"I'll meet you at our bench": adaptation, innovation and resilience among VCSE organisations who supported marginalised and minoritised communities during the Covid-19 pandemic in Northern England - a qualitative focus group study.

BACKGROUND: The Covid-19 pandemic has exacerbated pre-existing inequalities and increased adversity and challenges for vulnerable and marginalised communities worldwide. In the UK, the Voluntary Community and Social Enterprise (VCSE) sector play a vital role in supporting the health and wellbeing of people who are marginalised or experiencing multiple complex needs. However, only a small number of studies have focused on the impact that Covid-19 had on the VCSE sector. METHODS: As part of a Health Inequalities Impact Assessment (HIIA), we conducted qualitative focus groups with staff and volunteers from five organisations to examine short, medium and longer-term impacts of Covid-19 upon the VCSE sector in Northern England. Nine online focus groups were conducted between March and July 2021. FINDINGS: Focus group transcripts were analysed using Framework Analysis and yielded three central themes: (1) exacerbation of pre-existing inequalities, adversity and challenges for vulnerable and marginalised populations; (2) the 'price' of being flexible, innovative and agile for VCSE staff and volunteers; and (3) the voluntary sector as a 'lifeline' - organisational pride and resilience. CONCLUSIONS: While the voluntary sector 'adapted at pace' to provide support during Covid-19 and in its continued aftermath, this resilience has potentially come at the cost of workforce and volunteer wellbeing, compounded by political obstacles and chronic shortage in funding and support. The VCSE sector has a vital role to play in the post-lockdown 'levelling up' agenda. The expertise, capacity and resilience of VCSE organisations, and their ability to respond to Covid-19, should be celebrated, recognised and supported adequately to maintain its resilience. To not do so threatens the sector's sustainability and risks jeopardising attempts to involve the sector in addressing the social determinants of health.

Deregulation and epigenetic modification of BCL2-family genes cause resistance to venetoclax in hematologic malignancies.

The BCL2 inhibitor venetoclax has been approved to treat different hematological malignancies. Because there is no common genetic alteration causing resistance to venetoclax in chronic lymphocytic leukemia (CLL) and B-cell lymphoma, we asked if epigenetic events might be involved in venetoclax resistance. Therefore, we employed whole-exome sequencing, methylated DNA immunoprecipitation sequencing, and genome-wide clustered regularly interspaced short palindromic repeats (CRISPR)/CRISPR-associated protein 9 screening to investigate venetoclax resistance in aggressive lymphoma and high-risk CLL patients. We identified a regulatory CpG island within the PUMA promoter that is methylated upon venetoclax treatment, mediating PUMA downregulation on transcript and protein level. PUMA expression and sensitivity toward venetoclax can be restored by inhibition of methyltransferases. We can demonstrate that loss of PUMA results in metabolic reprogramming with higher oxidative phosphorylation and adenosine triphosphate production, resembling the metabolic phenotype that is seen upon venetoclax resistance. Although PUMA loss is specific for acquired venetoclax resistance but not for acquired MCL1 resistance and is not seen in CLL patients after chemotherapy-resistance, BAX is essential for sensitivity toward both venetoclax and MCL1 inhibition. As we found loss of BAX in Richter's syndrome patients after venetoclax failure, we defined BAX-mediated apoptosis to be critical for drug resistance but not for disease progression of CLL into aggressive diffuse large B-cell lymphoma in vivo. A compound screen revealed TRAIL-mediated apoptosis as a target to overcome BAX deficiency. Furthermore, antibody or CAR T cells eliminated venetoclax resistant lymphoma cells, paving a clinically applicable way to overcome venetoclax resistance.

Osimertinib and anti-HER3 combination therapy engages immune dependent tumor toxicity via STING activation in trans.

Over the past decade, immunotherapy delivered novel treatments for many cancer types. However, lung cancer still leads cancer mortality, and non-small-cell lung carcinoma patients with mutant EGFR cannot benefit from checkpoint inhibitors due to toxicity, relying only on palliative chemotherapy and the third-generation tyrosine kinase inhibitor (TKI) osimertinib. This new drug extends lifespan by 9-months vs. second-generation TKIs, but unfortunately, cancers relapse due to resistance mechanisms and the lack of antitumor immune responses. Here we explored the combination of osimertinib with anti-HER3 monoclonal antibodies and observed that the immune system contributed to eliminate tumor cells in mice and co-culture experiments using bone marrow-derived macrophages and human PBMCs. Osimertinib led to apoptosis of tumors but simultaneously, it triggered inositol-requiring-enzyme (IRE1α)-dependent HER3 upregulation, increased macrophage infiltration, and activated cGAS in cancer cells to produce cGAMP (detected by a lentivirally transduced STING activity biosensor), transactivating STING in macrophages. We sought to target osimertinib-induced HER3 upregulation with monoclonal antibodies, which engaged Fc receptor-dependent tumor elimination by macrophages, and STING agonists enhanced macrophage-mediated tumor elimination further. Thus, by engaging a tumor non-autonomous mechanism involving cGAS-STING and innate immunity, the combination of osimertinib and anti-HER3 antibodies could improve the limited therapeutic and stratification options for advanced stage lung cancer patients with mutant EGFR.

A systematic review of risk of HIV transmission through biting or spitting: implications for policy.

OBJECTIVES: The perceived threat of HIV transmission through spitting and biting is evidenced by the increasing use of "spit hoods" by Police Forces in the UK. In addition, a draft parliamentary bill has called for increased penalties for assaults on emergency workers, citing the risk of communicable disease transmission as one justification. We aimed to review literature relating to the risk of HIV transmission through biting or spitting. METHODS: A systematic literature search was conducted using Medline, Embase and Northern Lights databases and conference websites using search terms relating to HIV, AIDS, bite, spit and saliva. Inclusion and exclusion criteria were applied to identified citations. We classified plausibility of HIV transmission as low, medium, high or confirmed based on pre-specified criteria. RESULTS: A total of 742 abstracts were reviewed, yielding 32 articles for full-text review and 13 case reports/series after inclusion and exclusion criteria had been applied. There were no reported cases of HIV transmission related to spitting and nine cases identified following a bite, in which the majority occurred between family (six of nine), in fights involving serious wounds (three of nine), or to untrained first-aiders placing fingers in the mouth of someone having a seizure (two of nine). Only four cases were classified as highly plausible or confirmed transmission. None related to emergency workers and none were in the UK. CONCLUSIONS: There is no risk of transmitting HIV through spitting, and the risk through biting is negligible. Post-exposure prophylaxis is not indicated after a bite in all but exceptional circumstances. Policies to protect emergency workers should be developed with this evidence in mind.

The adaptation and translation of the PEACH™ RCT intervention: the process and outcomes of the PEACH™ in the community trial.

OBJECTIVE: To describe the process and report selected outcomes of translating an effective child weight management initiative (PEACH™) from a randomised controlled trial intervention to a community health programme. STUDY DESIGN AND METHODS: Pre-post study design utilising the reach, effectiveness, adoption, implementation and maintenance (RE-AIM) evaluation framework. Adaptation of PEACH™ required significant promotional activity and consideration of legal, ethical and financial issues. PEACH™ components were revised and an evaluation design based on the RE-AIM framework was developed. Facilitator training workshops were made available to South Australian health or education professionals initially, then opened up to new graduates, interstate dietitians and others interested in professional development. Facilitators completed pretraining and post-training questionnaires and a third questionnaire following programme delivery. Data were collected from families by facilitators and returned to university staff for assessment of change (baseline to programme end) in body mass index (BMI) and waist circumference (WC) z-scores. RESULTS: Changes to organisational and political environments prevented maximum programme reach and adoption. Nonetheless, data indicated that PEACH™ was effective at improving facilitators' confidence (P < 0.05) and children's (n = 37) BMI z-score (-0.17, 95% confidence interval [CI]: 0.03:0.30, P = 0.016), WC z-score (-0.14, 95% CI: -0.02:0.30, P = 0.09) and lifestyle behaviours. Collection of maintenance data was prevented due to time and financial constraints. CONCLUSIONS: Translational research needs to develop ways to effectively and efficiently bridge the gap between behavioural research and practice to improve the adoption of evidence-based approaches to child weight management. Nutrition educators and researchers can drive these nutrition-focussed translational research efforts forward. Funding bodies and health service organisations are encouraged to provide financial and structural support for such activity.

Surgical management of complicated and medically refractory inflammatory bowel disease during pregnancy.

AIM: The medical management of inflammatory bowel disease (IBD) in pregnancy and the puerperium is well defined. Data on surgical management of complicated IBD in this setting are lacking. This study aimed to determine the optimal surgical strategy for medically refractory IBD during pregnancy and the puerperium. METHOD: Three databases were systematically reviewed to identify all published series or case reports of women undergoing surgery for Crohn's disease (CD) or ulcerative colitis (UC) while pregnant or during the puerperium. RESULTS: Thirty-two papers were identified, including 86 patients. Nearly one-fifth (18%) of cases were de novo presentations and intervention was required at all stages of pregnancy. UC refractory to medical treatment and perforated small bowel CD were the commonest indications for surgery. Operations used included colectomy, colectomy with mucous fistula and Turnbull-blowhole colostomy for complicated UC and open or laparoscopic small bowel resection with stoma formation for CD. Surgical intervention during the third trimester universally resulted in the onset of labour. Endoscopic and radiological interventions were rarely employed. In studies after 1980 there was no maternal or foetal mortality but there was an almost 50% preterm delivery rate. CONCLUSION: Surgical management of complicated IBD during pregnancy and the puerperium needs to be tailored to disease severity, the type of complications and foetal status. It should involve gastroenterologists, colorectal surgeons, obstetricians and neonatal specialists in a multidisciplinary manner within a single unit.

Successful therapy for protein-losing enteropathy caused by chronic neuronopathic Gaucher disease.

Gaucher disease (OMIM #230800) is caused by ß-glucosidase deficiency and primarily involves the mononuclear phagocyte system (also called Reticuloendothelial System or Macrophage System). The disease is classified into three main phenotypes based on the presence or absence of neurological manifestations: non-neuronopathic (type 1), acute neuronopathic (type 2) and chronic neuronopathic (type 3). Typical manifestations include hepatosplenomegaly, skeletal deformities, hematological abnormalities, interstitial lung fibrosis and neurodegeneration in neuronopathic cases. Mesenteric lymphadenopathy with resultant protein losing enteropathy (PLE) has only been rarely described. Mesenteric lymphadenopathy may lead to intestinal lymphatic obstruction and secondary lymphangiectasia resulting in chronic diarrhea, abdominal pain and weight loss. Fecal protein loss with secondary hypoalbuminemia can be significant. We report a male with Chronic Neuronopathic Gaucher disease (GD) (homozygous for c.1448T > C (NM_000157.3) GBA mutation) who at 16 years of age developed intractable abdominal pain, diarrhea and weight loss. This was caused by PLE secondary to intestinal lymphangiectasia caused by calcified mesenteric lymphadenopathy despite prior long term enzyme replacement therapy (ERT) and/or substrate reduction therapy (SRT). His older similarly affected sister who had been receiving treatment with ERT and/or SRT remains stable on these treatments with no evidence of mesenteric lymphadenopathy. Medical management with total parenteral nutrition, daily medium chain triglyceride-oil (MCT) supplementation, low dose oral budesonide, continued oral SRT and an increased dose of parenteral ERT has stabilized his condition with resolution of the gastrointestinal symptoms and appropriate weight gain.

Increased sensitivity to platinum drugs of cancer cells with acquired resistance to trabectedin.

BACKGROUND: In order to investigate the mechanisms of acquired resistance to trabectedin, trabectedin-resistant human myxoid liposarcoma (402-91/T) and ovarian carcinoma (A2780/T) cell lines were derived and characterised in vitro and in vivo. METHODS: Resistant cell lines were obtained by repeated exposures to trabectedin. Characterisation was performed by evaluating drug sensitivity, cell cycle perturbations, DNA damage and DNA repair protein expression. In vivo experiments were performed on A2780 and A2780/T xenografts. RESULTS: 402-91/T and A2780/T cells were six-fold resistant to trabectedin compared with parental cells. Resistant cells were found to be hypersensitive to UV light and did not express specific proteins involved in the nucleotide excision repair (NER) pathway: XPF and ERCC1 in 402-91/T and XPG in A2780/T. NER deficiency in trabectedin-resistant cells was associated with the absence of a G2/M arrest induced by trabectedin and with enhanced sensitivity (two-fold) to platinum drugs. In A2780/T, this collateral sensitivity, confirmed in vivo, was associated with an increased formation of DNA interstrand crosslinks. CONCLUSIONS: Our finding that resistance to trabectedin is associated with the loss of NER function, with a consequent increased sensitivity to platinum drugs, provides the rational for sequential use of these drugs in patients who have acquired resistance to trabectedin.

WHITE COATS AND NO TROUSERS: NARRATING THE EXPERIENCES OF WOMEN TECHNICIANS IN MEDICAL LABORATORIES, 1930-90.

Laboratory technicians are a vital part of any working lab. Not only is their knowledge and expertise important for the success of research, but they also often maintain the lab's intellectual and social life. Despite the importance of their work, they are rarely acknowledged in publications, and leave only a few traces within the historical recordthe voices of women laboratory technicians are even harder to uncover. This paper attempts to correct this imbalance by presenting the narratives of women who worked as laboratory technicians at places such as the National Institute for Medical Research (NIMR), the Wellcome Research Laboratories, and established hospital and university labs in Cambridge, Oxford and London. The data were collected though narrative interviews. Specifically, the paper looks at the roles of these women within the lab, their experiences of the social and gender dynamics of the lab, and the development of expertise in regard to the work they carried out and the extent to which they received credit for their contributions to science.

No evidence of transfusion transmission of Adenovirus and Epstein-Barr virus infections in paediatric recipients post-bone marrow transplant.

Adenovirus and Epstein-Barr virus can cause significant morbidity and mortality in paediatric patients post-bone marrow transplant. The source of infection is thought to be either reactivation of latent viruses or primary infection. We have investigated whether transfusion of blood components from viraemic donors could provide a route of primary infection in these patients and sought the prevalence of viraemia in the blood donor population from England. In 32 linked donor/recipient samples and 300 unselected blood donors, we found no evidence to suggest that these infections in paediatric bone marrow transplant recipients had been acquired from transfused blood components.

Fatal herpes simplex virus hepatitis following neoadjuvant chemoradiotherapy and anterior resection for rectal cancer.

We describe the case of a young patient who contracted fatal herpes simplex virus hepatitis following neoadjuvant chemoradiotherapy and anterior resection for rectal cancer. The rarity and non-specific presentation of this treatable disease, which masqueraded as the sequelae of postoperative sepsis, resulted in a diagnosis following death. Features that should prompt inclusion of herpes simplex virus hepatitis in the differential diagnoses are suggested and the case is a reminder of how neoadjuvant therapy may subtly alter a patient's immunocompetency.

Selenium homocholic acid taurocholate scanning, selenium-75-labeled bile acid, a novel method for testing the function of the terminal ileum in small bowel transplant recipients: a pilot study.

INTRODUCTION: The terminal ileum (TI) is important for the active reabsorption of bile salts and is the site of allograft rejection; disruption of enterohepatic circulation (EHC) may give insights to inflammatory and other physiologic processes at the TI. SUBJECTS AND METHODS: Four children aged 5 to 12 years who had received small bowel transplantation (SBTx), 3 recovering from post-transplant lymphoproliferative disease (PTLD) and 1 with acute rejection, were studied. Two of the 4 had stoma reversal. Another child (15 years) with progressive familial intrahepatic cholestasis (PFIC) and pruritus, despite liver transplantation and biliary diversion, was studied. Selenium homocholic acid taurocholate scanning ((75)SeHCAT) capsule was given orally (n = 3) or via introducer during endoscopy (n = 2); a baseline whole-body gamma camera scan was done 4 hours later and on days 1 to 5. RESULTS: The normal 3-day bile salt retention is 30% to 70% of baseline and normal adult biological half-life, t½ is 62 ± 17 hours. The results in children with a stoma were very low (0.1% at 7.6 hours; 5% at 17 hours). The children with reversed stoma had retention and t½ closer to the reference range (18% at 29 hours; 22% at 33 hours). The child with PFIC + biliary diversion had an initial very high gamma emission from the stoma bag suggesting excellent reabsorption of bile salts from his TI, but retention was 0.6% and t½ 9.8 hours, demonstrating efficient biliary diversion. CONCLUSION: These results confirm children with stomas malabsorb bile acids, which can be ameliorated after stoma closure. SeHCAT demonstrated that the biliary diversion was working well and may be helpful in preoperative assessment of abnormal EHC. The role of SeHCAT in SBTx requires further evaluation.

Central nervous system infection after Onyx embolisation of arterio-venous malformations in two paediatric patients.

BACKGROUND: Increasingly, Onyx is used for endovascular embolization of aneurysms and arterio-venous malformations. Although reports in the literature on the use of Onyx are favourable, there have been so far no reports on the central nervous system (CNS) infection rate after embolisation with Onyx and no recommendations as to the management of these infections. CASE REPORTS: We present two cases of paediatric patients who acquired CNS infection with Pseudomonas aeruginosa after Onyx embolisation of AVMs and describe their subsequent management. CONCLUSIONS: Presence of established infection after Onyx embolisation should be dealt with by removal of infected material, administration of appropriate antibiotic therapy and supportive treatment.

Service evaluation to establish the sensitivity, specificity and additional value of broad-range 16S rDNA PCR for the diagnosis of infective endocarditis from resected endocardial material in patients from eight UK and Ireland hospitals.

Infective endocarditis (IE) can be diagnosed in the clinical microbiology laboratory by culturing explanted heart valve material. We present a service evaluation that examines the sensitivity and specificity of a broad-range 16S rDNA polymerase chain reaction (PCR) assay for the detection of the causative microbe in culture-proven and culture-negative cases of IE. A clinical case-note review was performed for 151 patients, from eight UK and Ireland hospitals, whose endocardial specimens were referred to the Microbiology Laboratory at Great Ormond Street Hospital (GOSH) for broad-range 16S rDNA PCR over a 12-year period. PCR detects the causative microbe in 35/47 cases of culture-proven IE and provides an aetiological agent in 43/69 cases of culture-negative IE. The sensitivity, specificity, positive predictive value (PPV) and negative predictive value (NPV) of the 16S rDNA PCR assay were calculated for this series of selected samples using the clinical diagnosis of IE as the reference standard. The values obtained are as follows: sensitivity = 67 %, specificity = 91 %, PPV = 96 % and NPV = 46 %. A wide range of organisms are detected by PCR, with Streptococcus spp. detected most frequently and a relatively large number of cases of Bartonella spp. and Tropheryma whipplei IE. PCR testing of explanted heart valves is recommended in addition to culture techniques to increase diagnostic yield. The data describing the aetiological agents in a large UK and Ireland series of culture-negative IE will allow future development of the diagnostic algorithm to include real-time PCR assays targeted at specific organisms.

The success of rectus and gracilis muscle flaps in the treatment of chronic pelvic sepsis and persistent perineal sinus: a systematic review.

AIM: Chronic pelvic sepsis is a challenging problem, which may require muscle flaps to fill the pelvic cavity. The aim of this systematic review was to determine the relative success of rectus and gracilis flaps used for this purpose. METHOD: A systematic review was conducted to identify papers that reported the outcome of rectus or gracilis myocutaneous flaps in the treatment of persistent perineal sinuses or chronic pelvic sepsis. Reports of muscle flaps used for reconstruction or treatment of fistula in the absence of chronic sepsis were excluded. A successful outcome was defined as complete perineal healing within 12 months of surgery. RESULTS: The review identified 19 studies reporting the outcome of 73 rectus and 87 gracilis flaps. Their respective success was 84% and 64%. Heterogeneity of the underlying cases did not allow for direct comparison of the flaps. Full healing of the flaps was generally achieved within 3 months. Donor site morbidity was minimal. CONCLUSION: The surgical treatment of chronic pelvic sepsis should be tailored to the individual, but the rectus flap has a reasonable success rate with little morbidity.