence was 878 000 cases (95%CI 573 000-1 675 000), corresponding to a rate of 497/100 000 (95%CI 324-948) annually in the population. CONCLUSION: The study estimated that the proportion of cases notified to the NTP was low, with actual incidence rates being higher than official estimates. TB surveillance should be strengthened to reduce under-reporting.