Base-Edited CAR7 T Cells for Relapsed T-Cell Acute Lymphoblastic Leukemia.

BACKGROUND: Cytidine deamination that is guided by clustered regularly interspaced short palindromic repeats (CRISPR) can mediate a highly precise conversion of one nucleotide into another - specifically, cytosine to thymine - without generating breaks in DNA. Thus, genes can be base-edited and rendered inactive without inducing translocations and other chromosomal aberrations. The use of this technique in patients with relapsed childhood T-cell leukemia is being investigated. METHODS: We used base editing to generate universal, off-the-shelf chimeric antigen receptor (CAR) T cells. Healthy volunteer donor T cells were transduced with the use of a lentivirus to express a CAR with specificity for CD7 (CAR7), a protein that is expressed in T-cell acute lymphoblastic leukemia (ALL). We then used base editing to inactivate three genes encoding CD52 and CD7 receptors and the ß chain of the αß T-cell receptor to evade lymphodepleting serotherapy, CAR7 T-cell fratricide, and graft-versus-host disease, respectively. We investigated the safety of these edited cells in three children with relapsed leukemia. RESULTS: The first patient, a 13-year-old girl who had relapsed T-cell ALL after allogeneic stem-cell transplantation, had molecular remission within 28 days after infusion of a single dose of base-edited CAR7 (BE-CAR7). She then received a reduced-intensity (nonmyeloablative) allogeneic stem-cell transplant from her original donor, with successful immunologic reconstitution and ongoing leukemic remission. BE-CAR7 cells from the same bank showed potent activity in two other patients, and although fatal fungal complications developed in one patient, the other patient underwent allogeneic stem-cell transplantation while in remission. Serious adverse events included cytokine release syndrome, multilineage cytopenia, and opportunistic infections. CONCLUSIONS: The interim results of this phase 1 study support further investigation of base-edited T cells for patients with relapsed leukemia and indicate the anticipated risks of immunotherapy-related complications. (Funded by the Medical Research Council and others; ISRCTN number, ISRCTN15323014.).

CD19/CD22 targeting with cotransduced CAR T cells to prevent antigen-negative relapse after CAR T-cell therapy for B-cell ALL.

ABSTRACT: CD19-negative relapse is a leading cause of treatment failure after chimeric antigen receptor (CAR) T-cell therapy for acute lymphoblastic leukemia. We investigated a CAR T-cell product targeting CD19 and CD22 generated by lentiviral cotransduction with vectors encoding our previously described fast-off rate CD19 CAR (AUTO1) combined with a novel CD22 CAR capable of effective signaling at low antigen density. Twelve patients with advanced B-cell acute lymphoblastic leukemia were treated (CARPALL [Immunotherapy with CD19/22 CAR Redirected T Cells for High Risk/Relapsed Paediatric CD19+ and/or CD22+ Acute Lymphoblastic Leukaemia] study, NCT02443831), a third of whom had failed prior licensed CAR therapy. Toxicity was similar to that of AUTO1 alone, with no cases of severe cytokine release syndrome. Of 12 patients, 10 (83%) achieved a measurable residual disease (MRD)-negative complete remission at 2 months after infusion. Of 10 responding patients, 5 had emergence of MRD (n = 2) or relapse (n = 3) with CD19- and CD22-expressing disease associated with loss of CAR T-cell persistence. With a median follow-up of 8.7 months, there were no cases of relapse due to antigen-negative escape. Overall survival was 75% (95% confidence interval [CI], 41%-91%) at 6 and 12 months. The 6- and 12-month event-free survival rates were 75% (95% CI, 41%-91%) and 60% (95% CI, 23%-84%), respectively. These data suggest dual targeting with cotransduction may prevent antigen-negative relapse after CAR T-cell therapy.

Uptake of diabetes follow-up checks by minority community groups: a rapid review of the evidence for the CYMELL study.

BACKGROUND: Type 2 diabetes is a public health priority for the UK. A growing body of evidence has indicated ethnic and socioeconomic disparities in rates of diabetes prevalence and complications. Attendance at diabetes follow-up checks is key to ensuring complications are identified and managed at an early stage. The aim of this rapid review was to identify and summarise evidence of ways to improve diabetes management in ethnic minority groups. METHODS: In this rapid review, we searched PubMed, PsycInfo, and CINAHL for studies published in English between Jan 1, 2000, and Jan 31, 2023. Studies were included if the population was from ethnic minority groups and if the intervention was community-based and aimed to improve diabetes self-care. The comparisons were persuasion and behaviour change, and the outcomes were improved diabetes self-management including, glycaemic control, attending eye tests, kidney, and foot screening follow-up checks. This study is registered with PROSPERO 2023, CRD42023399283. FINDINGS: Nine studies were included, from Mexico (n=1), USA (n=7), and UK (n=1). Most studies reported on community engagement (n=8), and one focussed on peer support and diabetes self-management. Peer support and diabetes self-management education were found to significantly improve diabetes control in a Mayan community (n=29) in Mexico (p<0·0001) and in the Korean American (n=105), African American (n=107), and Latino American (n=56) communities in the USA. Another study showed that women from the Pakistani community in England also benefitted from a culturally appropriate and socially supportive environment when learning about diabetes self-management. Diabetic eye screening rates could be increased through education but not through incentive payments. INTERPRETATION: Culturally competent health-care policies and programmes have been shown to increase diabetes self-management including uptake of diabetes screening for people with diabetes from ethnic minority communities to avoid potential harmful and life limiting conditions. A strength of this review is that robust, recent, and relevant papers regarding self-management of diabetes were included. The main limitations were that none of the nine studies included any cost analyses, and only one UK-based study was included, indicating that further research is required to fill the evidence gap. FUNDING: Research for Patient and Public Benefit (RfPPB), Health and Care Research Wales.

Safety and Efficacy of Oxaliplatin Pressurized Intraperitoneal Aerosolized Chemotherapy (PIPAC) in Colorectal and Appendiceal Cancer with Peritoneal Metastases: Results of a Multicenter Phase I Trial in the USA.

BACKGROUND: Pressurized intraperitoneal aerosolized chemotherapy (PIPAC) is a laparoscopic locoregional treatment for peritoneal metastases (PM) from colorectal cancer (CRC) or appendiceal cancer (AC) in patients who cannot undergo cytoreductive surgery (CRS). While PIPAC has been studied in Europe and Asia, it has not been investigated in the USA. PATIENTS AND METHODS: We evaluated PIPAC with 90 mg/m2 oxaliplatin alone (cycle 1) and preceded by systemic chemotherapy with fluorouracil (5-FU) and leucovorin (LV) (cycle 2-3) as a multicenter prospective phase I clinical trial (NCT04329494). The primary endpoint was treatment-related adverse events (AEs). Secondary endpoints included survival and laparoscopic, histologic, and radiographic response. RESULTS: 12 patients were included: 8 with CRC and 4 with AC. Median prior chemotherapy cycles was 2 (interquartile range (IQR) 2-3). All patients were refractory to systemic oxaliplatin-based chemotherapy. Median peritoneal carcinomatosis index (PCI) was 28 (IQR 19-32). Six (50%) of twelve patients completed three PIPAC cycles. No surgical complications or dose-limiting toxicities were observed. Two patients developed grade 3 treatment-related toxicities (one abdominal pain and one anemia). Median overall survival (OS) was 12.0 months, and median progression-free survival (PFS) was 2.9 months. OS was correlated with stable disease by Response Evaluation Criteria in Solid Tumors (RECIST) criteria but not with laparoscopic response by PCI or histologic response by peritoneal regression grading system (PRGS). CONCLUSIONS: This phase I trial in the USA demonstrated safety, feasibility, and early efficacy signal of PIPAC with oxaliplatin and chemotherapy in patients with PM from AC or CRC who are refractory to standard lines of systemic chemotherapy.

Impact of severe hypoglycaemia requiring hospitalization on mortality in people with type 1 diabetes: A national retrospective observational cohort study.

AIMS: To assess if the risk of all-cause mortality increases in people with type 1 diabetes (T1D) with increasing number of severe hypoglycaemia episodes requiring hospitalization. MATERIALS AND METHODS: We conducted a national retrospective observational cohort study in people with T1D (diagnosed between 2000 and 2018). Clinical, comorbidity and demographic variables were assessed for impact on mortality for people with no, one, two and three or more episodes of severe hypoglycaemia requiring hospitalization. The time to death (all-cause mortality) from the timepoint of the last episode of severe hypoglycaemia was modelled using a parametric survival model. RESULTS: A total of 8224 people had a T1D diagnosis in Wales during the study period. The mortality rate (95% confidence interval [CI]) was 6.9 (6.1-7.8) deaths/ 1000 person-years (crude) and 15.31 (13.3-17.63) deaths/ 1000 person-years (age-adjusted) for those with no occurrence of severe hypoglycaemia requiring hospitalization. For those with one episode of severe hypoglycaemia requiring hospitalization the mortality rate (95% CI) was 24.9 (21.0-29.6; crude) and 53.8 (44.6-64.7) deaths/ 1000 person-years (age-adjusted), for those with two episodes of severe hypoglycaemia requiring hospitalization it was 28.0 (23.1-34.0; crude) and 72.8 (59.2-89.5) deaths/ 1000 person-years (age-adjusted), and for those with three or more episodes of severe hypoglycaemia requiring hospitalization it was 33.5 (30.0-37.3; crude) and 86.3 (71.7-103.9) deaths/ 1000 person years (age-adjusted; P < 0.001). A parametric survival model showed that having two episodes of severe hypoglycaemia requiring hospitalization was the strongest predictor for time to death (accelerated failure time coefficient 0.073 [95% CI 0.009-0.565]), followed by having one episode of severe hypoglycaemia requiring hospitalization (0.126 [0.036-0.438]) and age at most recent episode of severe hypoglycaemia requiring hospitalization (0.917 [0.885-0.951]). CONCLUSIONS: The strongest predictor for time to death was having two or more episodes of severe hypoglycaemia requiring hospitalization.

Evidence for strain-specific virulence of Trichomonas gallinae in African columbiformes.

Infection by parasites or pathogens can have marked physiological impacts on individuals. In birds, infection may affect moult and feather growth, which is an energetically demanding time in the annual cycle. Previous work has suggested a potential link between clinically visible Trichomonas gallinae infection and wing length in turtle doves Streptopelia turtur arriving on breeding grounds. First, T. gallinae infection was characterized in 149 columbids from 5 species, sampled on turtle dove wintering grounds in Senegal during the moulting period, testing whether infection by T. gallinae is linked to moult. Trichomonas gallinae prevalence was 100%, so rather than testing for differences between infected and uninfected birds, we tested for differences in moult progression between birds infected by different T. gallinae strains. Twelve strains of T. gallinae were characterized at the internal transcribed spacer 1 (ITS1)/5.8S/ITS2 region, of which 6 were newly identified within this study. In turtle doves only, evidence for differences in wing length by strain was found, with birds infected by strain Tcl-1 having wings nearly 6 mm longer than those infected with strain GEO. No evidence was found for an effect of strain identity within species on moult progression, but comparisons between infected and uninfected birds should be further investigated in species where prevalence is lower.

The impact of the COVID-19 pandemic on community prescription of opioid and antineuropathic analgesics for cancer patients in Wales, UK.

PURPOSE: Public health measures instituted at the onset of the COVID-19 pandemic in the UK in 2020 had profound effects on the cancer patient pathway. We hypothesise that this may have affected analgesic prescriptions for cancer patients in primary care. METHODS: A whole-nation retrospective, observational study of opioid and antineuropathic analgesics prescribed in primary care for two cohorts of cancer patients in Wales, using linked anonymised data to evaluate the impact of the pandemic and variation between different demographic backgrounds. RESULTS: We found a significant increase in strong opioid prescriptions during the pandemic for patients within their first 12 months of diagnosis with a common cancer (incidence rate ratio (IRR) 1.15, 95% CI: 1.12-1.18, p < 0.001 for strong opioids) and significant increases in strong opioid and antineuropathic prescriptions for patients in the last 3 months prior to a cancer-related death (IRR = 1.06, 95% CI: 1.04-1.07, p < 0.001 for strong opioids; IRR = 1.11, 95% CI: 1.08-1.14, p < 0.001 for antineuropathics). A spike in opioid prescriptions for patients diagnosed in Q2 2020 and those who died in Q2 2020 was observed and interpreted as stockpiling. More analgesics were prescribed in more deprived quintiles. This differential was less pronounced in patients towards the end of life, which we attribute to closer professional supervision. CONCLUSIONS: We demonstrate significant changes to community analgesic prescriptions for cancer patients related to the UK pandemic and illustrate prescription patterns linked to patients' demographic background.

Risk factors and prognostic implications of diagnosis of cancer within 30 days after an emergency hospital admission (emergency presentation): an International Cancer Benchmarking Partnership (ICBP) population-based study.

BACKGROUND: Greater understanding of international cancer survival differences is needed. We aimed to identify predictors and consequences of cancer diagnosis through emergency presentation in different international jurisdictions in six high-income countries. METHODS: Using a federated analysis model, in this cross-sectional population-based study, we analysed cancer registration and linked hospital admissions data from 14 jurisdictions in six countries (Australia, Canada, Denmark, New Zealand, Norway, and the UK), including patients with primary diagnosis of invasive oesophageal, stomach, colon, rectal, liver, pancreatic, lung, or ovarian cancer during study periods from Jan 1, 2012, to Dec 31, 2017. Data were collected on cancer site, age group, sex, year of diagnosis, and stage at diagnosis. Emergency presentation was defined as diagnosis of cancer within 30 days after an emergency hospital admission. Using logistic regression, we examined variables associated with emergency presentation and associations between emergency presentation and short-term mortality. We meta-analysed estimates across jurisdictions and explored jurisdiction-level associations between cancer survival and the percentage of patients diagnosed as emergencies. FINDINGS: In 857 068 patients across 14 jurisdictions, considering all of the eight cancer sites together, the percentage of diagnoses through emergency presentation ranged from 24·0% (9165 of 38 212 patients) to 42·5% (12 238 of 28 794 patients). There was consistently large variation in the percentage of emergency presentations by cancer site across jurisdictions. Pancreatic cancer diagnoses had the highest percentage of emergency presentations on average overall (46·1% [30 972 of 67 173 patients]), with the jurisdictional range being 34·1% (1083 of 3172 patients) to 60·4% (1317 of 2182 patients). Rectal cancer had the lowest percentage of emergency presentations on average overall (12·1% [10 051 of 83 325 patients]), with a jurisdictional range of 9·1% (403 of 4438 patients) to 19·8% (643 of 3247 patients). Across the jurisdictions, older age (ie, 75-84 years and 85 years or older, compared with younger patients) and advanced stage at diagnosis compared with non-advanced stage were consistently associated with increased emergency presentation risk, with the percentage of emergency presentations being highest in the oldest age group (85 years or older) for 110 (98%) of 112 jurisdiction-cancer site strata, and in the most advanced (distant spread) stage category for 98 (97%) of 101 jurisdiction-cancer site strata with available information. Across the jurisdictions, and despite heterogeneity in association size (I2=93%), emergency presenters consistently had substantially greater risk of 12-month mortality than non-emergency presenters (odds ratio >1·9 for 112 [100%] of 112 jurisdiction-cancer site strata, with the minimum lower bound of the related 95% CIs being 1·26). There were negative associations between jurisdiction-level percentage of emergency presentations and jurisdiction-level 1-year survival for colon, stomach, lung, liver, pancreatic, and ovarian cancer, with a 10% increase in percentage of emergency presentations in a jurisdiction being associated with a decrease in 1-year net survival of between 2·5% (95% CI 0·28-4·7) and 7·0% (1·2-13·0). INTERPRETATION: Internationally, notable proportions of patients with cancer are diagnosed through emergency presentation. Specific types of cancer, older age, and advanced stage at diagnosis are consistently associated with an increased risk of emergency presentation, which strongly predicts worse prognosis and probably contributes to international differences in cancer survival. Monitoring emergency presentations, and identifying and acting on contributing behavioural and health-care factors, is a global priority for cancer control. FUNDING: Canadian Partnership Against Cancer; Cancer Council Victoria; Cancer Institute New South Wales; Cancer Research UK; Danish Cancer Society; National Cancer Registry Ireland; The Cancer Society of New Zealand; National Health Service England; Norwegian Cancer Society; Public Health Agency Northern Ireland, on behalf of the Northern Ireland Cancer Registry; the Scottish Government; Western Australia Department of Health; and Wales Cancer Network.

Environmental DNA provides quantitative estimates of Pacific hake abundance and distribution in the open ocean.

All species inevitably leave genetic traces in their environments, and the resulting environmental DNA (eDNA) reflects the species present in a given habitat. It remains unclear whether eDNA signals can provide quantitative metrics of abundance on which human livelihoods or conservation successes depend. Here, we report the results of a large eDNA ocean survey (spanning 86 000 km2 to depths of 500 m) to understand the abundance and distribution of Pacific hake (Merluccius productus), the target of the largest finfish fishery along the west coast of the USA. We sampled eDNA in parallel with a traditional acoustic-trawl survey to assess the value of eDNA surveys at a scale relevant to fisheries management. Despite local differences, the two methods yield comparable information about the broad-scale spatial distribution and abundance. Furthermore, we find depth and spatial patterns of eDNA closely correspond to acoustic-trawl estimates for hake. We demonstrate the power and efficacy of eDNA sampling for estimating abundance and distribution and move the analysis eDNA data beyond sample-to-sample comparisons to management relevant scales. We posit that eDNA methods are capable of providing general quantitative applications that will prove especially valuable in data- or resource-limited contexts.

Assessing rates of parasite coinfection and spatiotemporal strain variation via metabarcoding: Insights for the conservation of European turtle doves Streptopelia turtur.

Understanding the frequency, spatiotemporal dynamics and impacts of parasite coinfections is fundamental to developing control measures and predicting disease impacts. The European turtle dove (Streptopelia turtur) is one of Europe's most threatened bird species. High prevalence of infection by the protozoan parasite Trichomonas gallinae has previously been identified, but the role of this and other coinfecting parasites in turtle dove declines remains unclear. Using a high-throughput sequencing approach, we identified seven strains of T. gallinae, including two novel strains, from ITS1/5.8S/ITS2 ribosomal sequences in turtle doves on breeding and wintering grounds, with further intrastrain variation and four novel subtypes revealed by the iron-hydrogenase gene. High spatiotemporal turnover was observed in T. gallinae strain composition, and infection was prevalent in all populations (89%-100%). Coinfection by multiple Trichomonas strains was rarer than expected (1% observed compared to 38.6% expected), suggesting either within-host competition, or high mortality of coinfected individuals. In contrast, coinfection by multiple haemosporidians was common (43%), as was coinfection by haemosporidians and T. gallinae (90%), with positive associations between strains of T. gallinae and Leucocytozoon suggesting a mechanism such as parasite-induced immune modulation. We found no evidence for negative associations between coinfections and host body condition. We suggest that longitudinal studies involving the recapture and investigation of infection status of individuals over their lifespan are crucial to understand the epidemiology of coinfections in natural populations.

Community views on mass drug administration for filariasis: a qualitative evidence synthesis.

BACKGROUND: The World Health Organization (WHO) recommends mass drug administration (MDA), giving a drug at regular intervals to a whole population, as part of the strategy for several disease control programmes in low- and middle-income countries. MDA is currently WHO policy for areas endemic with lymphatic filariasis, which is a parasitic disease that can result in swollen limbs and disability. The success depends on communities adhering to the drugs given, and this will be influenced by the perception of the drug, the programme, and those delivering it.  OBJECTIVES: To synthesize qualitative research evidence about community experience with, and understanding and perception of, MDA programmes for lymphatic filariasis. To explore whether programme design and delivery influence the community experience identified in the analysis. SEARCH METHODS: We searched CENTRAL, MEDLINE, Embase, and seven other databases up to 8 April 2021, together with reference checking, citation searching, and contact with study authors to identify additional studies. SELECTION CRITERIA: This review synthesized qualitative research and mixed-methods studies when it was possible to extract qualitative data. Eligible studies explored community experiences, perceptions, or attitudes towards MDA programmes for lymphatic filariasis in any country, conducted between 2000 and 2019.  DATA COLLECTION AND ANALYSIS: We extracted data on study design including: authors, aims, participants, methods, and qualitative data collection methods. We also described programme delivery factors including: country, urban or rural setting, endemicity, drug regimen, rounds of MDA received at the time of the study, who delivered the drugs, how the drugs were delivered, use of health education, and sensitization and adherence monitoring. We conducted a thematic analysis and developed codes inductively using ATLAS.ti software. We examined codes for underlying ideas, connections, and interpretations and, from this, generated analytical themes. We assessed the confidence in the findings using the GRADE-CERQual approach, and produced a conceptual model to display our findings.  MAIN RESULTS: From 902 results identified in the search, 29 studies met our inclusion criteria. The studies covered a broad range of countries in Africa, South-East Asia, and South America, and explored the views and experiences of community members and community drug distributors in low-income countries endemic for lymphatic filariasis. Four themes emerged. People weigh up benefits and harms before participating. People understand the potential benefits in terms of relief of suffering, stigma, and avoiding costs (high confidence); however, these theoretical benefits do not always mesh with their experiences (high confidence). In particular, adverse effects are frightening and unwelcome (high confidence); and these effects are amplified through rumour and social media (moderate confidence). Many people are suspicious of MDA programmes. When people lack a scientific explanation for the programme and their experiences of it, they often develop social explanations instead. These are largely shaped on the historical backdrop and level of trust people have in relevant authority figures (high confidence), although some have unwavering faith in their government and, by extension, the programme (moderate confidence). Programmes expect compliance, and this can become coercive and blaming. Health workers and community members stigmatize non-compliance, which can become coercive (moderate confidence), so communities may appear to comply publicly, but privately reject treatment (moderate confidence). Community distributors are often not respected or valued. They have little authority (moderate confidence), and the behaviour of some distributors damages the MDA programme's reputation (high confidence). Communities want information about programmes to help make decisions about participation, but drug distributors are not sufficiently informed, or skilled in this communication (high confidence). We intended to assess whether programme designs influenced communities' perceptions of the programme and decision to adhere but were unable to do so as few studies adequately reported the design and implementation of the local programme. We have moderate to high confidence in the evidence contributing to the review themes and subthemes. AUTHORS' CONCLUSIONS: Adherence with MDA for filariasis is influenced by individual direct experience of benefit and harm; social influences in the community; political influences and their relationship to government; and historical influences. Fear of adverse effects was frequently described and this appears to be particularly important for communities. When views were negative, we were surprised by the strength of feeling expressed. Enthusiasm for these schemes as a strategy in global policy needs debate in the light of these findings.

Monkeypox DNA levels correlate with virus infectivity in clinical samples, Israel, 2022.

The current monkeypox virus global spread and lack of data regarding clinical specimens' infectivity call for examining virus infectivity, and whether this correlates with results from PCR, the available diagnostic tool. We show strong correlation between viral DNA amount in clinical specimens and virus infectivity toward BSC-1 cell line. Moreover, we define a PCR threshold value (Cq ≥ 35, ≤ 4,300 DNA copies/mL), corresponding to negative viral cultures, which may assist risk-assessment and decision-making regarding protective-measures and guidelines for patients with monkeypox.

Impact of age at type 2 diabetes mellitus diagnosis on mortality and vascular complications: systematic review and meta-analyses.

AIMS/HYPOTHESIS: Few studies examine the association between age at diagnosis and subsequent complications from type 2 diabetes. This paper aims to summarise the risk of mortality, macrovascular complications and microvascular complications associated with age at diagnosis of type 2 diabetes. METHODS: Data were sourced from MEDLINE and All EBM (Evidence Based Medicine) databases from inception to July 2018. Observational studies, investigating the effect of age at diabetes diagnosis on macrovascular and microvascular diabetes complications in adults with type 2 diabetes were selected according to pre-specified criteria. Two investigators independently extracted data and evaluated all studies. If data were not reported in a comparable format, data were obtained from authors, presented as minimally adjusted ORs (and 95% CIs) per 1 year increase in age at diabetes diagnosis, adjusted for current age for each outcome of interest. The study protocol was recorded with PROSPERO International Prospective Register of Systematic Reviews (CRD42016043593). RESULTS: Data from 26 observational studies comprising 1,325,493 individuals from 30 countries were included. Random-effects meta-analyses with inverse variance weighting were used to obtain the pooled ORs. Age at diabetes diagnosis was inversely associated with risk of all-cause mortality and macrovascular and microvascular disease (all p < 0.001). Each 1 year increase in age at diabetes diagnosis was associated with a 4%, 3% and 5% decreased risk of all-cause mortality, macrovascular disease and microvascular disease, respectively, adjusted for current age. The effects were consistent for the individual components of the composite outcomes (all p < 0.001). CONCLUSIONS/INTERPRETATION: Younger, rather than older, age at diabetes diagnosis was associated with higher risk of mortality and vascular disease. Early and sustained interventions to delay type 2 diabetes onset and improve blood glucose levels and cardiovascular risk profiles of those already diagnosed are essential to reduce morbidity and mortality. Graphical abstract.

Characteristics of repeat non-attenders at Diabetes Eye Screening Wales, a national community-based diabetes-related retinopathy screening service, during 2003-2018.

AIMS: To understand factors associated with repeat non-attendance at screening for diabetes-related retinopathy. METHODS: Retrospective observational study using anonymised data from Diabetic Eye Screening Wales for people with a full history of screening invitations and attendances was linked with primary and secondary care records held in the Secure Anonymised Information Linkage Databank. Repeat non-attendance was defined as no record of attendance during any 36-month period despite three cycles of annual screening invitations. The associations between repeat non-attendance and potential risk factors were examined using multivariable logistic regression analysis, stratified according to type 1 and type 2 diabetes. RESULTS: A total of 18% with type 1 diabetes (1146/6513) and 8% with type 2 diabetes (12,475/156,525) were repeat non-attenders. Participants attending their very first appointment were least likely to become repeat non-attenders [odds ratio (95% confidence interval)]: type 1 diabetes: 0.12 (0.09, 0.17) and type 2 diabetes: 0.08 (0.07, 0.09). For both types of diabetes, those of a younger age, living in areas of higher deprivation and subject to multiple house moves were at greater risk of becoming repeat non-attenders. CONCLUSION/INTERPRETATION: A more tailored approach is needed for the younger population, those living in areas of higher deprivation and/or undergoing multiple residential relocation and to ensure attendance at their initial appointment to minimise future repeat non-attendance.

The Ethics of Tobacco Harm Reduction: An Analysis of E-Cigarette Availability From the Perspectives of Utilitarianism, Bioethics, and Public Health Ethics.

Much evidence suggests e-cigarettes are substantially less harmful than combustible cigarettes. Assuming this is true, we analyze the ethical case for a policy of e-cigarette availability (ECA) as a tobacco harm reduction strategy. ECA involves making e-cigarettes available to allow smokers to switch to them, and informing smokers of the lower risks of e-cigarettes vis-à-vis smoking. After suggesting that utilitarian/consequentialist considerations do not provide an adequate ethical analysis, we analyze ECA using two other ethical frameworks. First, ECA is supported by a public health ethics framework. ECA is a population-level intervention consistent with respecting individual autonomy by using the least restrictive means to accomplish public health goals, and it supports equity and justice. Second, ECA is supported by four principles that form a biomedical ethics framework. By reducing smokers' health risks and not harming them, ECA fulfills principles of beneficence and non-maleficence. Because ECA allows smokers to make informed health decisions for themselves, it fulfills the principle requiring respect for persons and their autonomy. Here, we consider whether nicotine addiction and thus ECA undermine autonomy, and also discuss the ethical warrant for special protections for youth. Finally, ECA can also advance justice by providing a harm reduction alternative for disadvantaged groups that disproportionately bear the devastating consequences of smoking. Policies of differential taxation of cigarettes and e-cigarettes can facilitate adoption of less harmful alternatives by those economically disadvantaged. We conclude that public health and biomedical ethics frameworks are mutually reinforcing and supportive of ECA as a tobacco harm reduction strategy. Implications: Making e-cigarettes and information about them available is supported as ethical from multiple ethical perspectives.

Features of Intestinal Disease Associated With COVID-Related Multisystem Inflammatory Syndrome in Children.

ABSTRACT: Multisystem inflammatory syndrome in children (MIS-C) is a recently identified syndrome that appears to be temporally associated with novel coronavirus 2019 infection. MIS-C presents with fever and evidence of systemic inflammation, which can manifest as cardiovascular, pulmonary, neurologic, and gastrointestinal (GI) system dysfunction. Presenting GI symptoms are seen in the majority, including abdominal pain, diarrhea, and vomiting. Any segment of the GI tract may be affected; however, inflammation in the ileum and colon predominates. Progressive bowel wall thickening can lead to luminal narrowing and obstruction. Most will have resolution of intestinal inflammation with medical therapies; however, in rare instances, surgical resection may be required.

Ivermectin treatment in humans for reducing malaria transmission.

BACKGROUND: Malaria is transmitted through the bite of Plasmodium-infected adult female Anopheles mosquitoes. Ivermectin, an anti-parasitic drug, acts by killing mosquitoes that are exposed to the drug while feeding on the blood of people (known as blood feeds) who have ingested the drug. This effect on mosquitoes has been demonstrated by individual randomized trials. This effect has generated interest in using ivermectin as a tool for malaria control. OBJECTIVES: To assess the effect of community administration of ivermectin on malaria transmission. SEARCH METHODS: We searched the Cochrane Infectious Diseases Group (CIDG) Specialized Register, CENTRAL, MEDLINE, Embase, LILACS, Science Citation index - expanded, the World Health Organization (WHO) International Clinical Trials Registry Platform, ClinicalTrials.gov, and the National Institutes of Health (NIH) RePORTER database to 14 January 2021. We checked the reference lists of included studies for other potentially relevant studies, and contacted researchers working in the field for unpublished and ongoing trials. SELECTION CRITERIA: We included cluster-randomized controlled trials (cRCTs) that compared ivermectin, as single or multiple doses, with a control treatment or placebo given to populations living in malaria-endemic areas, in the context of mass drug administration. Primary outcomes were prevalence of malaria parasite infection and incidence of clinical malaria in the community. DATA COLLECTION AND ANALYSIS: Two review authors independently extracted data on the number of events and the number of participants in each trial arm at the time of assessment. For rate data, we noted the total time at risk in each trial arm. To assess risk of bias, we used Cochrane's RoB 2 tool for cRCTs. We documented the method of data analysis, any adjustments for clustering or other covariates, and recorded the estimate of the intra-cluster correlation (ICC) coefficient. We re-analysed the trial data provided by the trial authors to adjust for cluster effects. We used a Poisson mixed-effect model with small sample size correction, and a cluster-level analysis using the linear weighted model to adequately adjust for clustering.  MAIN RESULTS: We included one cRCT and identified six ongoing trials.  The included cRCT examined the incidence of malaria in eight villages in Burkina Faso, randomized to two arms. Both trial arms received a single dose of ivermectin 150 µg/kg to 200 µg/kg, together with a dose of albendazole. The villages in the intervention arm received an additional five doses of ivermectin, once every three weeks. Children were enrolled into an active cohort, in which they were repeatedly screened for malaria infection.  The primary outcome was the cumulative incidence of uncomplicated malaria in a cohort of children aged five years and younger, over the 18-week study. We judged the study to be at high risk of bias, as the analysis did not account for clustering or correlation between participants in the same village. The study did not demonstrate an effect of Ivermectin on the cumulative incidence of uncomplicated malaria in the cohort of children over the 18-week study (risk ratio 0.86, 95% confidence interval (CI) 0.62 to 1.17; P = 0.2607; very low-certainty evidence). AUTHORS' CONCLUSIONS: We are uncertain whether community administration of ivermectin has an effect on malaria transmission, based on one trial published to date.

Ventilation Techniques and Risk for Transmission of Coronavirus Disease, Including COVID-19: A Living Systematic Review of Multiple Streams of Evidence.

BACKGROUND: Mechanical ventilation is used to treat respiratory failure in coronavirus disease 2019 (COVID-19). PURPOSE: To review multiple streams of evidence regarding the benefits and harms of ventilation techniques for coronavirus infections, including that causing COVID-19. DATA SOURCES: 21 standard, World Health Organization-specific and COVID-19-specific databases, without language restrictions, until 1 May 2020. STUDY SELECTION: Studies of any design and language comparing different oxygenation approaches in patients with coronavirus infections, including severe acute respiratory syndrome (SARS) or Middle East respiratory syndrome (MERS), or with hypoxemic respiratory failure. Animal, mechanistic, laboratory, and preclinical evidence was gathered regarding aerosol dispersion of coronavirus. Studies evaluating risk for virus transmission to health care workers from aerosol-generating procedures (AGPs) were included. DATA EXTRACTION: Independent and duplicate screening, data abstraction, and risk-of-bias assessment (GRADE for certainty of evidence and AMSTAR 2 for included systematic reviews). DATA SYNTHESIS: 123 studies were eligible (45 on COVID-19, 70 on SARS, 8 on MERS), but only 5 studies (1 on COVID-19, 3 on SARS, 1 on MERS) adjusted for important confounders. A study in hospitalized patients with COVID-19 reported slightly higher mortality with noninvasive ventilation (NIV) than with invasive mechanical ventilation (IMV), but 2 opposing studies, 1 in patients with MERS and 1 in patients with SARS, suggest a reduction in mortality with NIV (very-low-certainty evidence). Two studies in patients with SARS report a reduction in mortality with NIV compared with no mechanical ventilation (low-certainty evidence). Two systematic reviews suggest a large reduction in mortality with NIV compared with conventional oxygen therapy. Other included studies suggest increased odds of transmission from AGPs. LIMITATION: Direct studies in COVID-19 are limited and poorly reported. CONCLUSION: Indirect and low-certainty evidence suggests that use of NIV, similar to IMV, probably reduces mortality but may increase the risk for transmission of COVID-19 to health care workers. PRIMARY FUNDING SOURCE: World Health Organization. (PROSPERO: CRD42020178187).

The likely association between wandering spleen and absent left kidney.

Wandering spleen is a cause of acute surgical abdomen with serious consequences. It arises from an absence or weakness of the supporting suspensory splenic ligaments. There is often a delayed diagnosis due to its non-specific clinical presentation. This leads to stalled acquisition of confirmatory diagnostic imaging with resultant increased morbidity and mortality. Congenital or acquired absence of the left kidney results in loss of the splenorenal ligament, a key ligament to maintain normal splenic position in the abdomen. Two patients, one with OHVIRA (obstructed hemivagina ipsilateral renal anomaly) syndrome and another who underwent a left nephrectomy during infancy, developed a wandering spleen with acute splenic torsion in the setting of an absent left kidney. This case series aims to increase awareness to the likely predisposition for individuals with an absent left kidney to develop a wandering spleen.

Evaluation of a national lung cancer symptom awareness campaign in Wales.

BACKGROUND: Lung cancer is the leading cause of cancer mortality in Wales. We conducted a before- and after- study to evaluate the impact of a four-week mass-media campaign on awareness, presentation behaviour and lung cancer outcomes. METHODS: Population-representative samples were surveyed for cough symptom recall/recognition and worry about wasting doctors' time pre-campaign (June 2016; n = 1001) and post-campaign (September 2016; n = 1013). GP cough symptom visits, urgent suspected cancer (USC) referrals, GP-ordered radiology, new lung cancer diagnoses and stage at diagnosis were compared using routine data during the campaign (July-August 2016) and corresponding control (July-August 2015) periods. RESULTS: Increased cough symptom recall (p < 0.001), recognition (p < 0.001) and decreased worry (p < 0.001) were observed. GP visits for cough increased by 29% in the target 50+ age-group during the campaign (p < 0.001) and GP-ordered chest X-rays increased by 23% (p < 0.001). There was no statistically significant change in USC referrals (p = 0.82), new (p = 0.70) or early stage (p = 0.27) diagnoses, or in routes to diagnosis. CONCLUSIONS: Symptom awareness, presentation and GP-ordered chest X-rays increased during the campaign but did not translate into increased USC referrals or clinical outcomes changes. Short campaign duration and follow-up, and the small number of new lung cancer cases observed may have hampered detection effects.