Tracking progress on Antimicrobial Resistance by the Quadripartite Country Self-Assessment Survey (TrACSS) in G7 countries, 2017-2023: opportunities and gaps.

Antimicrobial resistance (AMR) poses serious challenges to the healthcare systems worldwide. Multiple factors and activities contribute to the development and spread of antimicrobial-resistant microorganisms. Monitoring progress in combating AMR is fundamental at both global and national levels to drive multisectoral actions, identify priorities, and coordinate strategies. Since 2017, the World Health Organization (WHO) has collected data through the Tracking AMR Country Self-Assessment Survey (TrACSS). TrACSS data are published in a publicly-available database. In 2023, 71 (59.9%) out of 177 responding countries reported the existence of a monitoring and evaluation plan for their National Action Plan (NAP) on AMR, and just 20 countries (11.3%) the allocation of funding to support NAP implementation. Countries reported challenges including limited financial and human resources, lack of technical capacity, and variable political commitment. Even across the Group of Seven (G7) countries, which represent some of the world's most advanced economies, many areas still need improvement, such as full implementation of infection prevention and control measures, adoption of WHO access/watch/reserve (AWaRe) classification of antibiotics, effective integration of laboratories in AMR surveillance in the animal health and food safety sectors, training and education, good manufacturing and hygiene practices in food processing, optimising pesticides use and environmental residues of antimicrobial drugs. Continuous and coordinated efforts are needed to strengthen multisectoral engagement to fight AMR.

24-Year-Old Patient with Klippel-Trenaunay Syndrome Underwent Cementless Robotic Cruciate-Retaining TKA: A Case Report.

CASE: A 24-year-old man with Klippel-Trenaunay syndrome (KTS) presented with severe knee osteoarthritis unresponsive to conservative measures. Owing to end-stage, debilitating arthritic symptoms, surgery was pursued. Careful preoperative, multidisciplinary planning/treatment included magnetic resonance imaging to characterize the venous malformations throughout the right lower extremity, preoperative sclerotherapy, sirolimus, and robotic-assisted cementless total knee arthroplasty (TKA). CONCLUSION: Cementless robotic-assisted TKA with selective patellar resurfacing can be a viable option for young KTS patients with severe osteoarthritis when a meticulous multidisciplinary approach, including sclerotherapy and advanced imaging, is undertaken to analyze vascular abnormalities, minimize surgical risks, preserve bone stock, and optimize outcomes.

Sepsis and case fatality rates and associations with deprivation, ethnicity, and clinical characteristics: population-based case-control study with linked primary care and hospital data in England.

PURPOSE: Sepsis is a life-threatening organ dysfunction caused by dysregulated host response to infection. The purpose of the study was to measure the associations of specific exposures (deprivation, ethnicity, and clinical characteristics) with incident sepsis and case fatality. METHODS: Two research databases in England were used including anonymized patient-level records from primary care linked to hospital admission, death certificate, and small-area deprivation. Sepsis cases aged 65-100 years were matched to up to six controls. Predictors for sepsis (including 60 clinical conditions) were evaluated using logistic and random forest models; case fatality rates were analyzed using logistic models. RESULTS: 108,317 community-acquired sepsis cases were analyzed. Severe frailty was strongly associated with the risk of developing sepsis (crude odds ratio [OR] 14.93; 95% confidence interval [CI] 14.37-15.52). The quintile with most deprived patients showed an increased sepsis risk (crude OR 1.48; 95% CI 1.45-1.51) compared to least deprived quintile. Strong predictors for sepsis included antibiotic exposure in prior 2 months, being house bound, having cancer, learning disability, and diabetes mellitus. Severely frail patients had a case fatality rate of 42.0% compared to 24.0% in non-frail patients (adjusted OR 1.53; 95% CI 1.41-1.65). Sepsis cases with recent prior antibiotic exposure died less frequently compared to non-users (adjusted OR 0.7; 95% CI 0.72-0.76). Case fatality strongly decreased over calendar time. CONCLUSION: Given the variety of predictors and their level of associations for developing sepsis, there is a need for prediction models for risk of developing sepsis that can help to target preventative antibiotic therapy.

Evaluation of models to estimate the bioaccumulation of organic chemicals in earthworms.

Modelling approaches to estimate the bioaccumulation of organic chemicals by earthworms are important for improving the realism in risk assessment of chemicals. However, the applicability of existing models is uncertain, partly due to the lack of independent datasets to test them. This study therefore conducted a comprehensive literature review on existing empirical and kinetic models that estimate the bioaccumulation of organic chemicals in earthworms and gathered two independent datasets from published literature to evaluate the predictive performance of these models. The Belfroid et al. (1995a) model is the best-performing empirical model, with 91.2% of earthworm body residue simulations within an order of magnitude of observation. However, this model is limited to the more hydrophobic pesticides and to the earthworm species Eisenia fetida or Eisenia andrei. The kinetic model proposed by Jager et al. (2003b) which out-performs that of Armitage and Gobas (2007), predicted uptake of PCB 153 in the earthworm E. andrei to within a factor of 10. However, the applicability of Jager et al.'s model to other organic compounds and other earthworm species is unknown due to the limited evaluation dataset. The model needs to be parameterised for different chemical, soil, and species types prior to use, which restricts its applicability to risk assessment on a broad scale. Both the empirical and kinetic models leave room for improvement in their ability to reliably predict bioaccumulation in earthworms. Whether they are fit for purpose in environmental risk assessment needs careful consideration on a case by case basis.

Multi-sample ζ-mixup: richer, more realistic synthetic samples from a p-series interpolant.

Modern deep learning training procedures rely on model regularization techniques such as data augmentation methods, which generate training samples that increase the diversity of data and richness of label information. A popular recent method, mixup, uses convex combinations of pairs of original samples to generate new samples. However, as we show in our experiments, mixup  can produce undesirable synthetic samples, where the data is sampled off the manifold and can contain incorrect labels. We propose ζ-mixup, a generalization of mixup  with provably and demonstrably desirable properties that allows convex combinations of T≥2 samples, leading to more realistic and diverse outputs that incorporate information from T original samples by using a p-series interpolant. We show that, compared to mixup, ζ-mixup  better preserves the intrinsic dimensionality of the original datasets, which is a desirable property for training generalizable models. Furthermore, we show that our implementation of ζ-mixup  is faster than mixup, and extensive evaluation on controlled synthetic and 26 diverse real-world natural and medical image classification datasets shows that ζ-mixup  outperforms mixup, CutMix, and traditional data augmentation techniques. The code will be released at https://github.com/kakumarabhishek/zeta-mixup.

Community-acquired Staphylococcus aureus bacteraemia among people who inject drugs: a national cohort study in England, 2017-2020.

BACKGROUND: People who inject drugs (PWID) are at increased risk of community-acquired Staphylococcus aureus bacteraemia (CA-SAB), but little is known about clinical outcomes of CA-SAB in PWID compared with the wider population of patients with CA-SAB. METHODS: Three national datasets were linked to provide clinical and mortality data on patients hospitalised with CA-SAB in England between 1 January 2017 and 31 December 2020. PWID were identified using the ICD-10 code for "mental health and behavioural disorder due to opioid use" (F11). Multivariable logistic regression was used to estimate adjusted odds ratios (aORs) for associations of PWID with 30-day all-cause mortality and 90-day hospital readmission. RESULTS: In 10,045 cases of CA-SAB, 1,612 (16.0%) were PWID. Overall, 796 (7.9%) patients died within 30 days of CA-SAB admission and 1,189 (11.8%) patients were readmitted to hospital within 90 days of CA-SAB. In those without infective endocarditis there was strong evidence of lower odds of mortality among PWID compared with non-PWID (aOR: 0.47, 95% confidence interval, CI: 0.33-0.68, p < 0.001) whereas there was no association in CA-SAB case fatality with endocarditis (aOR 1.40, CI 0.87-2.25, p = 0.163). PWID were less likely to be re-admitted within 90 days of CA-SAB (aOR 0.79, CI 0.65-0.95, p = 0.011). CONCLUSIONS: In this large cohort study of patients with CA-SAB in England, PWID had lower odds of death in the absence of endocarditis and lower odds of re-admission within 90 days compared to non-PWID patients. This study highlights the over-representation of PWID among patients with CA-SAB nationally.

Rapid systematic review on risks and outcomes of sepsis: the influence of risk factors associated with health inequalities.

BACKGROUND AND AIMS: Sepsis is a serious and life-threatening condition caused by a dysregulated immune response to an infection. Recent guidance issued in the UK gave recommendations around recognition and antibiotic treatment of sepsis, but did not consider factors relating to health inequalities. The aim of this study was to summarise the literature investigating associations between health inequalities and sepsis. METHODS: Searches were conducted in Embase for peer-reviewed articles published since 2010 that included sepsis in combination with one of the following five areas: socioeconomic status, race/ethnicity, community factors, medical needs and pregnancy/maternity. RESULTS: Five searches identified 1,402 studies, with 50 unique studies included in the review after screening (13 sociodemographic, 14 race/ethnicity, 3 community, 3 care/medical needs and 20 pregnancy/maternity; 3 papers examined multiple health inequalities). Most of the studies were conducted in the USA (31/50), with only four studies using UK data (all pregnancy related). Socioeconomic factors associated with increased sepsis incidence included lower socioeconomic status, unemployment and lower education level, although findings were not consistent across studies. For ethnicity, mixed results were reported. Living in a medically underserved area or being resident in a nursing home increased risk of sepsis. Mortality rates after sepsis were found to be higher in people living in rural areas or in those discharged to skilled nursing facilities while associations with ethnicity were mixed. Complications during delivery, caesarean-section delivery, increased deprivation and black and other ethnic minority race were associated with post-partum sepsis. CONCLUSION: There are clear correlations between sepsis morbidity and mortality and the presence of factors associated with health inequalities. To inform local guidance and drive public health measures, there is a need for studies conducted across more diverse setting and countries.

Histopathological findings from the investigation of paediatric acute hepatitis of unknown aetiology, United Kingdom 2022.

In 2022, there were global reports of increased numbers of acute hepatitis not explained by hepatitis A-E virus infection in children. This manuscript summarises histopathology results from 20 patients in the United Kingdom who underwent liver transplant or had a liver biopsy as part of aetiological investigations. All available histopathological samples were reviewed centrally as part of the outbreak investigation. A working group comprised of infection specialists, hepatologists and histopathologists met virtually to review the cases, presentation, investigations and histopathology. All 20 liver samples had evidence of inflammation without significant interface activity, and submassive confluent pan-lobular or multilobular hepatocellular necrosis. Overall, the predominant histopathological findings were of acute nonspecific hepatitis with submassive hepatic necrosis and central vein perivenulitis and endothelitis. Histopathological findings were a poor indicator of aetiology.

Earthworm lipid content and size help account for differences in pesticide bioconcentration between species.

The uptake and elimination kinetics of pesticides from soil to earthworms are important in characterising the risk of pesticides to soil organisms and the risk from secondary poisoning. However, the understanding of the relative importance of chemical, soil, and species differences in determining pesticide bioconcentration into earthworms is limited. Furthermore, there is insufficient independent data in the literature to fully evaluate existing predictive bioconcentration models. We conducted kinetic uptake and elimination experiments for three contrasting earthworm species (Lumbricus terrestris, Aporrectodea caliginosa, Eisenia fetida) in five soils using a mixture of five pesticides (log Kow 1.69 - 6.63). Bioconcentration increased with pesticide hydrophobicity and decreased with soil organic matter. Bioconcentration factors were comparable between earthworm species for hydrophilic pesticides due to the similar water content of earthworm species. Inter-species variations in bioconcentration of hydrophobic pesticides were primarily accounted for by earthworm lipid content and specific surface area (SSA). Existing bioconcentration models either failed to perform well across earthworm species and for more hydrophilic compounds (log Kow < 2) or were not parameterised for a wide range of compounds and earthworm species. Refined models should incorporate earthworm properties (lipid content and SSA) to account for inter-species differences in pesticide uptake from soil.

Clinical outcomes of Staphylococcus capitis isolation from neonates, England, 2015-2021: a retrospective case-control study.

OBJECTIVE: Staphylococcus capitis, a coagulase-negative staphylococci (CoNS) species, has been increasingly detected from UK sterile site samples and has caused neonatal unit outbreaks worldwide. We compared survival to discharge and 30-day mortality for the detection of S. capitis versus other CoNS species. METHODS: In this retrospective case-control study, we included hospitalised infants with any CoNS species detected from a normally sterile body site up to 90 days of age. We linked English laboratory reports from the Second Generation Surveillance System database, mortality data from the Personal Demographics Service, and neonatal unit admissions from the National Neonatal Research Database. In primary analysis, multivariable logistic regression was used, with two co-primary outcomes: survival to discharge and death within 30 days of positive specimen date. Sensitivity analyses using multiply imputed datasets followed. RESULTS: We identified 16 636 CoNS episodes relating to 13 745 infants. CoNS episodes were highest among infants born extremely preterm (22-27 weeks) and with extremely low birth weight (400-999 g). In primary analysis, there were no differences in survival to discharge (p=0.71) or 30-day mortality (p=0.77) between CoNS species. In sensitivity analyses, there were no differences in outcomes between infection with four of the most common CoNS species (Staphylococcus epidermidis, S. capitis, Staphylococcus haemolyticus and Staphylococcus warneri) but the remaining CoNS species were at higher risk of adverse outcomes when treated in aggregate. CONCLUSION: Infants with S. capitis detected from sterile site samples did not experience significant differences in either survival to discharge or 30-day mortality compared with infants with detection of other common CoNS species.

Significance of Organic Anion Transporter 2 and Organic Cation Transporter 2 in Creatinine Clearance: Mechanistic Evaluation Using Freshly Prepared Human Primary Renal Proximal Tubule Cells.

Creatinine, a clinical marker for kidney function, is predominantly cleared by glomerular filtration, with active tubular secretion contributing to about 30% of its renal clearance. Recent studies suggested the potential involvement of organic anion transporter (OAT)2, in addition to the previously known organic cation transporter (OCT)2-mediated basolateral uptake, in creatinine active secretion. Here we characterized the transport mechanisms of creatinine using transfected human embryonic kidney (HEK)293 cells and freshly prepared human primary renal proximal tubule epithelial cells (hPTCs). Creatinine showed transport by OAT2 in transfected HEK293 cells. In addition, both creatinine and metformin showed transport by OCT2 and multidrug and toxin extrusion pump (MATE)1 and MATE2K, while penciclovir was selective for OAT2. Time-dependent cell accumulation was observed for creatinine and metformin in hPTCs. Their accumulation was increased by pyrimethamine but inhibited by decynium-22, likely due to differential inhibition of OCT2 versus MATEs. Additionally, indomethacin (an OAT2 inhibitor) reduced penciclovir uptake (∼75%) in hPTCs illustrating functional OAT2 activity. However, no modulation of creatinine and metformin cell accumulation was apparent with indomethacin. Creatinine transport characteristics in the presence of inhibitors approached those of metformin, an OCT2/MATE substrate, but were distinct from those of penciclovir, an OAT2-selective substrate. Moreover, indomethacin showed no significant effect on the basolateral-to-apical transport and net secretion of creatinine across hPTC monolayers. Collectively, the functional studies suggest OCT2 as the primary basolateral uptake mechanism and that OAT2 has a minimal role, in creatinine renal secretion. Our results highlight the utility of hPTCs to enable the functional assessment of renal transport mechanisms. SIGNIFICANCE STATEMENT: Our results obtained with primary hPTCs indicate that OCT2/MATE (vs. OAT2) play a major role in the active renal secretion of creatinine. Quantitative pharmacokinetic models should therefore focus on OCT2/MATE when describing serum creatinine and creatinine clearance modulation by inhibitor drugs and genotype- or disease-related activity changes. The present study highlights the utility of freshly isolated hPTCs to support solute carrier phenotyping to enable the functional assessment of renal transport mechanisms.

Effectiveness of BNT162b2 mRNA vaccine third doses and previous infection in protecting against SARS-CoV-2 infections during the Delta and Omicron variant waves; the UK SIREN cohort study September 2021 to February 2022.

Third doses of COVID-19 vaccines were widely deployed following the primary vaccine course waning and the emergence of the Omicron-variant. We investigated protection from third-dose vaccines and previous infection against SARS-CoV-2 infection during Delta-variant and Omicron-variant (BA.1 & BA.2) waves in our frequently PCR-tested cohort of healthcare-workers. Relative effectiveness of BNT162b2 third doses and infection-acquired immunity was assessed by comparing the time to PCR-confirmed infection in boosted participants with those with waned dose-2 protection (≥254 days after dose-2), by primary series vaccination type. Follow-up time was divided by dominant circulating variant: Delta 07 September 2021 to 30 November 2021, Omicron 13 December 2021t o 28 February 2022. We used a Cox regression model with adjustment/stratification for demographic characteristics and staff-type. We explored protection associated with vaccination, infection and both. We included 19,614 participants, 29% previously infected. There were 278 primary infections (4 per 10,000 person-days of follow-up) and 85 reinfections (0.8/10,000 person-days) during the Delta period and 2467 primary infections (43/10,000 person-days) and 881 reinfections (33/10,000) during the Omicron period. Relative Vaccine Effectiveness (VE) 0-2 months post-3rd dose (3rd dose) (3-doses BNT162b2) in the previously uninfected cohort against Delta infections was 63% (95% Confidence Interval (CI) 40%-77%) and was lower (35%) against Omicron infection (95% CI 21%-47%). The relative VE of 3rd dose (heterologous BNT162b2) was greater for primary course ChAdOX1 recipients, with VE 0-2 months post-3rd dose over ≥68% higher for both variants. Third-dose protection waned rapidly against Omicron, with no significant difference between two and three BNT162b2 doses observed after 4-months. Previous infection continued to provide additional protection against Omicron (67% (CI 56%-75%) 3-6 months post-infection), but this waned to about 25% after 9-months, approximately three times lower than against Delta. Infection rates surged with Omicron emergence. Third doses of BNT162b2 vaccine provided short-term protection, with rapid waning against Omicron infections. Protection associated with infections incurred before Omicron was markedly diminished against the Omicron wave. Our findings demonstrate the complexity of an evolving pandemic with the potential emergence of immune-escape variants and the importance of continued monitoring.

pyCapsid: identifying dominant dynamics and quasi-rigid mechanical units in protein shells.

SUMMARY: pyCapsid is a Python package developed to facilitate the characterization of the dynamics and quasi-rigid mechanical units of protein shells and other protein complexes. The package was developed in response to the rapid increase of high-resolution structures, particularly capsids of viruses, requiring multiscale biophysical analyses. Given a protein shell, pyCapsid generates the collective vibrations of its amino-acid residues, identifies quasi-rigid mechanical regions associated with the disassembly of the structure, and maps the results back to the input proteins for interpretation. pyCapsid summarizes the main results in a report that includes publication-quality figures. AVAILABILITY AND IMPLEMENTATION: pyCapsid's source code is available under MIT License on GitHub. It is compatible with Python 3.8-3.10 and has been deployed in two leading Python package-management systems, PIP and Conda. Installation instructions and tutorials are available in the online documentation and in the pyCapsid's YouTube playlist. In addition, a cloud-based implementation of pyCapsid is available as a Google Colab notebook. pyCapsid Colab does not require installation and generates the same report and outputs as the installable version. Users can post issues regarding pyCapsid in the repository's issues section.

Effect of second booster vaccinations and prior infection against SARS-CoV-2 in the UK SIREN healthcare worker cohort.

Background: The protection of fourth dose mRNA vaccination against SARS-CoV-2 is relevant to current global policy decisions regarding ongoing booster roll-out. We aimed to estimate the effect of fourth dose vaccination, prior infection, and duration of PCR positivity in a highly-vaccinated and largely prior-COVID-19 infected cohort of UK healthcare workers. Methods: Participants underwent fortnightly PCR and regular antibody testing for SARS-CoV-2 and completed symptoms questionnaires. A multi-state model was used to estimate vaccine effectiveness (VE) against infection from a fourth dose compared to a waned third dose, with protection from prior infection and duration of PCR positivity jointly estimated. Findings: 1298 infections were detected among 9560 individuals under active follow-up between September 2022 and March 2023. Compared to a waned third dose, fourth dose VE was 13.1% (95% CI 0.9 to 23.8) overall; 24.0% (95% CI 8.5 to 36.8) in the first 2 months post-vaccination, reducing to 10.3% (95% CI -11.4 to 27.8) and 1.7% (95% CI -17.0 to 17.4) at 2-4 and 4-6 months, respectively. Relative to an infection >2 years ago and controlling for vaccination, 63.6% (95% CI 46.9 to 75.0) and 29.1% (95% CI 3.8 to 43.1) greater protection against infection was estimated for an infection within the past 0-6, and 6-12 months, respectively. A fourth dose was associated with greater protection against asymptomatic infection than symptomatic infection, whilst prior infection independently provided more protection against symptomatic infection, particularly if the infection had occurred within the previous 6 months. Duration of PCR positivity was significantly lower for asymptomatic compared to symptomatic infection. Interpretation: Despite rapid waning of protection, vaccine boosters remain an important tool in responding to the dynamic COVID-19 landscape; boosting population immunity in advance of periods of anticipated pressure, such as surging infection rates or emerging variants of concern. Funding: UK Health Security Agency, Medical Research Council, NIHR HPRU Oxford, Bristol, and others.

COVID-19 therapeutics: stewardship in England and considerations for antimicrobial resistance.

The COVID-19 pandemic saw unprecedented resources and funds driven into research for the development, and subsequent rapid distribution, of vaccines, diagnostics and directly acting antivirals (DAAs). DAAs have undeniably prevented progression and life-threatening conditions in patients with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. However, there are concerns of antimicrobial resistance (AMR), antiviral resistance specifically, for DAAs. To preserve activity of DAAs for COVID-19 therapy, as well as detect possible mutations conferring resistance, antimicrobial stewardship and surveillance were rapidly implemented in England. This paper expands on the ubiquitous ongoing public health activities carried out in England, including epidemiologic, virologic and genomic surveillance, to support the stewardship of DAAs and assess the deployment, safety, effectiveness and resistance potential of these novel and repurposed therapeutics.

A novel stabilization mechanism accommodating genome length variation in evolutionarily related viral capsids.

Tailed bacteriophages are one of the most numerous and diverse group of viruses. They store their genome at quasi-crystalline densities in capsids built from multiple copies of proteins adopting the HK97-fold. The high density of the genome exerts an internal pressure, requiring a maturation process that reinforces their capsids. However, it is unclear how capsid stabilization strategies have adapted to accommodate the evolution of larger genomes in this virus group. Here we characterized a novel capsid reinforcement mechanism in two evolutionary-related actinobacteriophages that modifies the length of a stabilization protein to accommodate a larger genome while maintaining the same capsid size. We used cryo-EM to reveal that capsids contained split hexamers of HK97-fold proteins with a stabilization protein in the chasm. The observation of split hexamers in mature capsids was unprecedented, so we rationalized this result mathematically, discovering that icosahedral capsids can be formed by all split or skewed hexamers as long as their T-number is not a multiple of three. Our results suggest that analogous stabilization mechanisms can be present in other icosahedral capsids, and they provide a strategy for engineering capsids accommodating larger DNA cargoes as gene delivery systems.

Surge of lower respiratory tract group A streptococcal infections in England in winter 2022: epidemiology and clinical profile.

BACKGROUND: Following low incidence of invasive group A streptococcal (iGAS) infections during the COVID-19 pandemic, marked increases were noted in many countries during 2022, particularly in children. In November 2022, severe presentations of lower respiratory tract infections (LRTIs), including empyema, were notified by clinicians across the UK. UKHSA investigated this rise with the aim of informing clinical management and public health response. METHODS: We undertook a case-series analysis using multiple routine data sources, exempted from ethics approval or patient consent. We identified iGAS cases in England in children younger than 15 years with an LRTI reported between Oct 1 and Dec 21, 2022, using UKHSA laboratory surveillance data (GAS detected in LRT specimens) and notifications by clinicians and Health Protection Teams (HPTs). Symptoms, diagnoses, health-care interactions, and outcome (death or recovery) data were obtained from HPT case management notes, the National Child Mortality Database, and the NHS Digital Emergency Care Dataset. FINDINGS: We identified 147 cases of LRTI iGAS in children across England (77 [52%] male, 70 [48%] female; median age 4 years [IQR 2-6]). Predominant ethnicities were White (74 [65%] of 113 with known ethnicity) and Asian (18 [16%] of 113). Most reported symptoms were fever (90 [75%] of 120 children with ≥1 symptom) and cough (60 [50%] of 120), and 71 (48%) of all 147 children had a diagnosed respiratory viral coinfection (most commonly hMPV and RSV). 127 (86%) of children attended an emergency department, 31% (n=36/114 with onset date) at least twice within 21 days after symptom onset. 37 (25%) of 147 children died, with a median time from symptom onset to death of 4 days (IQR 3-7). Of 32 children with sample dates, 16 (84%) were tested for GAS on or after the day they died. Over half of deaths (21 [57%] of 37 deaths) occurred in the community after rapid deterioration, of whom 18 had previous contact with health-care services documented. INTERPRETATION: The UK saw an unusual rise in iGAS LRTIs in children in late 2022. One in four cases died, over half in the community. Non-specific symptoms, viral symptoms, or positive virology might have lowered suspicion of bacterial infection. Although the use of multiple available data sources expedited the analysis, varying data completeness limited interpretation. Our study highlights the need for earlier detection and identification of effective measures to prevent death. FUNDING: None.

Distinct monkeypox virus lineages co-circulating in humans before 2022.

The 2022 global mpox outbreak raises questions about how this zoonotic disease established effective human-to-human transmission and its potential for further adaptation. The 2022 outbreak virus is related to an ongoing outbreak in Nigeria originally reported in 2017, but the evolutionary path linking the two remains unclear due to a lack of genomic data between 2018, when virus exportations from Nigeria were first recorded, and 2022, when the global mpox outbreak began. Here, 18 viral genomes obtained from patients across southern Nigeria in 2019-2020 reveal multiple lineages of monkeypox virus (MPXV) co-circulated in humans for several years before 2022, with progressive accumulation of mutations consistent with APOBEC3 activity over time. We identify Nigerian A.2 lineage isolates, confirming the lineage that has been multiply exported to North America independently of the 2022 outbreak originated in Nigeria, and that it has persisted by human-to-human transmission in Nigeria for more than 2 years before its latest exportation. Finally, we identify a lineage-defining APOBEC3-style mutation in all A.2 isolates that disrupts gene A46R, encoding a viral innate immune modulator. Collectively, our data demonstrate MPXV capacity for sustained diversification within humans, including mutations that may be consistent with established mechanisms of poxvirus adaptation.

Blood transfusions post kidney transplantation are associated with inferior allograft and patient survival-it is time for rigorous patient blood management.

Background: Patient Blood Management (PBM), endorsed by the World Health Organisation is an evidence-based, multi-disciplinary approach to minimise inappropriate blood product transfusions. Kidney transplantation presents a particular challenge to PBM, as comprehensive evidence of the risk of transfusion is lacking. The aim of this study is to investigate the prevalence of post-transplant blood transfusions across multiple centres, to analyse risk factors for transfusion and to compare transplant outcomes by transfusion status. Methods: This analysis was co-ordinated via the UK Transplant Registry within NHS Blood and Transplant (NHSBT), and was performed across 4 centres. Patients who had received a kidney transplant over a 1-year period, had their transfusion status identified and linked to data held within the national registry. Results: Of 720 patients, 221(30.7%) were transfused, with 214(29.7%) receiving a red blood cell (RBC) transfusion. The proportion of patients transfused at each centre ranged from 20% to 35%, with a median time to transfusion of 4 (IQR:0-12) days post-transplant. On multivariate analysis, age [OR: 1.02(1.01-1.03), p=0.001], gender [OR: 2.11(1.50-2.98), p<0.0001], ethnicity [OR: 1.28(1.28-2.60), p=0.0008], and dialysis dependence pre-transplant [OR: 1.67(1.08-2.68), p=0.02], were associated with transfusion. A risk-adjusted Cox proportional hazards model showed transfusion was associated with inferior 1-year patient survival [HR 7.94(2.08-30.27), p=0.002] and allograft survival [HR: 3.33(1.65-6.71), p=0.0008], and inferior allograft function. Conclusion: RBC transfusions are common and are independently associated with inferior transplant outcomes. We urge that further research is needed to understand the mechanisms behind the outcomes, to support the urgent development of transplant-specific anaemia guidelines.