Anomalies in the review process and interpretation of the evidence in the NICE guideline for chronic fatigue syndrome and myalgic encephalomyelitis.

Chronic fatigue syndrome/myalgic encephalomyelitis (CFS/ME) is a disabling long-term condition of unknown cause. The National Institute for Health and Care Excellence (NICE) published a guideline in 2021 that highlighted the seriousness of the condition, but also recommended that graded exercise therapy (GET) should not be used and cognitive-behavioural therapy should only be used to manage symptoms and reduce distress, not to aid recovery. This U-turn in recommendations from the previous 2007 guideline is controversial.We suggest that the controversy stems from anomalies in both processing and interpretation of the evidence by the NICE committee. The committee: (1) created a new definition of CFS/ME, which 'downgraded' the certainty of trial evidence; (2) omitted data from standard trial end points used to assess efficacy; (3) discounted trial data when assessing treatment harm in favour of lower quality surveys and qualitative studies; (4) minimised the importance of fatigue as an outcome; (5) did not use accepted practices to synthesise trial evidence adequately using GRADE (Grading of Recommendations, Assessment, Development and Evaluations trial evidence); (6) interpreted GET as mandating fixed increments of change when trials defined it as collaborative, negotiated and symptom dependent; (7) deviated from NICE recommendations of rehabilitation for related conditions, such as chronic primary pain and (8) recommended an energy management approach in the absence of supportive research evidence.We conclude that the dissonance between this and the previous guideline was the result of deviating from usual scientific standards of the NICE process. The consequences of this are that patients may be denied helpful treatments and therefore risk persistent ill health and disability.

An integrated model of care for neurological infections: the first six years of referrals to a specialist service at a university teaching hospital in Northwest England.

BACKGROUND: A specialist neurological infectious disease service has been run jointly by the departments of infectious disease and neurology at the Royal Liverpool University Hospital since 2005. We sought to describe the referral case mix and outcomes of the first six years of referrals to the service. METHODS: Retrospective service review. RESULTS: Of 242 adults referred to the service, 231 (95%) were inpatients. Neurological infections were confirmed in 155 (64%), indicating a high degree of selection before referral. Viral meningitis (35 cases), bacterial meningitis (33) and encephalitis (22) accounted for 38% of referrals and 61% of confirmed neurological infections. Although an infrequent diagnosis (n = 19), neurological TB caused the longest admission (median 23, range 5-119 days). A proven or probable microbiological diagnosis was found in 100/155 cases (64.5%). For the whole cohort, altered sensorium, older age and longer hospital stay were associated with poor outcome (death or neurological disability); viral meningitis was associated with good outcome. In multivariate analysis altered sensorium remained significantly associated with poor outcome, adjusted odds ratio 3.04 (95% confidence interval 1.28-7.22, p = 0.01). CONCLUSIONS: A service of this type provides important specialist care and a focus for training and clinical research on complex neurological infections.

Less than full-time training (LTFT), is this the new norm? A cross-sectional study using a UK-wide online survey to evaluate trainees' views and intentions for LTFT.

OBJECTIVES: Interest in less than full-time training (LTFT) is growing among doctors in training. LTFT applications have previously been limited to fulfilment of specific criteria such as childcare or health reasons, but Health Education for England (HEE) has recently completed a pilot into LTFT for a third category: lifestyle choice. This was recognised as an opportunity to canvas trainee perspectives and intentions on LTFT and implications for workforce planning. DESIGN: A cross-sectional study of UK trainees via an online questionnaire. SETTING/PARTICIPANTS: The survey was distributed via email to trainees in all specialities and stages of training across the UK. The survey focused on three key themes: experiences of current LTFT trainees, perspectives of trainees considering LTFT in the future and experience of working with LTFT colleagues. RESULTS: Responses were received from 783 trainees across the UK, with most responses received from physician trainees (76%). Current LTFT trainees represented one-third of respondents. Of those not currently working LTFT, 75% expressed an intention to do so in future with lifestyle being the most common reason. Almost half of this group were concerned about the impact on their training. Stigma, reduced training opportunities, prolonged training and the application process were commonly cited barriers. These difficulties were experienced by several current LTFT trainees, 32% of whom described a negative impact on their training. Almost two-thirds (62%) of respondents stated they wish to work LTFT as a consultant. CONCLUSION: Systems must adapt to increase access to LTFT training to promote trainee well-being and retention. Progress is being made and we suggest HEE's category three pilot be rolled out across the UK as a priority. Workforce planning needs to consider the substantial rise in popularity of LTFT among trainees to offset any shortfalls in the present and future workforce.

Viral capture sequencing detects unexpected viruses in the cerebrospinal fluid of adults with meningitis.

OBJECTIVES: Many patients with meningitis have no aetiology identified leading to unnecessary antimicrobials and prolonged hospitalisation. We used viral capture sequencing to identify possible pathogenic viruses in adults with community-acquired meningitis. METHODS: Cerebrospinal fluid (CSF) from 73 patients was tested by VirCapSeq-VERT, a probe set designed to capture viral targets using high throughput sequencing. Patients were categorised as suspected viral meningitis - CSF pleocytosis, no pathogen identified (n = 38), proven viral meningitis - CSF pleocytosis with a pathogen identified (n = 15) or not meningitis - no CSF pleocytosis (n = 20). RESULTS: VirCapSeq-VERT detected virus in the CSF of 16/38 (42%) of those with suspected viral meningitis, including twelve individual viruses. A potentially clinically relevant virus was detected in 9/16 (56%). Unexpectedly Toscana virus, rotavirus and Saffold virus were detected and assessed to be potential causative agents. CONCLUSION: VirCapSeq-VERT increases the probability of detecting a virus. Using this agnostic approach we identified Toscana virus and, for the first time in adults, rotavirus and Saffold virus, as potential causative agents in adult meningitis. Further work is needed to determine the prevalence of atypical viral candidates as well as the clinical impact of using sequencing methods in real time. This knowledge can help to reduce antimicrobial use and hospitalisations leading to both patient and health system benefits.

Effect of delayed lumbar punctures on the diagnosis of acute bacterial meningitis in adults.

INTRODUCTION: Bacterial meningitis is a medical emergency, the outcome of which is improved by prompt antibiotic treatment. For patients with suspected meningitis and no features of severe disease, the British Infection Society recommends immediate lumbar puncture (LP) before antibiotics, to maximise the chance of a positive cerebrospinal (CSF) culture. In such patients, CT scanning before LP is not needed. METHODS: The case notes of adults with meningitis admitted to a large district general hospital over 3 years were reviewed. Patients were classified as Likely Bacterial Meningitis or Likely Viral Meningitis based on their CSF and peripheral blood results using the Meningitest Criteria, with microbiological and virological confirmation. RESULTS: Of 92 patients studied, 24 had Likely Bacterial Meningitis, including 16 with microbiologically confirmed disease (none had PCR tests for bacteria). Sixty-eight had Likely Viral Meningitis, four of whom had viral PCR, including one with herpes simplex virus. No patient had an LP before antibiotics. CSF culture was positive for eight (73%) of the 11 patients who had an LP up to 4 h after starting antibiotics, compared with eight (11%) of 71 patients with a later LP (p<0.001). None of the 34 LPs performed more than 8 h after antibiotics was culture-positive. For 62 (67%) of the 92 patients, the delay was due to a CT scan, although only 20 of these patients had a contraindication to an immediate LP. CONCLUSIONS: Too many patients with acute bacterial meningitis are being sent for unnecessary CT scans, causing delays in the LP, and reducing the chances of a positive CSF culture after starting antibiotics. However, even if antibiotics have been started, an LP within 4 h is still likely to be positive. Molecular tests for diagnosis should also be requested.

Quality criteria for Core Medical Training: a resume of their development, impact and future plans.

BACKGROUND: In 2015 the Joint Royal Colleges of Physicians Training Board (JRCPTB), acting on behalf of the three UK Royal Colleges of Physicians, launched a set of quality criteria designed to improve the educational experience of Core Medical Trainees. METHODS: The criteria were developed with key stakeholders from Core Medical Training (CMT) and monitored via the General Medical Council's annual National Training Survey. This paper describes the development, implementation and impact of these criteria, which have been implemented by UK postgraduate schools of medicine since 2015. RESULTS: There were trainee-reported improvements from baseline (2015-18) in at least eight out of the 13 core criteria measured. CONCLUSIONS: The results demonstrate that a coordinated UK-wide approach to quality improvement, focused on a specific set of clearly defined and measurable outcomes that galvanise trainer engagement, can lead to greater trainee satisfaction in a demanding area of medicine without significant additional resources.

The future of internal medicine: a new curriculum for 2019.

A new 3-year curriculum for training in internal medicine was approved by the General Medical Council in December 2017. This will replace core medical training in August 2019. It mandates specific experiences and introduces a novel assessment strategy that hopefully will lessen the perceived 'burden of assessment' on trainees (and trainers). It is hoped that it will improve the experience of and enthusiasm for training in internal medicine.

Incidence, aetiology, and sequelae of viral meningitis in UK adults: a multicentre prospective observational cohort study.

BACKGROUND: Viral meningitis is increasingly recognised, but little is known about the frequency with which it occurs, or the causes and outcomes in the UK. We aimed to determine the incidence, causes, and sequelae in UK adults to improve the management of patients and assist in health service planning. METHODS: We did a multicentre prospective observational cohort study of adults with suspected meningitis at 42 hospitals across England. Nested within this study, in the National Health Service (NHS) northwest region (now part of NHS England North), was an epidemiological study. Patients were eligible if they were aged 16 years or older, had clinically suspected meningitis, and either underwent a lumbar puncture or, if lumbar puncture was contraindicated, had clinically suspected meningitis and an appropriate pathogen identified either in blood culture or on blood PCR. Individuals with ventricular devices were excluded. We calculated the incidence of viral meningitis using data from patients from the northwest region only and used these data to estimate the population-standardised number of cases in the UK. Patients self-reported quality-of-life and neuropsychological outcomes, using the EuroQol EQ-5D-3L, the 36-Item Short Form Health Survey (SF-36), and the Aldenkamp and Baker neuropsychological assessment schedule, for 1 year after admission. FINDINGS: 1126 patients were enrolled between Sept 30, 2011, and Sept 30, 2014. 638 (57%) patients had meningitis: 231 (36%) cases were viral, 99 (16%) were bacterial, and 267 (42%) had an unknown cause. 41 (6%) cases had other causes. The estimated annual incidence of viral meningitis was 2·73 per 100 000 and that of bacterial meningitis was 1·24 per 100 000. The median length of hospital stay for patients with viral meningitis was 4 days (IQR 3-7), increasing to 9 days (6-12) in those treated with antivirals. Earlier lumbar puncture resulted in more patients having a specific cause identified than did those who had a delayed lumbar puncture. Compared with the age-matched UK population, patients with viral meningitis had a mean loss of 0·2 quality-adjusted life-years (SD 0·04) in that first year. INTERPRETATION: Viruses are the most commonly identified cause of meningitis in UK adults, and lead to substantial long-term morbidity. Delays in getting a lumbar puncture and unnecessary treatment with antivirals were associated with longer hospital stays. Rapid diagnostics and rationalising treatments might reduce the burden of meningitis on health services. FUNDING: Meningitis Research Foundation and UK National Institute for Health Research.

Destabilizing role of cathepsin S in murine atherosclerotic plaques.

OBJECTIVE: Lysosomal proteinases have been implicated in a number of pathologies associated with extracellular matrix breakdown. Therefore, we investigated the possibility that the lysosomal proteinase cathepsin S may be involved in atherosclerotic plaque destabilization. METHODS AND RESULTS: Atherosclerotic plaques in the brachiocephalic arteries of fat-fed apolipoprotein E/cathepsin S double knockout mice had 73% fewer acute plaque ruptures (P=0.026) and were 46% smaller (P=0.025) than those in age-, strain-, and sex-matched apolipoprotein E single knockout controls. When the incidence of acute plaque rupture was normalized for plaque size, the reduction in the double knockouts was 72% (P=0.039). The number of buried fibrous layers, indicative of an unstable plaque phenotype, was reduced by 67% in the double knockouts (P=0.008). The cysteine proteinase inhibitor, egg white cystatin, was biotinylated and used as an active-site-directed probe for cathepsins. Biotinylated cystatin selectively detected cathepsin S in extracts of human carotid atherosclerotic plaque. Active cathepsin S was detectable in extracts of human atherosclerotic plaque but not in nondiseased carotid arteries. Active cathepsins were especially prominent in macrophages in the shoulder regions of plaques, areas considered to be vulnerable to rupture. Cathepsin S protein colocalized with regions of elastin degradation in human coronary plaques. CONCLUSIONS: These data provide direct evidence that an endogenous proteinase, cathepsin S, plays an important role in atherosclerotic plaque destabilization and rupture.

Community-acquired pneumonia: doctors do not follow national guidelines.

OBJECTIVES: Appropriate assessment of community-acquired pneumonia (CAP) allows accurate severity scoring and hence optimal management, leading to reduced morbidity and mortality. British Thoracic Society (BTS) guidelines provide an appropriate score. Adherence to BTS guidelines was assessed in our medical assessment unit (MAU) in 2001/2 and again in 2005/6, 3 years after introducing an educational programme. METHODS: A retrospective case-note study, comparing diagnosis, documentation of severity, management and outcome of CAP during admission to MAU during 3 months of each winter in 2001/2 and 2005/6. RESULTS: In 2001/2, 65/165 patients were wrongly coded as CAP and 100 were included in the study. In 2005/6 43/130 were excluded and 87 enrolled. In 2005/6, 87% did not receive a severity score, a significant increase from 48% in 2001/2 (p<0.0001). Parenteral antibiotics were given to 79% of patients in 2001/2 and 77% in 2005/6, and third generation cephalosporins were given to 63% in 2001/2 and 54% in 2005/6 (p = NS). In 2001, 15 different antibiotic regimens were prescribed, increasing to 19 in 2005/6. CONCLUSIONS: Coding remains poor. Adherence to CAP management guidelines was poor and has significantly worsened. Educational programmes, alone, do not improve adherence. Restriction of antibiotic prescribing should be considered.

Vitamin D status in chronic fatigue syndrome/myalgic encephalomyelitis: a cohort study from the North-West of England.

OBJECTIVE: Severe vitamin D deficiency is a recognised cause of skeletal muscle fatigue and myopathy. The aim of this study was to examine whether chronic fatigue syndrome/myalgic encephalomyelitis (CFS/ME) is associated with altered circulating vitamin D metabolites. DESIGN: Cohort study. SETTING: UK university hospital, recruiting from April 2014 to April 2015. PARTICIPANTS: Ninety-two patients with CFS/ME and 94 age-matched healthy controls (HCs). MAIN OUTCOME MEASURES: The presence of a significant association between CFS/ME, fatigue and vitamin D measures. RESULTS: No evidence of a deficiency in serum total 25(OH) vitamin D (25(OH)D2 and 25(OH)D3 metabolites) was evident in individuals with CFS/ME. Liquid chromatography tandem mass spectrometry (LC-MS/MS) analysis revealed that total 25(OH)D was significantly higher (p=0.001) in serum of patients with CFS/ME compared with HCs (60.2 and 47.3 nmol/L, respectively). Analysis of food/supplement diaries with WinDiets revealed that the higher total 25(OH) vitamin D concentrations observed in the CFS/ME group were associated with increased vitamin D intake through use of supplements compared with the control group. Analysis of Chalder Fatigue Questionnaire data revealed no association between perceived fatigue and vitamin D levels. CONCLUSIONS: Low serum concentrations of total 25(OH)D do not appear to be a contributing factor to the level of fatigue of CFS/ME.

Differential effects of low and high dose folic acid on endothelial dysfunction in a murine model of mild hyperhomocysteinaemia.

The exact mechanism(s) by which hyperhomocysteinaemia promotes vascular disease remains unclear. Moreover, recent evidence suggests that the beneficial effect of folic acid on endothelial function is independent of homocysteine-lowering. In the present study the effect of a low (400 microg/70 kg/day) and high (5 mg/70 kg/day) dose folic acid supplement on endothelium-dependent relaxation in the isolated perfused mesenteric bed of heterozygous cystathionine beta-synthase deficient mice was investigated. Elevated total plasma homocysteine and impaired relaxation responses to methacholine were observed in heterozygous mice. In the presence of N(G)-nitro-L-arginine methyl ester relaxation responses in wild-type tissues were reduced, but in heterozygous tissues were abolished. Clotrimazole and 18alpha-glycyrrhetinic acid, both inhibitors of non-nitric oxide/non-prostanoid-induced endothelium-dependent relaxation, reduced responses to methacholine in wild-type but not heterozygous tissues. The combination of N(G)-nitro-L-arginine methyl ester and either clotrimazole or 18alpha-glycyrrhetinic acid completely inhibited relaxation responses in wild-type tissues. Both low and high dose folic acid increased plasma folate, reduced total plasma homocysteine and reversed endothelial dysfunction in heterozygous mice. A greater increase in plasma folate in the high dose group was accompanied by a more significant effect on endothelial function. In the presence of N(G)-nitro-L-arginine methyl ester, a significant residual relaxation response was evident in tissues from low and high dose folic acid treated heterozygous mice. These data suggest that the impaired mesenteric relaxation in heterozygous mice is largely due to loss of the non-nitric oxide/non-prostanoid component. While low dose folic acid may restore this response in a homocysteine-dependent manner, the higher dose has an additional effect on nitric oxide-mediated relaxation that would appear to be independent of homocysteine lowering.

Serum creatine phosphokinase monitoring in patients infected with HIV.

Creatine phosphokinase (CPK) estimations are done routinely in some HIV clinics, irrespective of patient symptoms. We studied patients attending the Worcestershire HIV clinic between 1987 and 2001 to identify whether routine elevations in serum levels of CPK in patients with HIV were associated with clinical features of muscle disease (CFMD), and whether such elevations influenced patient management. There was no association between CFMD and a rise in CPK. Major rises of CPK >400 IU/L were significantly associated with CFMD. No individual had a persistent CPK rise >200 IU/L without CFMD. In the great majority of cases, there was no change in management consequent to enzyme rises. In patients with HIV infection and no CFMD, the chance of finding a major and persistent CPK rise is low. This study does not support the practice of routine monitoring of CPK in asymptomatic patients attending HIV clinics.

A case of relapsed visceral Kaposi's sarcoma with bilateral chylothoraces successfully treated with paclitaxel.

Chylothorax is a rare complication of visceral Kaposi's sarcoma. We report a case with bilateral chylothoraces secondary to relapsed visceral Kaposi's sarcoma who was successfully treated with paclitaxel chemotherapy.

Moderately elevated plasma homocysteine impairs functional endothelial recovery following denudation of mouse carotid arteries.

Increased total plasma homocysteine is an independent risk factor for cardiovascular disease. This study was designed to determine whether it can impair endothelial function, by examining the recovery of acetylcholine-evoked relaxation following mechanical denudation of the endothelium in the arteries of cystathionine beta-synthase knockout (CbetaS(+/-)) mice. Heterozygous CbetaS(+/-) mice had total plasma homocysteine concentrations significantly higher (8.9 +/- 1.1 micromol/L, n = 12) than strain-matched wild-types (4.6 +/- 0.4 micromol/L, n = 5; P =.003). Left common carotid arteries were denuded of endothelium using a 250-microm polytetrafluoroethylene filament. After 10 days, when the endothelium had completely regrown, relaxation to acetylcholine was measured in precontracted segments of artery. Uninjured right carotid arteries from the same animals served as internal controls. Relaxation to acetylcholine was significantly attenuated in the injured arteries of the CbetaS(+/-) mice, compared to wild-types (P =.017); furthermore, there was a significant negative correlation between sensitivity to acetylcholine and total plasma homocysteine concentration measured in the same animal (r = -0.69, P <.003). These data suggest that even modest homocysteinemia has a deleterious effect on the function of healed endothelium in mouse arteries. This may account for its adverse influence on chronic cardiovascular disease.

Schistosomiasis japonicum diagnosed on liver biopsy in a patient with hepatitis B co-infection: a case report.

INTRODUCTION: Chronic hepatitis B virus and schistosomiasis are independently associated with significant mortality and morbidity worldwide. Despite much geographic overlap between these conditions and no reason why co-infection should not exist, we present what is, to the best of our knowledge, the first published report of a proven histological diagnosis of hepatic Schistosomiasis japonicum and chronic hepatitis B co-infection. A single case of hepatitis B and hepatic Schistosomiasis mansoni diagnosed by liver biopsy has previously been reported in the literature. CASE PRESENTATION: A 38-year-old Chinese man with known chronic hepatitis B virus infection presented with malaise, nausea and headache. Blood tests revealed increased transaminases and serology in keeping with hepatitis B virus e-antigen seroconversion. A liver biopsy was performed because some investigations, particularly transient elastography, suggested cirrhosis. Two schistosome ova were seen on liver histology, identified as S. japonicum, probably acquired in China as a youth. His peripheral eosinophil count was normal, schistosomal serology and stool microscopy for ova, cysts and parasites were negative. CONCLUSION: Hepatic schistosomiasis co-infection should be considered in patients with hepatitis B virus infection who are from countries endemic for schistosomiasis. Screening for schistosomiasis using a peripheral eosinophil count, schistosomal serology and stool microscopy may be negative despite infection, therefore presumptive treatment could be considered. Transient elastography should not be used to assess liver fibrosis during acute flares of viral hepatitis because readings are falsely elevated. The impact of hepatic schistosomiasis on the sensitivity and specificity of transient elastography measurement for the assessment of hepatitis B is as yet unknown.

General physicians do not take adequate travel histories.

BACKGROUND: Our aim was to document how often travel histories were taken and the quality of their content. METHODS: Patients admitted over 2 months to acute medical units of two hospitals in the Northwest of England with a history of fever, rash, diarrhea, vomiting, jaundice, or presenting as "unwell post-travel" were identified. The initial medical clerking was assessed. RESULTS: A total of 132 relevant admissions were identified. A travel history was documented in only 26 patients (19.7%). Of the 16 patients who had traveled, there was no documentation of pretravel advice or of sexual/other activities abroad in 15 (93.8%) and 12 (75.0%) patients, respectively. CONCLUSIONS: There needs to be better awareness and education about travel-related illness and the importance of taking an adequate travel history.