South Tees Hospitals NHS Foundation Trust

BACKGROUND: Long-term hormone therapy has been the standard of care for advanced prostate cancer since the 1940s. STAMPEDE is a randomised controlled trial using a multiarm, multistage platform design. It recruits men with high-risk, locally advanced, metastatic or recurrent prostate cancer who are starting first-line long-term hormone therapy. We report primary survival results for three research comparisons testing the addition of zoledronic acid, docetaxel, or their combination to standard of care versus standard of care alone. METHODS: Standard of care was hormone therapy for at least 2 years; radiotherapy was encouraged for men with N0M0 disease to November, 2011, then mandated; radiotherapy was optional for men with node-positive non-metastatic (N+M0) disease. Stratified randomisation (via minimisation) allocated men 2:1:1:1 to standard of care only (SOC-only; control), standard of care plus zoledronic acid (SOC + ZA), standard of care plus docetaxel (SOC + Doc), or standard of care with both zoledronic acid and docetaxel (SOC + ZA + Doc). Zoledronic acid (4 mg) was given for six 3-weekly cycles, then 4-weekly until 2 years, and docetaxel (75 mg/m(2)) for six 3-weekly cycles with prednisolone 10 mg daily. There was no blinding to treatment allocation. The primary outcome measure was overall survival. Pairwise comparisons of research versus control had 90% power at 2·5% one-sided α for hazard ratio (HR) 0·75, requiring roughly 400 control arm deaths. Statistical analyses were undertaken with standard log-rank-type methods for time-to-event data, with hazard ratios (HRs) and 95% CIs derived from adjusted Cox models. This trial is registered at ClinicalTrials.gov (NCT00268476) and ControlledTrials.com (ISRCTN78818544). FINDINGS: 2962 men were randomly assigned to four groups between Oct 5, 2005, and March 31, 2013. Median age was 65 years (IQR 60-71). 1817 (61%) men had M+ disease, 448 (15%) had N+/X M0, and 697 (24%) had N0M0. 165 (6%) men were previously treated with local therapy, and median prostate-specific antigen was 65 ng/mL (IQR 23-184). Median follow-up was 43 months (IQR 30-60). There were 415 deaths in the control group (347 [84%] prostate cancer). Median overall survival was 71 months (IQR 32 to not reached) for SOC-only, not reached (32 to not reached) for SOC + ZA (HR 0·94, 95% CI 0·79-1·11; p=0·450), 81 months (41 to not reached) for SOC + Doc (0·78, 0·66-0·93; p=0·006), and 76 months (39 to not reached) for SOC + ZA + Doc (0·82, 0·69-0·97; p=0·022). There was no evidence of heterogeneity in treatment effect (for any of the treatments) across prespecified subsets. Grade 3-5 adverse events were reported for 399 (32%) patients receiving SOC, 197 (32%) receiving SOC + ZA, 288 (52%) receiving SOC + Doc, and 269 (52%) receiving SOC + ZA + Doc. INTERPRETATION: Zoledronic acid showed no evidence of survival improvement and should not be part of standard of care for this population. Docetaxel chemotherapy, given at the time of long-term hormone therapy initiation, showed evidence of improved survival accompanied by an increase in adverse events. Docetaxel treatment should become part of standard of care for adequately fit men commencing long-term hormone therapy. FUNDING: Cancer Research UK, Medical Research Council, Novartis, Sanofi-Aventis, Pfizer, Janssen, Astellas, NIHR Clinical Research Network, Swiss Group for Clinical Cancer Research.

Abstract The genetic make-up of an individual contributes to the susceptibility and response to viral infection. Although environmental, clinical and social factors have a role in the chance of exposure to SARS-CoV-2 and the severity of COVID-19 1,2 , host genetics may also be important. Identifying host-specific genetic factors may reveal biological mechanisms of therapeutic relevance and clarify causal relationships of modifiable environmental risk factors for SARS-CoV-2 infection and outcomes. We formed a global network of researchers to investigate the role of human genetics in SARS-CoV-2 infection and COVID-19 severity. Here we describe the results of three genome-wide association meta-analyses that consist of up to 49,562 patients with COVID-19 from 46 studies across 19 countries. We report 13 genome-wide significant loci that are associated with SARS-CoV-2 infection or severe manifestations of COVID-19. Several of these loci correspond to previously documented associations to lung or autoimmune and inflammatory diseases 3–7 . They also represent potentially actionable mechanisms in response to infection. Mendelian randomization analyses support a causal role for smoking and body-mass index for severe COVID-19 although not for type II diabetes. The identification of novel host genetic factors associated with COVID-19 was made possible by the community of human genetics researchers coming together to prioritize the sharing of data, results, resources and analytical frameworks. This working model of international collaboration underscores what is possible for future genetic discoveries in emerging pandemics, or indeed for any complex human disease.

BACKGROUND: In patients with ST-segment elevation myocardial infarction (STEMI), percutaneous coronary intervention (PCI) of the culprit lesion reduces the risk of cardiovascular death or myocardial infarction. Whether PCI of nonculprit lesions further reduces the risk of such events is unclear. METHODS: We randomly assigned patients with STEMI and multivessel coronary artery disease who had undergone successful culprit-lesion PCI to a strategy of either complete revascularization with PCI of angiographically significant nonculprit lesions or no further revascularization. Randomization was stratified according to the intended timing of nonculprit-lesion PCI (either during or after the index hospitalization). The first coprimary outcome was the composite of cardiovascular death or myocardial infarction; the second coprimary outcome was the composite of cardiovascular death, myocardial infarction, or ischemia-driven revascularization. RESULTS: At a median follow-up of 3 years, the first coprimary outcome had occurred in 158 of the 2016 patients (7.8%) in the complete-revascularization group as compared with 213 of the 2025 patients (10.5%) in the culprit-lesion-only PCI group (hazard ratio, 0.74; 95% confidence interval [CI], 0.60 to 0.91; P = 0.004). The second coprimary outcome had occurred in 179 patients (8.9%) in the complete-revascularization group as compared with 339 patients (16.7%) in the culprit-lesion-only PCI group (hazard ratio, 0.51; 95% CI, 0.43 to 0.61; P<0.001). For both coprimary outcomes, the benefit of complete revascularization was consistently observed regardless of the intended timing of nonculprit-lesion PCI (P = 0.62 and P = 0.27 for interaction for the first and second coprimary outcomes, respectively). CONCLUSIONS: Among patients with STEMI and multivessel coronary artery disease, complete revascularization was superior to culprit-lesion-only PCI in reducing the risk of cardiovascular death or myocardial infarction, as well as the risk of cardiovascular death, myocardial infarction, or ischemia-driven revascularization. (Funded by the Canadian Institutes of Health Research and others; COMPLETE ClinicalTrials.gov number, NCT01740479.).

The discovery of malignant cells in pleural fluid and/or parietal pleura signifies disseminated or advanced disease and a reduced life expectancy in patients with cancer.1 Median survival following diagnosis ranges from 3 to 12 months and is dependent on the stage and type of the underlying malignancy. The shortest survival time is observed in malignant effusions secondary to lung cancer and the longest in ovarian cancer, while malignant effusions due to an unknown primary have an intermediate survival time.2–6 Historically, studies showed that median survival times in effusions due to carcinoma of the breast are 5–6 months. However, more recent studies have suggested longer survival times of up to 15 months.7–10 A comparison of survival times in breast cancer effusions in published studies to 1994 calculated a median survival of 11 months.9 Currently, lung cancer is the most common metastatic tumour to the pleura in men and breast cancer in women.4 11 Together, both malignancies account for 50–65% of all malignant effusions (table 1). Lymphomas, tumours of the genitourinary tract and gastrointestinal tract account for a further 25%.2 12–14 Pleural effusions from an unknown primary are responsible for 7–15% of all malignant pleural effusions.3 13 14 Few studies have estimated the proportion of pleural effusions due to mesothelioma: studies from 1975, 1985 and 1987 identified mesothelioma in 1/271, 3/472 and 22/592 patients, respectively, but there are no more recent data to update this in light of the increasing incidence of mesothelioma.4 13 14 View this table: Table 1 Primary tumour site in patients with malignant pleural effusion Attempts have been made to predict survival based on the clinical characteristics of pleural fluid. None has shown a definite correlation: a recent systematic review of studies including 433 patients assessing the predictive value of pH concluded that low pH does not reliably predict …

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.

OBJECTIVE: The objective of this study is to estimate life expectancies of HIV-positive patients conditional on response to antiretroviral therapy (ART). METHODS: Patients aged more than 20 years who started ART during 2000-2010 (excluding IDU) in HIV clinics contributing to the UK CHIC Study were followed for mortality until 2012. We determined the latest CD4 cell count and viral load before ART and in each of years 1-5 of ART. For each duration of ART, life tables based on estimated mortality rates by sex, age, latest CD4 cell count and viral suppression (HIV-1 RNA <400 copies/ml), were used to estimate expected age at death for ages 20-85 years. RESULTS: Of 21 388 patients who started ART, 961 (4.5%) died during 110 697 person-years. At start of ART, expected age at death [95% confidence interval (CI)] of 35-year-old men with CD4 cell count less than 200, 200-349, at least 350 cells/μl was 71 (68-73), 78 (74-82) and 77 (72-81) years, respectively, compared with 78 years for men in the general UK population. Thirty-five-year-old men who increased their CD4 cell count in the first year of ART from less than 200 to 200-349 or at least 350 cells/μl and achieved viral suppression gained 7 and 10 years, respectively. After 5 years on ART, expected age at death of 35-year-old men varied from 54 (48-61) (CD4 cell count <200 cells/μl and no viral suppression) to 80 (76-83) years (CD4 cell count ≥350 cells/μl and viral suppression). CONCLUSION: Successfully treated HIV-positive individuals have a normal life expectancy. Patients who started ART with a low CD4 cell count significantly improve their life expectancy if they have a good CD4 cell count response and undetectable viral load.

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.

Electrochemotherapy is now in routine clinical use to treat cutaneous metastases of any histology, and is listed in national and international guidelines for cutaneous metastases and primary skin cancer. Electrochemotherapy is used by dermatologists, surgeons, and oncologists, and for different degrees and manifestations of metastases to skin and primary skin tumours not amenable to surgery. This treatment utilises electric pulses to permeabilize cell membranes in tumours, thus allowing a dramatic increase of the cytotoxicity of anti-cancer agents. Response rates, often after only one treatment, are very high across all tumour types. The most frequent indications are cutaneous metastases from malignant melanoma and breast cancer. In 2006, standard operating procedures (SOPs) were written for this novel technology, greatly facilitating introduction and dissemination of the therapy. Since then considerable experience has been obtained treating a wider range of tumour histologies and increasing size of tumours which was not originally thought possible. A pan-European expert panel drawn from a range of disciplines from dermatology, general surgery, head and neck surgery, plastic surgery, and oncology met to form a consensus opinion to update the SOPs based on the experience obtained. This paper contains these updated recommendations for indications for electrochemotherapy, pre-treatment information and evaluation, treatment choices, as well as follow-up.

Primary biliary cirrhosis (PBC) is a classical autoimmune liver disease for which effective immunomodulatory therapy is lacking. Here we perform meta-analyses of discovery data sets from genome-wide association studies of European subjects (n=2,764 cases and 10,475 controls) followed by validation genotyping in an independent cohort (n=3,716 cases and 4,261 controls). We discover and validate six previously unknown risk loci for PBC (Pcombined<5 × 10(-8)) and used pathway analysis to identify JAK-STAT/IL12/IL27 signalling and cytokine-cytokine pathways, for which relevant therapies exist.

BACKGROUND: Malignant pleural effusion affects more than 750,000 persons each year across Europe and the United States. Pleurodesis with the administration of talc in hospitalized patients is the most common treatment, but indwelling pleural catheters placed for drainage offer an ambulatory alternative. We examined whether talc administered through an indwelling pleural catheter was more effective at inducing pleurodesis than the use of an indwelling pleural catheter alone. METHODS: Over a period of 4 years, we recruited patients with malignant pleural effusion at 18 centers in the United Kingdom. After the insertion of an indwelling pleural catheter, patients underwent drainage regularly on an outpatient basis. If there was no evidence of substantial lung entrapment (nonexpandable lung, in which lung expansion and pleural apposition are not possible because of visceral fibrosis or bronchial obstruction) at 10 days, patients were randomly assigned to receive either 4 g of talc slurry or placebo through the indwelling pleural catheter on an outpatient basis. Talc or placebo was administered on a single-blind basis. Follow-up lasted for 70 days. The primary outcome was successful pleurodesis at day 35 after randomization. RESULTS: The target of 154 patients undergoing randomization was reached after 584 patients were approached. At day 35, a total of 30 of 69 patients (43%) in the talc group had successful pleurodesis, as compared with 16 of 70 (23%) in the placebo group (hazard ratio, 2.20; 95% confidence interval, 1.23 to 3.92; P=0.008). No significant between-group differences in effusion size and complexity, number of inpatient days, mortality, or number of adverse events were identified. No significant excess of blockages of the indwelling pleural catheter was noted in the talc group. CONCLUSIONS: Among patients without substantial lung entrapment, the outpatient administration of talc through an indwelling pleural catheter for the treatment of malignant pleural effusion resulted in a significantly higher chance of pleurodesis at 35 days than an indwelling catheter alone, with no deleterious effects. (Funded by Becton Dickinson; EudraCT number, 2012-000599-40 .).

BACKGROUND: Microalbuminuria in diabetes is strongly predictive of nephropathy, end-stage renal disease, and premature cardiovascular morbidity and mortality. Effective preventive therapies are therefore a clinical priority. OBJECTIVE: To determine whether the angiotensin-receptor blocker candesartan compared with placebo affects microalbuminuria incidence or rate of change in albuminuria in type 1 and type 2 diabetes. DESIGN: 3 randomized trials of the DIRECT (Diabetic Retinopathy Candesartan Trials) Program. SETTING: 309 secondary care centers. PATIENTS: 3326 and 1905 patients with type 1 and type 2 diabetes, respectively. Most were normotensive, and all had normoalbuminuria (median urinary albumin excretion rate, 5.0 microg/min). INTERVENTION: Candesartan, 16 mg/d increasing to 32 mg/d, versus placebo. Assignment was done centrally using an interactive voice-response system. Patients, caregivers, and researchers were blinded to treatment assignment. During a median follow-up of 4.7 years, 793 patients discontinued therapy and 63 were lost to follow-up. MEASUREMENTS: Urinary albumin excretion rate, assessed annually by 2 overnight collections; if it was 20 microg/min or greater, then 2 further collections were done. The primary end point was new microalbuminuria (3 or 4 collections of urinary albumin excretion rate >or=20 microg/min). The secondary end point was rate of change in albuminuria. RESULTS: Individual and pooled results of the 3 trials showed that candesartan had little effect on risk for microalbuminuria (pooled hazard ratio, 0.95 [95% CI, 0.78 to 1.16]; P = 0.60). Pooled results showed that the annual rate of change in albuminuria was 5.53% lower (CI, 0.73% to 10.14%; P = 0.024) with candesartan than with placebo. LIMITATIONS: Investigators recruited mainly normotensive patients or patients with well-controlled hypertension who were at low overall vascular risk, which resulted in a low rate of microalbuminuria. Studies were powered for retinal and not renal end points. CONCLUSION: Candesartan, 32 mg/d, for 4.7 years did not prevent microalbuminuria in mainly normotensive patients with type 1 or type 2 diabetes.

Background: Adding abiraterone acetate with prednisolone (AAP) or docetaxel with prednisolone (DocP) to standard-of-care (SOC) each improved survival in systemic therapy for advanced or metastatic prostate cancer: evaluation of drug efficacy: a multi-arm multi-stage platform randomised controlled protocol recruiting patients with high-risk locally advanced or metastatic PCa starting long-term androgen deprivation therapy (ADT). The protocol provides the only direct, randomised comparative data of SOC + AAP versus SOC + DocP. Method: Recruitment to SOC + DocP and SOC + AAP overlapped November 2011 to March 2013. SOC was long-term ADT or, for most non-metastatic cases, ADT for ≥2 years and RT to the primary tumour. Stratified randomisation allocated pts 2 : 1 : 2 to SOC; SOC + docetaxel 75 mg/m2 3-weekly×6 + prednisolone 10 mg daily; or SOC + abiraterone acetate 1000 mg + prednisolone 5 mg daily. AAP duration depended on stage and intent to give radical RT. The primary outcome measure was death from any cause. Analyses used Cox proportional hazards and flexible parametric models, adjusted for stratification factors. This was not a formally powered comparison. A hazard ratio (HR) <1 favours SOC + AAP, and HR > 1 favours SOC + DocP. Results: A total of 566 consenting patients were contemporaneously randomised: 189 SOC + DocP and 377 SOC + AAP. The patients, balanced by allocated treatment were: 342 (60%) M1; 429 (76%) Gleason 8-10; 449 (79%) WHO performance status 0; median age 66 years and median PSA 56 ng/ml. With median follow-up 4 years, 149 deaths were reported. For overall survival, HR = 1.16 (95% CI 0.82-1.65); failure-free survival HR = 0.51 (95% CI 0.39-0.67); progression-free survival HR = 0.65 (95% CI 0.48-0.88); metastasis-free survival HR = 0.77 (95% CI 0.57-1.03); prostate cancer-specific survival HR = 1.02 (0.70-1.49); and symptomatic skeletal events HR = 0.83 (95% CI 0.55-1.25). In the safety population, the proportion reporting ≥1 grade 3, 4 or 5 adverse events ever was 36%, 13% and 1% SOC + DocP, and 40%, 7% and 1% SOC + AAP; prevalence 11% at 1 and 2 years on both arms. Relapse treatment patterns varied by arm. Conclusions: This direct, randomised comparative analysis of two new treatment standards for hormone-naïve prostate cancer showed no evidence of a difference in overall or prostate cancer-specific survival, nor in other important outcomes such as symptomatic skeletal events. Worst toxicity grade over entire time on trial was similar but comprised different toxicities in line with the known properties of the drugs. Trial registration: Clinicaltrials.gov: NCT00268476.

In this article, we review the evidence underpinning the broader prehabilitation concept and the target behavioural and lifestyle risk factors including their perioperative impact and evidence for prehabilitation intervention. We also identify principles for delivering prehabilitation in practice, alongside lessons for the perioperative setting from well-established allied interventions; cardiac and pulmonary rehabilitation.

In rodents, exposure to high-level noise can destroy synapses between inner hair cells and auditory nerve fibers, without causing hair cell loss or permanent threshold elevation. Such "cochlear synaptopathy" is associated with amplitude reductions in wave I of the auditory brainstem response (ABR) at moderate-to-high sound levels. Similar ABR results have been reported in humans with tinnitus and normal audiometric thresholds, leading to the suggestion that tinnitus in these cases might be a consequence of synaptopathy. However, the ABR is an indirect measure of synaptopathy and it is unclear whether the results in humans reflect the same mechanisms demonstrated in rodents. Measures of noise exposure were not obtained in the human studies, and high frequency audiometric loss may have impacted ABR amplitudes. To clarify the role of cochlear synaptopathy in tinnitus with a normal audiogram, we recorded ABRs, envelope following responses (EFRs), and noise exposure histories in young adults with tinnitus and matched controls. Tinnitus was associated with significantly greater lifetime noise exposure, despite close matching for age, sex, and audiometric thresholds up to 14 kHz. However, tinnitus was not associated with reduced ABR wave I amplitude, nor with significant effects on EFR measures of synaptopathy. These electrophysiological measures were also uncorrelated with lifetime noise exposure, providing no evidence of noise-induced synaptopathy in this cohort, despite a wide range of exposures. In young adults with normal audiograms, tinnitus may be related not to cochlear synaptopathy but to other effects of noise exposure.

BACKGROUND: Accurate optical characterisation and removal of small adenomas (<10 mm) at colonoscopy would allow hyperplastic polyps to be left in situ and surveillance intervals to be determined without the need for histopathology. Although accurate in specialist practice the performance of narrow band imaging (NBI), colonoscopy in routine clinical practice is poorly understood. METHODS: NBI-assisted optical diagnosis was compared with reference standard histopathological findings in a prospective, blinded study, which recruited adults undergoing routine colonoscopy in six general hospitals in the UK. Participating colonoscopists (N=28) were trained using the NBI International Colorectal Endoscopic (NICE) classification (relating to colour, vessel structure and surface pattern). By comparing the optical and histological findings in patients with only small polyps, test sensitivity was determined at the patient level using two thresholds: presence of adenoma and need for surveillance. Accuracy of identifying adenomatous polyps <10 mm was compared at the polyp level using hierarchical models, allowing determinants of accuracy to be explored. FINDINGS: Of 1688 patients recruited, 722 (42.8%) had polyps <10 mm with 567 (78.5%) having only polyps <10 mm. Test sensitivity (presence of adenoma, N=499 patients) by NBI optical diagnosis was 83.4% (95% CI 79.6% to 86.9%), significantly less than the 95% sensitivity (p<0.001) this study was powered to detect. Test sensitivity (need for surveillance) was 73.0% (95% CI 66.5% to 79.9%). Analysed at the polyp level, test sensitivity (presence of adenoma, N=1620 polyps) was 76.1% (95% CI 72.8% to 79.1%). In fully adjusted analyses, test sensitivity was 99.4% (95% CI 98.2% to 99.8%) if two or more NICE adenoma characteristics were identified. Neither colonoscopist expertise, confidence in diagnosis nor use of high definition colonoscopy independently improved test accuracy. INTERPRETATION: This large multicentre study demonstrates that NBI optical diagnosis cannot currently be recommended for application in routine clinical practice. Further work is required to evaluate whether variation in test accuracy is related to polyp characteristics or colonoscopist training. TRIAL REGISTRATION NUMBER: The study was registered with clinicaltrials.gov (NCT01603927).

BACKGROUND: Early physical rehabilitation in the intensive care unit (ICU) has been shown to improve short-term clinical outcomes but long-term benefit has not been proven and the optimum intensity of rehabilitation is not known. METHODS: We conducted a randomised, parallel-group, allocation-concealed, assessor-blinded, controlled trial in patients who had received at least 48 hours of invasive or non-invasive ventilation. Participants were randomised in a 1:1 ratio, stratified by admitting ICU, admission type and level of independence. The intervention group had a target of 90 min physical rehabilitation per day, the control group a target of 30 min per day (both Monday to Friday). The primary outcome was the Physical Component Summary (PCS) measure of SF-36 at 6 months. RESULTS: We recruited 308 participants over 34 months: 150 assigned to the intervention and 158 to the control group. The intervention group received a median (IQR) of 161 (67-273) min of physical rehabilitation on ICU compared with 86 (31-139) min in the control group. At 6 months, 62 participants in the intervention group and 54 participants in the control group contributed primary outcome data. In the intervention group, 43 had died, 11 had withdrawn and 34 were lost to follow-up, while in the control group, 56 had died, 5 had withdrawn and 43 were lost to follow-up. There was no difference in the primary outcome at 6 months, mean (SD) PCS 37 (12.2) in the intervention group and 37 (11.3) in the control group. CONCLUSIONS: In this study, ICU-based physical rehabilitation did not appear to improve physical outcomes at 6 months compared with standard physical rehabilitation. TRIAL REGISTRATION NUMBER: ISRCTN 20436833.

AIM: Lung metastases from colorectal cancer are resected in selected patients in the belief that this confers a significant survival advantage. It is generally assumed that the 5-year survival of these patients would be near zero without metastasectomy. We tested the clinical effectiveness of this practice in Pulmonary Metastasectomy in Colorectal Cancer (PulMiCC), a randomized, controlled noninferiority trial. METHOD: Multidisciplinary teams in 14 hospitals recruited patients with resectable lung metastases into a two-arm trial. Randomization was remote and stratified according to site, with minimization for age, sex, primary cancer stage, interval since primary resection, prior liver involvement, number of metastases and carcinoembryonic antigen level. The trial management group was blind to patient allocation until after intention-to-treat analysis. RESULTS: From 2010 to 2016, 93 participants were randomized. These patients were 35-86 years of age and had between one and six lung metastases at a median of 2.7 years after colorectal cancer resection; 29% had prior liver metastasectomy. The patient groups were well matched and the characteristics of these groups were similar to those of observational studies. The median survival after metastasectomy was 3.5 (95% CI: 3.1-6.6) years compared with 3.8 (95% CI: 3.1-4.6) years for controls. The estimated unadjusted hazard ratio for death within 5 years, comparing the metastasectomy group with the control group, was 0.93 (95% CI: 0.56-1.56). Use of chemotherapy or local ablation was infrequent and similar in each group. CONCLUSION: Patients in the control group (who did not undergo lung metastasectomy) have better survival than is assumed. Survival in the metastasectomy group is comparable with the many single-arm follow-up studies. The groups were well matched with features similar to those reported in case series.

Contents The effective development and maintenance of satisfactory standards in pre-transfusion testing requires a structured approach in the adoption of a quality management system. Technical errors, clerical errors, the use of non-validated techniques or equipment and non-compliance with established procedures may result in missed incompatibilities and immediate or delayed haemolytic transfusion reactions (SHOT, 1996–2010; Stainsby et al., 2006). The purpose of these guidelines, which replace those published in 2004 (Chapman et al., 2004), is to define the laboratory processes and procedures that should be adopted to undertake pre-transfusion testing. The guideline group was selected to be representative of UK-based medical, scientific and technical experts. The writing group produced the draft guideline which was subsequently revised by consensus by members of the Transfusion Task Force of the British Committee for Standards in Haematology. The guideline was then reviewed by a sounding board of approximately 50 UK haematologists, the BCSH (British Committee for Standards in Haematology) and the Transfusion Laboratory Managers Working Group of the National Blood Transfusion Committee and its equivalent in the other three countries, and comments incorporated where appropriate. These guidelines are formulated from expert opinion and based on the requirements of the Blood Safety and Quality Regulations (BSQR, 2005), and the recommendations of Clinical Pathology Accreditation (CPA, 2010), Guidelines for Blood Transfusion Services in the UK (UK Blood Transfusion Services, 2012), the UK Transfusion Laboratory Collaborative (Chaffe et al., 2009), and data from UK NEQAS (BTLP) (Knowles et al., 2002; UK NEQAS ANNUAL REPORTS) and the Serious Hazards of Transfusion (SHOT) haemovigilance scheme annual reports (SHOT, 1996–2010). Where evidence exists to support new and potentially contentious recommendations, this is referenced in the text. The quality section includes all of the quality recommendations from the whole guideline, so those using this guideline should refer back to the quality section for advice relating to individual sections. All aspects of testing relating to emergency situations have been put into a separate section – Section 8. Other sections now relate solely to routine testing. Efforts have been made to avoid duplication and overlap with other guidelines. This guidance is complementary to the BCSH guidelines that cover transfusion of paediatric patients, antenatal serology, information technology (IT) systems, administration of blood components and validation in the transfusion laboratory (BCSH, 2004, 2006a,2006b, 2009, 2010a), and these should be available for reference. The referenced versions of these guidelines were current at the time of publication of this document but it is recognised that they may be updated during the lifetime of this guideline, and reference should always be made to the current version. Where expansion on the decision making on the recommendations is required, this is covered in a series of appendices. Recommendations are based on overriding principles, but it is recognised that a safe outcome may be achieved using a different approach, whilst still complying with minimum standards. In these circumstances, a fully documented risk assessment is required. Exceptions to policy relating to individual patients are now covered by a statement relating to concessionary release and an example is given in Appendix APPENDIX 9. There is an additional section relating to what happens after components have been issued, and the serological investigation of a suspected transfusion reaction. There are new flow charts for anomalous D typing and selection of blood in this circumstance, and for anomalous ABO typing (Appendix APPENDIX 3). There are worked examples of antibody identification in Appendix APPENDIX 4. KEY RECOMMENDATION: The laboratory must identify all critical control points in pre-transfusion testing and build in security at these points. KEY RECOMMENDATION: Laboratories must have contingency plans for actions to be taken when normal systems are not available. KEY RECOMMENDATION: The laboratory should have a policy with respect to the manual editing and authorisation of test results. Errors in patient identification and sample labelling may lead to ABO-incompatible transfusions. Evidence for this is well documented in the annual reports of the SHOT steering group (SHOT, 1996–2010) and by others (Stainsby et al., 2006; Sazama, 1990). KEY RECOMMENDATION: Serological studies should be performed using blood collected no more than 3 days in advance of the actual transfusion when the patient has been transfused or pregnant within the preceding 3 months. Whole-blood samples will deteriorate over a period of time. Problems associated with storage include red cell lysis, bacterial contamination, decrease in potency of red cell antibodies, particularly immunoglobulin M (IgM) antibodies and the loss of complement activity in serum samples. Table 1 gives suggestions for working limits (if times are extended this must be supported by local risk assessment prior to implementation). KEY RECOMMENDATION: A pre-transfusion sample should be retained for at least 3 days post-transfusion, to ensure that repeat ABO grouping of the pre-transfusion sample can be performed in the event of an acute transfusion reaction. For more discussion on the recommendations regarding timing of sample collection, storage of samples and use of physical separators, see Appendix APPENDIX 2. KEY RECOMMENDATION: ABO grouping is the single most important serological test performed on pre-transfusion samples and the sensitivity and security of testing systems must not be compromised. KEY RECOMMENDATION: Fully automated systems should be used where possible to reduce the risks of interpretation and transcription errors. KEY RECOMMENDATION: Any abbreviation of the ABO group must be fully risk assessed. KEY RECOMMENDATION AND CRITICAL POINT: The patient demographics on the sample should be checked against the computer record prior to validation of results (preferably prior to testing), to ensure that they match and no errors have been made during data entry onto the LIMS. KEY RECOMMENDATION: If the patient is known to have formed a red cell alloantibody, each new sample should be fully tested to identify or exclude the presence of further alloantibodies. CRITICAL POINT: A check should be made to ensure that the panel results do not conflict with the antibody screening results which may reflect manual tests being performed on the wrong sample. KEY RECOMMENDATION: When one antibody specificity has been identified, it is essential that the presence or absence of additional clinically significant antibodies is established. KEY RECOMMENDATION: Unless secure electronic patient identification systems are in place, a second sample should be requested for confirmation of the ABO group of a first time patient prior to transfusion, where this does not impede the delivery of urgent red cells or other components. KEY RECOMMENDATION: The indirect antiglobulin test (IAT) crossmatch is the default technique which should be used in the absence of functioning, validated IT or when electronic issue is contra-indicated. KEY RECOMMENDATION: An IAT crossmatch must be used if the patient's plasma contains, or has been known to contain, red cell alloantibodies of likely clinical significance. KEY RECOMMENDATION: The overall process for determining eligibility for EI must be controlled by the LIMS and not rely on manual intervention or decision making. KEY RECOMMENDATION: Laboratories should have written protocols in place which define the responsibilities of all staff in dealing with urgent requests. KEY RECOMMENDATION: For genuinely unknown patients, the minimum identifiers are gender and a unique number. KEY RECOMMENDATION: Following an emergency rapid group, a second test to detect ABO incompatibility should be undertaken prior to release of group specific red cells. KEY RECOMMENDATION: If the DAT is positive, an eluate made from the patient's red cells should be prepared and tested for the presence of specific alloantibodies. It is not unusual for the causative antibody to be present in an eluate but absent in the plasma. None of the authors have declared a conflict of interest. While the advice and information in these guidelines is believed to be true and accurate at the time of going to press, neither the authors, the British Society for Haematology, nor the publishers accept any legal responsibility for the content of these guidelines. Table A1 shows examples of critical control points in the compatibility process and risk reduction strategies. The list is not exhaustive but gives examples of some critical control points. Mapping the full compatibility process in each laboratory will aid in identifying these points. • Checking sample barcode against LIMS system after booking in • Automated testing – possible interface / testing errors • Validation of testing system and interface • Special requirements missed • Labelling wrong donations – mix up between patients • Warning in LIMS system if wrong component is selected • Highlighting requirements on request form • Performing only one crossmatch / electronic issue labelling at a time There is a dearth of published data regarding when red cell alloantibodies form and are first detectable following a stimulating event (be it a primary or secondary response). Of the papers available for review it is clear that only a very small percentage of antibodies which are below detectable level pre-transfusion become detectable in the first 72 h, estimated at 2.3% (Schonewille et al., 2006), and supported by SHOT data (SHOT, 1996–2010). Mollison reports that red cell destruction does not begin before the 4th day post-transfusion (Klein & Anstee, 2005b). Following this time, most developing antibodies will manifest themselves within the next 30 days (there are occasional stragglers), and by 3 months post-transfusion very few antibodies will develop. SHOT data shows that the majority of delayed haemolytic transfusion reactions are noted 3–14 days post-transfusion. It was on this basis that the previous guidelines recommended a 24-h lifespan for a sample when the patient had been transfused within the previous 3–14 days. A survey of UK laboratory practice, undertaken by the writing group (through UK NEQAS), revealed that a minority of laboratories comply with this guideline. However, when taking into account the combination of the age of the sample and the length of time that the blood sits in the issue fridge, approximately 80% transfuse within 72 h of a new sample being taken (Milkins et al., 2010). The vast majority of all UK laboratories report through SHOT, and there do not appear to be significant numbers of additional delayed haemolytic transfusion reactions being reported as a result of this. It would seem that empirical evidence would point to the previous 24 h recommendation being unnecessarily tight. The writing group also noted recommendations from other countries which have longer times, e.g. the Joint Commission on Accreditation of Healthcare Organizations (JCAHO) in the USA require an antibody test within 3 days prior to red cell transfusion, while the Canadian Society for Transfusion Medicine recommends that a specimen be collected within 96 h prior to transfusion. With a significant number of laboratories unable to achieve the existing guideline combined with the empirical evidence above, the writing group felt that a change that represented a balance of safety with achievability was required. With this in mind, the group took the decision to change the model to the length of time of red cell units issued against a particular sample are available. With regard to the published data on alloantibody formation, transfusion reaction reporting, and the survey, it was felt that a blanket 3-day period up to 3 months post-transfusion, offered the best balance of safety and achievability. A laboratory could interpret this as a 24-h sample life + 48-h reservation period, or as a 48-h sample life with 24-h dereservation period, or some other combination as they felt best met local conditions. It is recognised by the group that the scientific evidence for such a decision is limited and that this should be considered as a baseline only. Those laboratories wishing to have stricter time frames more in line with the existing guidance could do so; those wishing to use more lenient time frames would have to support their decision through a local risk assessment. It may be that some feel able to accept these new time frames for patients with no previous antibody history but may be more reluctant for patients with existing antibody histories (there is some evidence that the presence of an antibody is likely to predict further formation of antibodies as it indicates ‘good responders’) or those in high risk groups, e.g. those with sickle cell disease. One size fits all does have the benefit of being understandable by all staff (clinical and laboratory). There is almost no published data on storage times, storage temperature or length of time a sample remains suitable for testing, so the writing group has decided not to significantly alter the existing recommendations until new data become available. Because of a number of unpublished communications within and outside the writing group where patients not seen for some time appear for treatment and have, unknown to laboratory, been transfused elsewhere, it was felt that a period of no more than 3 months should be recommended as a maximum for samples to remain suitable for issue of red cells. This should allow laboratories to cater for electronic issue of blood on preoperative assessed patients' samples while limiting the possibility of unexpected transfusion at an alternative site. The availability of pre-transfusion samples to investigate transfusion reactions varies considerably from site to site. The group felt that having such a sample to test as part of a transfusion reaction investigation represented best practice, allowing determination of whether the antibody was previously undetectable or had been missed as a result of system frailty. It is usual in Good Manufacturing Practice (GMP) industries to ensure sample availability for testing in the event of subsequent product problems. The group particularly felt that having a pre-transfusion sample to test for ABO status in the event of an acute transfusion reaction was highly desirable and so recommended that systems are put in place to ensure that a sample for testing was available for a minimum of 3 days post-transfusion. The writing group suggests that being able to retain a plasma/serum sample for up to 14 days post-transfusion would be desirable for delayed transfusion reaction testing for similar reasons to those of an acute transfusion reaction. This would require separation and freezing of the plasma from the red cells. Laboratories are, for good reasons, not comfortable with separation and the risk associated with the labelling, into separate plasma pots. However, if physical separators (these are devices that are commercially available that can be introduced post routine testing into the primary sample, inserting a physical barrier between the red cells and plasma) are used this then negates the need for plasma separation while retaining plasma for testing and the original sample tube for inspection of patient ID as necessary. The writing group noted that other countries also required retention of samples post-transfusion (e.g. JCAHO in USA requires samples to be retained for at least 7 days following a transfusion and 10 days following a crossmatch). The writing group recognises that implementation of these recommendations and suggestions may entail changes in laboratory procedures and investment in new equipment. However, it feels that the benefits of ensuring a full audit trail of transfusion reaction events to patient, individual laboratories and transfusion medicine as a whole (by allowing collection of data in an area of non-existent data) are substantial enough to support their inclusion. Figure A1 shows a flowchart for the resolution of ABO grouping anomalies. In the following examples, the shaded cells show specificities which can be excluded with one or more examples of homozygous expression (or in the case of Kell, Kk) on ID panel or screening panel. In addition, antibodies to antigens of unlikely clinical significance or low incidence are also shaded where appropriate, to demonstrate their exclusion. However, it is not necessary to routinely exclude such specificities, unless there are positive reactions unaccounted for once all antibodies of likely clinical significance have been identified. Where reference is made to exclusion based on negative results using an enzyme panel, this assumes that a validated two-stage test has been used, i.e. using enzyme cells. Figure shows the results of the identification for cells show that all antibodies of likely clinical significance can be excluded on the identification panel and can be excluded by the negative result with the cell which still be excluded IAT with all cells and negative with all negative cells available cell to exclude if cells are selected for transfusion it is to do of cells may be required for antenatal samples. Figure shows the results of the identification for 2. specificities can be excluded using negative enzyme panel results. cells show that all other specificities can be excluded IAT with all cells and negative with all negative cells M Figure shows the results of the identification for specificities other than and can be excluded using negative enzyme panel results. are excluded using screening cell cells show that all other specificities of likely clinical significance can be excluded using enzyme panel all cells positive and all cells negative additional with all cells and negative with all negative cells which are also and be excluded but the reactions do not with the identification for the test plasma additional cell to Figure shows the results of the identification for 4. IAT positive with all cells positive with all cells to identify to exclude IAT result indicates one or more alloantibody, than can Figure shows the results of the additional panel cells used to additional excluded on patient or cells and Table gives examples of additional techniques than can be for antibody Table shows the likely clinical significance of red cell and recommendations for the selection of blood for patients with their This recommendation is based on the evidence from the studies as referenced in and on data from the and the in SHOT reports (SHOT, 1996–2010) – of blood in were reported as in possible a second sample should be The of the should always be as in of blood could patient in an urgent it is not possible to a second sample, red cells should not be issued a second ABO check for ABO The for this are a second group on the sample, undertaken using a different from a a serological In these a local risk identification of clinical where errors have previously systems in place for of clinical and laboratory and electronic systems for patient identification and sample collection, should be on the outcome of the local risk assessment should be given to whether it is safe to issue red cells or whether group units should be transfused in an emergency until a second sample has been It should be noted that this could it to a clear group from subsequent samples as reactions may be Where the patient as on the first sample, there is an for not a second sample prior to transfusion, as the patient will group red cells. There are to and risk before such a the first is whether this decision can be controlled by the LIMS for electronic the second is the for transfusion of of potentially group and should be given to selection of group plasma and group A in these circumstances, until the ABO group has been on a second sample. have been that the samples may be taken at the time, but one to to the transfusion laboratory at a time. It is important to have a policy and process in place to that the samples have been taken of one and those taking samples for transfusion, need to the reasons for a second sample and the risk of in Section the LIMS to be in full control of the associated with selection of patients for electronic and one of the are patients with clinically significant red cell antibodies, whether in the current sample or This it to issue blood by EI if the antibody is recommends that there are no manual for selection of patients 2010). It is recognised that the of a positive to is likely to be above, the is the for patient for laboratories use a of screening cells in these circumstances, which would result in a negative antibody allowing the sample to the for However, this in requires a decision process which is not controlled by the and is on the clinical information being with could be It should also be that there is no of between and and have been made as in SHOT reports (SHOT, 1996–2010). If electronic issue is undertaken in these there should a full risk assessment. It should be recognised that these patients are a small minority of those transfusion support and for these few patients it should not be to a serological However, in a concessionary release could be used to issue D negative red cells a serological release of blood components or blood or to an is the necessary and of in the best of to an requires prior or authorisation as after as is by a or other should the clinical with the in of the An example is in

BACKGROUND: Methadone is an opioid used in the management of cancer pain both in opioid naïve patients and in rotation from other opioids. A particular role in neuropathic pain has been suggested. The quest for evidence based palliative care prompted a formal appraisal of methadone in comparison with other analgesics. OBJECTIVES: To determine the effectiveness and safety of methadone analgesia in cancer pain patients. SEARCH STRATEGY: MEDLINE (1966 to August 2002), EMBASE (1980 to August 2002), CancerLit (1993 to August 2002), CINAHL (1982 to August 2002) and Cochrane databases were searched using a strategy developed with the Cochrane Pain, Palliative and Supportive Care Group. Assiduous efforts were made to identify unpublished or current trial work. SELECTION CRITERIA: Randomised controlled trials of methadone against active or placebo comparator in patients with cancer pain were included. Outcome measures sought were reduction in pain intensity measured by an appropriate scale, adverse effects, attrition, patient satisfaction and quality of life. There were no language restrictions. Absence of patient reported data was an exclusion criterion. DATA COLLECTION AND ANALYSIS: Eligible studies were selected with independent collaboration from a colleague in Bristol (AND). Full text was retrieved if any uncertainty about eligibility remained. Non-English texts were screened by Cochrane contacts aware of the eligibility criteria. Quality assessment and data extraction were conducted using standardised data forms. Drug and placebo dose, titration, route and formulation were compared and detail of all outcome measures (if available) recorded. MAIN RESULTS: Eight randomised controlled trials (five double blinded, two crossover) with 356 recruits and 326 completing patients were included. All involved active placebo (five morphine, one dextromoramide or pethidine, one diamorphine with cocaine mixture). All employed different starting doses, titration regimens and pain scoring scales. Few presented complete pain data sets and no meta-analysis has been possible. No differentiation by cancer pain syndrome was made. Complete adverse events data were recorded in every study, and were similar in incidence and severity to those experienced with morphine. REVIEWERS' CONCLUSIONS: There is evidence to suggest that methadone is an analgesic with similar efficacy to morphine and a comparable side effect profile. However, the majority of studies involved single dose comparisons or short term use. This methodology fails to reproduce clinical practice. Therefore there is a very significant danger that the effects of methadone accumulation leading to delayed onset of adverse effects which occurs with chronic administration has not been represented. Fixed interval dosing schedules conducted over several days are associated with a high risk of serious morbidity and mortality. There is no trial evidence to support the proposal that methadone has a particular role in neuropathic pain of malignant origin. Conclusions have been limited by the variations in trial design, dosing regimens and limited presentation of primary outcome data. The complex and highly individual pharmacokinetics of methadone require that experienced clinicians take responsibility for initiating, titrating and monitoring this drug.

BACKGROUND: Available therapeutic surfactants are either animal-derived or non-protein-containing synthetic products. Animal-derived surfactants contain variable amounts of surfactant apoproteins, whereas the older-generation synthetic products contain only phospholipids and lack surfactant proteins (SPs). Both decrease morbidity and mortality rates associated with respiratory distress syndrome (RDS) among preterm infants, compared with placebo. However, excess mortality rates have been observed with non-protein-containing synthetic surfactants, compared with the animal-derived products. Evidence suggests that synthetic surfactants consisting solely of phospholipids can be improved with the addition of peptides that are functional analogs of SPs. Lucinactant is a new synthetic peptide-containing surfactant that contains sinapultide, a novel, 21-amino acid peptide (leucine and lysine repeating units, KL4 peptide) designed to mimic human SP-B. It is completely devoid of animal-derived components. OBJECTIVE: We hypothesized that the outcomes for premature infants treated with lucinactant and poractant alfa would be similar. Therefore, we compared lucinactant (Surfaxin; Discovery Laboratories, Doylestown, PA) with porcine-derived, poractant alfa (Curosurf; Chiesi Farmaceutici, Parma, Italy) in a trial to test for noninferiority. METHODS: A total of 252 infants born between 24 and 28 weeks of completed gestation, with birth weights between 600 and 1250 g, were assigned randomly in a multicenter, multinational, noninferiority, randomized, controlled study to receive either lucinactant (n = 124) or poractant alfa (n = 128) within 30 minutes of life. The primary outcome was the incidence of being alive without bronchopulmonary dysplasia (BPD) through 28 days of age. Key secondary outcomes included death at day 28 and 36 weeks postmenstrual age (PMA), air leaks, neuroimaging abnormalities, and other complications related to either prematurity or RDS. An independent, international, data and safety monitoring committee monitored the trial. RESULTS: The treatment difference between lucinactant and poractant alfa for survival without BPD through 28 days was 4.75% (95% confidence interval [CI]: -7.3% to 16.8%) in favor of lucinactant, with the lower boundary of the 95% CI for the difference, ie, -7.3%, being greater than the prespecified noninferiority margin of -14.5%. At 28 days, 45 of 119 infants given lucinactant were alive without BPD (37.8%; 95% CI: 29.1-46.5%), compared with 41 of 124 given poractant alfa (33.1%; 95% CI: 24.8-41.3%); at 36 weeks PMA, the rates were 64.7% and 66.9%, respectively. The corresponding mortality rate through day 28 for the lucinactant group was lower than that for the poractant alfa group (11.8% [95% CI: 6.0-17.6%] vs 16.1% [95% CI: 9.7-22.6%]), as was the rate at 36 weeks PMA (16% and 18.5%, respectively). There were no differences in major dosing complications. In addition, no significant differences were observed in the incidences of common complications of prematurity, including intraventricular hemorrhage (grades 3 and 4) and cystic periventricular leukomalacia (lucinactant: 14.3%; poractant alfa: 16.9%). CONCLUSIONS: Lucinactant and poractant alfa were similar in terms of efficacy and safety when used for the prevention and treatment of RDS among preterm infants. The ability to enhance the performance of a synthetic surfactant with the addition of a peptide that mimics the action of SP-B, such as sinapultide, brings potential advantages to exogenous surfactant therapy.