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The 1840s witnessed widespread hunger and malnutrition at home and mass starvation in Ireland. And yet the aptly named ‘Hungry 40s’ came amidst claims that, notwithstanding Malthusian prophecies, absolute biological want had been eliminated in England. The eighteenth and early nineteenth centuries were supposedly the period in which the threat of famine lifted for the peoples of England. But hunger remained, in the words of Marx, an ‘unremitted pressure’. The politics of hunger offers the first systematic analysis of the ways in which hunger continued to be experienced and feared, both as a lived and constant spectral presence. It also examines how hunger was increasingly used as a disciplining device in new modes of governing the population. Drawing upon a rich archive, this innovative and conceptually-sophisticated study throws new light on how hunger persisted as a political and biological force.

The same pneumococcal conjugate vaccines (PCVs) have been used in adults and children in many settings. Differences in the epidemiology of pneumococcal disease between populations necessitates an adult-specific PCV. We aimed to assess the safety, tolerability, and immunogenicity of V116, an investigational 21-valent PCV designed for adults. This randomised, double-blind, active comparator controlled, international phase 3 trial enrolled adults with or without stable chronic medical conditions at 112 clinical sites in 11 countries or territories. Random assignment was performed using a central electronic interactive response technology system. Cohort 1 (≥50 years) was stratified by age (50–64, 65–74, 75–84, and ≥85 years) and randomised 1:1 to receive one intramuscular dose of V116, or the active comparator, PCV20. Cohort 2 (18–49 years) was randomised 2:1 to receive one intramuscular dose of V116 or PCV20. Pneumococcal serotype-specific opsonophagocytic activity (OPA) and IgG responses were measured before (day 1) and after vaccination (day 30). Four primary immunogenicity outcomes were assessed per-protocol. First, in cohort 1, non-inferiority of V116 to PCV20 was tested using serotype-specific OPA geometric mean titres (GMT) ratios for serotypes common to both vaccines; the lower bound of the 95% CI had to be greater than 0·5 for non-inferiority. Second, superiority of V116 to PCV20 was tested for OPA GMT ratios for the serotypes unique to V116; the lower bound of the 95% CI had to be greater than 2·0 for superiority. Third, superiority of V116 to PCV20 was evaluated by the proportions of participants with a four-fold or greater rise from day 1 to day 30 for serotypes unique to V116; the lower bound of the 95% CI of the differences in proportions (V116 – PCV20) had to be greater than 10% for superiority. Finally, in cohort 2, immunobridging was assessed for all 21 serotypes in V116 for adults aged 18–49 years to 50–64 years; the lower bound of the 95% CI for the OPA GMTs had to be greater than 0·5 for non-inferiority. The safety analysis included all randomly assigned participants who received study vaccine. The primary safety outcome was the proportion of participants with solicited injection site and solicited systemic adverse events until day 5 and vaccine-related serious adverse events up to 6 months after vaccination. This trial is registered at ClinicalTrials.gov (NCT05425732). Between July 13, and Nov 22, 2022, 2754 individuals were screened and 2663 participants were randomly assigned. 2656 individuals were vaccinated (1179 in V116 cohort 1; 1177 in PCV20 cohort 1; 200 in V116 cohort 2; and 100 in PCV20 cohort 2). V116 met non-inferiority criteria compared with PCV20 for the ten serotypes common to both vaccines at day 30 in cohort 1 (p<0·0001 for each common serotype). V116 met superiority criteria compared with PCV20 in cohort 1 for ten of the 11 serotypes unique to V116 at day 30 (OPA GMT ratio: p<0·0001 for all unique serotypes except 15C, which was p=0·41; four-fold or greater rise in OPA from day 1–30: p<0·0001 for all serotypes except 15C, which was p=0·67). Immune responses in V116 participants aged 18–49 years were non-inferior compared with V116 participants aged 50–64 years for all V116 serotypes (p<0·0001 for all V116 serotypes). In cohort 1, 685 (58·2%) of participants in V116, and 778 (66·2%) of participants in PCV20 reported one or more adverse event. In cohort 2, 164 (82·0%) participants in V116 and 79 participants (79·0%) in PCV20 reported one or more adverse event. Six deaths were reported, all in cohort 1, none of which were considered vaccine-related (in V116: one due to sepsis, one due to cerebrovascular accident, one due to myocardial infarction, and one due to hepatic cirrhosis and hepatic encephalopathy; in PCV20: one due to cardiac arrest and one due to abdominal abscess). There were no vaccine-related serious adverse events. V116 was non-inferior to PCV20 for the ten serotypes common to both vaccines and superior to PCV20 for all serotypes unique to V116, except for 15C. Immune responses successfully immunobridged between younger and older adults for all serotypes in V116. V116 was generally well tolerated with safety profile similar to PCV20. Merck Sharp & Dohme, subsidiary of Merck & Co, Rahway, NJ, USA (MSD).

ObjectiveThe objective of this study is to determine research priorities for the management of major trauma, representing the shared priorities of patients, their families, carers and healthcare professionals.Design/settingAn international research priority-setting partnership.ParticipantsPeople who have experienced major trauma, their carers and relatives, and healthcare professionals involved in treating patients after major trauma. The scope included chest, abdominal and pelvic injuries as well as major bleeding, multiple injuries and those that threaten life or limb.MethodsA multiphase priority-setting exercise was conducted in partnership with the James Lind Alliance over 24 months (November 2021–October 2023). An international survey asked respondents to submit their research uncertainties which were then combined into several indicative questions. The existing evidence was searched to ensure that the questions had not already been sufficiently answered. A second international survey asked respondents to prioritise the research questions. A final shortlist of 19 questions was taken to a stakeholder workshop, where consensus was reached on the top 10 priorities.ResultsA total of 1572 uncertainties, submitted by 417 respondents (including 132 patients and carers), were received during the initial survey. These were refined into 53 unique indicative questions, of which all 53 were judged to be true uncertainties after reviewing the existing evidence. 373 people (including 115 patients and carers) responded to the interim prioritisation survey and 19 questions were taken to a final consensus workshop between patients, carers and healthcare professionals. At the final workshop, a consensus was reached for the ranking of the top 10 questions.ConclusionsThe top 10 research priorities for major trauma include patient-centred questions regarding pain relief and prehospital management, multidisciplinary working, novel technologies, rehabilitation and holistic support. These shared priorities will now be used to guide funders and teams wishing to research major trauma around the globe.

Dementia research lacks appropriate representation of diverse groups who often face substantial adversity and greater risk of dementia. Current research participants are primarily well‐resourced, non‐Hispanic White, cisgender adults who live close to academic medical centers where much of the research is based. Consequently, the field faces a knowledge gap about Alzheimer's‐related risk factors in those other groups. The Alzheimer's Association hosted a virtual conference on June 14–16, 2021, supported in part by the National Institute on Aging (R13 AG072859‐01), focused on health disparities. The conference was held entirely online and consisted of 2 days of core programming and a day of focused meetings centered on American Indian and Alaska Natives and on LGBTQIA+ populations. Over 1300 registrants attended discussions focused on the structural and systemic inequities experienced across diverse groups, as well as ways to investigate and address these inequities.

ObjectiveTo determine the association of dysnatremia in the first postnatal week and risk of acute kidney injury (AKI) and mortality.Study designA secondary analysis of 1979 neonates in the AWAKEN cohort evaluated the association of dysnatremia with (1) AKI in the first postnatal week and (2) mortality, utilizing time-varying Cox proportional hazard models.ResultDysnatremia developed in 50.2% of the cohort and was not associated with AKI. Mortality was associated with hyponatremia (HR 2.15, 95% CI 1.07–4.31), hypernatremia (HR 4.23, 95% CI 2.07–8.65), and combined hypo/hypernatremia (HR 6.39, 95% CI 2.01–14.01). In stratified models by AKI-status, hypernatremia and hypo/hypernatremia increased risk of mortality in neonates without AKI.ConclusionDysnatremia within the first postnatal week was associated with increased risk of mortality. Hypernatremia and combined hypo/hypernatremia remained significantly associated with mortality in neonates without AKI. This may reflect fluid strategies kidney injury independent of creatinine and urine-output defined AKI, and/or systemic inflammation.

Background The diagnostic rate of Mendelian disorders in sequencing studies continues to increase, along with the pace of novel disease gene discovery. However, variant interpretation in novel genes not currently associated with disease is particularly challenging and strategies combining gene functional evidence with approaches that evaluate the phenotypic similarities between patients and model organisms have proven successful. A full spectrum of intolerance to loss-of-function variation has been previously described, providing evidence that gene essentiality should not be considered as a simple and fixed binary property. Methods Here we further dissected this spectrum by assessing the embryonic stage at which homozygous loss-of-function results in lethality in mice from the International Mouse Phenotyping Consortium, classifying the set of lethal genes into one of three windows of lethality: early, mid, or late gestation lethal. We studied the correlation between these windows of lethality and various gene features including expression across development, paralogy and constraint metrics together with human disease phenotypes. We explored a gene similarity approach for novel gene discovery and investigated unsolved cases from the 100,000 Genomes Project. Results We found that genes in the early gestation lethal category have distinct characteristics and are enriched for genes linked with recessive forms of inherited metabolic disease. We identified several genes sharing multiple features with known biallelic forms of inborn errors of the metabolism and found signs of enrichment of biallelic predicted pathogenic variants among early gestation lethal genes in patients recruited under this disease category. We highlight two novel gene candidates with phenotypic overlap between the patients and the mouse knockouts. Conclusions Information on the developmental period at which embryonic lethality occurs in the knockout mouse may be used for novel disease gene discovery that helps to prioritise variants in unsolved rare disease cases.

Premature infants with severe respiratory failure may be treated with inhaled nitric oxide, a controversial treatment that may reduce mortality or prevent bronchopulmonary dysplasia. In a randomized, placebo-controlled trial in neonates with respiratory failure after treatment with surfactant there was no difference in the rates of death or bronchopulmonary dysplasia. In neonates with respiratory failure after treatment with surfactant there was no difference in the rates of death or bronchopulmonary dysplasia. Premature infants in respiratory failure can have dramatic improvements after treatment with exogenous surfactant. However, a subset of premature infants have suboptimal responses to surfactant 1 and may have pulmonary hypertension in association with severe respiratory failure. 2 – 6 Inhaled nitric oxide may benefit such infants by selectively dilating pulmonary vasculature, improving ventilation–perfusion matching, and decreasing the pulmonary inflammatory response. 7 – 9 Inhaled nitric oxide had been shown to provide only short-term improvement in oxygenation in premature infants 10 – 14 until a recent single-center study reported an association between the administration of inhaled nitric oxide and a decrease in the incidence of bronchopulmonary dysplasia . . .

Objectives Rheumatoid arthritis (RA) shares some similar clinical and pathological features with juvenile idiopathic arthritis (JIA); indeed, the strategy of investigating whether RA susceptibility loci also confer susceptibility to JIA has already proved highly successful in identifying novel JIA loci. A plethora of newly validated RA loci has been reported in the past year. Therefore, the aim of this study was to investigate these single nucleotide polymorphisms (SNP) to determine if they were also associated with JIA. Methods Thirty-four SNP that showed validated association with RA and had not been investigated previously in the UK JIA cohort were genotyped in JIA cases (n=1242), healthy controls (n=4281), and data were extracted for approximately 5380 UK Caucasian controls from the Wellcome Trust Case–Control Consortium 2. Genotype and allele frequencies were compared between cases with JIA and controls using PLINK. A replication cohort of 813 JIA cases and 3058 controls from the USA was available for validation of any significant findings. Results Thirteen SNP showed significant association (p<0.05) with JIA and for all but one the direction of association was the same as in RA. Of the eight loci that were tested, three showed significant association in the US cohort. Conclusions A novel JIA susceptibility locus was identified, CD247, which represents another JIA susceptibility gene whose protein product is important in T-cell activation and signalling. The authors have also confirmed association of the PTPN2 and IL2RA genes with JIA, both reaching genome-wide significance in the combined analysis.