Rapid antigen testing in COVID-19 management for school-aged children: an observational study in Cheshire and Merseyside, UK.

BACKGROUND: Twice weekly lateral flow tests (LFTs) for secondary school children was UK Government policy from 8 March 2021. We evaluate use of LFTs (both supervised at test centres, and home test kits) in school-aged children in Cheshire and Merseyside. METHODS: We report (i) number of LFT positives (ii) proportion of LFT positive with confirmatory reverse transcription polymerase chain reaction (PCR) test within 2 days, and (iii) agreement between LFT-positive and confirmatory PCR, and dependence of (i-iii) on COVID-19 prevalence. FINDINGS: 1 248 468 LFTs were taken by 211 255 12-18 years old, and 163 914 by 52 116 5-11 years old between 6 November 2020 and 31 July 2021. Five thousand three hundred and fourteen (2.5%) 12-18 years old and 1996 (3.8%) 5-11 years old returned LFT positives, with 3829 (72.1%) and 1535 (76.9%) confirmatory PCRs, and 3357 (87.7%) and 1383 (90.1%) confirmatory PCR-positives, respectively.Monthly proportions of LFT positive with PCR negative varied between 4.7% and 35.3% in 12-18 years old (corresponding proportion of all tests positive: 9.7% and 0.3%).Deprivation and non-White ethnicity were associated with reduced uptake of confirmatory PCR. INTERPRETATION: Substantial inequalities in confirmatory testing need more attention to avoid further disadvantage through education loss. When prevalence is low additional measures, including confirmatory testing, are needed. Local Directors of Public Health taking more control over schools testing may be needed. FUNDING: DHSC, MRC, NIHR, EPSRC.

Breast cancer incidence and survival in Scotland by socio-economic deprivation and tumour subtype.

BACKGROUND: Women from socio-economically deprived areas are less likely to develop and then to survive breast cancer (BC). Whether associations between deprivation and BC incidence and survival differ by tumour molecular subtypes and mode of detection in Scotland are unknown. METHODS: Data consisted of 62,378 women diagnosed with invasive BC between 2000 and 2016 in Scotland. Incidence rates and time trends were calculated for oestrogen receptor positive (ER+) and negative (ER-) tumours and stratified by the Scottish Index of Multiple Deprivation (SIMD) quintiles and screening status. SIMD is an area-based measure derived across seven domains: income, employment, education, health, access to services, crime and housing. We calculated adjusted hazard ratios (aHR [95% confidence intervals]) for BC death by immunohistochemical surrogates of molecular subtypes for the most versus the least deprived quintile. We adjusted for mode of detection and other confounders. RESULTS: In Scotland, screen-detected ER+tumour incidence increased over time, particularly in the least deprived quintile [Average Annual Percentage Change (AAPC) = 2.9% with 95% CI from 1.2 to 4.7]. No marked differences were observed for non-screen-detected ER+tumours or ER- tumours by deprivation. BC mortality was higher in the most compared to the least deprived quintile irrespective of ER status (aHR = 1.29 [1.18, 1.41] for ER+ and 1.27 [1.09, 1.47] for ER- tumours). However, deprivation was associated with significantly higher mortality for luminal A and HER2-enriched tumours (aHR = 1.46 [1.13, 1.88] and 2.10 [1.23, 3.59] respectively) but weaker associations for luminal B and TNBC tumours that were not statistically significant. CONCLUSIONS: Deprivation is associated with differential BC incidence trends for screen-detected ER+tumours and with higher mortality for select tumour subtypes. Future efforts should evaluate factors that might be associated with reduced survival in deprived populations and monitor progress stratified by tumour subtypes and mode of detection.

Study-design in pandemics: From surveillance and performance-evaluation to licensing and pharmacovigilance.

Andy Grieve, the first pharmaceutical statistician to be President of the Royal Statistical Society, practiced in the regulated world of drug development. With reduction in drug development costs as his motivation, Grieve advanced Bayesian methods for developing predictive methods for efficacy and toxicity - to be used as early as possible in the drug development process; and his presidential address exhorted statisticians to weigh-in wherever data are used to make decisions. Diagnostic tests for infectious diseases are less regulated than drugs and vaccines unless the blood supply is at risk. Unlike in the HIV and HCV pandemics of the late 20th century, even well-designed surveys linked to a volunteered biological sample (to be tested for SARS-CoV-2 antigen or antibodies) have had modest or low consent rates. Record-linkage, statistical design and reporting standards have seen triumph and tragedy. Among the triumphs are: Liverpool's insistence on dual testing (lateral flow device; polymerase chain reaction [PCR]) of some 6000 asymptomatic citizens who attended for SARS-CoV-2-screening; two tricky randomized controlled public-policy trials on daily contact testing for close contacts of index cases of SARS-CoV-2 infection versus self-isolation (with or without initial PCR); and among already-consented participants in surveillance, over 80% secondary consent for linkage to their health records, including the Immunization Management Service. Before the next pandemic we need to entrench better regulation of diagnostic tests, better informed consent (not via weblinks), better feedback to participants, and transparency about basic safety data.

Quality of care for adult in-patients with malaria in a tertiary hospital in Uganda.

BACKGROUND: Prompt detection and appropriate treatment of malaria prevents severe disease and death. The quality of care for adult malaria in-patients is not well documented in sub-Saharan Africa, particularly in Uganda. The study sought to describe the patterns of malaria diagnosis and treatment among adult in-patients admitted to the medical and gynaecological wards of Uganda's 1790-bed Mulago National Referral Hospital from December 2013 to April 2014. METHODS: A prospective cohort of 762 consented in-patients aged ≥ 18 years was assembled. Proportions of in-patients who received preadmission and in-hospital anti-malarials, missed Day 1 dosing of hospital-initiated anti-malarials and/or had malaria microscopy done were determined. Multivariable logistic regression was used to identify risk-factors for missed Day 1 dosing of anti-malarials. RESULTS: One in five (19%, 146/762) in-patients had an admission or discharge malaria diagnosis or both; with median age of 29 years (IQR, 22-42 years). Microscopy was requested in 77% (108/141) of in-patients with an admission malaria diagnosis; results were available for 46% (50/108), of whom 42% (21/50) tested positive for Plasmodium falciparum malaria parasitaemia. Only 13% (11/83) of in-patients who received in-hospital injectable artesunate (AS) or quinine (Q) received follow-up oral artemether-lumefantrine (AL); 2 of 18 severe malaria cases received follow-up oral AL. Injectable AS only (47%, 47/100) was the most frequent hospital-initiated anti-malarial treatment followed by injectable Q only (23%, 23/100) amongst in-patients who received in-hospital anti-malarials. A quarter (25%, 25/100; 95% CI: 17-35%) of in-patients missed Day 1 dosing of hospital-initiated anti-malarials. Each additional admission diagnosis was more than two-fold likely to increase the odds of missed Day 1 dosing of in-hospital anti-malarials (aOR = 2.6, 95% CI: 1.52-4.56; P-value = 0.001). CONCLUSIONS: Half the malaria microscopy results were not available; yet, the rate of testing was high. The majority of in-patients initiated on injectable AS or Q did not receive the recommended follow-up oral AL. One in four in-patients delayed to initiate hospital anti-malarials by at least one calendar day. The hospital should encourage prompt availability of malaria test-results to promote the timely initiation and completion of anti-malarial treatment, thereby improving the quality of care for hospitalized malaria patients in Uganda.

Scotland's 2009-2015 methadone-prescription cohort: Quintiles for daily dose of prescribed methadone and risk of methadone-specific death.

AIMS: As methadone clients age, their drug-related death (DRD) risks increase, more than doubling at 45+ years for methadone-specific DRDs. METHODS: Using Community Health Index (CHI) numbers, mortality to 31 December 2015 was ascertained for 36 347 methadone-prescription clients in Scotland during 2009-2015. Cohort entry, quantity of prescribed methadone and daily dose (actual or recovered by effective, simple rules) were defined by clients' first CHI-identified methadone prescription after 30 June 2009 and used in proportional hazards analysis. As custodian of death records, National Records of Scotland identified non-DRDs from DRDs. Methadone-specific DRD means methadone was implicated but neither heroin nor buprenorphine. RESULTS: The cohort's 192 928 person-years included 1857 non-DRDs and 1323 DRDs (42%), 546 of which were methadone specific. Actual/recovered daily dose was available for 26 533 (73%) clients who experienced 420 methadone-specific DRDs. Top quintile for daily dose at first CHI-identified methadone prescription was >90 mg. Age 45+ years at cohort-entry (hazard ratio vs 25-34 years: 3.1, 95% confidence interval: 2.4-4.2), top quintile for baseline daily dose of prescribed methadone (vs 50-70 mg: 1.9, 1.1-3.1) and being female (1.3, 1.0-1.6) significantly increased clients' risk of methadone-specific DRD. CONCLUSION: Extra care is needed when methadone daily dose exceeds 90 mg. Females' higher risk for methadone-specific DRD is new and needs validation. Further analyses of prescribed daily dose linked to mortality for large cohorts of methadone clients are needed internationally, together with greater pharmacodynamic and pharmacokinetic understanding of methadone by age and sex. Balancing age-related risks is challenging for prescribers who manage chronic opiate dependency against additional uncertainty about the nature, strength and pharmacological characteristics of drugs from illegal markets.

Distinct temporal trends in breast cancer incidence from 1997 to 2016 by molecular subtypes: a population-based study of Scottish cancer registry data.

BACKGROUND: We describe temporal trends in breast cancer incidence by molecular subtypes in Scotland because public health prevention programmes, diagnostic and therapeutic services are shaped by differences in tumour biology. METHODS: Population-based cancer registry data on 72,217 women diagnosed with incident primary breast cancer from 1997 to 2016 were analysed. Age-standardised rates (ASR) and age-specific incidence were estimated by tumour subtype after imputing the 8% of missing oestrogen receptor (ER) status. Joinpoint regression and age-period-cohort models were used to assess whether significant differences were observed in incidence trends by ER status. RESULTS: Overall, ER-positive tumour incidence increased by 0.4%/year (95% confidence interval (CI): -0.1, 1.0). Among routinely screened women aged 50-69 years, we observed an increase in ASR from 1997 to 2011 (1.6%/year, 95% CI: 1.2-2.1). ER-negative tumour incidence decreased among all ages by 2.5%/year (95% CI: -3.9 to -1.1%) over the study period. Compared with the 1941-1959 birth cohort, women born in 1912-1940 had lower incidence rate ratios (IRR) for ER+ tumours and women born in 1960-1986 had lower IRR for ER- tumours. CONCLUSIONS: Future incidence and survival reporting should be monitored by molecular subtypes to inform clinical planning and cancer control programmes.

Statistical issues in first-in-human studies on BIA 10-2474: Neglected comparison of protocol against practice.

By setting the regulatory-approved protocol for a suite of first-in-human studies on BIA 10-2474 against the subsequent French investigations, we highlight 6 key design and statistical issues, which reinforce recommendations by a Royal Statistical Society Working Party, which were made in the aftermath of cytokine release storm in 6 healthy volunteers in the United Kingdom in 2006. The 6 issues are dose determination, availability of pharmacokinetic results, dosing interval, stopping rules, appraisal by safety committee, and clear algorithm required if combining approvals for single and multiple ascending dose studies.

Extensive antibiotic prescription rate among hospitalized patients in Uganda: but with frequent missed-dose days.

OBJECTIVES: To describe the patterns of systemic antibiotic use and missed-dose days and detail the prescription, dispensing and administration of frequently used hospital-initiated antibiotics among Ugandan inpatients. METHODS: This was a prospective cohort of consented adult inpatients admitted on the medical and gynaecological wards of the 1790 bed Mulago National Referral Hospital. RESULTS: Overall, 79% (603/762; 95% CI: 76%-82%) of inpatients received at least one antibiotic during hospitalization while 39% (300/762; 95% CI: 36%-43%) had used at least one antibiotic in the 4 weeks pre-admission; 1985 antibiotic DDDs, half administered parenterally, were consumed in 3741 inpatient-days. Two-fifths of inpatients who received at least one of the five frequently used hospital-initiated antibiotics (ceftriaxone, metronidazole, ciprofloxacin, amoxicillin and azithromycin) missed at least one antibiotic dose-day (44%, 243/558). The per-day risk of missed antibiotic administration was greatest on day 1: ceftriaxone (36%, 143/398), metronidazole (27%, 67/245), ciprofloxacin (34%, 39/114) and all inpatients who missed at least one dose-day of prescribed amoxicillin and azithromycin. Most patients received fewer doses than were prescribed: ceftriaxone (74%, 273/371), ciprofloxacin (90%, 94/105) and metronidazole (97%, 222/230). Of prescribed doses, only 62% of ceftriaxone doses (1178/1895), 35% of ciprofloxacin doses (396/1130) and 27% of metronidazole doses (1043/3862) were administered. Seven percent (13/188) of patients on intravenous metronidazole and 6% (5/87) on intravenous ciprofloxacin switched to oral route. CONCLUSIONS: High rates of antibiotic use both pre-admission and during hospitalization were observed, with low parenteral/oral switch of hospital-initiated antibiotics. Underadministration of prescribed antibiotics was common, especially on the day of prescription, risking loss of efficacy and antibiotic resistance.

Herbal medicine use and linked suspected adverse drug reactions in a prospective cohort of Ugandan inpatients.

BACKGROUND: Clinical history-taking can be employed as a standardized approach to elucidate the use of herbal medicines and their linked suspected adverse drug reactions (ADRs) among hospitalized patients. We sought to identify herbal medicines nominated by Ugandan inpatients; compare nomination rates by ward and gender; confirm the herbs' known pharmacological properties from published literature; and identify ADRs linked to pre-admission use of herbal medicines. METHODS: Prospective cohort of consented adult inpatients designed to assess medication use and ADRs on one gynaecological and three medical wards of 1790-bed Mulago National Referral Hospital. Baseline and follow-up data were obtained on patients' characteristics, including pre-admission use of herbal medicines. RESULTS: Fourteen percent (26/191) of females in Gynaecology nominated at least one specific herbal medicine compared with 20 % (114/571) of inpatients on medical wards [20 % (69/343) of females; 20 % (45/228) of males]. Frequent nominations were Persea americana (30), Mumbwa/multiple-herb clay rods (23), Aloe barbadensis (22), Beta vulgaris (12), Vernonia amygdalina (11), Commelina africana (7), Bidens pilosa (7), Hoslundia opposita (6), Mangifera indica (4), and Dicliptera laxata (4). Four inpatients experienced 10 suspected ADRs linked to pre-admission herbal medicine use including Commelina africana (4), multiple-herb-mumbwa (1), or unspecified local-herbs (5): three ADR-cases were abortion-related and one kidney-related. CONCLUSIONS: The named herbal medicines and their nomination rates generally differed by specialized ward, probably guided by local folklore knowledge of their use. Clinical elicitation from inpatients can generate valuable safety data on herbal medicine use. However, larger routine studies might increase the utility of our method to assess herbal medicine use and detect herb-linked ADRs. Future studies should take testable samples of ADR-implicated herbal medicines for further analysis.

Modeling the initiation of others into injection drug use, using data from 2,500 injectors surveyed in Scotland during 2008-2009.

The prevalence of injection drug use has been of especial interest for assessment of the impact of blood-borne viruses. However, the incidence of injection drug use has been underresearched. Our 2-fold aim in this study was to estimate 1) how many other persons, per annum, an injection drug user (IDU) has the equivalent of full responsibility (EFR) for initiating into injection drug use and 2) the consequences for IDUs' replacement rate. EFR initiation rates are strongly associated with incarceration history, so that our analysis of IDUs' replacement rate must incorporate when, in their injecting career, IDUs were first incarcerated. To do so, we have first to estimate piecewise constant incarceration rates in conjunction with EFR initiation rates, which are then combined with rates of cessation from injecting to model IDUs' replacement rate over their injecting career, analogous to the reproduction number of an epidemic model. We apply our approach to Scotland's IDUs, using over 2,500 anonymous injector participants who were interviewed in Scotland's Needle Exchange Surveillance Initiative during 2008-2009. Our approach was made possible by the inclusion of key questions about initiations. Finally, we extend our model to include an immediate quit rate, as a reasoned compensation for higher-than-expected replacement rates, and we estimate how high initiates' quit rate should be for IDUs' replacement rate to be 1.

Take-home naloxone to prevent fatalities from opiate-overdose: Protocol for Scotland's public health policy evaluation, and a new measure to assess impact.

Aims: Scotland was the first country to adopt take-home naloxone (THN) as a funded public health policy. We summarise the background and rigorous set-up for before/after monitoring to assess the impact on high-risk opiate-fatalities. Methods: Evidence-synthesis of prospectively monitored small-scale THN schemes led to a performance indicator for distribution of THN-kits relative to opiate-related deaths. Next, we explain the primary outcome and statistical power for Scotland's before/after monitoring. Results: Fatality-rate at opiate overdoses witnessed by THN-trainees was 6% (9/153, 95% CI: 2-11%). National THN-schemes should aim to issue 20 times as many THN-kits as there are opiate-related deaths per annum; and at least nine times as many. Primary outcome for evaluating Scotland's THN policy is reduction in the percentage of all opiate-related deaths with prison-release as a 4-week antecedent. Scotland's baseline period is 2006-10, giving a denominator of 1970 opiate-related deaths. A priori plausible effectiveness was 20-30% reduction, relative to baseline, in the proportion of opiate-related deaths that had prison-release as a 4-week antecedent. A secondary outcome was also defined. Conclusion: If Scotland's THN evaluation shifts the policy ground seismically, our new performance measure may prove useful on how many THN-kits nations should provide annually.

Incomplete contingency tables with censored cells with application to estimating the number of people who inject drugs in Scotland.

Estimating the size of hidden or difficult to reach populations is often of interest for economic, sociological or public health reasons. In order to estimate such populations, administrative data lists are often collated to form multi-list cross-counts and displayed in the form of an incomplete contingency table. Log-linear models are typically fitted to such data to obtain an estimate of the total population size by estimating the number of individuals not observed by any of the data-sources. This approach has been taken to estimate the current number of people who inject drugs (PWID) in Scotland, with the Hepatitis C virus diagnosis database used as one of the data-sources to identify PWID. However, the Hepatitis C virus diagnosis data-source does not distinguish between current and former PWID, which, if ignored, will lead to overestimation of the total population size of current PWID. We extend the standard model-fitting approach to allow for a data-source, which contains a mixture of target and non-target individuals (i.e. in this case, current and former PWID). We apply the proposed approach to data for PWID in Scotland in 2003, 2006 and 2009 and compare with the results from standard log-linear models.

Correction: Tracking the incidence and risk factors for SARS-CoV-2 infection using historical maternal booking serum samples.

[This corrects the article DOI: 10.1371/journal.pone.0273966.].

Take-home emergency naloxone to prevent heroin overdose deaths after prison release: rationale and practicalities for the N-ALIVE randomized trial.

The naloxone investigation (N-ALIVE) randomized trial commenced in the UK in May 2012, with the preliminary phase involving 5,600 prisoners on release. The trial is investigating whether heroin overdose deaths post-prison release can be prevented by prior provision of a take-home emergency supply of naloxone. Heroin contributes disproportionately to drug deaths through opiate-induced respiratory depression. Take-home emergency naloxone is a novel preventive measure for which there have been encouraging preliminary reports from community schemes. Overdoses are usually witnessed, and drug users themselves and also family members are a vast intervention workforce who are willing to intervene, but whose responses are currently often inefficient or wrong. Approximately 10% of provided emergency naloxone is thought to be used in subsequent emergency resuscitation but, as yet, there have been no definitive studies. The period following release from prison is a time of extraordinarily high mortality, with heroin overdose deaths increased more than sevenfold in the first fortnight after release. Of prisoners with a previous history of heroin injecting who are released from prison, 1 in 200 will die of a heroin overdose within the first 4 weeks. There are major scientific and logistical challenges to assessing the impact of take-home naloxone. Even in recently released prisoners, heroin overdose death is a relatively rare event: hence, large numbers of prisoners need to enter the trial to assess whether take-home naloxone significantly reduces the overdose death rate. The commencement of pilot phase of the N-ALIVE trial is a significant step forward, with prisoners being randomly assigned either to treatment-as-usual or to treatment-as-usual plus a supply of take-home emergency naloxone. The subsequent full N-ALIVE trial (contingent on a successful pilot) will involve 56,000 prisoners on release, and will give a definitive conclusion on lives saved in real-world application. Advocates call for implementation, while naysayers raise concerns. The issue does not need more public debate; it needs good science.

Injecting drug users in Scotland, 2006: Listing, number, demography, and opiate-related death-rates.

Using Bayesian capture-recapture analysis, we estimated the number of current injecting drug users (IDUs) in Scotland in 2006 from the cross-counts of 5670 IDUs listed on four data-sources: social enquiry reports (901 IDUs listed), hospital records (953), drug treatment agencies (3504), and recent Hepatitis C virus (HCV) diagnoses (827 listed as IDU-risk). Further, we accessed exact numbers of opiate-related drugs-related deaths (DRDs) in 2006 and 2007 to improve estimation of Scotland's DRD rates per 100 current IDUs. Using all four data-sources, and model-averaging of standard hierarchical log-linear models to allow for pairwise interactions between data-sources and/or demographic classifications, Scotland had an estimated 31700 IDUs in 2006 (95% credible interval: 24900-38700); but 25000 IDUs (95% CI: 20700-35000) by excluding recent HCV diagnoses whose IDU-risk can refer to past injecting. Only in the younger age-group (15-34 years) were Scotland's opiate-related DRD rates significantly lower for females than males. Older males' opiate-related DRD rate was 1.9 (1.24-2.40) per 100 current IDUs without or 1.3 (0.94-1.64) with inclusion of recent HCV diagnoses. If, indeed, Scotland had only 25000 current IDUs in 2006, with only 8200 of them aged 35+ years, the opiate-related DRD rate is higher among this older age group than has been appreciated hitherto. There is counter-balancing good news for the public health: the hitherto sharp increase in older current IDUs had stalled by 2006.