King's College Hospital NHS Foundation Trust

BACKGROUND: Lu)-Dotatate in patients with advanced, progressive, somatostatin-receptor-positive midgut neuroendocrine tumors. METHODS: Lu-Dotatate group) or octreotide LAR alone (113 patients) administered intramuscularly at a dose of 60 mg every 4 weeks (control group). The primary end point was progression-free survival. Secondary end points included the objective response rate, overall survival, safety, and the side-effect profile. The final analysis of overall survival will be conducted in the future as specified in the protocol; a prespecified interim analysis of overall survival was conducted and is reported here. RESULTS: Lu-Dotatate group as compared with no patients in the control group, with no evidence of renal toxic effects during the observed time frame. CONCLUSIONS: Lu-Dotatate group. (Funded by Advanced Accelerator Applications; NETTER-1 ClinicalTrials.gov number, NCT01578239 ; EudraCT number 2011-005049-11 .).

Ulcerative colitis and Crohn's disease are the principal forms of inflammatory bowel disease. Both represent chronic inflammation of the gastrointestinal tract, which displays heterogeneity in inflammatory and symptomatic burden between patients and within individuals over time. Optimal management relies on understanding and tailoring evidence-based interventions by clinicians in partnership with patients. This guideline for management of inflammatory bowel disease in adults over 16 years of age was developed by Stakeholders representing UK physicians (British Society of Gastroenterology), surgeons (Association of Coloproctology of Great Britain and Ireland), specialist nurses (Royal College of Nursing), paediatricians (British Society of Paediatric Gastroenterology, Hepatology and Nutrition), dietitians (British Dietetic Association), radiologists (British Society of Gastrointestinal and Abdominal Radiology), general practitioners (Primary Care Society for Gastroenterology) and patients (Crohn's and Colitis UK). A systematic review of 88 247 publications and a Delphi consensus process involving 81 multidisciplinary clinicians and patients was undertaken to develop 168 evidence- and expert opinion-based recommendations for pharmacological, non-pharmacological and surgical interventions, as well as optimal service delivery in the management of both ulcerative colitis and Crohn's disease. Comprehensive up-to-date guidance is provided regarding indications for, initiation and monitoring of immunosuppressive therapies, nutrition interventions, pre-, peri- and postoperative management, as well as structure and function of the multidisciplinary team and integration between primary and secondary care. Twenty research priorities to inform future clinical management are presented, alongside objective measurement of priority importance, determined by 2379 electronic survey responses from individuals living with ulcerative colitis and Crohn's disease, including patients, their families and friends.

IMPORTANCE: Survivors of critical illness demonstrate skeletal muscle wasting with associated functional impairment. OBJECTIVE: To perform a comprehensive prospective characterization of skeletal muscle wasting, defining the pathogenic roles of altered protein synthesis and breakdown. DESIGN, SETTING, AND PARTICIPANTS: Sixty-three critically ill patients (59% male; mean age: 54.7 years [95% CI, 50.0-59.6 years]) with an Acute Physiology and Chronic Health Evaluation II score of 23.5 (95% CI, 21.9-25.2) were prospectively recruited within 24 hours following intensive care unit (ICU) admission from August 2009 to April 2011 at a university teaching and a community hospital in England. Patients were recruited if older than 18 years and were anticipated to be intubated for longer than 48 hours, to spend more than 7 days in critical care, and to survive ICU stay. MAIN OUTCOMES AND MEASURES: Muscle loss was determined through serial ultrasound measurement of the rectus femoris cross-sectional area (CSA) on days 1, 3, 7, and 10. In a subset of patients, the fiber CSA area was quantified along with the ratio of protein to DNA on days 1 and 7. Histopathological analysis was performed. In addition, muscle protein synthesis, breakdown rates, and respective signaling pathways were characterized. RESULTS: There were significant reductions in the rectus femoris CSA observed at day 10 (−17.7% [95% CI, −25.9% to 8.1%]; P < .001). In the 28 patients assessed by all 3 measurement methods on days 1 and 7, the rectus femoris CSA decreased by 10.3% (95% CI, 6.1% to 14.5%), the fiber CSA by 17.5% (95% CI, 5.8% to 29.3%), and the ratio of protein to DNA by 29.5% (95% CI, 13.4% to 45.6%). Decrease in the rectus femoris CSA was greater in patients who experienced multiorgan failure by day 7 (−15.7%; 95% CI, −27.7% to 11.4%) compared with single organ failure (−3.0%; 95% CI, −5.3% to 2.1%) (P < .001), even by day 3 (−8.7% [95% CI, −59.3% to 50.6%] vs −1.8% [95% CI, −12.3% to 10.5%], respectively; P = .03). Myofiber necrosis occurred in 20 of 37 patients (54.1%). Protein synthesis measured by the muscle protein fractional synthetic rate was depressed in patients on day 1 (0.035%/hour; 95% CI, 0.023% to 0.047%/hour) compared with rates observed in fasted healthy controls (0.039%/hour; 95% CI, 0.029% to 0.048%/hour) (P = .57) and increased by day 7 (0.076% [95% CI, 0.032%-0.120%/hour]; P = .03) to rates associated with fed controls (0.065%/hour [95% CI, 0.049% to 0.080%/hour]; P = .30), independent of nutritional load. Leg protein breakdown remained elevated throughout the study (8.5 [95% CI, 4.7 to 12.3] to 10.6 [95% CI, 6.8 to 14.4] μmol of phenylalanine/min/ideal body weight × 100; P = .40). The pattern of intracellular signaling supported increased breakdown (n = 9, r = −0.83, P = .005) and decreased synthesis (n = 9, r = −0.69, P = .04). CONCLUSIONS AND RELEVANCE: Among these critically ill patients, muscle wasting occurred early and rapidly during the first week of critical illness and was more severe among those with multiorgan failure compared with single organ failure. These findings may provide insights into skeletal muscle wasting in critical illness.

BACKGROUND: Randomised placebo-controlled trials have shown that daily oral pre-exposure prophylaxis (PrEP) with tenofovir-emtricitabine reduces the risk of HIV infection. However, this benefit could be counteracted by risk compensation in users of PrEP. We did the PROUD study to assess this effect. METHODS: PROUD is an open-label randomised trial done at 13 sexual health clinics in England. We enrolled HIV-negative gay and other men who have sex with men who had had anal intercourse without a condom in the previous 90 days. Participants were randomly assigned (1:1) to receive daily combined tenofovir disoproxil fumarate (245 mg) and emtricitabine (200 mg) either immediately or after a deferral period of 1 year. Randomisation was done via web-based access to a central computer-generated list with variable block sizes (stratified by clinical site). Follow-up was quarterly. The primary outcomes for the pilot phase were time to accrue 500 participants and retention; secondary outcomes included incident HIV infection during the deferral period, safety, adherence, and risk compensation. The trial is registered with ISRCTN (number ISRCTN94465371) and ClinicalTrials.gov (NCT02065986). FINDINGS: We enrolled 544 participants (275 in the immediate group, 269 in the deferred group) between Nov 29, 2012, and April 30, 2014. Based on early evidence of effectiveness, the trial steering committee recommended on Oct 13, 2014, that all deferred participants be offered PrEP. Follow-up for HIV incidence was complete for 243 (94%) of 259 patient-years in the immediate group versus 222 (90%) of 245 patient-years in the deferred group. Three HIV infections occurred in the immediate group (1·2/100 person-years) versus 20 in the deferred group (9·0/100 person-years) despite 174 prescriptions of post-exposure prophylaxis in the deferred group (relative reduction 86%, 90% CI 64-96, p=0·0001; absolute difference 7·8/100 person-years, 90% CI 4·3-11·3). 13 men (90% CI 9-23) in a similar population would need access to 1 year of PrEP to avert one HIV infection. We recorded no serious adverse drug reactions; 28 adverse events, most commonly nausea, headache, and arthralgia, resulted in interruption of PrEp. We detected no difference in the occurrence of sexually transmitted infections, including rectal gonorrhoea and chlamydia, between groups, despite a suggestion of risk compensation among some PrEP recipients. INTERPRETATION: In this high incidence population, daily tenofovir-emtricitabine conferred even higher protection against HIV than in placebo-controlled trials, refuting concerns that effectiveness would be less in a real-world setting. There was no evidence of an increase in other sexually transmitted infections. Our findings strongly support the addition of PrEP to the standard of prevention for men who have sex with men at risk of HIV infection. FUNDING: MRC Clinical Trials Unit at UCL, Public Health England, and Gilead Sciences.

BACKGROUND: A simple treatment regimen that is effective in a broad range of patients who are chronically infected with the hepatitis C virus (HCV) remains an unmet medical need. METHODS: We conducted a phase 3, double-blind, placebo-controlled study involving untreated and previously treated patients with chronic HCV genotype 1, 2, 4, 5, or 6 infection, including those with compensated cirrhosis. Patients with HCV genotype 1, 2, 4, or 6 were randomly assigned in a 5:1 ratio to receive the nucleotide polymerase inhibitor sofosbuvir and the NS5A inhibitor velpatasvir in a once-daily, fixed-dose combination tablet or matching placebo for 12 weeks. Because of the low prevalence of genotype 5 in the study regions, patients with genotype 5 did not undergo randomization but were assigned to the sofosbuvir-velpatasvir group. The primary end point was a sustained virologic response at 12 weeks after the end of therapy. RESULTS: Of the 624 patients who received treatment with sofosbuvir-velpatasvir, 34% had HCV genotype 1a, 19% genotype 1b, 17% genotype 2, 19% genotype 4, 6% genotype 5, and 7% genotype 6. A total of 8% of patients were black, 19% had cirrhosis, and 32% had been previously treated for HCV. The rate of sustained virologic response among patients receiving sofosbuvir-velpatasvir was 99% (95% confidence interval, 98 to >99). Two patients receiving sofosbuvir-velpatasvir, both with HCV genotype 1, had a virologic relapse. None of the 116 patients receiving placebo had a sustained virologic response. Serious adverse events were reported in 15 patients (2%) in the sofosbuvir-velpatasvir group and none in the placebo group. CONCLUSIONS: Once-daily sofosbuvir-velpatasvir for 12 weeks provided high rates of sustained virologic response among both previously treated and untreated patients infected with HCV genotype 1, 2, 4, 5, or 6, including those with compensated cirrhosis. (Funded by Gilead Sciences; ClinicalTrials.gov number, NCT02201940.).

Non-motor symptoms (NMS) in Parkinson's disease (PD) are common, significantly reduce quality of life and at present there is no validated clinical tool to assess the progress or potential response to treatment of NMS. A new 30-item scale for the assessment of NMS in PD (NMSS) was developed. NMSS contains nine dimensions: cardiovascular, sleep/fatigue, mood/cognition, perceptual problems, attention/memory, gastrointestinal, urinary, sexual function, and miscellany. The metric attributes of this instrument were analyzed. Data from 242 patients mean age 67.2 +/- 11 years, duration of disease 6.4 +/- 6 years, and 57.3% male across all stages of PD were collected from the centers in Europe, USA, and Japan. The mean NMSS score was 56.5 +/- 40.7, (range: 0-243) and only one declared no NMS. The scale provided 99.2% complete data for the analysis with the total score being free of floor and ceiling effect. Satisfactory scaling assumptions (multitrait scaling success rate >95% for all domains except miscellany) and internal consistency were reported for most of the domains (mean alpha, 0.61). Factor analysis supported the a prori nine domain structure (63% of the variance) while a small test-retest study showed satisfactory reproducibility (ICC > 0.80) for all domains except cardiovascular (ICC = 0.45). In terms of validity, the scale showed modest association with indicators of motor symptom severity and disease progression but a high correlation with other measures of NMS (NMSQuest) and health-related quality of life measure (PDQ-8) (both, rS = 0.70). In conclusion, NMSS can be used to assess the frequency and severity of NMS in PD patients across all stages in conjunction with the recently validated non-motor questionnaire.

BACKGROUND: Psilocybin is being studied for use in treatment-resistant depression. METHODS: In this phase 2 double-blind trial, we randomly assigned adults with treatment-resistant depression to receive a single dose of a proprietary, synthetic formulation of psilocybin at a dose of 25 mg, 10 mg, or 1 mg (control), along with psychological support. The primary end point was the change from baseline to week 3 in the total score on the Montgomery-Åsberg Depression Rating Scale (MADRS; range, 0 to 60, with higher scores indicating more severe depression). Secondary end points included response at week 3 (≥50% decrease from baseline in the MADRS total score), remission at week 3 (MADRS total score ≤10), and sustained response at 12 weeks (meeting response criteria at week 3 and all subsequent visits). RESULTS: A total of 79 participants were in the 25-mg group, 75 in the 10-mg group, and 79 in the 1-mg group. The mean MADRS total score at baseline was 32 or 33 in each group. Least-squares mean changes from baseline to week 3 in the score were -12.0 for 25 mg, -7.9 for 10 mg, and -5.4 for 1 mg; the difference between the 25-mg group and 1-mg group was -6.6 (95% confidence interval [CI], -10.2 to -2.9; P<0.001) and between the 10-mg group and 1-mg group was -2.5 (95% CI, -6.2 to 1.2; P = 0.18). In the 25-mg group, the incidences of response and remission at 3 weeks, but not sustained response at 12 weeks, were generally supportive of the primary results. Adverse events occurred in 179 of 233 participants (77%) and included headache, nausea, and dizziness. Suicidal ideation or behavior or self-injury occurred in all dose groups. CONCLUSIONS: In this phase 2 trial involving participants with treatment-resistant depression, psilocybin at a single dose of 25 mg, but not 10 mg, reduced depression scores significantly more than a 1-mg dose over a period of 3 weeks but was associated with adverse effects. Larger and longer trials, including comparison with existing treatments, are required to determine the efficacy and safety of psilocybin for this disorder. (Funded by COMPASS Pathfinder; EudraCT number, 2017-003288-36; ClinicalTrials.gov number, NCT03775200.).

OBJECTIVE: To update evidence-based medicine recommendations for treating nonmotor symptoms in Parkinson's disease (PD). BACKGROUND: The International Parkinson and Movement Disorder Society Evidence-Based Medicine Committee's recommendations for treatments of PD were first published in 2002, updated in 2011, and now updated again through December 31, 2016. METHODS: Level I studies testing pharmacological, surgical, or nonpharmacological interventions for the treatment of nonmotor symptoms in PD were reviewed. Criteria for inclusion and quality scoring were as previously reported. The disorders covered were a range of neuropsychiatric symptoms, autonomic dysfunction, disorders of sleep and wakefulness, pain, fatigue, impaired olfaction, and ophthalmologic dysfunction. Clinical efficacy, implications for clinical practice, and safety conclusions are reported. RESULTS: A total of 37 new studies qualified for review. There were no randomized controlled trials that met inclusion criteria for the treatment of anxiety disorders, rapid eye movement sleep behavior disorder, excessive sweating, impaired olfaction, or ophthalmologic dysfunction. We identified clinically useful or possibly useful interventions for the treatment of depression, apathy, impulse control and related disorders, dementia, psychosis, insomnia, daytime sleepiness, drooling, orthostatic hypotension, gastrointestinal dysfunction, urinary dysfunction, erectile dysfunction, fatigue, and pain. There were no clinically useful interventions identified to treat non-dementia-level cognitive impairment. CONCLUSIONS: The evidence base for treating a range of nonmotor symptoms in PD has grown substantially in recent years. However, treatment options overall remain limited given the high prevalence and adverse impact of these disorders, so the development and testing of new treatments for nonmotor symptoms in PD remains a top priority. © 2019 International Parkinson and Movement Disorder Society.

BACKGROUND: Non-motor symptoms are detrimental to health-related quality of life (HRQoL) of Parkinson's disease patients. In this study, the Non-Motor Symptoms Scale (NMSS) was used to assess the impact of the non-motor symptoms on HRQoL of Parkinson's disease patients. METHODS: In a multicenter, international, cross sectional study on 411 Parkinson's disease patients, the NMSS was applied along with clinical (Hoehn and Yahr staging and SCOPA-Motor) and HRQoL measures (PDQ-39, and EQ-5D). Prevalence of non-motor symptoms was determined also through the NMSS. The association of NMSS and SCOPA-Motor with HRQoL measures and the differences in HRQoL scores between patients with and without non-motor symptoms in each NMSS domain were estimated by non-parametric statistics. Predictors of HRQoL were sought through multiple linear regression analyses. RESULTS: Nocturia (68.4% of the sample), fatigue (65.9%), and dribbling saliva (56.7%), were the most frequent complaints. Total NMSS score: (1) showed a higher correlation coefficient (r(S) = 0.70) with the PDQ-39 Summary Index (SI) than SCOPA-Motor (r(S) = 0.58); (2) showed high-moderate correlation (r(S) = 0.60 - 0.38) with all PDQ-39 domains; and (3) was the best predictor of HRQoL as measured by the PDQ-39 SI. For each NMSS domain, patients with symptoms had significantly worse HRQoL scores than patients without symptoms. DISCUSSION: To our knowledge, this is the first study to determine in a holistic manner the impact of the non-motor symptoms on HRQoL of Parkinson's disease patients. The results show that non-motor symptoms have, as a whole, a greater impact on HRQoL than motor symptoms and non-motor symptoms progression contributes importantly to HRQoL decline in patients with Parkinson's disease.

BACKGROUND: Irreversible inhibition of Bruton's tyrosine kinase (BTK) by ibrutinib represents an important therapeutic advance for the treatment of chronic lymphocytic leukemia (CLL). However, ibrutinib also irreversibly inhibits alternative kinase targets, which potentially compromises its therapeutic index. Acalabrutinib (ACP-196) is a more selective, irreversible BTK inhibitor that is specifically designed to improve on the safety and efficacy of first-generation BTK inhibitors. METHODS: In this uncontrolled, phase 1-2, multicenter study, we administered oral acalabrutinib to 61 patients who had relapsed CLL to assess the safety, efficacy, pharmacokinetics, and pharmacodynamics of acalabrutinib. Patients were treated with acalabrutinib at a dose of 100 to 400 mg once daily in the dose-escalation (phase 1) portion of the study and 100 mg twice daily in the expansion (phase 2) portion. RESULTS: The median age of the patients was 62 years, and patients had received a median of three previous therapies for CLL; 31% had chromosome 17p13.1 deletion, and 75% had unmutated immunoglobulin heavy-chain variable genes. No dose-limiting toxic effects occurred during the dose-escalation portion of the study. The most common adverse events observed were headache (in 43% of the patients), diarrhea (in 39%), and increased weight (in 26%). Most adverse events were of grade 1 or 2. At a median follow-up of 14.3 months, the overall response rate was 95%, including 85% with a partial response and 10% with a partial response with lymphocytosis; the remaining 5% of patients had stable disease. Among patients with chromosome 17p13.1 deletion, the overall response rate was 100%. No cases of Richter's transformation (CLL that has evolved into large-cell lymphoma) and only one case of CLL progression have occurred. CONCLUSIONS: In this study, the selective BTK inhibitor acalabrutinib had promising safety and efficacy profiles in patients with relapsed CLL, including those with chromosome 17p13.1 deletion. (Funded by the Acerta Pharma and others; ClinicalTrials.gov number, NCT02029443.).

OBJECTIVE: Proton pump inhibitors (PPIs) are drugs used to suppress gastric acid production and treat GI disorders such as peptic ulcers and gastro-oesophageal reflux. They have been considered low risk, have been widely adopted, and are often over-prescribed. Recent studies have identified an increased risk of enteric and other infections with their use. Small studies have identified possible associations between PPI use and GI microbiota, but this has yet to be carried out on a large population-based cohort. DESIGN: We investigated the association between PPI usage and the gut microbiome using 16S ribosomal RNA amplification from faecal samples of 1827 healthy twins, replicating results within unpublished data from an interventional study. RESULTS: We identified a significantly lower abundance in gut commensals and lower microbial diversity in PPI users, with an associated significant increase in the abundance of oral and upper GI tract commensals. In particular, significant increases were observed in Streptococcaceae. These associations were replicated in an independent interventional study and in a paired analysis between 70 monozygotic twin pairs who were discordant for PPI use. We propose that the observed changes result from the removal of the low pH barrier between upper GI tract bacteria and the lower gut. CONCLUSIONS: Our findings describe a significant impact of PPIs on the gut microbiome and should caution over-use of PPIs, and warrant further investigation into the mechanisms and their clinical consequences.

OBJECTIVE: To evaluate the diagnostic accuracy of clinical diagnosis of Parkinson disease (PD) reported in the last 25 years by a systematic review and meta-analysis. METHODS: We searched for articles published between 1988 and August 2014. Studies were included if reporting diagnostic parameters regarding clinical diagnosis of PD or crude data. The selected studies were subclassified based on different study setting, type of test diagnosis, and gold standard. Bayesian meta-analyses of available data were performed. RESULTS: We selected 20 studies, including 11 using pathologic examination as gold standard. Considering only these 11 studies, the pooled diagnostic accuracy was 80.6% (95% credible interval [CrI] 75.2%-85.3%). Accuracy was 73.8% (95% CrI 67.8%-79.6%) for clinical diagnosis performed mainly by nonexperts. Accuracy of clinical diagnosis performed by movement disorders experts rose from 79.6% (95% CrI 46%-95.1%) of initial assessment to 83.9% (95% CrI 69.7%-92.6%) of refined diagnosis after follow-up. Using UK Parkinson's Disease Society Brain Bank Research Center criteria, the pooled diagnostic accuracy was 82.7% (95% CrI 62.6%-93%). CONCLUSION: The overall validity of clinical diagnosis of PD is not satisfying. The accuracy did not significantly improve in the last 25 years, particularly in the early stages of disease, where response to dopaminergic treatment is less defined and hallmarks of alternative diagnoses such as atypical parkinsonism may not have emerged. Misclassification rate should be considered to calculate the sample size both in observational studies and randomized controlled trials. Imaging and biomarkers are urgently needed to improve the accuracy of clinical diagnosis in vivo.

AIMS: This European Association Cardiovascular Imaging (EACVI) Expert Consensus document aims at defining the main quantitative information on cardiac structure and function that needs to be included in standard echocardiographic report following recent ASE/EACVI chamber quantification, diastolic function, and heart valve disease recommendations. The document focuses on general reporting and specific pathological conditions such as heart failure, coronary artery and valvular heart disease, cardiomyopathies, and systemic diseases. METHODS AND RESULTS: Demographic data (age, body surface area, blood pressure, and heart rhythm and rate), type (vendor and model) of ultrasound system used and image quality need to be reported. In addition, measurements should be normalized for body size. Reference normal values, derived by ASE/EACVI recommendations, shall always be reported to differentiate normal from pathological conditions. This Expert Consensus document suggests avoiding the surveillance of specific variable using different ultrasound techniques (e.g. in echo labs with high expertise in left ventricular ejection fraction by 3D and not by 2D echocardiography). The report should be also tailored in relation with different cardiac pathologies, quality of images, and needs of the caregivers. CONCLUSION: The conclusion should be concise reflecting the status of left ventricular structure and function, the presence of left atrial and/or aortic dilation, right ventricular dysfunction, and pulmonary hypertension, leading to an objective communication with the patient health caregiver. Variation over time should be considered carefully, taking always into account the consistency of the parameters used for comparison.

Abstract Medical artificial intelligence (AI) offers great potential for recognizing signs of health conditions in retinal images and expediting the diagnosis of eye diseases and systemic disorders 1 . However, the development of AI models requires substantial annotation and models are usually task-specific with limited generalizability to different clinical applications 2 . Here, we present RETFound, a foundation model for retinal images that learns generalizable representations from unlabelled retinal images and provides a basis for label-efficient model adaptation in several applications. Specifically, RETFound is trained on 1.6 million unlabelled retinal images by means of self-supervised learning and then adapted to disease detection tasks with explicit labels. We show that adapted RETFound consistently outperforms several comparison models in the diagnosis and prognosis of sight-threatening eye diseases, as well as incident prediction of complex systemic disorders such as heart failure and myocardial infarction with fewer labelled data. RETFound provides a generalizable solution to improve model performance and alleviate the annotation workload of experts to enable broad clinical AI applications from retinal imaging.

BackgroundPregnant women with type 1 diabetes are a high-risk population who are recommended to strive for optimal glucose control, but neonatal outcomes attributed to maternal hyperglycaemia remain suboptimal. Our aim was to examine the effectiveness of continuous glucose monitoring (CGM) on maternal glucose control and obstetric and neonatal health outcomes.MethodsIn this multicentre, open-label, randomised controlled trial, we recruited women aged 18–40 years with type 1 diabetes for a minimum of 12 months who were receiving intensive insulin therapy. Participants were pregnant (≤13 weeks and 6 days' gestation) or planning pregnancy from 31 hospitals in Canada, England, Scotland, Spain, Italy, Ireland, and the USA. We ran two trials in parallel for pregnant participants and for participants planning pregnancy. In both trials, participants were randomly assigned to either CGM in addition to capillary glucose monitoring or capillary glucose monitoring alone. Randomisation was stratified by insulin delivery (pump or injections) and baseline glycated haemoglobin (HbA1c). The primary outcome was change in HbA1c from randomisation to 34 weeks' gestation in pregnant women and to 24 weeks or conception in women planning pregnancy, and was assessed in all randomised participants with baseline assessments. Secondary outcomes included obstetric and neonatal health outcomes, assessed with all available data without imputation. This trial is registered with ClinicalTrials.gov, number NCT01788527.FindingsBetween March 25, 2013, and March 22, 2016, we randomly assigned 325 women (215 pregnant, 110 planning pregnancy) to capillary glucose monitoring with CGM (108 pregnant and 53 planning pregnancy) or without (107 pregnant and 57 planning pregnancy). We found a small difference in HbA1c in pregnant women using CGM (mean difference −0·19%; 95% CI −0·34 to −0·03; p=0·0207). Pregnant CGM users spent more time in target (68% vs 61%; p=0·0034) and less time hyperglycaemic (27% vs 32%; p=0·0279) than did pregnant control participants, with comparable severe hypoglycaemia episodes (18 CGM and 21 control) and time spent hypoglycaemic (3% vs 4%; p=0·10). Neonatal health outcomes were significantly improved, with lower incidence of large for gestational age (odds ratio 0·51, 95% CI 0·28 to 0·90; p=0·0210), fewer neonatal intensive care admissions lasting more than 24 h (0·48; 0·26 to 0·86; p=0·0157), fewer incidences of neonatal hypoglycaemia (0·45; 0·22 to 0·89; p=0·0250), and 1-day shorter length of hospital stay (p=0·0091). We found no apparent benefit of CGM in women planning pregnancy. Adverse events occurred in 51 (48%) of CGM participants and 43 (40%) of control participants in the pregnancy trial, and in 12 (27%) of CGM participants and 21 (37%) of control participants in the planning pregnancy trial. Serious adverse events occurred in 13 (6%) participants in the pregnancy trial (eight [7%] CGM, five [5%] control) and in three (3%) participants in the planning pregnancy trial (two [4%] CGM and one [2%] control). The most common adverse events were skin reactions occurring in 49 (48%) of 103 CGM participants and eight (8%) of 104 control participants during pregnancy and in 23 (44%) of 52 CGM participants and five (9%) of 57 control participants in the planning pregnancy trial. The most common serious adverse events were gastrointestinal (nausea and vomiting in four participants during pregnancy and three participants planning pregnancy).InterpretationUse of CGM during pregnancy in patients with type 1 diabetes is associated with improved neonatal outcomes, which are likely to be attributed to reduced exposure to maternal hyperglycaemia. CGM should be offered to all pregnant women with type 1 diabetes using intensive insulin therapy. This study is the first to indicate potential for improvements in non-glycaemic health outcomes from CGM use.FundingJuvenile Diabetes Research Foundation, Canadian Clinical Trials Network, and National Institute for Health Research.

The guideline group was selected to be representative of UK-based aplastic anaemia (AA) medical experts. Recommendations are based on review of the literature using MEDLINE and PUBMED up to December 2014 under the heading: ‘aplastic anemia’. The Grading of Recommendations Assessment, Development and Evaluation (GRADE) nomenclature was used to evaluate levels of evidence and to assess the strength of recommendations. The GRADE criteria are specified in the BCSH guidance pack http://www.bcshguidelines.com/BCSH_PROCESS/EVIDENCE_LEVELS_AND_GRADES_OF_RECOMMENDATION/43_GRADE.html and the GRADE working group website http://www.gradeworkinggroup.org The objective of this guideline is to provide healthcare professionals with clear guidance on the management of patients with AA. The guidance may not be appropriate to every patient and in all cases individual patient circumstances may dictate an alternative approach. Review of the manuscript was performed by the British Committee for Standards in Haematology (BCSH) Haemato-Oncology Task Force, BCSH Executive Committee and then reviewed by a sounding board of the British Society for Haematology (BSH). This compromises 50 or more members of the BSH who have reviewed this guidance and commented on its content and applicability in the UK setting. It has also been reviewed by the Aplastic Anaemia Trust patient group but they do not necessarily approve or endorse the contents. Aplastic anaemia is a rare and heterogeneous disorder. It is defined as pancytopenia with a hypocellular bone marrow in the absence of an abnormal infiltrate or marrow fibrosis. To diagnose AA there must be at least two of the following (Camitta et al, 1975) haemoglobin concentration (Hb) <100 g/l, platelet count <50 × 109/l, neutrophil count <1·5 × 109/l. The majority (70-80%) of cases are idiopathic (Marsh et al, 2009). The remainder mainly consist of IBMFS. The incidence is 2-3 per million per year in Europe, but higher in East Asia (Montane et al, 2008). There is a biphasic distribution, with peaks at 10-25 years and over 60 years. AA not fulfilling the criteria for SAA or VSAA Patients commonly present with symptoms of anaemia and thrombocytopenia. Serious infection is not a frequent symptom early in the course of the disease. A preceding history of jaundice may suggest a post-hepatitic AA. Whilst the majority of cases are idiopathic, a careful drug, occupational exposure and family history should be obtained. Any putative drugs should be discontinued and the patient should not be re-challenged. If a possible drug association is suspected, this must be reported to the Medicines and MHRA using the Yellow Card Scheme (http://yellowcard.gov.uk). There is usually no hepatosplenomegaly or lymphadenopathy (except in infection). In young adults the presence of short stature, skin hyper/hypo pigmented areas and skeletal abnormalities, particularly affecting the thumb is suggestive of FA (Shimamura & Alter, 2010). The triad of nail dystrophy, reticular skin pigmentation and oral leucoplakia is characteristic of dyskeratosis congenita (DC) (Shimamura & Alter, 2010). The finding of peripheral lymphoedema may indicate a diagnosis of Emberger syndrome due to germline GATA2 mutation. See Table 1 for the summary of investigations for the diagnosis and further evaluation of AA; this table also summarizes the emerging diagnostics incorporating the latest molecular technologies that are likely to feature in the diagnosis and differential diagnosis within the next couple of years. Both a bone marrow aspirate and trephine biopsy are required for the diagnosis of AA, and the key bone marrow findings are summarized in Table 2. Karyotyping may fail in very hypocellular marrows with there being insufficient metaphases. In this situation perform FISH analysis for chromosomes 5, 7, 8 and 13 It was previously assumed that the presence of an abnormal cytogenetic clone indicated a diagnosis of MDS and not AA. However it is now evident that abnormal cytogenetic clones [such as del(13q), trisomy 8 and others], which may be transient, are present in up to 12% of patients with otherwise typical AA at diagnosis (Gupta et al, 2006; Afable et al, 2011b). Although monosomy 7 may indicate the likelihood of MDS in children, in adults monosomy 7 can also be seen in AA. Abnormal cytogenetic clones may arise during the course of the disease and the appearance of a new cytogenetic abnormality may provide evidence of clonal evolution (Maciejewski et al, 2002) The investigations in Table 1 should exclude non-AA causes of pancytopenia with a hypocellular bone marrow, which are listed in Table 3. A MDT meeting approach is recommended to collate relevant results and develop a treatment plan. Consideration should be given for seeking expert advice on the diagnosis and management of patients where there is uncertainty, or when an IBMFS is being considered. A number of inherited/genetic disorders are characterized by BMF/AA, usually in association with one or more somatic abnormality (Alter, 2007). The BMF typically presents in childhood but this can sometimes be in adulthood. The two syndromes frequently associated with generalized BMF/AA are FA and DC (Dokal, 2011; Soulier, 2011), which can sometimes present with AA alone as their initial manifestation. These syndromes are genetically heterogeneous; 16 FA genes and 10 DC genes have been identified. The FA genes are important in DNA repair, the DC genes in telomere maintenance. Based on the DNA repair defect a diagnostic test-‘chromosomal breakage test’ is available for FA. Patients with DC usually have very short telomeres and this measurement [using flow cytometric fluorescence in situ hybridization or multiplex quantitative polymerase chain reaction (PCR)] can be useful in the assessment of DC. Genetic testing for known DC genes (representing c. 60% of cases) is possible in specialized centres. In addition there are other genetic syndromes that are sometimes associated with AA/cytopenias. This includes Shwachman‒Diamond syndrome ‒ SDS (Dror et al, 2011) (mutations in SBDS), congenital amegakaryocytic thrombocytopenia ‒ CAMT (Ballmaier & Germeshausen, 2011) (mutations in MPL) and GATA2 deficiency (Emberger syndrome) (Horwitz, 2014) as well as genetically uncharacterized cases. Some cases of inherited AA first present in adulthood and it is important to recognize these as their management differs from that of idiopathic AA. Where there are sufficient characteristic abnormalities a diagnosis may be straightforward (e.g. mucocutaneous features in DC). Where the presentation is only with AA and with minimal non-haematological abnormalities, inherited BMF should be considered and testing for known BMF syndromes should be undertaken. Investigations for inherited forms of AA should be re-appraised in patients initially classified as “idiopathic AA” and who fail to respond to anti-thymocyte globulin (ATG). For most patients with AA, transfusion with red blood cells (RBC) is essential to maintain a safe blood count, improve symptoms of anaemia and maintain quality of life. The decision to transfuse RBC should be based on clinical symptoms (signs of anaemia), taking into consideration the patient's age and co-morbidities (cardiac, pulmonary or vascular). Although no specific pre-transfusion haemoglobin concentration (Hb) trigger can be recommended, it is important to maintain quality of life and avoid symptoms. A higher trigger may be needed for elderly patients and those with co-morbidities. Optimal use of RBC transfusion involves administration of enough red cells to maximize clinical outcome whilst avoiding unnecessary transfusions (Carson et al, 2012). Alloimmunization against red cell antigens and iron overload are the commonest risks associated with regular transfusion therapy. Provision of phenotype-matched blood (for Rh and Kell) should be considered to reduce the risk of alloimmunization. Regular platelet transfusion support may be required for AA patients. With the exception of one publication (Sagmeister et al, 1999), literature specific to platelet transfusion support in AA is lacking, and evidence is taken from studies addressing the need for platelet transfusion support in patients with reversible thrombocytopenia (Estcourt et al, 2012; Stanworth et al, 2013; Killick et al, 2014). It is recommended that prophylactic platelet transfusions should be given to stable AA patients on active therapy (where the treatment aims to reverse the severe thrombocytopenia) with a platelet count <10 × 109/l. For patients with sepsis, the platelet count should be kept >20 × 109/l. For thrombocytopenic patients requiring invasive procedures, platelet transfusions must be administered, aiming to achieve a platelet count in line with BCSH guidelines for the relevant procedures (British Committee for Standards in Haematology, 2003), and a pre-procedure platelet count should be checked. During treatment with ATG, worsening thrombocytopenia can occur. This is due to increased platelet consumption in the presence of cross-reacting antibodies in ATG binding to platelets. Although there are no studies to support the exact threshold for platelet transfusion support prior to ATG, most authors use a threshold of 20 × 109/l (Scheinberg et al, 2011; Scheinberg & Young, 2012). Regular support with RBC and platelet transfusions increases the risk of HLA and non-HLA (minor histocompatibility) alloimmunization, leading to poor platelet increments and increased risk of graft rejection after HSCT. Leucodepletion of cellular blood components may reduce, but not eliminate, alloimmunization (Killick et al, 1997; Desmarets et al, 2009). The possibility of HLA alloimmunization and provision of HLA-selected platelets should be considered for patients refractory to platelet transfusion, provided other causes of refractoriness have been excluded. In the absence of HLA antibodies and for patients failing to increment with HLA-matched platelets, investigation and matching for human platelet antigen antibodies should be considered. The use of irradiated granulocytes should be considered in patients with life-threatening infection related to severe neutropenia (Quillen et al, 2009), and anecdotally may be life saving. Data about the effectiveness of granulocyte concentrates are limited and usage is linked with a number of adverse events, such as transfusion-related acute lung injury, alloimmunization and febrile reactions. Irradiation of cellular blood components prevents transfusion-associated graft-versus-host disease (TA-GVHD). This is a rare complication of blood transfusion with 100% mortality. Irradiation may also reduce the risk of alloimmunization in AA, as reported from animal data (Bean et al, 1994). Following universal leucodepletion in the UK, the Committee on the of and no the use of blood components they have been for patients with and those should be considered To there has not been a from the British Society of blood and granulocyte components should be provided for Aplastic anaemia patients on regular RBC transfusion support develop iron but there on the clinical of iron In the of a is an adverse of outcome in cell et al, 2007). Although the most for assessment of iron or can and and is a useful its in AA has not been There are data iron therapy in AA. A was the Evaluation of with et al, 2010). This that with can be in patients with AA and can reduce the are required to those who are transfusion is with and the drug should be used with in AA patients who are taking is for use in but only as line therapy when is or is but not recommended in patients et al, For those to or after a is recommended for iron the of in AA (Marsh & In to patients in SAA neutropenia is and in a higher incidence of invasive infection and severe of to ATG in the two has and this has in with and of et al, Aplastic anaemia patients who are should be in when in In the UK it is to prophylactic and regular an as or and of content et al, two (e.g. and or (e.g. may be but the should be to A active or should be used as In the UK, against is not in patients with AA is not with or should be used during and after ATG therapy. During ATG of and is but and not need disease has only very been reported after ATG, most after It is not UK to with and guidelines for the management of febrile the assessment and management of are well and should and for and guidance et al, 2012). as per should be early for patients with as these patients have transfusions may be life in severe sepsis, such as invasive particularly for patients due to to (Quillen et al, 2009). such as and granulocyte are usually in blood in AA patients (Marsh et al, results are reported with the et al, also on of AA in the first line is the of ATG and ATG is no available (Marsh et al, & Scheinberg & Young, 2012). A from the of and a at and and with ATG to ATG for first line (Scheinberg et al, 2011; et al, 2012). There is no for use of with ATG et al, is used with ATG for the of of of There is no age for ATG, but there is increased in patients years with ATG et al, 2011) on of AA in the A course of ATG may be indicated for to respond or after a first course or the patient is for (Marsh et al, & Scheinberg & Young, For a ATG may be A course of ATG is an alternative but this may be associated with more and (Marsh et al, 2012). to ATG, ATG more and in more It is important to that patients prophylactic support when using The of ATG is for It is given as an over to the risk of a must be is to use an of the SAA data the first of the first is given over 1 ATG should be given a or other as it is to peripheral and also for of administration of other drugs and blood of ATG should be with 1 and platelet transfusions aiming to the platelet count × 109/l (Marsh et al, Scheinberg & Young, 2012). to should be given for febrile of the neutrophil commonly during ATG in careful to is is on the after ATG is at a of 1 for by over the should be as the is at a of to achieve blood levels of should be whilst the blood count to A of the drug every can be after at least a further of to reduce the risk of et al, of ATG are early acute pulmonary syndrome and and from the of ATG, most commonly with and is with a and it usually a of platelet transfusions are needed during the of due to platelet There is no for using with ATG as studies have that given for after ATG not improve or et al, to ATG defined in Table is after an of The to a first course of ATG is is 100% for age for for years and for years et al, In the to a first course of ATG is only with (Scheinberg et al, 2011; et al, 2012; Scheinberg & Young, 2012). For ATG results in higher to alone (Marsh et al, after ATG in up to of the risk of clonal evolution to is and in et al, Scheinberg & Young, 2012). previously or or of at least one cell line or of to a course of ATG from most studies is for refractory AA and for AA (Marsh et al, & Scheinberg & Young, 2012). for are summarized in Table It is recommended that expert advice be when the use of other and are not recommended in the treatment of AA Table There is a risk of AA following in those patients who have to The evidence is limited and based on as well as an that a is likely to be an important trigger in the of AA et al, et al, should be following when AA patients should be as recommended for all bone marrow The for are based on the guidelines et al, Patients should be in Society for and centres. from a is indicated for SAA in young and patients who have a data for patients to those years et al, co-morbidities should be to for of for patients years. is indicated for SAA after to respond to one course of There is no age but this should be on an individual patient and to co-morbidities at the The should be or based on HLA for and using a family or a may be other treatment after to respond to and in the absence of a and a et al, 2012; & should be for HLA the presence of which is associated with a very risk of graft There is clear guidance on the exact for alternative as this is or but new to alternative are being using In the rare situation where there is a should be considered in all patients of age as (Marsh & For all AA patients who may be HLA should be performed at of that can as as and the patient not only to HLA but also to and the of is that there is no to a course of ATG and the patient can then to the patient's is of with severe for to is usually at MDT approach is essential for the The aims of the up are to the diagnosis and clonal evolution assess co-morbidities the cell and and the transfusion of the and review of transfusion The of to use on patient age of for of ATG et al, et al, 2011) or (Marsh et al, 2011; et al, 2012). See Table For the is but is the of and 50 years. A analysis has that after are no to in that is not a of et al, 2013; et al, 2014). to AA early management and management of are summarized in Table The treatment of elderly patients with AA is more in patients. In the outcome is due to of the patients should be for co-morbidities and their specific should be as quality of life is an important outcome in this With to it is important to exclude as MDS is more AA in this age group diagnostic age per is not a to treatment in the very is considered the treatment of There is no for as first line therapy in patients can be considered in selected patients with a the least and most treatment should be consideration is a is such that those with life count × or a severe infection requiring should be more those with severe disease. with ATG and results in a more and alone in patients with (Marsh et al, patients and have a higher risk of acute and the risks and of treatment should be up for individual Patients must be as the risk of and with ATG is higher in the patients have an after ATG to patients et al, or Although the of alone is to the of ATG and in is not as patients may respond to line therapy with ATG and (Marsh et al, alone has the of being but patients must be for and may be used as a in AA, but medical very careful assessment in patients prior to this as a possible (Scheinberg et al, 2012). or can be considered in or to et al, et al, has may be a alternative for of is required as it can and blood Patients who are or who should be is a oral In an of an at patients with refractory SAA with et al, 2014). in of patients. The drug was well in most patients. levels may and there are about clonal monosomy 7, which further has been by the and in the for treatment of SAA refractory to It has as of been by the for SAA refractory to or patients who are and for HSCT. It should be used with for clonal or following a clinical It is that a bone marrow is performed prior to treatment to exclude an abnormal cytogenetic clone typical of particularly monosomy Although the or AA and is it a to and with a clinical AA can be for the first during in early or during but the disease may after or or after et al, is during in AA patients who have previously to ATG, those with et al, not trigger of the disease in patients who HSCT. et in previously with for AA. reported a complication in the two cases of and of AA in and a further needed transfusion during blood not from of AA during in particularly in of blood has to in and outcome et al, it is important to with the patient and family the risks to the and et al, It is essential that the patient be frequently initially but more frequently and to disease and with very with the and of a clone should with a The of should be on is the of treatment of AA in and the platelet count be 20 × 109/l with platelet The risk of alloimmunization and platelet refractoriness to be considered. is safe during & and is recommended for those ATG, or for AA during are not should be by flow et al, et al, 2010). of is a and quantitative for the of clones which in up to of AA the on the of the flow cytometric analysis used et al, et al, clones are most in the neutrophil and in AA and be by flow If the patient has a blood transfusion, a of red cells may be by flow in the granulocyte and the clinical of a clone in AA as by flow clones can in or the need for the is important is the presence of a clone associated with clinical or evidence of should be for as this is a feature of when the patient not have of associated with should be with the count, and Patients should be for at the diagnosis of AA. If for years and then to testing If the or for the first years and only reduce the the of the cells has The presence of a clone in the of AA not the of therapy for the There is evidence that the finding of a clone a to but this is not universal in all Patients with a clone ATG, should be for of AA may in patients in the presence of patients should be to one of the two specialized and to be for and for consideration for following MDT Patients be seen in of the two or in one of 10 Data from the to the that cell has an outcome in and to when indicated et al, 2012). the finding of a clone not or on the decision to the advice and in these guidelines is to be and at the of to the the British Committee for Standards in Haematology (BCSH) the for the content of these These guidelines are only to patients with AA. to and for their review of this The authors to the BCSH and the BSH sounding BCSH and the Aplastic Trust for their support in these the guidelines was the authors in and of the authors the of the authors have a of to the BCSH and Task which may be reviewed on In summary the following authors have the following of has from for at and from for at and has from has from for has from for at has from and has from has from and and have from for The of the authors have no of of the group the group new evidence available that the strength of the in this or it The be and from the BCSH guidelines website it If new are an be on the BCSH guidelines website at If are required due to in of evidence or evidence a new of the guidance be on the BCSH

BACKGROUND: Initiation of antiretroviral therapy (ART) often leads to weight gain. While some of this weight gain may be an appropriate return-to-health effect, excessive increases in weight may lead to obesity. We sought to explore factors associated with weight gain in several randomized comparative clinical trials of ART initiation. METHODS: We performed a pooled analysis of weight gain in 8 randomized controlled clinical trials of treatment-naive people living with human immunodeficiency virus (HIV) initiating ART between 2003 and 2015, comprising >5000 participants and 10 000 person-years of follow-up. We used multivariate modeling to explore relationships between demographic factors, HIV disease characteristics, and ART components and weight change following ART initiation. RESULTS: Weight gain was greater in more recent trials and with the use of newer ART regimens. Pooled analysis revealed baseline demographic factors associated with weight gain including lower CD4 cell count, higher HIV type 1 RNA, no injection drug use, female sex, and black race. Integrase strand transfer inhibitor use was associated with more weight gain than were protease inhibitors or nonnucleoside reverse transcriptase inhibitors (NNRTIs), with dolutegravir and bictegravir associated with more weight gain than elvitegravir/cobicistat. Among the NNRTIs, rilpivirine was associated with more weight gain than efavirenz. Among nucleoside/nucleotide reverse transcriptase inhibitors, tenofovir alafenamide was associated with more weight gain than tenofovir disoproxil fumarate, abacavir, or zidovudine. CONCLUSIONS: Weight gain is ubiquitous in clinical trials of ART initiation and is multifactorial in nature, with demographic factors, HIV-related factors, and the composition of ART regimens as contributors. The mechanisms by which certain ART agents differentially contribute to weight gain are unknown.

Vaccines based on the spike protein of SARS-CoV-2 are a cornerstone of the public health response to COVID-19. The emergence of hypermutated, increasingly transmissible variants of concern (VOCs) threaten this strategy. Omicron (B.1.1.529), the fifth VOC to be described, harbours multiple amino acid mutations in spike, half of which lie within the receptor-binding domain. Here we demonstrate substantial evasion of neutralization by Omicron BA.1 and BA.2 variants in vitro using sera from individuals vaccinated with ChAdOx1, BNT162b2 and mRNA-1273. These data were mirrored by a substantial reduction in real-world vaccine effectiveness that was partially restored by booster vaccination. The Omicron variants BA.1 and BA.2 did not induce cell syncytia in vitro and favoured a TMPRSS2-independent endosomal entry pathway, these phenotypes mapping to distinct regions of the spike protein. Impaired cell fusion was determined by the receptor-binding domain, while endosomal entry mapped to the S2 domain. Such marked changes in antigenicity and replicative biology may underlie the rapid global spread and altered pathogenicity of the Omicron variant.

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OBJECTIVE: To develop and validate new classification criteria for adult and juvenile idiopathic inflammatory myopathies (IIM) and their major subgroups. METHODS: Candidate variables were assembled from published criteria and expert opinion using consensus methodology. Data were collected from 47 rheumatology, dermatology, neurology, and pediatric clinics worldwide. Several statistical methods were utilized to derive the classification criteria. RESULTS: Based on data from 976 IIM patients (74% adults; 26% children) and 624 non-IIM patients with mimicking conditions (82% adults; 18% children), new criteria were derived. Each item is assigned a weighted score. The total score corresponds to a probability of having IIM. Subclassification is performed using a classification tree. A probability cutoff of 55%, corresponding to a score of 5.5 (6.7 with muscle biopsy) "probable IIM," had best sensitivity/specificity (87%/82% without biopsies, 93%/88% with biopsies) and is recommended as a minimum to classify a patient as having IIM. A probability of ≥90%, corresponding to a score of ≥7.5 (≥8.7 with muscle biopsy), corresponds to "definite IIM." A probability of <50%, corresponding to a score of <5.3 (<6.5 with muscle biopsy), rules out IIM, leaving a probability of ≥50-<55% as "possible IIM." CONCLUSION: The European League Against Rheumatism/American College of Rheumatology (EULAR/ACR) classification criteria for IIM have been endorsed by international rheumatology, dermatology, neurology, and pediatric groups. They employ easily accessible and operationally defined elements, and have been partially validated. They allow classification of "definite," "probable," and "possible" IIM, in addition to the major subgroups of IIM, including juvenile IIM. They generally perform better than existing criteria.