Effect of Covid-19 Vaccination on Transmission of Alpha and Delta Variants.

BACKGROUND: Before the emergence of the B.1.617.2 (delta) variant of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), vaccination reduced transmission of SARS-CoV-2 from vaccinated persons who became infected, potentially by reducing viral loads. Although vaccination still lowers the risk of infection, similar viral loads in vaccinated and unvaccinated persons who are infected with the delta variant call into question the degree to which vaccination prevents transmission. METHODS: We used contact-testing data from England to perform a retrospective observational cohort study involving adult contacts of SARS-CoV-2-infected adult index patients. We used multivariable Poisson regression to investigate associations between transmission and the vaccination status of index patients and contacts and to determine how these associations varied with the B.1.1.7 (alpha) and delta variants and time since the second vaccination. RESULTS: Among 146,243 tested contacts of 108,498 index patients, 54,667 (37%) had positive SARS-CoV-2 polymerase-chain-reaction (PCR) tests. In index patients who became infected with the alpha variant, two vaccinations with either BNT162b2 or ChAdOx1 nCoV-19 (also known as AZD1222), as compared with no vaccination, were independently associated with reduced PCR positivity in contacts (adjusted rate ratio with BNT162b2, 0.32; 95% confidence interval [CI], 0.21 to 0.48; and with ChAdOx1 nCoV-19, 0.48; 95% CI, 0.30 to 0.78). Vaccine-associated reductions in transmission of the delta variant were smaller than those with the alpha variant, and reductions in transmission of the delta variant after two BNT162b2 vaccinations were greater (adjusted rate ratio for the comparison with no vaccination, 0.50; 95% CI, 0.39 to 0.65) than after two ChAdOx1 nCoV-19 vaccinations (adjusted rate ratio, 0.76; 95% CI, 0.70 to 0.82). Variation in cycle-threshold (Ct) values (indicative of viral load) in index patients explained 7 to 23% of vaccine-associated reductions in transmission of the two variants. The reductions in transmission of the delta variant declined over time after the second vaccination, reaching levels that were similar to those in unvaccinated persons by 12 weeks in index patients who had received ChAdOx1 nCoV-19 and attenuating substantially in those who had received BNT162b2. Protection in contacts also declined in the 3-month period after the second vaccination. CONCLUSIONS: Vaccination was associated with a smaller reduction in transmission of the delta variant than of the alpha variant, and the effects of vaccination decreased over time. PCR Ct values at diagnosis of the index patient only partially explained decreased transmission. (Funded by the U.K. Government Department of Health and Social Care and others.).

A self-controlled case series study to measure the risk of SARS-CoV-2 infection associated with attendance at sporting and cultural events: the UK Events Research Programme events.

BACKGROUND: In 2021, whilst societies were emerging from major social restrictions during the SARS-CoV-2 pandemic, the UK government instigated an Events Research Programme to examine the risk of COVID-19 transmission from attendance at cultural events and explore ways to enable people to attend a range of events whilst minimising risk of transmission. We aimed to measure any impact on risk of COVID-19 transmission from attendance at events held at or close to commercially viable capacity using routinely collected data. METHODS: Data were obtained on attendees at Phase 3 Events Research Programme events, for which some infection risk mitigation measures were in place (i.e. evidence of vaccination or a negative lateral flow test). Attendance data were linked with COVID-19 test result data from the UK Test and Trace system. Using a self-controlled case series design, we measured the within person incidence rate ratio for testing positive for COVID-19, comparing the rate in days 3 to 9 following event attendance (high risk period) with days 1 and 2 and 10-16 (baseline period). Rate ratios were adjusted for estimates of underlying regional COVID-19 prevalence to account for population level fluctuations in infection risk, and events were grouped into broadly similar types. RESULTS: From attendance data available for 188,851 attendees, 3357 people tested positive for COVID-19 during the observation period. After accounting for total testing trends over the period, incidence rate ratios and 95% confidence intervals for positive tests were 1.16 (0.53-2.57) for indoor seated events, 1.12 (0.95-1.30) for mainly outdoor seated events, 0.65 (0.51-0.83) for mainly outdoor partially seated events, and 1.70 (1.52-1.89) for mainly outdoor unseated multi-day events. CONCLUSIONS: For the majority of event types studied in the third phase of the UK Events Research Programme, we found no evidence of an increased risk of COVID-19 transmission associated with event attendance. However, we found a 70% increased risk of infection associated with attendance at mainly outdoor unseated multi-day events. We have also demonstrated a novel use for self-controlled case series methodology in monitoring infection risk associated with event attendance.

SARS-CoV-2, influenza A/B and respiratory syncytial virus positivity and association with influenza-like illness and self-reported symptoms, over the 2022/23 winter season in the UK: a longitudinal surveillance cohort.

BACKGROUND: Syndromic surveillance often relies on patients presenting to healthcare. Community cohorts, although more challenging to recruit, could provide additional population-wide insights, particularly with SARS-CoV-2 co-circulating with other respiratory viruses. METHODS: We estimated the positivity and incidence of SARS-CoV-2, influenza A/B, and RSV, and trends in self-reported symptoms including influenza-like illness (ILI), over the 2022/23 winter season in a broadly representative UK community cohort (COVID-19 Infection Survey), using negative-binomial generalised additive models. We estimated associations between test positivity and each of the symptoms and influenza vaccination, using adjusted logistic and multinomial models. RESULTS: Swabs taken at 32,937/1,352,979 (2.4%) assessments tested positive for SARS-CoV-2, 181/14,939 (1.2%) for RSV and 130/14,939 (0.9%) for influenza A/B, varying by age over time. Positivity and incidence peaks were earliest for RSV, then influenza A/B, then SARS-CoV-2, and were highest for RSV in the youngest and for SARS-CoV-2 in the oldest age groups. Many test positives did not report key symptoms: middle-aged participants were generally more symptomatic than older or younger participants, but still, only ~ 25% reported ILI-WHO and ~ 60% ILI-ECDC. Most symptomatic participants did not test positive for any of the three viruses. Influenza A/B-positivity was lower in participants reporting influenza vaccination in the current and previous seasons (odds ratio = 0.55 (95% CI 0.32, 0.95)) versus neither season. CONCLUSIONS: Symptom profiles varied little by aetiology, making distinguishing SARS-CoV-2, influenza and RSV using symptoms challenging. Most symptoms were not explained by these viruses, indicating the importance of other pathogens in syndromic surveillance. Influenza vaccination was associated with lower rates of community influenza test positivity.

Self-swabbing versus assisted swabbing for viral detection by qRT-PCR: the experience from SARS-CoV-2 based on a meta-analysis of six prospectively designed evaluations conducted in a UK setting.

PURPOSE: In April 2020, the UK Government implemented NHS Test and Trace to provide SARS-CoV-2 quantitative reverse transcription polymerase chain reaction (qRT-PCR) testing for the public, with nose-and-throat swabbing for samples performed by trained staff. Self-swabbing (SS) would allow rapid scale-up of testing capacity and access. Six studies were undertaken to determine whether SS was as effective for detecting SARS-CoV-2 as swabbing performed by trained staff. METHODS: Six prospective studies were conducted between April-October 2020, using six swab/media combinations. Differences between assisted swabbing (AS) and SS were evaluated for concordance, positivity, sensitivity, cycle threshold (Ct) values and void rates. Statistical analysis was performed using 95% confidence intervals (CIs), paired t-tests and model-based methods. RESULTS: Overall, 3,253 individuals were recruited (median age 37 years, 49% female), with 2,933 having valid paired qRT-PCR results. Pooled concordance rate was 98% (95% CI: 96%, 99%). Positivity rate differences for SS (8.1%) and AS (8.4%) and differences in pooled sensitivities between SS (86%; 95% CI: 78%, 92%) and AS (91%; 95% CI: 78%, 96%) were nonsignificant. Both types of swabbing led to pooled void rates below 2% and strongly correlated Ct values. Age, sex and previous swabbing experience did not have a significant impact on concordance or sensitivity. CONCLUSION: The UK adopted a policy to promote self-testing for SARS-CoV-2 based on data demonstrating equivalence of SS versus AS. Positive outcomes with SS are likely generalisable to testing for other respiratory pathogens, and we consider self-sampling and self-testing essential for future pandemic preparedness.

The effectiveness and efficiency of asymptomatic SARS-CoV-2 testing strategies for patient and healthcare workers within acute NHS hospitals during an omicron-like period.

BACKGROUND: Asymptomatic SARS-CoV-2 testing of hospitalised patients began in April-2020, with twice weekly healthcare worker (HCW) testing introduced in November-2020. Guidance recommending asymptomatic testing was withdrawn in August-2022. Assessing the impact of this decision from data alone is challenging due to concurrent changes in infection prevention and control practices, community transmission rates, and a reduction in ascertainment rate from reduced testing. Computational modelling is an effective tool for estimating the impact of this change. METHODS: Using a computational model of SARS-CoV-2 transmission in an English hospital we estimate the effectiveness of several asymptomatic testing strategies, namely; (1) Symptomatic testing of patients and HCWs, (2) testing of all patients on admission with/without repeat testing on days 3 and 5-7, and (3) symptomatic testing plus twice weekly asymptomatic HCW testing with 70% compliance. We estimate the number of patient and HCW infections, HCW absences, number of tests, and tests per case averted or absence avoided, with differing community prevalence rates over a 12-week period. RESULTS: Testing asymptomatic patients on admission reduces the rate of nosocomial SARS-CoV-2 infection by 8.1-21.5%. Additional testing at days 3 and 5-7 post admission does not significantly reduce infection rates. Twice weekly asymptomatic HCW testing can reduce the proportion of HCWs infected by 1.0-4.4% and monthly absences by 0.4-0.8%. Testing asymptomatic patients repeatedly requires up to 5.5 million patient tests over the period, and twice weekly asymptomatic HCW testing increases the total tests to almost 30 million. The most efficient patient testing strategy (in terms of tests required to prevent a single patient infection) was testing asymptomatic patients on admission across all prevalence levels. The least efficient was repeated testing of patients with twice weekly asymptomatic HCW testing in a low prevalence scenario, and in all other prevalence levels symptomatic patient testing with regular HCW testing was least efficient. CONCLUSIONS: Testing patients on admission can reduce the rate of nosocomial SARS-CoV-2 infection but there is little benefit of additional post-admission testing. Asymptomatic HCW testing has little incremental benefit for reducing patient cases at low prevalence but has a potential role at higher prevalence or with low community transmission. A full health-economic evaluation is required to determine the cost-effectiveness of these strategies.

The evaluation of a multi-day testing approach with antigen lateral flow devices for people eligible for community-based COVID-19 treatments.

BACKGROUND: COVID-19 therapeutics including antiviral and monoclonal antibody treatments (hereafter 'COVID-19 treatments') require rapid administration to be effective. As part of the community-based antiviral and therapeutic treatment pathway for COVID-19 there has been a move from PCR testing in those eligible to a rapid antigen lateral flow testing regime. OBJECTIVES: To determine whether a multi-day lateral flow device (LFD) testing regime is a feasible alternative to PCR for diagnosing symptomatic patients eligible for COVID-19 treatments. An LFD regime might return a positive result more quickly than a PCR and hence expedite access to COVID-19 treatments. METHODS: A retrospective analysis was conducted of diagnostic testing for SARS-CoV-2 with a combination of PCR and LFDs of symptomatic patients eligible for COVID-19 treatments. LFD testing patterns were not assigned. Patients self-censored and the patterns were retro-fitted to the observed results. RESULTS: The LFD testing patterns offered high sensitivity, close to 92%; however, the false positive rate also increased, with most of the multi-day testing patterns having a false positive rate greater than 3%. The highest sensitivity was seen among patients who tested with LFD on the same day as PCR. CONCLUSIONS: There were multiple observed testing behaviours. We conclude that multi-day LFD testing for COVID-19 provides a feasible alternative to PCR to in eligible patients, allowing swift prescription of COVID-19 treatments in most cases. This approach requires acceptance of a trade-off for a small increase in false-positive and -negative results.

PCR testing of traced contacts for SARS-CoV-2 in England, January to July 2021.

BackgroundThe NHS Test and Trace (NHSTT) programme was established in May 2020 in England to deliver SARS-CoV-2 testing and contact tracing in order to identify infected individuals and reduce COVID-19 spread. To further control transmission, people identified as contacts were asked to self-isolate for 10 days and test only if they became symptomatic. From March 2021, eligibility criteria for PCR testing expanded to include asymptomatic contacts of confirmed cases.AimTo analyse testing patterns of contacts before and after the change in testing guidance in England to assess the impact on PCR testing behaviour with respect to symptom status and contact type.MethodsTesting and contact tracing data were extracted from the national data systems and linked. Subsequently, descriptive statistical analysis was applied to identify trends in testing behaviour.ResultsBetween 1 January and 31 July 2021, over 5 million contacts were identified and reached by contact tracers; 42.3% took a PCR test around the time they were traced. Overall positivity rate was 44.3% and consistently higher in symptomatic (60-70%) than asymptomatic (around 20%, March-June) contacts. The proportion of tests taken by asymptomatic contacts increased over time, especially after the change in testing guidance. No link was observed between uptake of PCR tests and vaccination coverage. Fully vaccinated contacts showed lower positivity (23.8%) than those with one dose (37.2%) or unvaccinated (51.0%).ConclusionAlmost 1 million asymptomatic contacts were tested for SARS-CoV-2, identifying 214,056 positive cases, demonstrating the value of offering PCR testing to this group.

High attack rate in a large care home outbreak of SARS-CoV-2 BA.2.86, East of England, August 2023.

We investigated an outbreak of SARS-CoV-2 variant BA.2.86 in an East of England care home. We identified 45 infections (33 residents, 12 staff), among 38 residents and 66 staff. Twenty-nine of 43 PCR swabs were sequenced, all of which were variant BA.2.86. The attack rate among residents was 87%, 19 were symptomatic, and one was hospitalised. Twenty-four days after the outbreak started, no cases were still unwell. Among the 33 resident cases, 29 had been vaccinated 4 months earlier.

Vaccine effectiveness against COVID-19 breakthrough infections in patients with cancer (UKCCEP): a population-based test-negative case-control study.

BACKGROUND: People with cancer are at increased risk of hospitalisation and death following infection with SARS-CoV-2. Therefore, we aimed to conduct one of the first evaluations of vaccine effectiveness against breakthrough SARS-CoV-2 infections in patients with cancer at a population level. METHODS: In this population-based test-negative case-control study of the UK Coronavirus Cancer Evaluation Project (UKCCEP), we extracted data from the UKCCEP registry on all SARS-CoV-2 PCR test results (from the Second Generation Surveillance System), vaccination records (from the National Immunisation Management Service), patient demographics, and cancer records from England, UK, from Dec 8, 2020, to Oct 15, 2021. Adults (aged ≥18 years) with cancer in the UKCCEP registry were identified via Public Health England's Rapid Cancer Registration Dataset between Jan 1, 2018, and April 30, 2021, and comprised the cancer cohort. We constructed a control population cohort from adults with PCR tests in the UKCCEP registry who were not contained within the Rapid Cancer Registration Dataset. The coprimary endpoints were overall vaccine effectiveness against breakthrough infections after the second dose (positive PCR COVID-19 test) and vaccine effectiveness against breakthrough infections at 3-6 months after the second dose in the cancer cohort and control population. FINDINGS: The cancer cohort comprised 377 194 individuals, of whom 42 882 had breakthrough SARS-CoV-2 infections. The control population consisted of 28 010 955 individuals, of whom 5 748 708 had SARS-CoV-2 breakthrough infections. Overall vaccine effectiveness was 69·8% (95% CI 69·8-69·9) in the control population and 65·5% (65·1-65·9) in the cancer cohort. Vaccine effectiveness at 3-6 months was lower in the cancer cohort (47·0%, 46·3-47·6) than in the control population (61·4%, 61·4-61·5). INTERPRETATION: COVID-19 vaccination is effective for individuals with cancer, conferring varying levels of protection against breakthrough infections. However, vaccine effectiveness is lower in patients with cancer than in the general population. COVID-19 vaccination for patients with cancer should be used in conjunction with non-pharmacological strategies and community-based antiviral treatment programmes to reduce the risk that COVID-19 poses to patients with cancer. FUNDING: University of Oxford, University of Southampton, University of Birmingham, Department of Health and Social Care, and Blood Cancer UK.

Daily testing for contacts of individuals with SARS-CoV-2 infection and attendance and SARS-CoV-2 transmission in English secondary schools and colleges: an open-label, cluster-randomised trial.

BACKGROUND: School-based COVID-19 contacts in England have been asked to self-isolate at home, missing key educational opportunities. We trialled daily testing of contacts as an alternative to assess whether this resulted in similar control of transmission, while allowing more school attendance. METHODS: We did an open-label, cluster-randomised, controlled trial in secondary schools and further education colleges in England. Schools were randomly assigned (1:1) to self-isolation of school-based COVID-19 contacts for 10 days (control) or to voluntary daily lateral flow device (LFD) testing for 7 days with LFD-negative contacts remaining at school (intervention). Randomisation was stratified according to school type and size, presence of a sixth form, presence of residential students, and proportion of students eligible for free school meals. Group assignment was not masked during procedures or analysis. Coprimary outcomes in all students and staff were COVID-19-related school absence and symptomatic PCR-confirmed COVID-19, adjusted for community case rates, to estimate within-school transmission (non-inferiority margin <50% relative increase). Analyses were done on an intention-to-treat basis using quasi-Poisson regression, also estimating complier average causal effects (CACE). This trial is registered with the ISRCTN registry, ISRCTN18100261. FINDINGS: Between March 18 and May 4, 2021, 204 schools were taken through the consent process, during which three decided not to participate further. 201 schools were randomly assigned (control group n=99, intervention group n=102) in the 10-week study (April 19-May 10, 2021), which continued until the pre-appointed stop date (June 27, 2021). 76 control group schools and 86 intervention group schools actively participated; additional national data allowed most non-participating schools to be included in analysis of coprimary outcomes. 2432 (42·4%) of 5763 intervention group contacts participated in daily contact testing. There were 657 symptomatic PCR-confirmed infections during 7 782 537 days-at-risk (59·1 per 100 000 per week) in the control group and 740 during 8 379 749 days-at-risk (61·8 per 100 000 per week) in the intervention group (intention-to-treat adjusted incidence rate ratio [aIRR] 0·96 [95% CI 0·75-1·22]; p=0·72; CACE aIRR 0·86 [0·55-1·34]). Among students and staff, there were 59 422 (1·62%) COVID-19-related absences during 3 659 017 person-school-days in the control group and 51 541 (1·34%) during 3 845 208 person-school-days in the intervention group (intention-to-treat aIRR 0·80 [95% CI 0·54-1·19]; p=0·27; CACE aIRR 0·61 [0·30-1·23]). INTERPRETATION: Daily contact testing of school-based contacts was non-inferior to self-isolation for control of COVID-19 transmission, with similar rates of symptomatic infections among students and staff with both approaches. Infection rates in school-based contacts were low, with very few school contacts testing positive. Daily contact testing should be considered for implementation as a safe alternative to home isolation following school-based exposures. FUNDING: UK Government Department of Health and Social Care.

Identification and validation of a novel pathogenic variant in GDF2 (BMP9) responsible for hereditary hemorrhagic telangiectasia and pulmonary arteriovenous malformations.

Hereditary hemorrhagic telangiectasia (HHT) is an autosomal dominant multisystemic vascular dysplasia, characterized by arteriovenous malformations (AVMs), mucocutaneous telangiectasia and nosebleeds. HHT is caused by a heterozygous null allele in ACVRL1, ENG, or SMAD4, which encode proteins mediating bone morphogenetic protein (BMP) signaling. Several missense and stop-gain variants identified in GDF2 (encoding BMP9) have been reported to cause a vascular anomaly syndrome similar to HHT, however none of these patients met diagnostic criteria for HHT. HHT families from UK NHS Genomic Medicine Centres were recruited to the Genomics England 100,000 Genomes Project. Whole genome sequencing and tiering protocols identified a novel, heterozygous GDF2 sequence variant in all three affected members of one HHT family who had previously screened negative for ACVRL1, ENG, and SMAD4. All three had nosebleeds and typical HHT telangiectasia, and the proband also had severe pulmonary AVMs from childhood. In vitro studies showed the mutant construct expressed the proprotein but lacked active mature BMP9 dimer, suggesting the mutation disrupts correct cleavage of the protein. Plasma BMP9 levels in the patients were significantly lower than controls. In conclusion, we propose that this heterozygous GDF2 variant is a rare cause of HHT associated with pulmonary AVMs.

An online compendium of treatable genetic disorders.

More than 4,000 genes have been associated with recognizable Mendelian/monogenic diseases. When faced with a new diagnosis of a rare genetic disorder, health care providers increasingly turn to internet resources for information to understand the disease and direct care. Unfortunately, it can be challenging to find information concerning treatment for rare diseases as key details are scattered across a number of authoritative websites and numerous journal articles. The website and associated mobile device application described in this article begin to address this challenge by providing a convenient, readily available starting point to find treatment information. The site, Rx-genes.com (https://www.rx-genes.com/), is focused on those conditions where the treatment is directed against the mechanism of the disease and thereby alters the natural history of the disease. The website currently contains 633 disease entries that include references to disease information and treatment guidance, a brief summary of treatments, the inheritance pattern, a disease frequency (if known), nonmolecular confirmatory testing (if available), and a link to experimental treatments. Existing entries are continuously updated, and new entries are added as novel treatments appear in the literature.

Prediction of Susceptibility to First-Line Tuberculosis Drugs by DNA Sequencing.

BACKGROUND: The World Health Organization recommends drug-susceptibility testing of Mycobacterium tuberculosis complex for all patients with tuberculosis to guide treatment decisions and improve outcomes. Whether DNA sequencing can be used to accurately predict profiles of susceptibility to first-line antituberculosis drugs has not been clear. METHODS: We obtained whole-genome sequences and associated phenotypes of resistance or susceptibility to the first-line antituberculosis drugs isoniazid, rifampin, ethambutol, and pyrazinamide for isolates from 16 countries across six continents. For each isolate, mutations associated with drug resistance and drug susceptibility were identified across nine genes, and individual phenotypes were predicted unless mutations of unknown association were also present. To identify how whole-genome sequencing might direct first-line drug therapy, complete susceptibility profiles were predicted. These profiles were predicted to be susceptible to all four drugs (i.e., pansusceptible) if they were predicted to be susceptible to isoniazid and to the other drugs or if they contained mutations of unknown association in genes that affect susceptibility to the other drugs. We simulated the way in which the negative predictive value changed with the prevalence of drug resistance. RESULTS: A total of 10,209 isolates were analyzed. The largest proportion of phenotypes was predicted for rifampin (9660 [95.4%] of 10,130) and the smallest was predicted for ethambutol (8794 [89.8%] of 9794). Resistance to isoniazid, rifampin, ethambutol, and pyrazinamide was correctly predicted with 97.1%, 97.5%, 94.6%, and 91.3% sensitivity, respectively, and susceptibility to these drugs was correctly predicted with 99.0%, 98.8%, 93.6%, and 96.8% specificity. Of the 7516 isolates with complete phenotypic drug-susceptibility profiles, 5865 (78.0%) had complete genotypic predictions, among which 5250 profiles (89.5%) were correctly predicted. Among the 4037 phenotypic profiles that were predicted to be pansusceptible, 3952 (97.9%) were correctly predicted. CONCLUSIONS: Genotypic predictions of the susceptibility of M. tuberculosis to first-line drugs were found to be correlated with phenotypic susceptibility to these drugs. (Funded by the Bill and Melinda Gates Foundation and others.).

SARS-CoV-2 (COVID-19): What Do We Know About Children? A Systematic Review.

BACKGROUND: Few pediatric cases of coronavirus disease 2019 (COVID-19) have been reported and we know little about the epidemiology in children, although more is known about other coronaviruses. We aimed to understand the infection rate, clinical presentation, clinical outcomes, and transmission dynamics for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), in order to inform clinical and public health measures. METHODS: We undertook a rapid systematic review and narrative synthesis of all literature relating to SARS-CoV-2 in pediatric populations. The search terms also included SARS-CoV and MERS-CoV. We searched 3 databases and the COVID-19 resource centers of 11 major journals and publishers. English abstracts of Chinese-language papers were included. Data were extracted and narrative syntheses conducted. RESULTS: Twenty-four studies relating to COVID-19 were included in the review. Children appear to be less affected by COVID-19 than adults by observed rate of cases in large epidemiological studies. Limited data on attack rate indicate that children are just as susceptible to infection. Data on clinical outcomes are scarce but include several reports of asymptomatic infection and a milder course of disease in young children, although radiological abnormalities are noted. Severe cases are not reported in detail and there are few data relating to transmission. CONCLUSIONS: Children appear to have a low observed case rate of COVID-19 but may have rates similar to adults of infection with SARS-CoV-2. This discrepancy may be because children are asymptomatic or too mildly infected to draw medical attention and be tested and counted in observed cases of COVID-19.

Missense variants in the X-linked gene PRPS1 cause retinal degeneration in females.

Retinal dystrophies are a heterogeneous group of disorders of visual function leading to partial or complete blindness. We report the genetic basis of an unusual retinal dystrophy in five families with affected females and no affected males. Heterozygous missense variants were identified in the X-linked phosphoribosyl pyrophosphate synthetase 1 (PRPS1) gene: c.47C > T, p.(Ser16Phe); c.586C > T, p.(Arg196Trp); c.641G > C, p.(Arg214Pro); and c.640C > T, p.(Arg214Trp). Missense variants in PRPS1 are usually associated with disease in male patients, including Arts syndrome, Charcot-Marie-Tooth, and nonsyndromic sensorineural deafness. In our study families, affected females manifested a retinal dystrophy with interocular asymmetry. Three unrelated females from these families had hearing loss leading to a diagnosis of Usher syndrome. Other neurological manifestations were also observed in three individuals. Our data highlight the unexpected X-linked inheritance of retinal degeneration in females caused by variants in PRPS1 and suggest that tissue-specific skewed X-inactivation or variable levels of pyrophosphate synthetase-1 deficiency are the underlying mechanism(s). We speculate that the absence of affected males in the study families suggests that some variants may be male embryonic lethal when inherited in the hemizygous state. The unbiased nature of next-generation sequencing enables all possible modes of inheritance to be considered for association of gene variants with novel phenotypic presentation.

For debate: a new wave in public health improvement.

The rising burden of chronic disease poses a challenge for all public health systems and requires innovative approaches to effectively improve population health. Persisting inequalities in health are of particular concern. Disadvantage because of education, income, or social position is associated with a larger burden of disease and, in particular, multimorbidity. Although much has been achieved to enhance population health, challenges remain, and approaches need to be revisited. In this paper, we join the debate about how a new wave of public health improvement might look. We start from the premise that population health improvement is conditional on a health-promoting societal context. It is characterised by a culture in which healthy behaviours are the norm, and in which the institutional, social, and physical environment support this mindset. Achievement of this ambition will require a positive, holistic, eclectic, and collaborative effort, involving a broad range of stakeholders. We emphasise three mechanisms: maximisation of the value of health and incentives for healthy behaviour; promotion of healthy choices as default; and minimisation of factors that create a culture and environment which promote unhealthy behaviour. We give examples of how these mechanisms might be achieved.

Excess winter deaths in Europe: a multi-country descriptive analysis.

BACKGROUND: Winter deaths are a known health and social care challenge for many countries. A previous international comparison showed significant differences in excess winter deaths across Europe in the 1990s, with the northern countries having lower excess winter mortality than those in southern Europe. METHODS: The Excess Winter Deaths Index (EWDI) is the ratio of deaths in the winter period (December to March) compared with deaths in the non-winter period. Data from the Eurostat database and national registries were used to calculate the EWDI for 31 countries in Europe across the time period 2002/2003 to 2010/2011. RESULTS: National EWDI values show heterogeneity, with a broad pattern of increasing EWDI values from northern to southern Europe and increasing mean winter temperature (r(2) = 0.50, P > 0.0001). Malta, Portugal, Spain, Cyprus and Belgium all had an EWDI that was statistically significantly higher than the average EWDI for the other 30 European countries. There was no clear association between country-level EWDI and the level of inter-annual variability in winter temperature across Europe. DISCUSSION: This article demonstrates the differences in EWDI that exist between European countries with implications for both research and policy. Many deaths may be avoidable as environmental, social and personal factors are known to contribute to winter mortality. We now need to work to better understand the causes of inter-country differences.

Detection of SARS-CoV-2 BA.2.86 by lateral flow devices.

We evaluated the performance of 12 lateral flow devices by assessing their analytical sensitivity for SARS-CoV-2 variant BA.2.86. Kits from ACON, Orient Gene, Xiamen Biotime, Getein, and SureScreen detected variant BA.2.86 to sufficient sensitivity levels, comparable to those observed with previous Omicron variants. The stocks of lateral flow devices currently held by the UK government do not currently need changing for deployment for this variant.

An evaluation of the national testing response during the COVID-19 pandemic in England: a multistage mixed-methods study protocol.

INTRODUCTION: In 2020, the UK government established a large-scale testing programme to rapidly identify individuals in England who were infected with SARS-CoV-2 and had COVID-19. This comprised part of the UK government's COVID-19 response strategy, to protect those at risk of severe COVID-19 disease and death and to reduce the burden on the health system. To assess the success of this approach, the UK Health Security Agency (UKHSA) commissioned an independent evaluation of the activities delivered by the National Health System testing programme in England. The primary purpose of this evaluation will be to capture key learnings from the roll-out of testing to different target populations via various testing services between October 2020 and March 2022 and to use these insights to formulate recommendations for future pandemic preparedness strategy. In this protocol, we detail the rationale, approach and study design. METHODS AND ANALYSIS: The proposed study involves a stepwise mixed-methods approach, aligned with established methods for the evaluation of complex interventions in health, to retrospectively assess the combined impact of key asymptomatic and symptomatic testing services nationally. The research team will first develop a theory of change, formulated in collaboration with testing service stakeholders, to understand the causal pathways and intended and unintended outcomes of each testing service and explore contextual impacts on each testing service's intended outcomes. Insights gained will help identify indicators to evaluate how the combined aims of the testing programme were achieved, using a mixed-methods approach. ETHICS AND DISSEMINATION: The study protocol was granted ethics approval by the UKHSA Research Ethics and Governance Group (reference NR0347). All relevant ethics guidelines will be followed throughout. Findings arising from this evaluation will be used to inform lessons learnt and recommendations for UKHSA on appropriate pandemic preparedness testing programme designs; findings will also be disseminated in peer-reviewed journals, a publicly available report to be published online and at academic conferences. The final report of findings from the evaluation will be used as part of a portfolio of evidence produced for the independent COVID-19 government inquiry in the UK. TRANSPARENCY DECLARATION: The lead author (the manuscript's guarantor) affirms that the manuscript is an honest, accurate and transparent account of the study being reported; no important aspects of the study have been omitted, and any discrepancies from the study as planned have been explained.