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No phase 3 trial has yet shown improved survival for patients with pleural or peritoneal malignant mesothelioma who have progressed following platinum-based chemotherapy. The aim of this study was to assess the efficacy and safety of nivolumab, an anti-PD-1 antibody, in these patients. This was a multicentre, placebo-controlled, double-blind, parallel group, randomised, phase 3 trial done in 24 hospitals in the UK. Adult patients (aged ≥18 years) with an Eastern Cooperative Oncology Group performance status of 0 or 1, with histologically confirmed pleural or peritoneal mesothelioma, who had received previous first-line platinum-based chemotherapy and had radiological evidence of disease progression, were randomly assigned (2:1) to receive nivolumab at a flat dose of 240 mg every 2 weeks over 30 min intravenously or placebo until disease progression or a maximum of 12 months. The randomisation sequence was generated within an interactive web response system (Alea); patients were stratified according to epithelioid versus non-epithelioid histology and were assigned in random block sizes of 3 and 6. Participants and treating clinicians were masked to group allocation. The co-primary endpoints were investigator-assessed progression-free survival and overall survival, analysed according to the treatment policy estimand (an equivalent of the intention-to-treat principle). All patients who were randomly assigned were included in the safety population, reported according to group allocation. This trial is registered with Clinicaltrials.gov, NCT03063450. Between May 10, 2017, and March 30, 2020, 332 patients were recruited, of whom 221 (67%) were randomly assigned to the nivolumab group and 111 (33%) were assigned to the placebo group). Median follow-up was 11·6 months (IQR 7·2–16·8). Median progression-free survival was 3·0 months (95% CI 2·8–4·1) in the nivolumab group versus 1·8 months (1·4–2·6) in the placebo group (adjusted hazard ratio [HR] 0·67 [95% CI 0·53–0·85; p=0·0012). Median overall survival was 10·2 months (95% CI 8·5–12·1) in the nivolumab group versus 6·9 months (5·0–8·0) in the placebo group (adjusted HR 0·69 [95% CI 0·52–0·91]; p=0·0090). The most frequently reported grade 3 or worse treatment-related adverse events were diarrhoea (six [3%] of 221 in the nivolumab group vs two [2%] of 111 in the placebo group) and infusion-related reaction (six [3%] vs none). Serious adverse events occurred in 90 (41%) patients in the nivolumab group and 49 (44%) patients in the placebo group. There were no treatment-related deaths in either group. Nivolumab represents a treatment that might be beneficial to patients with malignant mesothelioma who have progressed on first-line therapy. Stand up to Cancer–Cancer Research UK and Bristol Myers Squibb.

Background Thousands of injured, stray and relinquished cats are received at the RSPCA Greater Manchester Animal Hospital each year. A significant and challenging proportion of these cats are confiscated from multicat households by RSPCA Inspectors, due to the owners’ inability to care for them. These households share many characteristics of animal hoarding, including poor owner compliance with suggested welfare improvements and recidivism. The relatively poor adoption potential of animals from such households are a perennial problem for the charity. The aim of this study was to determine if offering female cat neutering assistance to multi-cat owners significantly improved colony welfare. Results Ten multicat households with a history of public complaint to the RSPCA were recruited. An RSPCA veterinary surgeon (VS) initially assessed the overall welfare of each household’s cat population, individual cat welfare and the living environment. All entire female cats aged over 8 weeks were neutered and basic animal care education provided. Follow up visits were completed two and 12 months later to reassess welfare parameters and population numbers. The total number of cats was 176 across ten households (range 7–33, median 16). All owners consented to having all entire female cats spayed. At the first visit, mean individual cat welfare scores ranged from 5.4–8.7/ 16 across the 10 households, where 16 represented best possible welfare. Overall household mean welfare scores were significantly improved at both the 2 month and 12 month revisits ( p  = 0.011 and p = 0.01 respectively) when compared to the initial visits. By the end of the study period, three out of the ten households had voluntarily relinquished all of their cats, and overall there was a 40% reduction in the number of cats. Conclusions Animal hoarding has previously been an intractable welfare concern with little evidence informing intervention techniques. These results show that positive veterinary engagement on site, focused on preventative care and population control, can yield significant improvement in welfare scoring systems in relatively short timescales. Promptly collecting and neutering all female cats at a site, combined with advice and support, show promise in improving welfare.

Leveraging adaptive tumour immunity to control mesothelioma via immune checkpoint blockade is now a standard therapeutic approach. However, the determinants of sensitivity remain elusive. Low non-synonymous mutation burden and programmed death-ligand 1 expression, an abundance of immunosuppressive immune cell infiltration, and 9p21 deletion should all mitigate responses to therapy. To address this knowledge gap, we conducted a double blind, placebo-controlled, randomized phase III trial of the PD1 inhibitor, nivolumab (ClinicalTrial.gov registration: NCT03063450). After 37.2 months of follow-up, the primary endpoint of progression free-survival, but not overall survival was met. The nivolumab response rate was 10.3%, and related grade 3 or above adverse events occurred in 20.4% versus 7.2% for placebo. Progression-free and overall survival were longer in nivolumab-treated responders versus non-responders. In an exploratory multiomic analysis, blinded whole exome, transcriptome and multiplex immune profiling were used to interrogate R- versus NR-subgroups. Non-synonymous and neoantigen mutation burden were no different between groups, however R-mesotheliomas were infiltrated with activated CD8 + T- and CD19 + B-lymphocytes, organised into tertiary lymphoid structures. B-cell infiltration correlated with pro-inflammatory chemokines including IL24 and CCL19. Conversely, epithelial-mesenchymal transition and mitosis were associated with resistance to nivolumab. These findings illuminate features which can be leveraged to advance precision immunotherapy in this rare cancer setting. The sensitivity of mesothelioma to the treatment of immune checkpoint blockade remains elusive. Here this group reports a double blind, placebo-controlled, randomized phase III trial of PD1 inhibitor (Nivolumab) on 332 patients with relapsed mesothelioma, and to uncover determinants of efficacy.

BackgroundMalignant mesothelioma is a rapidly lethal cancer that has been increasing at an epidemic rate over the last three decades. Targeted therapies for mesothelioma have been lacking. A previous study called MiST1 (NCT03654833), evaluated the efficacy of Poly (ADP-ribose) polymerase (PARP) inhibition in mesothelioma. This study met its primary endpoint with 15% of patients having durable responses exceeding 1 year. Therefore, there is a need to evaluate PARP inhibitors in relapsed mesothelioma patients, where options are limited. Niraparib is the PARP inhibitor used in NERO.MethodsNERO is a multicentre, two-arm, open-label UK randomised phase II trial designed to evaluate the efficacy of PARP inhibition in relapsed mesothelioma. 84 patients are being recruited. NERO is not restricted by line of therapy; however, eligible participants must have been treated with an approved platinum based systemic therapy. Participants will be randomised 2:1, stratified according to histology and response to prior platinum-based chemotherapy, to receive either active symptom control (ASC) and niraparib or ASC alone, for up to 24 weeks. Participants will be treated until disease progression, withdrawal, death or development of significant treatment limiting toxicity. Participants randomised to niraparib will receive 200 or 300 mg daily in a 3-weekly cycle. The primary endpoint is progression-free survival, where progression is determined by modified Response Evaluation Criteria in Solid Tumors (mRECIST) or RECIST 1.1; investigator reported progression; or death from any cause, whichever comes first. Secondary endpoints include overall survival, best overall response, 12-week and 24 week disease control, duration of response, treatment compliance and safety/tolerability. If NERO shows niraparib to be safe and biologically effective, it may lead to future late phase randomised controlled trials in relapsed mesothelioma.Ethics and disseminationThe study received ethical approval from London-Hampstead Research Ethics Committee on 06-May-2022 (22/LO/0281). Data from all centres will be analysed together and published as soon as possible.Trial registration numberISCRTN16171129; NCT05455424.

Individuals with Down syndrome (DS), the genetic condition caused by trisomy 21 (T21), display clear signs of immune dysregulation, including high rates of autoimmunity and severe complications from infections. Although it is well established that T21 causes increased interferon responses and JAK/STAT signaling, elevated autoantibodies, global immune remodeling, and hypercytokinemia, the interplay between these processes, the clinical manifestations of DS, and potential therapeutic interventions remain ill defined. We report a comprehensive analysis of immune dysregulation at the clinical, cellular, and molecular level in hundreds of individuals with DS, including autoantibody profiling, cytokine analysis, and deep immune mapping. We also report the interim analysis of a Phase II clinical trial investigating the safety and efficacy of the JAK inhibitor tofacitinib through multiple clinical and molecular endpoints. We demonstrate multi-organ autoimmunity of pediatric onset concurrent with unexpected autoantibody-phenotype associations in DS. Importantly, constitutive immune remodeling and hypercytokinemia occur from an early age prior to autoimmune diagnoses or autoantibody production. Analysis of the first 10 participants to complete 16 weeks of tofacitinib treatment shows a good safety profile and no serious adverse events. Treatment reduced skin pathology in alopecia areata, psoriasis, and atopic dermatitis, while decreasing interferon scores, cytokine scores, and levels of pathogenic autoantibodies without overt immune suppression. JAK inhibition is a valid strategy to treat autoimmune conditions in DS. Additional research is needed to define the effects of JAK inhibition on the broader developmental and clinical hallmarks of DS. NIAMS, Global Down Syndrome Foundation. NCT04246372.

To explore the perceptions of patients and healthcare professionals on Raman-faecal immunochemical test (FIT) as an alternative test for colorectal cancer exclusion in primary care. Semi-structured interviews within a feasibility study. Patients presenting to primary care with colorectal symptoms and healthcare professionals working in primary and secondary care. A total of 23 patients and 12 healthcare professionals. Patient participants were asked to complete a novel combined Raman-FIT test before being seen in secondary care. This study sought their opinions about the test. We also sought the views of healthcare professionals. Patients and healthcare professionals agreed that Raman-FIT was a suitable test to be given in primary care. It aligned with routine practice and was a simple test for most patients to complete. Patients are willing and able to complete the Raman-FIT test in primary care. Raman-FIT may accelerate access to diagnosis with the potential to improve cancer outcomes. Lay members (J. H. and I. H.) with experience and knowledge of colorectal cancer and screening contributed to developing, undertaking, and disseminating all aspects of the research. They were supported to collaborate as equal members of the research team. They were involved in developing the study as coapplicants, using personal experience to ensure that the research and its methods were relevant to the patient and public needs. Both prepared participant information sheets, coanalysed data, and contributed to study reporting and dissemination through papers, conference presentations and a lay summary.

During the COVID-19 pandemic, there was substantial reconfiguration of maternity care services, affecting both users and healthcare providers (HCPs), in the United Kingdom (UK) and globally. To further our understanding of the impact of maternity service reconfigurations in the UK, from the perspective of maternity HCPs. Scopus, MEDLINE, EMBASE, CINAHL, PsycINFO and the Cochrane COVID Study Register were searched for relevant studies reporting qualitative data from the UK, published in English between 01 June 2021 and 30 September 2023. Qualitative data on HCPs' experiences of maternity care reconfiguration during the pandemic were extracted from 15 studies. Data were subjected to thematic synthesis according to key service reconfigurations. Nine themes were identified: : Changes to existing care, Limitations placed on the partner, Mental health and lack of support networks, and Barriers to successful implementation of reconfiguration strategies; : Impact on quality of care, Increased convenience and flexibility, and Digital exclusion; and : Optimising patient care, and Service users and staff as the driving force for change. No studies reported on the concepts of or . The review findings highlight HCPs' views of the need for greater inclusion of partners, choice of virtual or in-person care for women and birthing people; and a need for co-designed services for future policy-making.

Generalized linear models were used to compare colonization positivity, duration of colonization, and AUC bacterial density, with generalized estimating equations used for comparison at multiple time points. Among pneumococcal-colonized individuals, the AUC of colonization density was higher in the LAIV group than in the control group, with borderline statistical significance at Days 2-14 (P = 0.05), and reached statistical significance after exclusion of participants who had nasal-swab PCR evidence of concurrent wild-type viral illness (three influenza B in the control arm, one rhinovirus in the LAIV arm; data not shown; P= 0.03) after presenting with symptoms of illness. Harvard Medical School Boston, Massachusetts Debby Bogaert, M.D., Ph.D.x University of Edinburgh Edinburgh, United Kingdom and University Medical Center Utrecht Utrecht, the Netherlands Neil French, M.B. Ch.B., Ph.D.x University of Liverpool Liverpool, United Kingdom Daniela M. Ferreira, Ph.D.x Liverpool School of Tropical Medicine Liverpool, United Kingdom The EHPC-LAIV Study Group ORCID IDs: 0000-0002-2323-3611 (J.R.); 0000-0001-7730-9477 (D.M.F.). *These authors contributed equally to this work. ‡Corresponding author (e-mail: jamie.rylance@lstmed.ac.uk). §Joint senior authors. Supported by the Bill and Melinda Gates Foundation and the UK Medical Research Council.

This book is the logical continuation of a series of collected essays examining the origins and evolution of myths and legends of the supernatural in Western and non-Western tradition and popular culture. The first two volumes of the series, The Universal Vampire: Origins and Evolution of a Legend (Fairleigh Dickinson University Press, 2013) and Images of the Modern Vampire: The Hip and the Atavistic. (Fairleigh Dickinson University Press, 2013) focused on the vampire legend. The essays in this collection expand that scope to include a multicultural and multigeneric discussion of a pantheon of supernatural creatures who interact and cross species-specific boundaries with ease. Angels and demons are discussed from the perspective of supernatural allegory, angelic ethics and supernatural heredity and genetics. Fairies, sorcerers, witches and werewolves are viewed from the perspectives of popular nightmare tales, depictions of race and ethnicity, popular public discourse and cinematic imagery. Discussions of the \"undead and still dead\" include images of death messengers and draugar, zombies and vampires in literature, popular media and Japanese anime.