Ipswich Hospital

Background The ESPAC-3 trial showed that adjuvant gemcitabine is the standard of care based on similar survival to and less toxicity than adjuvant 5-fluorouracil/folinic acid in patients with resected pancreatic cancer. Other clinical trials have shown better survival and tumour response with gemcitabine and capecitabine than with gemcitabine alone in advanced or metastatic pancreatic cancer. We aimed to determine the efficacy and safety of gemcitabine and capecitabine compared with gemcitabine monotherapy for resected pancreatic cancer. Methods We did a phase 3, two-group, open-label, multicentre, randomised clinical trial at 92 hospitals in England, Scotland, Wales, Germany, France, and Sweden. Eligible patients were aged 18 years or older and had undergone complete macroscopic resection for ductal adenocarcinoma of the pancreas (R0 or R1 resection). We randomly assigned patients (1:1) within 12 weeks of surgery to receive six cycles of either 1000 mg/m 2 gemcitabine alone administered once a week for three of every 4 weeks (one cycle) or with 1660 mg/m 2 oral capecitabine administered for 21 days followed by 7 days' rest (one cycle). Randomisation was based on a minimisation routine, and country was used as a stratification factor. The primary endpoint was overall survival, measured as the time from randomisation until death from any cause, and assessed in the intention-to-treat population. Toxicity was analysed in all patients who received trial treatment. This trial was registered with the EudraCT, number 2007-004299-38, and ISRCTN, number ISRCTN96397434. Findings Of 732 patients enrolled, 730 were included in the final analysis. Of these, 366 were randomly assigned to receive gemcitabine and 364 to gemcitabine plus capecitabine. The Independent Data and Safety Monitoring Committee requested reporting of the results after there were 458 (95%) of a target of 480 deaths. The median overall survival for patients in the gemcitabine plus capecitabine group was 28·0 months (95% CI 23·5–31·5) compared with 25·5 months (22·7–27·9) in the gemcitabine group (hazard ratio 0·82 [95% CI 0·68–0·98], p=0·032). 608 grade 3–4 adverse events were reported by 226 of 359 patients in the gemcitabine plus capecitabine group compared with 481 grade 3–4 adverse events in 196 of 366 patients in the gemcitabine group. Interpretation The adjuvant combination of gemcitabine and capecitabine should be the new standard of care following resection for pancreatic ductal adenocarcinoma. Funding Cancer Research UK.

BACKGROUND: Xerostomia is the most common late side-effect of radiotherapy to the head and neck. Compared with conventional radiotherapy, intensity-modulated radiotherapy (IMRT) can reduce irradiation of the parotid glands. We assessed the hypothesis that parotid-sparing IMRT reduces the incidence of severe xerostomia. METHODS: We undertook a randomised controlled trial between Jan 21, 2003, and Dec 7, 2007, that compared conventional radiotherapy (control) with parotid-sparing IMRT. We randomly assigned patients with histologically confirmed pharyngeal squamous-cell carcinoma (T1-4, N0-3, M0) at six UK radiotherapy centres between the two radiotherapy techniques (1:1 ratio). A dose of 60 or 65 Gy was prescribed in 30 daily fractions given Monday to Friday. Treatment was not masked. Randomisation was by computer-generated permuted blocks and was stratified by centre and tumour site. Our primary endpoint was the proportion of patients with grade 2 or worse xerostomia at 12 months, as assessed by the Late Effects of Normal Tissue (LENT SOMA) scale. Analyses were done on an intention-to-treat basis, with all patients who had assessments included. Long-term follow-up of patients is ongoing. This study is registered with the International Standard Randomised Controlled Trial register, number ISRCTN48243537. FINDINGS: 47 patients were assigned to each treatment arm. Median follow-up was 44·0 months (IQR 30·0-59·7). Six patients from each group died before 12 months and seven patients from the conventional radiotherapy and two from the IMRT group were not assessed at 12 months. At 12 months xerostomia side-effects were reported in 73 of 82 alive patients; grade 2 or worse xerostomia at 12 months was significantly lower in the IMRT group than in the conventional radiotherapy group (25 [74%; 95% CI 56-87] of 34 patients given conventional radiotherapy vs 15 [38%; 23-55] of 39 given IMRT, p=0·0027). The only recorded acute adverse event of grade 2 or worse that differed significantly between the treatment groups was fatigue, which was more prevalent in the IMRT group (18 [41%; 99% CI 23-61] of 44 patients given conventional radiotherapy vs 35 [74%; 55-89] of 47 given IMRT, p=0·0015). At 24 months, grade 2 or worse xerostomia was significantly less common with IMRT than with conventional radiotherapy (20 [83%; 95% CI 63-95] of 24 patients given conventional radiotherapy vs nine [29%; 14-48] of 31 given IMRT; p<0·0001). At 12 and 24 months, significant benefits were seen in recovery of saliva secretion with IMRT compared with conventional radiotherapy, as were clinically significant improvements in dry-mouth-specific and global quality of life scores. At 24 months, no significant differences were seen between randomised groups in non-xerostomia late toxicities, locoregional control, or overall survival. INTERPRETATION: Sparing the parotid glands with IMRT significantly reduces the incidence of xerostomia and leads to recovery of saliva secretion and improvements in associated quality of life, and thus strongly supports a role for IMRT in squamous-cell carcinoma of the head and neck. FUNDING: Cancer Research UK (CRUK/03/005).

BACKGROUND: Prostate cancer might have high radiation-fraction sensitivity that would give a therapeutic advantage to hypofractionated treatment. We present a pre-planned analysis of the efficacy and side-effects of a randomised trial comparing conventional and hypofractionated radiotherapy after 5 years follow-up. METHODS: CHHiP is a randomised, phase 3, non-inferiority trial that recruited men with localised prostate cancer (pT1b-T3aN0M0). Patients were randomly assigned (1:1:1) to conventional (74 Gy delivered in 37 fractions over 7·4 weeks) or one of two hypofractionated schedules (60 Gy in 20 fractions over 4 weeks or 57 Gy in 19 fractions over 3·8 weeks) all delivered with intensity-modulated techniques. Most patients were given radiotherapy with 3-6 months of neoadjuvant and concurrent androgen suppression. Randomisation was by computer-generated random permuted blocks, stratified by National Comprehensive Cancer Network (NCCN) risk group and radiotherapy treatment centre, and treatment allocation was not masked. The primary endpoint was time to biochemical or clinical failure; the critical hazard ratio (HR) for non-inferiority was 1·208. Analysis was by intention to treat. Long-term follow-up continues. The CHHiP trial is registered as an International Standard Randomised Controlled Trial, number ISRCTN97182923. FINDINGS: Between Oct 18, 2002, and June 17, 2011, 3216 men were enrolled from 71 centres and randomly assigned (74 Gy group, 1065 patients; 60 Gy group, 1074 patients; 57 Gy group, 1077 patients). Median follow-up was 62·4 months (IQR 53·9-77·0). The proportion of patients who were biochemical or clinical failure free at 5 years was 88·3% (95% CI 86·0-90·2) in the 74 Gy group, 90·6% (88·5-92·3) in the 60 Gy group, and 85·9% (83·4-88·0) in the 57 Gy group. 60 Gy was non-inferior to 74 Gy (HR 0·84 [90% CI 0·68-1·03], pNI=0·0018) but non-inferiority could not be claimed for 57 Gy compared with 74 Gy (HR 1·20 [0·99-1·46], pNI=0·48). Long-term side-effects were similar in the hypofractionated groups compared with the conventional group. There were no significant differences in either the proportion or cumulative incidence of side-effects 5 years after treatment using three clinician-reported as well as patient-reported outcome measures. The estimated cumulative 5 year incidence of Radiation Therapy Oncology Group (RTOG) grade 2 or worse bowel and bladder adverse events was 13·7% (111 events) and 9·1% (66 events) in the 74 Gy group, 11·9% (105 events) and 11·7% (88 events) in the 60 Gy group, 11·3% (95 events) and 6·6% (57 events) in the 57 Gy group, respectively. No treatment-related deaths were reported. INTERPRETATION: Hypofractionated radiotherapy using 60 Gy in 20 fractions is non-inferior to conventional fractionation using 74 Gy in 37 fractions and is recommended as a new standard of care for external-beam radiotherapy of localised prostate cancer. FUNDING: Cancer Research UK, Department of Health, and the National Institute for Health Research Cancer Research Network.

Importance: Post-COVID-19 condition (PCC) is a complex heterogeneous disorder that has affected the lives of millions of people globally. Identification of potential risk factors to better understand who is at risk of developing PCC is important because it would allow for early and appropriate clinical support. Objective: To evaluate the demographic characteristics and comorbidities that have been found to be associated with an increased risk of developing PCC. Data sources: Medline and Embase databases were systematically searched from inception to December 5, 2022. Study Selection: The meta-analysis included all published studies that investigated the risk factors and/or predictors of PCC in adult (≥18 years) patients. Data Extraction and Synthesis: Odds ratios (ORs) for each risk factor were pooled from the selected studies. For each potential risk factor, the random-effects model was used to compare the risk of developing PCC between individuals with and without the risk factor. Data analyses were performed from December 5, 2022, to February 10, 2023. Main Outcomes and Measures: The risk factors for PCC included patient age; sex; body mass index, calculated as weight in kilograms divided by height in meters squared; smoking status; comorbidities, including anxiety and/or depression, asthma, chronic kidney disease, chronic obstructive pulmonary disease, diabetes, immunosuppression, and ischemic heart disease; previous hospitalization or ICU (intensive care unit) admission with COVID-19; and previous vaccination against COVID-19. Results: The initial search yielded 5334 records of which 255 articles underwent full-text evaluation, which identified 41 articles and a total of 860 783 patients that were included. The findings of the meta-analysis showed that female sex (OR, 1.56; 95% CI, 1.41-1.73), age (OR, 1.21; 95% CI, 1.11-1.33), high BMI (OR, 1.15; 95% CI, 1.08-1.23), and smoking (OR, 1.10; 95% CI, 1.07-1.13) were associated with an increased risk of developing PCC. In addition, the presence of comorbidities and previous hospitalization or ICU admission were found to be associated with high risk of PCC (OR, 2.48; 95% CI, 1.97-3.13 and OR, 2.37; 95% CI, 2.18-2.56, respectively). Patients who had been vaccinated against COVID-19 with 2 doses had a significantly lower risk of developing PCC compared with patients who were not vaccinated (OR, 0.57; 95% CI, 0.43-0.76). Conclusions and Relevance: This systematic review and meta-analysis demonstrated that certain demographic characteristics (eg, age and sex), comorbidities, and severe COVID-19 were associated with an increased risk of PCC, whereas vaccination had a protective role against developing PCC sequelae. These findings may enable a better understanding of who may develop PCC and provide additional evidence for the benefits of vaccination. Trial Registration: PROSPERO Identifier: CRD42022381002.

OBJECTIVE: To evaluate the effectiveness of a structured group education programme on biomedical, psychosocial, and lifestyle measures in people with newly diagnosed type 2 diabetes. DESIGN: Multicentre cluster randomised controlled trial in primary care with randomisation at practice level. SETTING: 207 general practices in 13 primary care sites in the United Kingdom. PARTICIPANTS: 824 adults (55% men, mean age 59.5 years). INTERVENTION: A structured group education programme for six hours delivered in the community by two trained healthcare professional educators compared with usual care. MAIN OUTCOME MEASURES: Haemoglobin A(1c) levels, blood pressure, weight, blood lipid levels, smoking status, physical activity, quality of life, beliefs about illness, depression, and emotional impact of diabetes at baseline and up to 12 months. MAIN RESULTS: Haemoglobin A(1c) levels at 12 months had decreased by 1.49% in the intervention group compared with 1.21% in the control group. After adjusting for baseline and cluster, the difference was not significant: 0.05% (95% confidence interval -0.10% to 0.20%). The intervention group showed a greater weight loss: -2.98 kg (95% confidence interval -3.54 to -2.41) compared with 1.86 kg (-2.44 to -1.28), P=0.027 at 12 months. The odds of not smoking were 3.56 (95% confidence interval 1.11 to 11.45), P=0.033 higher in the intervention group at 12 months. The intervention group showed significantly greater changes in illness belief scores (P=0.001); directions of change were positive indicating greater understanding of diabetes. The intervention group had a lower depression score at 12 months: mean difference was -0.50 (95% confidence interval -0.96 to -0.04); P=0.032. A positive association was found between change in perceived personal responsibility and weight loss at 12 months (beta=0.12; P=0.008). CONCLUSION: A structured group education programme for patients with newly diagnosed type 2 diabetes resulted in greater improvements in weight loss and smoking cessation and positive improvements in beliefs about illness but no difference in haemoglobin A(1c) levels up to 12 months after diagnosis. TRIAL REGISTRATION: Current Controlled Trials ISRCTN17844016 [controlled-trials.com].

INTRODUCTION: Glycemic control in participants with insulin-treated diabetes remains challenging. We assessed safety and efficacy of new flash glucose-sensing technology to replace self-monitoring of blood glucose (SMBG). METHODS: This open-label randomized controlled study (ClinicalTrials.gov, NCT02082184) enrolled adults with type 2 diabetes on intensive insulin therapy from 26 European diabetes centers. Following 2 weeks of blinded sensor wear, 2:1 (intervention/control) randomization (centrally, using biased-coin minimization dependant on study center and insulin administration) was to control (SMBG) or intervention (glucose-sensing technology). Participants and investigators were not masked to group allocation. Primary outcome was difference in HbA1c at 6 months in the full analysis set. Prespecified secondary outcomes included time in hypoglycemia, effect of age, and patient satisfaction. RESULTS: Participants (n = 224) were randomized (149 intervention, 75 controls). At 6 months, there was no difference in the change in HbA1c between intervention and controls: -3.1 ± 0.75 mmol/mol, [-0.29 ± 0.07% (mean ± SE)] and -3.4 ± 1.04 mmol/mol (-0.31 ± 0.09%) respectively; p = 0.8222. A difference was detected in participants aged <65 years [-5.7 ± 0.96 mmol/mol (-0.53 ± 0.09%) and -2.2 ± 1.31 mmol/mol (-0.20 ± 0.12%), respectively; p = 0.0301]. Time in hypoglycemia <3.9 mmol/L (70 mg/dL) reduced by 0.47 ± 0.13 h/day [mean ± SE (p = 0.0006)], and <3.1 mmol/L (55 mg/dL) reduced by 0.22 ± 0.07 h/day (p = 0.0014) for intervention participants compared with controls; reductions of 43% and 53%, respectively. SMBG frequency, similar at baseline, decreased in intervention participants from 3.8 ± 1.4 tests/day (mean ± SD) to 0.3 ± 0.7, remaining unchanged in controls. Treatment satisfaction was higher in intervention compared with controls (DTSQ 13.1 ± 0.50 (mean ± SE) and 9.0 ± 0.72, respectively; p < 0.0001). No serious adverse events or severe hypoglycemic events were reported related to sensor data use. Forty-two serious events [16 (10.7%) intervention participants, 12 (16.0%) controls] were not device-related. Six intervention participants reported nine adverse events for sensor-wear reactions (two severe, six moderate, one mild). CONCLUSION: Flash glucose-sensing technology use in type 2 diabetes with intensive insulin therapy results in no difference in HbA1c change and reduced hypoglycemia, thus offering a safe, effective replacement for SMBG. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT02082184. FUNDING: Abbott Diabetes Care.

Introduction: Intravenous(IV) immunoglobulin(Ig) treatment is known to alleviate behavioral deficits in the experimentally induced model of sepsis. To delineate the mechanisms by which IVIg treatment prevents neuronal dysfunction, an array of immunological and apoptosis markers was investigated. Methods: Sepsis was induced by cecal ligation perforation(CLP) in rats. The animals were divided into five groups; sham, control, CLP + saline, CLP + immunoglobulin G IgG(250 mg/kg,iv), and CLP + immunoglobulins enriched with immunoglobulin M-IgGAM(250 mg/kg,iv). Blood and brain samples were taken in two sets of experiments after CLP to see the early(24 hrs) and late(10 days) effects of treatment. Total complement activity, complement 3(C3) and soluble complement C5b-9 levels were measured in sera of rats using ELISA-based methods. Cerebral complement content was analyzed by Western Blot. Immune cell infiltration and gliosis were examined by immunohistochemistry using cluster of differentiation 3, CD4, CD8, CD11b, CD19 and glial fibrillary acidic protein antibodies. Apoptotic neuronal death was investigated by TUNEL staining and Western Blot-based semi-quantitative evaluation of brain homogenates by bax and bcl-2 antibodies. Results: IV IgG and IgGAM administration significantly reduced systemic complement activity but increased serum C3 and soluble C5b-9 levels. Likewise, Western Blot data showed slightly increased C5b-9 expression and significantly reduced C1q expression in brain samples of IgGAM-treated but not IgG-treated septic rats especially in the first day of administration. No cerebral cellular infiltrates were observed in treated and non-treated septic rats. By contrast, IV IgG and IgGAM treatment induced considerable amelioration in glial cell proliferation which was increased in non-treated rats. IgG and IgGAM treated rats exhibited significantly reduced numbers of apoptotic neurons and cerebral expression levels of bax and bcl-2 as compared to nontreated rats. Conclusions: We suggest that IV IgG and IgGAM administration ameliorates neuronal dysfunction and behavioral deficits by reducing apoptotic cell death and glial cell proliferation. IgGAM treatment might be suppressing classical complement pathway by reducing C1q expression.

AIM: To estimate the healthcare costs of diabetic foot disease in England. METHODS: Patient-level data sets at a national and local level, and evidence from clinical studies, were used to estimate the annual cost of health care for foot ulceration and amputation in people with diabetes in England in 2014-2015. RESULTS: The cost of health care for ulceration and amputation in diabetes in 2014-2015 is estimated at between £837 million and £962 million; 0.8% to 0.9% of the National Health Service (NHS) budget for England. More than 90% of expenditure was related to ulceration, and 60% was for care in community, outpatient and primary settings. For inpatients, multiple regression analysis suggested that ulceration was associated with a length of stay 8.04 days longer (95% confidence interval 7.65 to 8.42) than that for diabetes admissions without ulceration. CONCLUSIONS: Diabetic foot care accounts for a substantial proportion of healthcare expenditure in England, more than the combined cost of breast, prostate and lung cancers. Much of this expenditure arises through prolonged and severe ulceration. If the NHS were to reduce the prevalence of diabetic foot ulcers in England by one-third, the gross annual saving would be more than £250 million. Diabetic foot ulceration is a large and growing problem globally, and it is likely that there is potential to improve outcomes and reduce expenditure in many countries.

BACKGROUND: The aim of this trial was to compare dose-escalated conformal radiotherapy with control-dose conformal radiotherapy in patients with localised prostate cancer. Preliminary findings reported after 5 years of follow-up showed that escalated-dose conformal radiotherapy improved biochemical progression-free survival. Based on the sample size calculation, we planned to analyse overall survival when 190 deaths occurred; this target has now been reached, after a median 10 years of follow-up. METHODS: RT01 was a phase 3, open-label, international, randomised controlled trial enrolling men with histologically confirmed T1b-T3a, N0, M0 prostate cancer with prostate specific antigen of less than 50 ng/mL. Patients were randomly assigned centrally in a 1:1 ratio, using a computer-based minimisation algorithm stratifying by risk of seminal vesicle invasion and centre to either the control group (64 Gy in 32 fractions, the standard dose at the time the trial was designed) or the escalated-dose group (74 Gy in 37 fractions). Neither patients nor investigators were masked to assignment. All patients received neoadjuvant androgen deprivation therapy for 3-6 months before the start of conformal radiotherapy, which continued until the end of conformal radiotherapy. The coprimary outcome measures were biochemical progression-free survival and overall survival. All analyses were done on an intention-to-treat basis. Treatment-related side-effects have been reported previously. This trial is registered, number ISRCTN47772397. FINDINGS: Between Jan 7, 1998, and Dec 20, 2001, 862 men were registered and 843 subsequently randomly assigned: 422 to the escalated-dose group and 421 to the control group. As of Aug 2, 2011, 236 deaths had occurred: 118 in each group. Median follow-up was 10·0 years (IQR 9·1-10·8). Overall survival at 10 years was 71% (95% CI 66-75) in each group (hazard ratio [HR] 0·99, 95% CI 0·77-1·28; p=0·96). Biochemical progression or progressive disease occurred in 391 patients (221 [57%] in the control group and 170 [43%] in the escalated-dose group). At 10 years, biochemical progression-free survival was 43% (95% CI 38-48) in the control group and 55% (50-61) in the escalated-dose group (HR 0·69, 95% CI 0·56-0·84; p=0·0003). INTERPRETATION: At a median follow-up of 10 years, escalated-dose conformal radiotherapy with neoadjuvant androgen deprivation therapy showed an advantage in biochemical progression-free survival, but this advantage did not translate into an improvement in overall survival. These efficacy data for escalated-dose treatment must be weighed against the increase in acute and late toxicities associated with the escalated dose and emphasise the importance of use of appropriate modern radiotherapy methods to reduce side-effects. FUNDING: UK Medical Research Council.

GCA is the commonest of all the vasculitides. Visual loss occurs in up to one-fifth of patients, which may be preventable by prompt recognition and treatment [1,2]. The aim of these guidelines is to encourage the prompt diagnosis and management of GCA, with emphasis on the prevention of visual loss. Their scope is to provide evidence-based advice for the assessment and diagnosis of GCA, for initial and further management and for monitoring of disease activity, complications and relapse. This is a summary of the guidelines and the full guideline is available at Rheumatology online. The recommendations for the guidelines are set out in points 1 to 9. (1) Early recognition and diagnosis of GCA is paramount [2]. Particular attention should be paid to the predictive features of ischaemic neuro-ophthalmic complications (C). A patient >50 years of age presenting with the following features should raise suspicion of GCA: Abrupt-onset headache (usually unilateral in the temporal area). Scalp tenderness. Jaw and tongue claudication. Visual symptoms (including diplopia). Constitutional symptoms. Polymyalgic symptoms. Limb claudication. Examination may show: Abnormal superficial temporal artery: tender, thickened with reduced or absent pulsation. Scalp tenderness. Transient or permanent visual loss. Visual field defect. Relative afferent papillary defect. Anterior ischaemic optic neuritis. Central retinal artery occlusion. Upper cranial nerve palsies. Features of large-vessel GCA: vascular bruits and asymmetry of pulses or blood pressure. Laboratory investigations include: Full blood count, urea and electrolytes, liver function tests, CRP, ESR. An acute-phase response is the characteristic of GCA (raised ESR, CRP, anaemia, thrombocytosis, abnormal liver function tests, particularly raised alkaline phosphatase, raised α1 and α2 globulins on serum electrophoresis). However, GCA can occur in the face of lower levels of inflammatory markers, if the clinical picture is typical. Chest radiograph. Urinalysis. Other relevant investigations to exclude mimicking conditions. Features predictive of ischaemic neuro-ophthalmic complications [3, 4]: Jaw claudication. Diplopia. Temporal artery abnormalities. (2) Urgent referral for specialist evaluation is suggested for all patients with GCA. Temporal artery biopsy (TAB) should be considered whenever a diagnosis of GCA is suspected. This should not delay the prompt institution of high-dose glucocorticosteroid therapy (C). TAB can remain positive for 2–6 weeks after the commencement of treatment. It should be performed by a surgical unit experienced in regular TAB, and samples should be at least 1 cm in length. Contralateral biopsy is usually unnecessary. TAB may be negative in some patients. They should be regarded as having GCA if there is a typical clinical picture and response to glucocorticosteroids. (3) Imaging techniques show promise for the diagnosis and monitoring of GCA. However, these do not replace TAB for cranial GCA. Their role in early diagnosis of cranial GCA is an important area of future research (B). The use of duplex ultrasound is currently limited as it requires a high level of experience and training. Other imaging modalities (PET and MRI) should be currently reserved for investigation of suspected large-vessel GCA. (4a) High-dose glucocorticosteroid therapy should be initiated immediately when clinical suspicion of GCA is raised (C). Recommended starting dosages of glucocorticosteroids are: Uncomplicated GCA (no jaw claudication or visual disturbance): 40–60 mg prednisolone daily. Evolving visual loss or amaurosis fugax (complicated GCA): 500 mg to 1 g of i.v. methylprednisolone for 3 days before oral glucocorticosteroids. Established visual loss: 60 mg prednisolone daily to protect the contralateral eye. Patients should also receive bone protection. Proton pump inhibitors for gastrointestinal protection should be considered. The symptoms of GCA should respond rapidly to high-dose glucocorticosteroid treatment, followed by resolution of the inflammatory response. Failure to do so should raise the question of an alternative diagnosis. (4b) Glucocorticosteroid reduction should be considered only in the absence of clinical symptoms, signs and laboratory abnormalities suggestive of active disease (C). This should be balanced against the need to use the lowest effective dose, patient wishes and glucocorticosteroid side effects. Steroid reduction may also be appropriate if the acute-phase response is deemed to be due to another cause. Suggested tapering regimen: 40–60 mg prednisolone continued until symptoms and laboratory abnormalities resolve (at least 3–4 weeks); then dose is reduced by 10 mg every 2 weeks to 20 mg; then by 2.5 mg every 2–4 weeks to 10 mg; and then by 1 mg every 1–2 months provided there is no relapse. The dose may need adjustment for disease severity, comorbid factors, fracture risk, patient wishes and adverse events. There are also some patients who will require long-term low-dose glucocorticosteroid therapy. (5) Low-dose aspirin should be considered in patients with GCA if no contraindications exist (C). (6) Large-vessel GCA should be suspected in patients with prominent systemic symptoms, limb claudication or persistently high-inflammatory markers despite adequate glucocorticosteroid therapy. Imaging techniques, such as PET and MRI scanning, should be reserved for the assessment of suspected large-vessel involvement [5] (C). (7) Monitoring of therapy should be clinical and supported by the measurement of inflammatory markers (C; this is a consensus statement). Patients should be monitored for evidence of relapse, disease-related complications and glucocorticosteroid-related complications. In particular, the following features should be sought: Jaw and tongue claudication. Visual symptoms. Vascular claudication of limbs, bruits and asymmetrical pulses. Polymyalgic symptoms. Osteoporotic risk factors and fractures. Other glucocorticosteroid-related complications. Other symptoms that may suggest an alternative diagnosis. The following investigations should be performed: At each visit: full blood count, ESR/CRP, urea and electrolytes, glucose. Every 2 years: chest radiograph to monitor for aortic aneurysm (echocardiography, PET and MRI may also be appropriate). Bone mineral density may be required. Routine follow-up should be planned at: Weeks 0, 1, 3, 6, then Months 3, 6, 9, 12 in the first year. Later (Month 3 onwards) follow-up can be undertaken under shared care. Relapse: Disease relapse should be suspected in patients with a return of symptoms of GCA, ischaemic complications, unexplained fever or polymyalgic symptoms. A rise in ESR/CRP is usually seen with relapse, but relapse can be seen with normal inflammatory markers. All patients in whom relapse is suspected should be treated as below, and discussed or referred for specialist assessment. Return of headache should be treated with the previous higher dose of glucocorticosteroids. Jaw claudication requires 60 mg prednisolone. Eye symptoms need the use of either 60 mg prednisolone or i.v. methylprednisolone. Symptoms of large-vessel disease should prompt further investigation with MRI or PET and the use of systemic vasculitis treatment protocols. For recurrent relapse, see below. (8) The early introduction of MTX or alternative immunosuppressants should be considered as adjuvant therapy (B). Recurrent relapse or failure to wean glucocorticosteroid dose requires the consideration of adjuvant therapy, such as MTX or other immunosuppressants. These immunosuppressive agents should be started at the third relapse. Biological therapies still require further study, and are not yet recommended. (9) Patient education (D). We suggest developing a new Arthritis Research Campaign booklet on GCA for the use of newly diagnosed patients. The approach to diagnosis and management of GCA is summarized in Figure 1. Approach to diagnosis and management of GCA. Audit standards should include the minimum baseline data set recorded, initial glucocorticosteroid dose and taper, monitoring frequency and outcomes. The key performance measure should be the time from symptoms to initial treatment. Disclosure statement: B.D. has received grant support from the American College of Rheumatology and European League Against Rheumatism. He has also received honoraria from Mercke, Aventis, Schering Plough, Wyeth and Roche. All other authors have declared no conflicts of interest.

BACKGROUND: Patients with functional motor disorder (FMD) including weakness and paralysis are commonly referred to physiotherapists. There is growing evidence that physiotherapy is an effective treatment, but the existing literature has limited explanations of what physiotherapy should consist of and there are insufficient data to produce evidence-based guidelines. We aim to address this issue by presenting recommendations for physiotherapy treatment. METHODS: A meeting was held between physiotherapists, neurologists and neuropsychiatrists, all with extensive experience in treating FMD. A set of consensus recommendations were produced based on existing evidence and experience. RESULTS: We recommend that physiotherapy treatment is based on a biopsychosocial aetiological framework. Treatment should address illness beliefs, self-directed attention and abnormal habitual movement patterns through a process of education, movement retraining and self-management strategies within a positive and non-judgemental context. We provide specific examples of these strategies for different symptoms. CONCLUSIONS: Physiotherapy has a key role in the multidisciplinary management of patients with FMD. There appear to be specific physiotherapy techniques which are useful in FMD and which are amenable to and require prospective evaluation. The processes involved in referral, treatment and discharge from physiotherapy should be considered carefully as a part of a treatment package.

Painful diabetic peripheral neuropathy (DPN) is common, is associated with significant reduction in quality of life and poses major treatment challenges to the practising physician. Although poor glucose control and cardiovascular risk factors have been proven to contribute to the aetiology of DPN, risk factors specific for painful DPN remain unknown. A number of instruments have been tested to assess the character, intensity and impact of painful DPN on quality of life, activities of daily living and mood. Management of the patient with DPN must be tailored to individual requirements, taking into consideration the co-morbidities and other factors. Pharmacological agents with proven efficacy for painful DPN include tricyclic anti-depressants, the selective serotonin and noradrenaline re-uptake inhibitors, anti-convulsants, opiates, membrane stabilizers, the anti-oxidant alpha-lipoic acid and topical agents including capsaicin. Current first-line therapies for painful DPN include tricyclic anti-depressants, the serotonin and noradrenaline re-uptake inhibitor duloxetine and the anti-convulsants pregabalin and gabapentin. When prescribing any of these agents, other co-morbidities and costs must be taken into account. Second-line approaches include the use of opiates such as synthetic opioid tramadol, morphine and oxycodone-controlled release. There is a limited literature with regard to combination treatment. In extreme cases of painful DPN unresponsive to pharmacotherapy, occasional use of electrical spinal cord stimulation might be indicated. There are a number of unmet needs in the therapeutic management of painful DPN. These include the need for randomized controlled trials with active comparators and data on the long-term efficacy of agents used, as most trials have lasted for less than 6 months. Finally, there is a need for appropriately designed studies to investigate non-pharmacological approaches.

OBJECTIVE: To evaluate olfactory function in Parkinson's disease. METHODS: A standardised odour identification test was used, together with an evoked potential assessment with hydrogen sulphide. In addition, histological analysis was performed on the olfactory bulbs of cadavers who died from Parkinson's disease. RESULTS: Over 70% of patients studied (71 of 96) were outside the 95% limit of normal on the identification test in an age matched sample and there was an unusual pattern of selective loss to certain odours, not hitherto described. The evoked potentials were significantly delayed but of comparable amplitude to a control matched population. Of the 73 patients studied only 37 had a technically satisfactory record containing a clear response to both gases and of these, 12 were delayed. For H2S there was more delay on stimulating the right nostril than the left. Some patients with normal smell identification test scores had delayed evoked potentials. In the pathological examination of olfactory bulbs from eight brains, changes characteristic of Parkinson's disease (Lewy bodies) were seen in every olfactory bulb, particularly in the anterior olfactory nucleus, and were sufficiently distinct to allow a presumptive diagnosis of Parkinson's disease. CONCLUSIONS: Olfactory damage in Parkinson's disease is consistent and severe and may provide an important clue to the aetiology of the disease.

The aim of this study was to examine the effect of playing formation on high-intensity running and technical performance during elite soccer matches. Twenty English FA Premier League games were analysed using a multiple-camera computerized tracking system (n = 153 players). Overall ball possession did not differ (P < 0.05) between 4-4-2, 4-3-3 and 4-5-1 formations (50%, s = 7 vs. 49%, s = 8 vs. 44%, s = 6). No differences were observed in high-intensity running between 4-4-2, 4-3-3 and 4-5-1 formations. Compared with 4-4-2 and 4-3-3 formations, players in a 4-5-1 formation performed less very high-intensity running when their team was in possession (312 m, s = 196 vs. 433 m, s = 261 vs. 410 m, s = 270; P 5 0.05) but more when their team was not in possession (547 m, s = 217 vs. 461 m, s = 156 vs. 459 m, s = 169; P < 0.05). Attackers in a 4-3-3 performed ~30% more (P < 0.05) high-intensity running than attackers in 4-4-2 and 4-5-1 formations. However, the fraction of successful passes was highest in a 4-4-2 (P < 0.05) compared with 4-3-3 and 4-5-1 formations. The results suggest that playing formation does not influence the overall activity profiles of players, except for attackers, but impacts on very high-intensity running activity with and without ball possession and some technical elements of performance.

BACKGROUND: Reduction and modification of dietary fats have differing effects on cardiovascular risk factors (such as serum cholesterol), but their effects on important health outcomes are less clear. OBJECTIVES: To assess the effect of reduction and/or modification of dietary fats on mortality, cardiovascular mortality, cardiovascular morbidity and individual outcomes including myocardial infarction, stroke and cancer diagnoses in randomised clinical trials of at least 6 months duration. SEARCH METHODS: For this review update, the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE and EMBASE, were searched through to June 2010. References of Included studies and reviews were also checked. SELECTION CRITERIA: Trials fulfilled the following criteria: 1) randomised with appropriate control group, 2) intention to reduce or modify fat or cholesterol intake (excluding exclusively omega-3 fat interventions), 3) not multi factorial, 4) adult humans with or without cardiovascular disease, 5) intervention at least six months, 6) mortality or cardiovascular morbidity data available. DATA COLLECTION AND ANALYSIS: Participant numbers experiencing health outcomes in each arm were extracted independently in duplicate and random effects meta-analyses, meta-regression, sub-grouping, sensitivity analyses and funnel plots were performed. MAIN RESULTS: This updated review suggested that reducing saturated fat by reducing and/or modifying dietary fat reduced the risk of cardiovascular events by 14% (RR 0.86, 95% CI 0.77 to 0.96, 24 comparisons, 65,508 participants of whom 7% had a cardiovascular event, I(2) 50%). Subgrouping suggested that this reduction in cardiovascular events was seen in studies of fat modification (not reduction - which related directly to the degree of effect on serum total and LDL cholesterol and triglycerides), of at least two years duration and in studies of men (not of women). There were no clear effects of dietary fat changes on total mortality (RR 0.98, 95% CI 0.93 to 1.04, 71,790 participants) or cardiovascular mortality (RR 0.94, 95% CI 0.85 to 1.04, 65,978 participants). This did not alter with sub-grouping or sensitivity analysis.Few studies compared reduced with modified fat diets, so direct comparison was not possible. AUTHORS' CONCLUSIONS: The findings are suggestive of a small but potentially important reduction in cardiovascular risk on modification of dietary fat, but not reduction of total fat, in longer trials. Lifestyle advice to all those at risk of cardiovascular disease and to lower risk population groups, should continue to include permanent reduction of dietary saturated fat and partial replacement by unsaturates. The ideal type of unsaturated fat is unclear.

The ANCA associated vasculitides (AAV) comprise are a group of conditions characterized by inflammation and necrosis of small and medium-sized blood vessels. They comprise Wegener's granulomatosis, Churg–Strauss syndrome and microscopic polyangiitis. Early diagnosis and treatment is important as the presence of advanced disease at diagnosis limits the potential benefit of therapy. The aim of this document is to provide guidelines for the management of adults with systemic vasculitis. The guidelines concentrate on the indications for using cyclophosphamide and the different therapeutic regimens available. The guideline does not cover the treatment of children or other types of systemic vasculitis. The target audience is rheumatologists, nephrologists and general physicians, together with trainees and nurse practitioners. This is a short summary of the whole guideline. The full guideline is available on the journal website. We have produced evidence-based recommendations for treatment giving a grade of recommendation (from A to C) and an algorithm to illustrate the approach to the management of a patient with newly diagnosed AAV. Eligibility for treatment and use of this guideline depends on the assumption that a definite diagnosis of vasculitis has been made. The following criteria must be fulfilled prior to a diagnosis of vasculitis: Symptoms and signs characteristic of systemic vasculitis. At least one of the following: Histological evidence of vasculitis and/or granuloma formation, Positive serology for ANCA (either cANCA/PR3 or pANCA/MPO), Specific indirect evidence of vasculitis. No other diagnosis to account for symptoms or signs. It is important to consider other causes of systemic illness, especially malignancy, infection (particularly bacterial endocarditis) and drugs. Treatment for vasculitis requires induction of remission followed by maintenance (A). Current treatment is based on assessing the severity and extent of disease and subdividing the disease into three groups: (i) localized and/or early, (ii) generalized disease with threatened organ involvement and (iii) severe/life threatening disease (C). Algorithm of guideline. Localized/early systemic disease Treatment should be with either cyclophosphamide or methotrexate. Methotrexate may be associated with a higher relapse rate (A). Evidence of progression or relapse should be treated with cyclophosphamide (B). Localized disease can cause significant local destruction and requires treatment with cyclophosphamide treatment (C). Generalized/threatened organ involvement Initial treatment of generalized/organ threatening disease should include cyclophosphamide and steroids (A). Cyclophosphamide may be given as continuous low dose oral treatment or by intravenous pulses initially at 2-week intervals and then 3 weekly (A). There is no difference in remission rates and no increased risk of relapse between IV and oral regimens (A). Continuous low dose oral cyclophosphamide was associated with a higher total cyclophosphamide dosage and a significant increase in infection risk. Transfer to maintenance therapy at 3 months when receiving continuous low dose oral cyclophosphamide and at 3–6 months when receiving pulsed intravenous cyclophosphamide if successful disease remission has been achieved (A). In both cases, the aim should be for a maximum duration of therapy of 6 months where successful disease remission has been achieved. Severe/life threatening disease Patients with AAV presenting with severe renal failure (creatinine >500 μmol/l) should be treated with cyclophosphamide (either pulsed IV or continuous low dose oral) and steroids, with adjuvant plasma exchange (A). Plasma exchange should also be considered in those with other life threatening manifestations of disease such as pulmonary haemorrhage (C). Steroids Steroids are usually given as daily oral prednisolone. Initially at relatively high doses; 1 mg/kg up to 60 mg (A). Intravenous steroids (250–500 mg methylpredinisolone) are sometimes given just prior to/with the first two pulses of cyclophosphamide (A). Patients intolerant of cyclophosphamide For cases where patients are intolerant of cyclophosphamide, alternative treatments such as methotrexate, azathioprine, leflunomide or mycophenolate mofetil may be used (B,C). Maintenance therapy Following achievement of successful remission, cyclophosphamide should be withdrawn and substituted with either azathioprine or methotrexate (A). Mycophenolate or leflunomide may be used as alternatives for intolerance or lack of efficacy of azathioprine or methotrexate (C). Patients should continue maintenance therapy for at least 24 months following successful disease remission (B). Patients with Wegener's granulomatosis or patients who remain ANCA positive should continue immunosuppression for up to 5 years (C). Relapsing disease Minor relapse is treated with an increase in prednisolone dosage and optimization of concurrent immunosuppression (C). Major relapse is treated with cyclophosphamide with an increase in prednisolone; intravenous methylprednisolone or plasma exchange may also be considered (C). Refractory disease The use of infliximab, intravenous immunoglobulin, antithymocyte globulin, CAMPATH-1H (alemtuzumab, anti-CD52), deoxyspergualin and rituximab in refractory disease is still under investigation (C). It is important to identify potential underlying factors influencing persistent or relapsing disease including infection and malignancy. Assessment and monitoring of disease activity Relapse may occur at anytime after diagnosis and remission induction. A validated tool should be used to assess disease activity and extent of disease (C). ANCA measurements are not closely associated with disease activity. Treatment should not be escalated solely on the basis of an increase in ANCA (B). Treatment withdrawal in patients with persistently positive ANCA is associated with relapse. Detection and prevention of potential adverse effects of immunosuppressive therapy 1. Mesna should be considered for protection against urothelial toxicity (C). 2. Trimethoprim/sulfamethoxazole (or aerolized pentamidine) should used as prophylaxis against pneumocystis jiroveci (B,C). 3. Antifungal prophylaxis treatment should be used (C). 4. Staphylococcal aureus treatment with long-term nasal mupirocin should be considered (C). 5. Female patients should be screened for cervical intraepithelial neoplasia (CIN) (C). 6. Patients should be counselled about the possibility of infertility following cyclophosphamide treatment (C). 7. Prophylaxis against osteoporosis should be used on all patients receiving high dose corticosteroids (C). 8. Patients receiving immunosuppression should be screened for TB (C). 9. Patients receiving immunosuppression should be vaccinated against pneumococcal infection and influenza (C). 10. Cardiovascular and thromboembolic risk should assessed (C). Audit This should include relapse rate, infection rate, mortality and cumulative doses of cyclophosphamide.

OBJECTIVE: To assess changes in diabetic lower-extremity amputation rates in a defined relatively static population over an 11-year period following the introduction of a multidisciplinary foot team. RESEARCH DESIGN AND METHODS: All diabetic patients with foot problems admitted to Ipswich Hospital, a large district general hospital, were identified by twice-weekly surveillance of all relevant in-patient areas and outcomes including amputations recorded. RESULTS: The incidence of major amputations fell 62%, from 7.4 to 2.8 per 100,000 of the general population. Total amputation rates also decreased (40.3%) but to a lesser extent due to a small increase in minor amputations. Expressed as incidence per 10,000 people with diabetes, total amputations fell 70%, from 53.2 to 16.0, and major amputations fell 82%, from 36.4 to 6.7. CONCLUSIONS: Significant reductions in total and major amputation rates occurred over the 11-year period following improvements in foot care services including multidisciplinary team work.

OBJECTIVE: To evaluate the effectiveness of continuous glucose monitoring during pregnancy on maternal glycaemic control, infant birth weight, and risk of macrosomia in women with type 1 and type 2 diabetes. DESIGN: Prospective, open label randomised controlled trial. SETTING: Two secondary care multidisciplinary obstetric clinics for diabetes in the United Kingdom. PARTICIPANTS: 71 women with type 1 diabetes (n=46) or type 2 diabetes (n=25) allocated to antenatal care plus continuous glucose monitoring (n=38) or to standard antenatal care (n=33). INTERVENTION: Continuous glucose monitoring was used as an educational tool to inform shared decision making and future therapeutic changes at intervals of 4-6 weeks during pregnancy. All other aspects of antenatal care were equal between the groups. MAIN OUTCOME MEASURES: The primary outcome was maternal glycaemic control during the second and third trimesters from measurements of HbA(1c) levels every four weeks. Secondary outcomes were birth weight and risk of macrosomia using birthweight standard deviation scores and customised birthweight centiles. Statistical analyses were done on an intention to treat basis. RESULTS: Women randomised to continuous glucose monitoring had lower mean HbA(1c) levels from 32 to 36 weeks' gestation compared with women randomised to standard antenatal care: 5.8% (SD 0.6) v 6.4% (SD 0.7). Compared with infants of mothers in the control arm those of mothers in the intervention arm had decreased mean birthweight standard deviation scores (0.9 v 1.6; effect size 0.7 SD, 95% confidence interval 0.0 to 1.3), decreased median customised birthweight centiles (69% v 93%), and a reduced risk of macrosomia (odds ratio 0.36, 95% confidence interval 0.13 to 0.98). CONCLUSION: Continuous glucose monitoring during pregnancy is associated with improved glycaemic control in the third trimester, lower birth weight, and reduced risk of macrosomia. TRIAL REGISTRATION: Current Controlled Trials ISRCTN84461581.

(1)H NMR spectroscopy of aqueous fecal extracts has been used to investigate differences in metabolic activity of gut microbiota in patients with ulcerative colitis (UC) (n = 13), irritable bowel syndrome (IBS) (n = 10), and healthy controls (C) (n = 22). Up to four samples per individual were collected over 2 years giving a total of 124 samples. Multivariate discriminant analysis, based on NMR data from all three groups, was able to predict UC and C group membership with good sensitivity and specificity; classification of IBS samples was less successful and could not be used for diagnosis. Trends were detected toward increased taurine and cadaverine levels in UC with increased bile acid and decreased branched chain fatty acids in IBS relative to controls; changes in short chain fatty acids and amino acids were not significant. Previous PCR-denaturing gradient gel electrophoresis (PCR-DGGE) analysis of the same fecal material had shown alterations of the gut microbiota when comparing UC and IBS groups with controls. Hierarchical cluster analysis showed that DGGE profiles from the same individual were stable over time, but NMR spectra were more variable; canonical correlation analysis of NMR and DGGE data partly separated the three groups and revealed a correlation between the gut microbiota profile and metabolite composition.

after infection with SARS-CoV-2. The GenOMICC (Genetics of Mortality in Critical Care) study enables the comparison of genomes from individuals who are critically ill with those of population controls to find underlying disease mechanisms. Here we use whole-genome sequencing in 7,491 critically ill individuals compared with 48,400 controls to discover and replicate 23 independent variants that significantly predispose to critical COVID-19. We identify 16 new independent associations, including variants within genes that are involved in interferon signalling (IL10RB and PLSCR1), leucocyte differentiation (BCL11A) and blood-type antigen secretor status (FUT2). Using transcriptome-wide association and colocalization to infer the effect of gene expression on disease severity, we find evidence that implicates multiple genes-including reduced expression of a membrane flippase (ATP11A), and increased expression of a mucin (MUC1)-in critical disease. Mendelian randomization provides evidence in support of causal roles for myeloid cell adhesion molecules (SELE, ICAM5 and CD209) and the coagulation factor F8, all of which are potentially druggable targets. Our results are broadly consistent with a multi-component model of COVID-19 pathophysiology, in which at least two distinct mechanisms can predispose to life-threatening disease: failure to control viral replication; or an enhanced tendency towards pulmonary inflammation and intravascular coagulation. We show that comparison between cases of critical illness and population controls is highly efficient for the detection of therapeutically relevant mechanisms of disease.