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BACKGROUND: We aimed to assess the efficacy and safety of two neutralising monoclonal antibody therapies (sotrovimab [Vir Biotechnology and GlaxoSmithKline] and BRII-196 plus BRII-198 [Brii Biosciences]) for adults admitted to hospital for COVID-19 (hereafter referred to as hospitalised) with COVID-19.METHODS: In this multinational, double-blind, randomised, placebo-controlled, clinical trial (Therapeutics for Inpatients with COVID-19 [TICO]), adults (aged ≥18 years) hospitalised with COVID-19 at 43 hospitals in the USA, Denmark, Switzerland, and Poland were recruited. Patients were eligible if they had laboratory-confirmed SARS-CoV-2 infection and COVID-19 symptoms for up to 12 days. Using a web-based application, participants were randomly assigned (2:1:2:1), stratified by trial site pharmacy, to sotrovimab 500 mg, matching placebo for sotrovimab, BRII-196 1000 mg plus BRII-198 1000 mg, or matching placebo for BRII-196 plus BRII-198, in addition to standard of care. Each study product was administered as a single dose given intravenously over 60 min. The concurrent placebo groups were pooled for analyses. The primary outcome was time to sustained clinical recovery, defined as discharge from the hospital to home and remaining at home for 14 consecutive days, up to day 90 after randomisation. Interim futility analyses were based on two seven-category ordinal outcome scales on day 5 that measured pulmonary status and extrapulmonary complications of COVID-19. The safety outcome was a composite of death, serious adverse events, incident organ failure, and serious coinfection up to day 90 after randomisation. Efficacy and safety outcomes were assessed in the modified intention-to-treat population, defined as all patients randomly assigned to treatment who started the study infusion. This study is registered with ClinicalTrials.gov, NCT04501978.FINDINGS: Between Dec 16, 2020, and March 1, 2021, 546 patients were enrolled and randomly assigned to sotrovimab (n=184), BRII-196 plus BRII-198 (n=183), or placebo (n=179), of whom 536 received part or all of their assigned study drug (sotrovimab n=182, BRII-196 plus BRII-198 n=176, or placebo n=178; median age of 60 years [IQR 50-72], 228 [43%] patients were female and 308 [57%] were male). At this point, enrolment was halted on the basis of the interim futility analysis. At day 5, neither the sotrovimab group nor the BRII-196 plus BRII-198 group had significantly higher odds of more favourable outcomes than the placebo group on either the pulmonary scale (adjusted odds ratio sotrovimab 1·07 [95% CI 0·74-1·56]; BRII-196 plus BRII-198 0·98 [95% CI 0·67-1·43]) or the pulmonary-plus complications scale (sotrovimab 1·08 [0·74-1·58]; BRII-196 plus BRII-198 1·00 [0·68-1·46]). By day 90, sustained clinical recovery was seen in 151 (85%) patients in the placebo group compared with 160 (88%) in the sotrovimab group (adjusted rate ratio 1·12 [95% CI 0·91-1·37]) and 155 (88%) in the BRII-196 plus BRII-198 group (1·08 [0·88-1·32]). The composite safety outcome up to day 90 was met by 48 (27%) patients in the placebo group, 42 (23%) in the sotrovimab group, and 45 (26%) in the BRII-196 plus BRII-198 group. 13 (7%) patients in the placebo group, 14 (8%) in the sotrovimab group, and 15 (9%) in the BRII-196 plus BRII-198 group died up to day 90.INTERPRETATION: Neither sotrovimab nor BRII-196 plus BRII-198 showed efficacy for improving clinical outcomes among adults hospitalised with COVID-19.FUNDING: US National Institutes of Health and Operation Warp Speed.

AimsTo evaluate 99th percentile upper reference limits (URLs) and investigate ethnic differences for the Abbott Architect high-sensitivity cardiac troponin I (hs-cTnI) in a middle-aged to elderly cosmopolitan population.MethodsIn subjects without cardiovascular disease and after outlier exclusion, data on hs-cTnI from 149 white men, 150 white women, 150 South Asian (SA) men and 150 SA women in their sixth, seventh and eight decades were analysed. Each ethnicity–gender–decade subgroup consisted of 50 patients except white men in their sixth decade (n=49).ResultsThe overall, women and men hs-cTnI 99th percentile URLs were 22.1, 17.9 and 24.8 ng/L, respectively. Median (IQR) hs-cTnI was higher in men (2.7 (1.8–4.1) ng/L) than in women (1.9 (1.1–3.2) ng/L; pConclusionWe report white–SA differences in hs-cTnI in men and a similar trend in women. We confirm age and gender differences in hs-cTnI, irrespective of ethnicity. Further studies are required to determine whether ethnicity-specific age and gender 99th percentile URLs improve detection or exclusion of myocardial injury.

Legally aided criminal defence work is under significant strain at present following fee stagnations and funding cuts over the last 20 years. This has obvious implications for those working in criminal defence practice, which have been examined in the literature on access to criminal justice. However, the implications for teaching and learning within criminal law and practice have been not been subject to much attention. Within we reflect on the teaching and learning challenges. Further, we use a Fineman vulnerability analysis to illustrate how the challenges faced by criminal defence practice – in the face of a crumbling criminal justice system – affect criminal law and process teaching and learning. Finally, we explore how the resilience of criminal defence can be provided (or bolstered) by and within the academe.

Summary Introduction This study evaluates COVID-19 related patient risk, when undergoing management within one of the largest specialist centres in Europe, which rapidly implemented national COVID-19 safety guidelines. Method A prospective cohort study was undertaken in all patients who underwent surgical (n = 1429) or non-operative (n = 191) management during the UK COVID-19 pandemic peak (April–May 2020); all were evaluated for 30-day COVID-19 related death. A representative sample of elective/trauma/burns patients (surgery group, n = 729) were selected and also sub-analysed within a controlled cohort study design. Comparison was made to a random selection of non-operatively managed (non-operative group, n = 100) or waiting list (control group, n = 250) patients. These groups were prospectively followed-up and telephoned from the end of June (control group) or at 30 days post-first assessment (non-operative group)/post-operatively (surgery group). Results Complex general (9.2%, 136/1483) or regional (5.0%, 74/1483) anaesthesia cases represented 14.2% (210/1483) of operations undertaken. There were no 30-day post-operative (0/1429)/first assessment (0/191) COVID-19 related deaths. Neither the three sub-speciality plastic surgery, or non-operative groups, displayed increases in post-operative/first assessment symptoms in comparison to each other, or to control. The proportion of COVID-19 positive tests were: 7.1% (1/14) (non-operative), 5.9% (2/34) (burns) and 3.0% (3/99) (trauma); there were however no significant differences between these groups, the elective (0%, 0/54) and control (0%, 0/24) groups (p = 0.236). Conclusion We demonstrate that even heterogeneous sub-speciality patient groups, who required operative/non-operative management, did not incur an increased COVID-19 risk compared to each other or to control. These highly encouraging results were achieved with described, rapidly implemented service changes that were tailored to protect each patient group and staff.

IMPORTANCE: A lack of consensus exists with regard to the optimal positioning regimen for patients after macula-involving retinal detachment (RD) repair. OBJECTIVE: To evaluate the effect of face-down positioning vs support-the-break positioning on retinal displacement and distortion after macula-involving RD repair. DESIGN, SETTING, AND PARTICIPANTS: A prospective 6-month single-masked randomized clinical trial was conducted at a multicenter tertiary referral setting from May 16, 2016, to May 1, 2018. Inclusion criteria were fovea-involving rhegmatogenous RD; central visual loss within 14 days; patients undergoing primary vitrectomy and gas surgery, under local anesthetic; patients able to give written informed consent; and 18 years old and older. Analysis was conducted following a modified intention-to-treat principle, with patients experiencing a redetachment or failure to attach the macula being excluded from analysis. INTERVENTIONS: Participants were randomized 1:1 to receive face-down positioning or support-the-break positioning for a 24-hour period postoperatively. Positioning compliance was not monitored. MAIN OUTCOMES AND MEASURES: The proportion of patients with retinal displacement on autofluorescence imaging at 6 months postoperatively. Secondary outcomes included proportion of patients with displacement at 2 months; amplitude of displacement at 2 and 6 months; corrected Early Treatment Diabetic Retinopathy Study visual acuity; objective Distortion Scores; and quality of life questionnaire scores at 6 months. RESULTS: Of the 262 randomized patients, 239 were analyzed (171 male [71.5%]; mean [SD] age, 60.8 [9.8] years). At 6 months, retinal displacement was detected in 42 of 100 (42%) in the face-down positioning group vs 58 of 103 (56%) in the support-the-break positioning group (odds ratio, 1.77; 95%CI, 1.01-3.11; P = .04). The degree of displacement was lower in the face-down group. Groups were similar in corrected visual acuity (face-down, 74 letters vs support-the-break, 75 letters), objective D Chart Distortion Scores (range: 0, no distortion to 41.6, severe distortion; with face-down at 4.5 vs support-the-break at 4.2), and quality of life scores (face-down 89.3 vs support-the-break 89.0) at 2 and 6 months. Retinal redetachment rate was similar in both groups (face-down group, 12.2% and support-the-break group, 13.7%). Retinal folds were less common in the face-down positioning group vs the support-the-break positioning group (5.3% vs 13.5%, respectively; odds ratio, 2.8; 95% CI, 1.2-7.4; P = .03). Binocular diplopia was more common in the support-the-break group compared with the face-down positioning group (7.6% vs 1.5%, respectively; odds ratio, 5.3; 95% CI, 1.3-24.6; P = .03). Amplitude of displacement was associated with worse visual acuity (r = −0.5; P

Purpose To test the hypothesis that adjunctive slow-release dexamethasone implant (Ozurdex; Allergan Inc, Irvine, CA) can improve the outcomes of vitreoretinal surgery for established proliferative vitreoretinopathy (PVR). Design A 2-year, single-center, prospective, participant- and surgeon-masked randomized controlled clinical trial (EudraCT No. 2011-004498-96). Participants A total of 140 patients requiring vitrectomy surgery with silicone oil for retinal detachment with established PVR (Grade C) were randomized to standard (control) or study treatment (adjunct) in a 1:1 allocation ratio. Methods Intraoperatively, the adjunct group received an injection of 0.7 mg of slow-release dexamethasone (Ozurdex) at the time of (1) vitrectomy surgery and (2) silicone oil removal. The control group received standard care. Main Outcome Measures Primary outcome measure was the proportion of patients with a stable retinal reattachment with removal of silicone oil without additional vitreoretinal surgical intervention at 6 months. Secondary outcomes included (1) final visual acuity (VA) (median and Early Treatment Diabetic Retinopathy Study [ETDRS] of 55 letters or better); (2) cystoid macular edema (CMO), foveal thickness, and macular volume; (3) development of overt PVR recurrence; (4) complete and posterior retinal reattachment; (5) tractional retinal detachment; (6) hypotony/increased intraocular pressure (IOP); (7) macula pucker/epiretinal membrane; (8) cataract; and (9) quality of life. Results All 140 patients were recruited within 25 months of study commencement; 138 patients had primary outcome data. Primary outcome assessment showed similar results in anatomic success between the 2 groups (49.3% vs. 46.3%, adjunct vs. control; odds ratio, 0.89; 95% confidence interval, 0.46–1.74; P = 0.733). Mean VA at 6 months was 38.3 ETDRS letters and 40.2 letters in the adjunct and control groups, respectively. Secondary anatomic outcomes (complete/posterior reattachment rates and PVR recurrence) were comparable between the 2 groups. At 6 months, fewer adjunct patients had CMO (42.7%) or a foveal thickness of >300 μm (47.6%) compared with controls (67.2% and 67.7%, respectively, P = 0.004, P = 0.023). Conclusions A slow-release dexamethasone implant did not improve the primary anatomic success rate in eyes undergoing vitrectomy surgery with silicone oil for PVR. Further clinical trials are indicated to improve anatomic and visual outcomes in these eyes, but this study suggests that there is a greater reduction in CMO observed at 6 months in vitrectomized eyes treated with slow-release dexamethasone.

TVM cells are antigen-naïve, semi-differentiated CD8 T cells that develop in response to common γ (γc) chain cytokines, like IL-15 and IL-4. TVM cells respond more rapidly than conventional naïve CD8 T cells to antigen stimulation, thereby providing early control of viral and bacterial infections. TVM cells comprise 20% of the naive CD8 T cell pool in young mice but are selectively retained and make up to 50% of all antigenically naïve CD8 T cells in aged mice. In addition, aged TVM cells exhibit markers of senescence and lose proliferative capacity compared to young TVM cells. Recently, it was shown that IL-4 generated during helminth infection drove TVM cell expansion and improved pathogen clearance in subsequent infections. However, it is not known if the expanded subset is maintained with age or whether helminth infections similarly expand or improve the function of aged TVM cells. To evaluate this, we infected young mice with the helminth, Heligmosomoides polygyrus, and aged them to over 18 months. There was no difference in number or function of TVM cells in previously infected as compared to naïve aged mice. We then infected aged mice with helminths and observed no increase in TVM cell numbers, but there was a reduction in IFN-γ production by aged TVM cells. When naïve TVM cells were transferred to a young helminth infected host, proliferation of aged TVM cells was markedly reduced as compared to young TVM cells. Collectively these data suggest that, the protective effect of helminth infection in young mice, mediated by TVM cell expansion, is firstly not maintained into advanced age. Secondly, this effect cannot be generated in aged mice due to aged TVM cells being intrinsically less responsive to the helminth-induced cytokine environment.

Interleukin-33 (IL-33) is a nuclear cytokine of the interleukin-1 family and is released upon cell damage thereby acting as an alarmin. IL-33 plays an essential role in promoting host-protective immune responses against helminth parasites at different mucosal surfaces including the intestine. However, early events after gastrointestinal nematode infection are poorly understood and the cellular source of IL-33 in the gut remains ill-defined. Here we show that Cxcl13-Cre-positive fibroblastic stromal cells (FSCs) of the lamina propria are the main source of IL-33 in the small intestine. Within the first days of nematode infection, lamina propria FSCs showed strongly increased IL-33 expression. Ablation of IL-33 in Cxcl-13-Cre-positive FSCs resulted in an increased infestation with the gastrointestinal nematode Heligmosomoides polygyrus bakeri. We found that myeloid cells were recruited to the site of worm invasion early after infection and that the upregulation of a distinct set of inflammatory cytokines was dependent on FSC-derived IL-33. Collectively, these data unveil that IL-33-mediated crosstalk between stromal and myeloid cells is a critical event during the initial immune response against gastrointestinal nematodes.

Background: Standard treatment for thyroid eye disease is with systemic corticosteroids. We aimed to establish whether orbital radiotherapy or antiproliferative immunosuppression would confer any additional benefit. Methods: CIRTED was a multicentre, double-blind, randomised controlled trial with a 2 × 2 factorial design done at six centres in the UK. Adults with active moderate-to-severe thyroid eye disease associated with proptosis or ocular motility restriction were recruited to the trial. Patients all received a 24 week course of oral prednisolone (80 mg per day, reduced to 20 mg per day by 6 weeks, 10 mg per day by 15 weeks, and 5 mg per day by 21 weeks) and were randomly assigned via remote computerised randomisation to receive either radiotherapy or sham radiotherapy and azathioprine or placebo in a 2 × 2 factorial design. Randomisation included minimisation to reduce baseline disparities in potential confounding variables between trial interventions. Patients and data analysts were masked to assignment, whereas trial coordinators (who monitored blood results), pharmacists, and radiographers were not. The radiotherapy dose was 20 Gy administered to the retrobulbar orbit in ten to 12 fractions over 2 to 3 weeks. Azathioprine treatment was provided for 48 weeks at 100–200 mg per day (dispensed as 50 mg tablets), depending on bodyweight (100 mg for interaction=0·86). The adjusted odds ratio (ORadj) for improvement in the binary clinical composite outcome measure was 2·56 (95% CI 0·98–6·66, p=0·054) for azathioprine and 0·89 (0·36–2·23, p=0·80) for radiotherapy. In a post-hoc analysis of patients who completed their allocated therapy the ORadj for improvement was 6·83 (1·66–28·1, p=0·008) for azathioprine and 1·32 (0·30–4·84, p=0·67) for radiotherapy. The ophthalmopathy index, clinical activity score, and numbers of adverse events (161 with azathioprine and 156 with radiotherapy) did not differ between treatment groups. In both groups, the most common adverse events were mild infections. No patients died during the study. Interpretation: In patients receiving oral prednisolone for 24 weeks, radiotherapy did not have added benefit. We also did not find added benefit for addition of azathioprine in the primary analysis; however, our conclusions are limited by the high number of patients who withdrew from treatment. Results of post-hoc analysis of those who completed the assigned treatment suggest improved clinical outcome at 48 weeks with azathioprine treatment. Funding: National Eye Research Centre, Above and Beyond, and Moorfields Eye Charity.

ObjectiveImproving quality of life (QOL) is the central focus of palliative care support for children with life-limiting illness (LLI), but achieving this can be challenging.InterventionMyQuality is an online tool that enables families to choose and monitor parameters they identify as having an impact on their QOL, which aims to improve patient–professional communications and also to enhance patient empowerment within healthcare dialogues.DesignA longitudinal, multisite mixed-method evaluation of MyQuality. Families were invited to use MyQuality and completed semi-structured interviews and a Family Empowerment Scale (FES) at T=0 and T+3 months.Patients and settingThirty-two families of children with LLIs, attending three children's hospices in one UK region.Outcome measuresWebsite access, usage patterns and parameter choice, FES scores and qualitative evaluation of interviews.Results23/32 families chose to use the website. Mean duration of use was 106 days (range 2–301), with families choosing two or three parameters (range 1–15), most commonly seizures (24/32), constipation (9/32), pain (6/32) and sleep problems (6/32). Mean FES scores increased over time (3.45–3.85). Interview feedback confirmed the acceptability and ease of use of the website, and the value of a graphic record of change over time to support ongoing management and collaborative review of medical, nursing or social interventions.ConclusionsThe identification and monitoring of patient-generated priorities via the MyQuality website empowers families and supports collaboration between parents and professionals to ensure that palliative care is truly patient and family centred.

Background Controlling seizures in children approaching death is often challenging. The evidence base to guide best practice is limited. We compared current practice in our region against the guidance for seizure management produced by the Association of Paediatric Palliative Medicine (APPM), seeking to identify any difficulties, barriers, and areas for improvement in symptom control. Methods Retrospective case note review of episodes of challenging seizure management in children receiving end-of-life care over a ten year period (2006–2015). Results We identified and reviewed eighteen cases. Six (33%) had a malignancy, eight (44%) had a progressive neurodegenerative condition, and four (22%) had a static neurological condition with associated epilepsy. Fifteen (83%) had seizures during their final admission/care episode, and the remaining three had had status epilepticus previously and were felt to be at high risk of recurrence. Thirteen (72%) died in their local hospice, four (22%) at home, and one (6%) in hospital. Seventeen (94%) involved the use of subcutaneous or intravenous midazolam infusion, for a mean of eleven days (range 3–27). There was a wide range of starting doses of midazolam, and 9/17 (53%) received final doses in excess of APPM dose recommendations. Six individuals (33%) received subcutaneous phenobarbital infusions, with four of these (67%) receiving final doses in excess of APPM dose recommendations. Plans for adjustments of infusion rates, maximal doses, or alternative approaches should treatment fail, were inconsistent. In 17/18 (94%) cases seizures were successfully controlled in the days or hours before the child died, but this was sometimes a prolonged process. Fear of apnoea or over-sedation were the main barriers to prompt symptom control. Staff found the experience of managing seizures at end-of-life challenging and stressful. Conclusions Pharmacological approaches to seizure management in end-of-life care are variable, often exceeding dose recommendations. Despite this, safe and effective seizure control was reported to be possible in all settings. Best-practice management guidance should be developed to support improved care and to increase staff confidence in this area. Project funded by Health Education England

This study investigated whether there is evidence of widespread niche partitioning based on environmental factors in the Black Sea and tested the hypothesis that physiographic factors may be employed as predictors. It addresses poorly researched areas with good habitat potential for the only three cetacean subspecies living in this area: the Black Sea short-beaked common dolphin (Delphinus delphis spp. ponticus), the Black Sea bottlenose dolphin (Tursiops truncatus spp. ponticus) and the Black Sea harbour porpoise (Phocoena phocoena spp. relicta). Generalized additive models (GAMs) were used to analyse data collected from multiple sources. In total, 745 sightings of the three species between 1998 and 2010 throughout the Black Sea were included. The analysis found depth and sea surface temperature to be the most important variables for separating the occurrence of the three species. Common dolphins occurred mainly in deep waters and in areas where the sea surface temperature was low, bottlenose dolphins were distributed primarily in shallower and warmer waters than common dolphins, and harbour porpoises were distributed in shallower waters with lower sea surface temperature than bottlenose dolphins. This study suggests strong niche segregation among the three cetacean species. The study is also the first contribution to the basic information of cetacean species distribution and habitat preferences in the Black Sea as a whole. Knowledge of the distribution of the three dolphin species in the study area is essential to establish conservation measures for these populations.

To test the hypothesis that adjunctive slow-release dexamethasone implant (Ozurdex; Allergan Inc, Irvine, CA) can improve the outcomes of vitreoretinal surgery for established proliferative vitreoretinopathy (PVR).A 2-year, single-center, prospective, participant- and surgeon-masked randomized controlled clinical trial (EudraCT No. 2011-004498-96).A total of 140 patients requiring vitrectomy surgery with silicone oil for retinal detachment with established PVR (Grade C) were randomized to standard (control) or study treatment (adjunct) in a 1:1 allocation ratio.Intraoperatively, the adjunct group received an injection of 0.7 mg of slow-release dexamethasone (Ozurdex) at the time of (1) vitrectomy surgery and (2) silicone oil removal. The control group received standard care.Primary outcome measure was the proportion of patients with a stable retinal reattachment with removal of silicone oil without additional vitreoretinal surgical intervention at 6 months. Secondary outcomes included (1) final visual acuity (VA) (median and Early Treatment Diabetic Retinopathy Study [ETDRS] of 55 letters or better); (2) cystoid macular edema (CMO), foveal thickness, and macular volume; (3) development of overt PVR recurrence; (4) complete and posterior retinal reattachment; (5) tractional retinal detachment; (6) hypotony/increased intraocular pressure (IOP); (7) macula pucker/epiretinal membrane; (8) cataract; and (9) quality of life.All 140 patients were recruited within 25 months of study commencement; 138 patients had primary outcome data. Primary outcome assessment showed similar results in anatomic success between the 2 groups (49.3% vs. 46.3%, adjunct vs. control; odds ratio, 0.89; 95% confidence interval, 0.46-1.74; P = 0.733). Mean VA at 6 months was 38.3 ETDRS letters and 40.2 letters in the adjunct and control groups, respectively. Secondary anatomic outcomes (complete/posterior reattachment rates and PVR recurrence) were comparable between the 2 groups. At 6 months, fewer adjunct patients had CMO (42.7%) or a foveal thickness of300 μm (47.6%) compared with controls (67.2% and 67.7%, respectively, P = 0.004, P = 0.023).A slow-release dexamethasone implant did not improve the primary anatomic success rate in eyes undergoing vitrectomy surgery with silicone oil for PVR. Further clinical trials are indicated to improve anatomic and visual outcomes in these eyes, but this study suggests that there is a greater reduction in CMO observed at 6 months in vitrectomized eyes treated with slow-release dexamethasone.

The intestinal epithelium forms an essential barrier between a host and its microbiota. Protozoa and helminths are members of the gut microbiota of mammals, including humans, yet the many ways that gut epithelial cells orchestrate responses to these eukaryotes remain unclear. Here we show that tuft cells, which are taste-chemosensory epithelial cells, accumulate during parasite colonization and infection. Disruption of chemosensory signaling through the loss of TRMP5 abrogates the expansion of tuft cells, goblet cells, eosinophils, and type 2 innate lymphoid cells during parasite colonization. Tuft cells are the primary source of the parasite-induced cytokine interleukin-25, which indirectly induces tuft cell expansion by promoting interleukin-13 production by innate lymphoid cells. Our results identify intestinal tuft cells as critical sentinels in the gut epithelium that promote type 2 immunity in response to intestinal parasites.

ObjectivesControlling seizures in children approaching death can be difficult, and there is a limited evidence base to guide best practice. We compared current practice against the guidance for seizure management produced by the Association of Paediatric Palliative Medicine (APPM).MethodsRetrospective case note review of episodes of challenging seizure management in children receiving end-of-life care over a 10-year period (2006–2015) in the south-west region of England.ResultsWe reviewed 19 admissions, in 18 individuals. Six (33%) had a malignancy, nine (50%) had a progressive neurodegenerative condition and three (17%) had a static neurological condition with associated epilepsy. Thirteen (72%) died in their local hospice, four (22%) at home, and one (6%) in hospital. Seventeen of 19 episodes involved the use of subcutaneous or intravenous midazolam infusion, for a mean of 11 days (range 3–27). There was a wide range of starting doses of midazolam, and 9/17 (53%) received final doses in excess of current dose recommendations. Six individuals received subcutaneous phenobarbital infusions, with four of these (67%) receiving final doses in excess of current dose recommendations. Plans for adjustments of infusion rates, maximal doses or alternative approaches should treatment fail were inconsistent or absent. In 16/18 (88%) cases seizures were successfully controlled prior to the day of the child’s death. Staff found the experience of managing seizures at end of life challenging and stressful.ConclusionsPharmacological approaches to seizure management in end-of-life care are variable, often exceeding APPM dose recommendations. Despite this, safe and effective seizure control was possible in all settings.

Forty percent of patients with autoimmune hepatitis (AIH) present with acute jaundice/hepatitis. Such patients, when treated promptly, are thought to have a good prognosis.The objective of this study was to describe the natural history of AIH in patients presenting with jaundice/hepatitis and to determine whether the diagnosis could have been made earlier, before presentation.This study is a retrospective review of 2249 consecutive patients who presented with jaundice to the Jaundice Hotline clinic, Truro, Cornwall, UK, over 15 years (1998-2013) and includes a review of the laboratory data over a 23-year period (1990-2013).Of the 955 patients with hepatocellular jaundice, 47 (5%) had criterion-referenced AIH: 35 female and 12 male, the median age was 65 years (range 15-91 years); the bilirubin concentration was 139 μmol/l (range 23-634 μmol/l) and the alanine transaminase level was 687 IU/l (range 22-2519 IU/l). Among the patients, 23/46 (50%) were cirrhotic on biopsy; 11/47 (23%) died: median time from diagnosis to death, 5 months (range 1-59); median age, 72 years (range 59-91 years). All 8/11 patients who died of liver-related causes were cirrhotic. Weight loss (P=0.04) and presence of cirrhosis (P=0.004) and varices (P=0.015) were more common among those who died. Among patients who died from liver-related causes, 6/8 (75%) died less than 6 months from diagnosis. Cirrhosis at presentation and oesophageal varices were associated with early liver-related deaths (P=0.011, 0.002 respectively). Liver function test results were available in 33/47 (70%) patients before presentation. Among these patients, 16 (49%) had abnormal alanine transaminase levels previously, and eight (50%) were cirrhotic at presentation.AIH presenting as jaundice/hepatitis was mainly observed in older women: 50% of the patients were cirrhotic, and liver-related mortality was high. Some of these deaths were potentially preventable by earlier diagnosis, as the patients had abnormal liver function test results previously, which had not been investigated.

Purpose: The aim of this study was to establish characteristics of patients with diabetes mellitus (DM) attending Moorfields Eye Hospital (MEH) before implementation of the national diabetic retinopathy (DR) screening programme. Methods: Patients with DM attending MEH Medical Retina Clinics during a 4 week time period were interviewed about DM, its complications and knowledge and expectations on laser treatment. Results: In 4 weeks, 830 patients with DM were identified, of whom 4.3% were registered partially sighted and 4.7% registered blind. 141 did not attend, 109 could/would not be interviewed and 580 interviews were conducted. Interviewed patients were similar to those not except for previous laser treatment (p=0.016). The median duration of DM was 10 years (0.3-52 years); 74.3% had Type 2 DM; 64.8% had hypertension. A high proportion of patients had at least one diabetic complication (heart disease 24%; stroke 9.7%; diabetic neuropathy 48.9%; diabetic nephropathy 13.4%); 13.1% did not understand the relationship of DM with DR. In the past 61.5% and 64.1% patients had fluorescein angiography (FFA) and laser treatment; on the day of the interview 5.8% had FFA and 13.4% laser. Despite full consent, 51.6% did not understand how long it took the laser treatment to work or expected it to take effect immediately; 16.6% expected to have only one treatment ever. Only 20.9% were members of Diabetes UK. Conclusions: Patients currently attending eye clinics have many diabetes related complications. With full implementation of the National Screening Programme for DR this percentage is expected to rise. Careful planning of ophthalmic services needs to be undertaken to accommodate the need for services for patients with multiple diabetes related complications.