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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., (© 2024. The Author(s).)

Objective: To estimate the incidence and HRs for bleeding for different dual antiplatelet therapies (DAPT) in a real-world population with acute coronary syndrome (ACS) undergoing percutaneous coronary intervention (PCI) in England., Design: A retrospective, population-based cohort study emulating a target randomised controlled trial (tRCT)., Data Sources: Linked Clinical Practice Research Datalink (CPRD) and Hospital Episode Statistics (HES)., Setting: Primary and secondary care., Participants: Patients ≥18 years old with ACS undergoing emergency PCI., Interventions: Aspirin and clopidogrel (AC, reference) versus aspirin and prasugrel (AP) or aspirin and ticagrelor (AT); AP evaluated only in patients with ST-elevation myocardial infarction (STEMI)., Main Outcome Measures: Primary: any bleeding up to 12 months after the index event (HES- or CPRD- recorded). Secondary: HES-recorded bleeding, CPRD-recorded bleeding, all-cause and cardiovascular mortality, mortality from bleeding, myocardial infarction, stroke, additional coronary intervention and major adverse cardiovascular and cerebrovascular events (MACCE)., Results: In ACS, the rates of any bleeding for AC and AT were 89 per 1000 person years and 134 per 1000 person years, respectively. In STEMI, rates for AC, AP and AT were 93 per 1000 person years, 138 per 1000 person years and 143 per 100 person years, respectively. In ACS, compared with AC, AT increased the hazard of any bleeding (HR: 1.47, 95% CI 1.19 to 1.82) but did not reduce MACCE (HR: 1.06, 95% CI 0.89 to 1.27). In STEMI, compared with AC, AP and AT increased the hazard of any bleeding (HR: 1.77, 95% CI 1.21 to 2.59 and HR: 1.50, 95% CI 1.10 to 2.05, respectively) but did not reduce MACCE (HR: 1.10, 95% CI 0.80 to 1.51 and HR: 1.21, 95% CI 0.94 to 1.51, respectively). Non-adherence to the prescribed DAPT regimen was 28% in AC (29% in STEMI only), 31% in AP (STEMI only) and 33% in AT (32% in STEMI only)., Conclusions: In a real-world population with ACS, DAPT with ticagrelor or prasugrel are associated with increased bleeding compared with DAPT with clopidogrel., Trial Registration Number: ISRCTN76607611., Competing Interests: Competing interests: TWJ reports grants, personal fees and other from AstraZeneca and Bayer, personal fees and other from Daiichi Sankyo and personal fees from The Medicines Company, outside the submitted work., (© Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY. Published by BMJ.)

Accurate surveillance of the COVID-19 pandemic can be weakened by under-reporting of cases, particularly due to asymptomatic or pre-symptomatic infections, resulting in bias. Quantification of SARS-CoV-2 RNA in wastewater can be used to infer infection prevalence, but uncertainty in sensitivity and considerable variability has meant that accurate measurement remains elusive. Here, we use data from 45 sewage sites in England, covering 31% of the population, and estimate SARS-CoV-2 prevalence to within 1.1% of estimates from representative prevalence surveys (with 95% confidence). Using machine learning and phenomenological models, we show that differences between sampled sites, particularly the wastewater flow rate, influence prevalence estimation and require careful interpretation. We find that SARS-CoV-2 signals in wastewater appear 4-5 days earlier in comparison to clinical testing data but are coincident with prevalence surveys suggesting that wastewater surveillance can be a leading indicator for symptomatic viral infections. Surveillance for viruses in wastewater complements and strengthens clinical surveillance, with significant implications for public health., (© 2022. Crown.)

Background: In 2017, approximately 73% of antibiotics in England were prescribed from primary care practices. It has been estimated that 9%-23% of antibiotic prescriptions between 2013 and 2015 were inappropriate. Reducing antibiotic prescribing in primary care was included as one of the national priorities in a financial incentive scheme in 2015-2016., Aim: To investigate whether the effects of the Quality Premium (QP), which provided performance-related financial incentives to clinical commissioning groups (CCGs), could be explained by practice characteristics that contribute to variations in antibiotic prescribing., Design & Setting: Longitudinal monthly prescribing data were analysed for 6251 primary care practices in England from April 2014 to March 2016., Method: Linear generalised estimating equations models were fitted, examining the effect of the 2015-2016 QP on the number of antibiotic items per specific therapeutic group age-sex related prescribing unit (STAR-PU) prescribed, adjusting for seasonality and months since implementation. Consistency of effects after further adjustment for variations in practice characteristics were also examined, including practice workforce, comorbidities prevalence, prescribing rates of non-antibiotic drugs, and deprivation., Results: Antibiotics prescribed in primary care practices in England reduced by -0.172 items per STAR-PU (95% confidence interval [CI] = -0.180 to -0.171) after 2015-2016 QP implementation, with slight increases in the months following April 2015 (+0.014 items per STAR-PU; 95% CI = +0.013 to +0.014). Adjusting the model for practice characteristics, the immediate and month-on-month effects following implementation remained consistent, with slight attenuation in immediate reduction from -0.172 to -0.166 items per STAR-PU. In subgroup analysis, the QP effect was significantly greater among the top 20% prescribing practices (interaction p <0.001). Practices with low workforce and those with higher diabetes prevalence had greater reductions in prescribing following 2015-2016 QP compared with other practices (interaction p <0.001)., Conclusion: In high-prescribing practices, those with low workforce and high diabetes prevalence had more reduction following the QP compared with other practices, highlighting the need for targeted support of these practices and appropriate resourcing of primary care., (Copyright © 2020, The Authors.)

Background: Catheter-associated urinary tract infection (CAUTI) and bloodstream infection (CABSI) are leading causes of healthcare-associated infection in England's National Health Service (NHS), but health-economic evidence to inform investment in prevention is lacking., Aims: To quantify the health-economic burden and value of prevention of urinary-catheter-associated infection among adult inpatients admitted to NHS trusts in 2016/17., Methods: A decision-analytic model was developed to estimate the annual prevalence of CAUTI and CABSI, and their associated excess health burdens [quality-adjusted life-years (QALYs)] and economic costs (£ 2017). Patient-level datasets and literature were synthesized to estimate population structure, model parameters and associated uncertainty. Health and economic benefits of catheter prevention were estimated. Scenario and probabilistic sensitivity analyses were conducted., Findings: The model estimated 52,085 [95% uncertainty interval (UI) 42,967-61,360] CAUTIs and 7529 (UI 6857-8622) CABSIs, of which 38,084 (UI 30,236-46,541) and 2524 (UI 2319-2956) were hospital-onset infections, respectively. Catheter-associated infections incurred 45,717 (UI 18,115-74,662) excess bed-days, 1467 (UI 1337-1707) deaths and 10,471 (UI 4783-13,499) lost QALYs. Total direct hospital costs were estimated at £54.4M (UI £37.3-77.8M), with an additional £209.4M (UI £95.7-270.0M) in economic value of QALYs lost assuming a willingness-to-pay threshold of £20,000/QALY. Respectively, CABSI accounted for 47% (UI 32-67%) and 97% (UI 93-98%) of direct costs and QALYs lost. Every catheter prevented could save £30 (UI £20-44) in direct hospital costs and £112 (UI £52-146) in QALY value., Conclusions: Hospital catheter prevention is poised to reap substantial health-economic gains, but community-oriented interventions are needed to target the large burden imposed by community-onset infection., (Crown Copyright © 2019. Published by Elsevier Ltd. All rights reserved.)

Background: Studies often ignore time-varying confounding or may use inappropriate methodology to adjust for time-varying confounding., Aim: To estimate the effect of intensive care unit (ICU)-acquired bacteraemia on ICU mortality and discharge using appropriate methodology., Methods: Marginal structural models with inverse probability weighting were used to estimate the ICU mortality and discharge associated with ICU-acquired bacteraemia among patients who stayed more than two days at the general ICU of a London teaching hospital and remained bacteraemia-free during those first two days. For comparison, the same associations were evaluated with (i) a conventional Cox model, adjusting only for baseline confounders and (ii) a Cox model adjusting for baseline and time-varying confounders., Findings: Using the marginal structural model with inverse probability weighting, bacteraemia was associated with an increase in ICU mortality (cause-specific hazard ratio (CSHR): 1.29; 95% confidence interval (CI): 1.02-1.63) and a decrease in discharge (CSHR: 0.52; 95% CI: 0.45-0.60). By 60 days, among patients still in the ICU after two days and without prior bacteraemia, 8.0% of ICU deaths could be prevented by preventing all ICU-acquired bacteraemia cases. The conventional Cox model adjusting for time-varying confounders gave substantially different results [for ICU mortality, CSHR: 1.08 (95% CI: 0.88-1.32); for discharge, CSHR: 0.68 (95% CI: 0.60-0.77)]., Conclusion: In this study, even after adjusting for the timing of acquiring bacteraemia and time-varying confounding using inverse probability weighting for marginal structural models, ICU-acquired bacteraemia was associated with a decreased daily ICU discharge risk and an increased risk of ICU mortality., (Crown Copyright © 2017. Published by Elsevier Ltd. All rights reserved.)

Background: Conflicting results have been found regarding outcomes of intensive care unit (ICU)-acquired Enterobacteriaceae bacteraemia and the potentially modifying effect of appropriate empiric antibiotic therapy., Aim: To evaluate these associations while adjusting for potential time-varying confounding using methods from the causal inference literature., Methods: Patients who stayed more than two days in two general ICUs in England between 2002 and 2006 were included in this cohort study. Marginal structural models with inverse probability weighting were used to estimate the mortality and discharge associated with Enterobacteriaceae bacteraemia and the impact of appropriate empiric antibiotic therapy on these outcomes., Findings: Among 3411 ICU admissions, 195 (5.7%) ICU-acquired Enterobacteriaceae bacteraemia cases occurred. Enterobacteriaceae bacteraemia was associated with an increased daily risk of ICU death [cause-specific hazard ratio (HR): 1.48; 95% confidence interval (CI): 1.10-1.99] and a reduced daily risk of ICU discharge (HR: 0.66; 95% CI: 0.54-0.80). Appropriate empiric antibiotic therapy did not significantly modify ICU mortality (HR: 1.08; 95% CI: 0.59-1.97) or discharge (HR: 0.91; 95% CI: 0.63-1.32)., Conclusion: ICU-acquired Enterobacteriaceae bacteraemia was associated with an increased daily risk of ICU mortality. Furthermore, the daily discharge rate was also lower after acquiring infection, even when adjusting for time-varying confounding using appropriate methodology. No evidence was found for a beneficial modifying effect of appropriate empiric antibiotic therapy on ICU mortality and discharge., (Crown Copyright © 2017. Published by Elsevier Ltd. All rights reserved.)

Objectives: Respiratory syncytial virus (RSV) is increasingly recognized as an important cause of morbidity, mortality and health-care utilization in the elderly population. A theoretical model was built to assess the levels of vaccine effectiveness and vaccine costs for which a hypothetical RSV-vaccine for Dutch elderly could be cost-effective., Methods: Different vaccination strategies were evaluated by changing the levels of vaccine effectiveness and the willingness to pay per quality-adjusted life year gained (QALY). Outcome measures included direct medical costs, QALYs, life years gained, incremental cost-effectiveness ratios (ICERs) and the maximum total vaccination costs per individual (i.e. (vaccine price+administration costs)×nr of doses) while remaining cost-effective., Results: Using base-case assumptions, it was estimated that vaccination of all persons 60 years and older would prevent 3402GP visits, 2989 antibiotic prescriptions, 535 hospitalizations and 249 deaths and would cost €73,261 per QALY, for a vaccine effectiveness of 70%. Vaccinating only the high risk population of 60 years and older would reduce the estimates to 2042GP visits, 2009 antibiotic prescriptions, 179 hospitalizations and 209 deaths and this reduced the cost per QALY to €34,796 per QALY. Using the same assumptions, the maximum total vaccination costs per individual ranged from €26 when vaccinating all persons 60 and older to €68 when vaccinating only persons aged 85 and above, using a willingness to pay threshold of €50,000 per QALY. For the high risk population aged 60 years and older the estimated maximum total vaccination costs ranged from €52 to €99., Conclusion: Vaccination of Dutch elderly against RSV was found cost-effective for several scenarios. As expected, vaccination is more likely to be cost-effective when only including persons who are at increased risk for contracting RSV or the potential complications of RSV. This theoretical study shows that based on the disease burden in the Dutch population aged 60yrs and older there is potential to develop a vaccine that might be considered cost-effective in the Netherlands., (Copyright © 2013 Elsevier Ltd. All rights reserved.)

To date, constitutively activating point mutations reported in hematopoietic growth factor receptors in patients with acute myeloid leukemia (AML) have been restricted to receptors with intrinsic tyrosine kinase activity such as c-kit and FLT3. We describe here a Thr617Asn mutation in the transmembrane domain of the non-tyrosine kinase receptor for granulocyte colony-stimulating factor (G-CSF) in the blast cells of two out of 555 AML patients examined. The mutant receptor conferred growth factor independence on factor-dependent Ba/F3 cells. In the absence of ligand, immunoblotting showed weak phosphorylation of JAK2, STAT3, ERKs 1 and 2 and the receptor itself, and there was approximately 70% of maximal growth in a proliferation assay. All signals were significantly enhanced in the presence of G-CSF. Retroviral transduction of mutant receptor into primary hematopoietic CD34+ cells induced G-CSF independent myeloid differentiation as assessed by the development of neutrophils and surface expression of CD11b and CD14. These results confirm the importance of the transmembrane domain for receptor function and suggest that introduction of an asparagine residue can cause sufficient stabilization of helix-helix interactions in the absence of ligand to activate downstream signaling pathways involved in directing proliferation and differentiation.

Interleukin-7 (IL-7) stimulates the proliferation of normal and leukemic B and T cell precursors and T lymphocytes. Activation of the JAK/STAT pathway has been implicated in IL-7R signaling. We investigated which STAT complexes are formed upon stimulation of B cell precursor acute lymphoblastic leukemia (BCP-ALL) cells with IL-7. Gel retardation assays with STAT-binding oligonucleotides showed that IL-7 induces the formation of two major STAT complexes in BCP-ALL cells. Supershifts with anti-STAT antibodies identified these as STAT1 and STAT5 complexes. This pattern of STAT activation was seen in all BCP-ALL cases that respond to IL-7 in proliferation assays. IL-7 also induced STAT/DNA binding in BCP-ALL cases that failed to proliferate in response to IL-7, suggesting that the ability of IL-7R to activate the JAK/STAT pathway per se is not sufficient for proliferation induction. To determine the contribution of the cytoplasmic domain of the IL-7 receptor alpha chain (IL-7R alpha) to activation of STAT proteins, transfectants of the murine pro-B cell line BAF3 were made that express chimeric receptors consisting of the extracellular domain of human granulocyte colony-stimulating factor receptor (G-CSF-R) and the transmembrane and intracellular domains of human IL-7R alpha. Activation of the chimeric G-CSF-R/IL-7R alpha with G-CSF resulted in a full proliferative response and induced the phosphorylation of JAK1 but not JAK2. Major STAT complexes activated by G-CSF-R/IL-7R alpha contained STAT1 or STAT5, while some formation of STAT3-containing complexes was also seen. These findings establish that STAT1 and STAT5, and possibly STAT3, are activated upon stimulation of precursor B cells with IL-7. The data further indicate that the IL-7R alpha chains are directly involved in the activation of JAKs and STATs and have a major role in proliferative signaling in precursor B cells.

Granulocyte colony-stimulating factor (G-CSF) promotes the survival and proliferation of myeloid progenitors and induces maturation of these cells toward terminally differentiated neutrophils. Using transfectants of the murine IL-3-dependent myeloid cell line 32D that express the human G-CSF receptor (32D/WT cells), we show here that G-CSF can also exert adverse effects on myeloid cell survival. Although initially enhancing IL-3-driven proliferation of 32D/WT cells, G-CSF strongly inhibited cell survival at later stages of culture. The loss of viability of 32D/WT cells following sustained G-CSF stimulation was not accompanied by progressive neutrophilic maturation. Instead, 32D/WT cells exhibited features characteristic of apoptosis. The apoptosis-inducing effect of G-CSF was seen at concentrations of IL-3 that could support long-term proliferation and survival of 32D/WT cells in the absence of G-CSF. Experiments with 32D cells expressing mutant forms of the G-CSF receptor revealed that the death signals were mediated exclusively through the membrane-distal cytoplasmic part of the G-CSF receptor, a region also involved in maturation signaling.

Interleukin 7 (IL-7) stimulates proliferation of normal human and murine B cell precursor (BCP) cells in a distinct fashion, depending on the stage of maturation of the cells. For instance, the productive rearrangement of the immunoglobulin heavy chain gene has been demonstrated to be essential for the response of BCP cells to IL-7 as the single proliferation stimulus. IL-7 activates a receptor that consists of the IL-7R protein and the common gamma chain (gamma c). BCP acute lymphoblastic leukemia (BCP-ALL) cells variably respond to IL-7. Among 72 cases of BCP-ALL IL-7 activated DNA synthesis in 34. In four cases inhibition of DNA synthesis was seen. In the remaining 38 cases IL-7 exerted no effects. We determined whether this heterogeneity in IL-7 response could be correlated with parameters that could influence the IL-7 response. Firstly we show that, in contrast to the murine BCP cells, the IL-7 response of human BCP-ALL cells did not correlate with the status of IgH chain gene rearrangement and expression, nor with the rearrangement of IgL chain genes. Subsequently, it is demonstrated that IL-7R protein and transcripts as well as gamma c transcripts are equally present in the IL-7 responsive and nonresponsive BCP-ALL samples, indicating that the defective expression of these chains could not be held responsible for IL-7 response failures. Finally, we observed that kit ligand (KL), known to synergize with IL-7 in the most primitive stages of normal B cell development, did not enhance the IL-7 responses of BCP-ALL cells.

Among 52 patients diagnosed as acute myeloid leukemia (AML), nine cases were found in which interleukin-5 (IL-5) induced a proliferative response in the leukemic cells, as measured by the stimulation of DNA synthesis or colony formation in vitro. All cases (n = 7) with the cytogenetic abnormality t(8;21)(q22;q22) belonged to this group of IL-5 responders. Of the additional two cases, one had an apparently normal karyotype, but the other expressed a dicentric chromosome 21, an abnormality also involving the breakpoint region 21q22. The leukemic cells of the IL-5 responsive patients could also be stimulated to proliferate by IL-3, GM-CSF and G-CSF, and in some cases by IL-6 or M-CSF. Immunophenotypic analysis revealed the presence of the immature hematopoietic cell antigen CD34, the myelomonocytic maturation antigens CD13 and CD33, in association with the B-cell related surface marker CD19 on the leukemic cells. Immunoglobulin mu and T-cell receptor beta-genes in the leukemic cells were in germline configuration. Upon incubation in colony culture, clonogenic cells were capable of producing progeny showing eosinophilic or neutrophilic maturation following stimulation with IL-5 or G-CSF, respectively. It is concluded that IL-5 responsive AML represents a subgroup of leukemia with distinct immunotypic and cytogenetic features.