Aberdeen Royal Infirmary

BACKGROUND: A regimen of epirubicin, cisplatin, and infused fluorouracil (ECF) improves survival among patients with incurable locally advanced or metastatic gastric adenocarcinoma. We assessed whether the addition of a perioperative regimen of ECF to surgery improves outcomes among patients with potentially curable gastric cancer. METHODS: We randomly assigned patients with resectable adenocarcinoma of the stomach, esophagogastric junction, or lower esophagus to either perioperative chemotherapy and surgery (250 patients) or surgery alone (253 patients). Chemotherapy consisted of three preoperative and three postoperative cycles of intravenous epirubicin (50 mg per square meter of body-surface area) and cisplatin (60 mg per square meter) on day 1, and a continuous intravenous infusion of fluorouracil (200 mg per square meter per day) for 21 days. The primary end point was overall survival. RESULTS: ECF-related adverse effects were similar to those previously reported among patients with advanced gastric cancer. Rates of postoperative complications were similar in the perioperative-chemotherapy group and the surgery group (46 percent and 45 percent, respectively), as were the numbers of deaths within 30 days after surgery. The resected tumors were significantly smaller and less advanced in the perioperative-chemotherapy group. With a median follow-up of four years, 149 patients in the perioperative-chemotherapy group and 170 in the surgery group had died. As compared with the surgery group, the perioperative-chemotherapy group had a higher likelihood of overall survival (hazard ratio for death, 0.75; 95 percent confidence interval, 0.60 to 0.93; P=0.009; five-year survival rate, 36 percent vs. 23 percent) and of progression-free survival (hazard ratio for progression, 0.66; 95 percent confidence interval, 0.53 to 0.81; P<0.001). CONCLUSIONS: In patients with operable gastric or lower esophageal adenocarcinomas, a perioperative regimen of ECF decreased tumor size and stage and significantly improved progression-free and overall survival. (Current Controlled Trials number, ISRCTN93793971 [controlled-trials.com].).

BACKGROUND: Among patients with non-small-cell lung cancer (NSCLC), data on intratumor heterogeneity and cancer genome evolution have been limited to small retrospective cohorts. We wanted to prospectively investigate intratumor heterogeneity in relation to clinical outcome and to determine the clonal nature of driver events and evolutionary processes in early-stage NSCLC. METHODS: In this prospective cohort study, we performed multiregion whole-exome sequencing on 100 early-stage NSCLC tumors that had been resected before systemic therapy. We sequenced and analyzed 327 tumor regions to define evolutionary histories, obtain a census of clonal and subclonal events, and assess the relationship between intratumor heterogeneity and recurrence-free survival. RESULTS: ), which remained significant in multivariate analysis. CONCLUSIONS: Intratumor heterogeneity mediated through chromosome instability was associated with an increased risk of recurrence or death, a finding that supports the potential value of chromosome instability as a prognostic predictor. (Funded by Cancer Research UK and others; TRACERx ClinicalTrials.gov number, NCT01888601 .).

BACKGROUND: We evaluated capecitabine (an oral fluoropyrimidine) and oxaliplatin (a platinum compound) as alternatives to infused fluorouracil and cisplatin, respectively, for untreated advanced esophagogastric cancer. METHODS: In a two-by-two design, we randomly assigned 1002 patients to receive triplet therapy with epirubicin and cisplatin plus either fluorouracil (ECF) or capecitabine (ECX) or triplet therapy with epirubicin and oxaliplatin plus either fluorouracil (EOF) or capecitabine (EOX). The primary end point was noninferiority in overall survival for the triplet therapies containing capecitabine as compared with fluorouracil and for those containing oxaliplatin as compared with cisplatin. RESULTS: For the capecitabine-fluorouracil comparison, the hazard ratio for death in the capecitabine group was 0.86 (95% confidence interval [CI], 0.80 to 0.99); for the oxaliplatin-cisplatin comparison, the hazard ratio for the oxaliplatin group was 0.92 (95% CI, 0.80 to 1.10). The upper limit of the confidence intervals for both hazard ratios excluded the predefined noninferiority margin of 1.23. Median survival times in the ECF, ECX, EOF, and EOX groups were 9.9 months, 9.9 months, 9.3 months, and 11.2 months, respectively; survival rates at 1 year were 37.7%, 40.8%, 40.4%, and 46.8%, respectively. In the secondary analysis, overall survival was longer with EOX than with ECF, with a hazard ratio for death of 0.80 in the EOX group (95% CI, 0.66 to 0.97; P=0.02). Progression-free survival and response rates did not differ significantly among the regimens. Toxic effects of capecitabine and fluorouracil were similar. As compared with cisplatin, oxaliplatin was associated with lower incidences of grade 3 or 4 neutropenia, alopecia, renal toxicity, and thromboembolism but with slightly higher incidences of grade 3 or 4 diarrhea and neuropathy. CONCLUSIONS: Capecitabine and oxaliplatin are as effective as fluorouracil and cisplatin, respectively, in patients with previously untreated esophagogastric cancer. (Current Controlled Trials number, ISRCTN51678883 [controlled-trials.com].).

<h3>Abstract</h3> <h3>Background</h3> Long Covid remains a relatively new phenomenon with emerging understanding. Estimated UK prevalence of Long Covid with three or more symptoms lasting for 12 weeks or more was 2.2% at the end of 2021. The population-based French SAPRIS-SERO cohort has novel information about the pattern of symptoms of Long Covid that has been obscured by controversy around the original paper. <h3>Methods</h3> Secondary analysis was used to describe and re-interpret the pattern of persistent symptoms by IgG seropositivity and self-reported Long Covid in the SAPRIS-SERO survey. Participants in the cross-sectional analysis were 26 823 individuals from the French population-based CONSTANCES cohort, included between 2012 and 2019, who took part in the nested SAPRIS and SAPRIS-SERO surveys. Between May and November 2020, the Euroimmun enzyme-linked immunosorbent assay was used to detect anti–SARS-CoV-2 antibodies. Surveyed online between December 2020 and January 2021, participants self-reported previous COVID-19 infection and physical symptoms during the previous four weeks that were new since March 2020, and had persisted for at least eight weeks. <h3>Results</h3> There was similarity of prevalence over the majority of symptoms in those self-reporting COVID-19 infection, regardless of blood test result. Persistent symptoms significantly associated with self-reported COVID-19 infection and common in both groups include respiratory tract symptoms and a group of symptoms that might be related to chronic fatigue, malaise or postural issues. Seropositivity for IgG antibodies did not predict symptoms independently of self-reported Long Covid, except for anosmia. <h3>Conclusions</h3> There may be three common sub-syndromes of Long Covid, one with persistent anosmia, another with other respiratory tract symptoms and a third, currently under researched, with symptoms relatable to chronic fatigue. Antibody tests are insufficient for case detection while Long Covid remains poorly understood. <h3>Key Messages</h3> IgG seropositivity is insufficient to identify potential cases of Long Covid Persistent anosmia is very strongly associated with IgG seropositivity and may define a subsyndrome of Long Covid Other potential subsyndromes are those with persistent respiratory symptoms and those with persistent symptoms relatable to fatigue, malaise or postural issues The Long Covid research effort should be rebalanced towards understanding the fatigue/tiredness subsyndrome.

BACKGROUND: Antibiotic resistance is a major public health problem. Infections caused by multidrug-resistant bacteria are associated with prolonged hospital stay and death compared with infections caused by susceptible bacteria. Appropriate antibiotic use in hospitals should ensure effective treatment of patients with infection and reduce unnecessary prescriptions. We updated this systematic review to evaluate the impact of interventions to improve antibiotic prescribing to hospital inpatients. OBJECTIVES: To estimate the effectiveness and safety of interventions to improve antibiotic prescribing to hospital inpatients and to investigate the effect of two intervention functions: restriction and enablement. SEARCH METHODS: We searched the Cochrane Central Register of Controlled Trials (CENTRAL) (the Cochrane Library), MEDLINE, and Embase. We searched for additional studies using the bibliographies of included articles and personal files. The last search from which records were evaluated and any studies identified incorporated into the review was January 2015. SELECTION CRITERIA: We included randomised controlled trials (RCTs) and non-randomised studies (NRS). We included three non-randomised study designs to measure behavioural and clinical outcomes and analyse variation in the effects: non- randomised trials (NRT), controlled before-after (CBA) studies and interrupted time series (ITS) studies. For this update we also included three additional NRS designs (case control, cohort, and qualitative studies) to identify unintended consequences. Interventions included any professional or structural interventions as defined by the Cochrane Effective Practice and Organisation of Care Group. We defined restriction as 'using rules to reduce the opportunity to engage in the target behaviour (or increase the target behaviour by reducing the opportunity to engage in competing behaviours)'. We defined enablement as 'increasing means/reducing barriers to increase capability or opportunity'. The main comparison was between intervention and no intervention. DATA COLLECTION AND ANALYSIS: Two review authors extracted data and assessed study risk of bias. We performed meta-analysis and meta-regression of RCTs and meta-regression of ITS studies. We classified behaviour change functions for all interventions in the review, including those studies in the previously published versions. We analysed dichotomous data with a risk difference (RD). We assessed certainty of evidence with GRADE criteria. MAIN RESULTS: This review includes 221 studies (58 RCTs, and 163 NRS). Most studies were from North America (96) or Europe (87). The remaining studies were from Asia (19), South America (8), Australia (8), and the East Asia (3). Although 62% of RCTs were at a high risk of bias, the results for the main review outcomes were similar when we restricted the analysis to studies at low risk of bias.More hospital inpatients were treated according to antibiotic prescribing policy with the intervention compared with no intervention based on 29 RCTs of predominantly enablement interventions (RD 15%, 95% confidence interval (CI) 14% to 16%; 23,394 participants; high-certainty evidence). This represents an increase from 43% to 58% .There were high levels of heterogeneity of effect size but the direction consistently favoured intervention.The duration of antibiotic treatment decreased by 1.95 days (95% CI 2.22 to 1.67; 14 RCTs; 3318 participants; high-certainty evidence) from 11.0 days. Information from non-randomised studies showed interventions to be associated with improvement in prescribing according to antibiotic policy in routine clinical practice, with 70% of interventions being hospital-wide compared with 31% for RCTs. The risk of death was similar between intervention and control groups (11% in both arms), indicating that antibiotic use can likely be reduced without adversely affecting mortality (RD 0%, 95% CI -1% to 0%; 28 RCTs; 15,827 participants; moderate-certainty evidence). Antibiotic stewardship interventions probably reduce length of stay by 1.12 days (95% CI 0.7 to 1.54 days; 15 RCTs; 3834 participants; moderate-certainty evidence). One RCT and six NRS raised concerns that restrictive interventions may lead to delay in treatment and negative professional culture because of breakdown in communication and trust between infection specialists and clinical teams (low-certainty evidence).Both enablement and restriction were independently associated with increased compliance with antibiotic policies, and enablement enhanced the effect of restrictive interventions (high-certainty evidence). Enabling interventions that included feedback were probably more effective than those that did not (moderate-certainty evidence).There was very low-certainty evidence about the effect of the interventions on reducing Clostridium difficile infections (median -48.6%, interquartile range -80.7% to -19.2%; 7 studies). This was also the case for resistant gram-negative bacteria (median -12.9%, interquartile range -35.3% to 25.2%; 11 studies) and resistant gram-positive bacteria (median -19.3%, interquartile range -50.1% to +23.1%; 9 studies). There was too much variance in microbial outcomes to reliably assess the effect of change in antibiotic use. Heterogeneity of intervention effect on prescribing outcomesWe analysed effect modifiers in 29 RCTs and 91 ITS studies. Enablement and restriction were independently associated with a larger effect size (high-certainty evidence). Feedback was included in 4 (17%) of 23 RCTs and 20 (47%) of 43 ITS studies of enabling interventions and was associated with greater intervention effect. Enablement was included in 13 (45%) of 29 ITS studies with restrictive interventions and enhanced intervention effect. AUTHORS' CONCLUSIONS: We found high-certainty evidence that interventions are effective in increasing compliance with antibiotic policy and reducing duration of antibiotic treatment. Lower use of antibiotics probably does not increase mortality and likely reduces length of stay. Additional trials comparing antibiotic stewardship with no intervention are unlikely to change our conclusions. Enablement consistently increased the effect of interventions, including those with a restrictive component. Although feedback further increased intervention effect, it was used in only a minority of enabling interventions. Interventions were successful in safely reducing unnecessary antibiotic use in hospitals, despite the fact that the majority did not use the most effective behaviour change techniques. Consequently, effective dissemination of our findings could have considerable health service and policy impact. Future research should instead focus on targeting treatment and assessing other measures of patient safety, assess different stewardship interventions, and explore the barriers and facilitators to implementation. More research is required on unintended consequences of restrictive interventions.

CONTEXT: The European Association of Urology (EAU) Renal Cell Carcinoma (RCC) Guideline Panel has prepared evidence-based guidelines and recommendations for the management of RCC. OBJECTIVE: To present a summary of the 2022 RCC guideline, which is based on a standardised methodology including systematic reviews (SRs) and provides transparent and reliable evidence for the management of RCC. EVIDENCE ACQUISITION: For the 2022 update, a new literature search was carried out with a cutoff date of May 28, 2021, covering the Medline, EMBASE, and Cochrane databases. The data search focused on randomised controlled trials (RCTs) and retrospective or controlled comparator-arm studies, SRs, and meta-analyses. Evidence synthesis was conducted using modified GRADE criteria as outlined for all the EAU guidelines. EVIDENCE SYNTHESIS: All chapters of the RCC guideline were updated on the basis of a structured literature assessment, and clinical practice recommendations were developed. The majority of the studies included were retrospective with matched or unmatched cohorts and were based on single- or multi-institution data or national registries. The exception was systemic treatment of metastatic RCC, for which there are several large RCTs, resulting in recommendations that are based on higher levels of evidence. CONCLUSIONS: The 2022 RCC guidelines have been updated by a multidisciplinary panel of experts using the highest methodological standards. These guidelines provide the most reliable contemporary evidence base for the management of RCC in 2022. PATIENT SUMMARY: The European Association of Urology panel for guidelines on kidney cancer has thoroughly evaluated the research data available to establish up-to-date international standards for the care of patients with kidney cancer.

PURPOSE: To compare the efficacy and safety of pegylated liposomal doxorubicin (PLD) and topotecan in patients with epithelial ovarian carcinoma that recurred after or didn't respond to first-line, platinum-based chemotherapy. PATIENTS AND METHODS: Patients with measurable and assessable disease were randomized to receive either PLD 50 mg/m(2) as a 1-hour infusion every 4 weeks or topotecan 1.5 mg/m(2)/d for 5 consecutive days every 3 weeks. Patients were stratified prospectively for platinum sensitivity and for the presence or absence of bulky disease. RESULTS: A total of 474 patients were treated (239 PLD and 235 topotecan). They comprised the intent-to-treat population. The overall progression-free survival rates were similar between the two arms (P =.095). The overall response rates for PLD and topotecan were 19.7% and 17.0%, respectively (P =.390). Median overall survival times were 60 weeks for PLD and 56.7 weeks for topotecan. Data analyzed in platinum-sensitive patients demonstrated a statistically significant benefit from PLD for progression-free survival (P =.037), with medians of 28.9 for PLD versus 23.3 weeks for topotecan. For overall survival, PLD was significantly superior to topotecan (P =.008), with a median of 108 weeks versus 71.1 weeks. The platinum-refractory subgroup demonstrated a nonstatistically significant survival trend in favor of topotecan (P =.455). Severe hematologic toxicity was more common with topotecan and was more likely to be associated with dosage modification, or growth factor or blood product utilization. CONCLUSION: The comparable efficacy, favorable safety profile, and convenient dosing support the role of PLD as a valuable treatment option in this patient population.

The diagnosis of disseminated intravascular coagulation (DIC) should encompass both clinical and laboratory information. The International Society for Thrombosis and Haemostasis (ISTH) DIC scoring system provides objective measurement of DIC. Where DIC is present the scoring system correlates with key clinical observations and outcomes. It is important to repeat the tests to monitor the dynamically changing scenario based on laboratory results and clinical observations. The cornerstone of the treatment of DIC is treatment of the underlying condition. Transfusion of platelets or plasma (components) in patients with DIC should not primarily be based on laboratory results and should in general be reserved for patients who present with bleeding. In patients with DIC and bleeding or at high risk of bleeding (e.g. postoperative patients or patients due to undergo an invasive procedure) and a platelet count of <50 x 10(9)/l transfusion of platelets should be considered. In non-bleeding patients with DIC, prophylactic platelet transfusion is not given unless it is perceived that there is a high risk of bleeding. In bleeding patients with DIC and prolonged prothrombin time (PT) and activated partial thromboplastin time (aPTT), administration of fresh frozen plasma (FFP) may be useful. It should not be instituted based on laboratory tests alone but should be considered in those with active bleeding and in those requiring an invasive procedure. There is no evidence that infusion of plasma stimulates the ongoing activation of coagulation. If transfusion of FFP is not possible in patients with bleeding because of fluid overload, consider using factor concentrates such as prothrombin complex concentrate, recognising that these will only partially correct the defect because they contain only selected factors, whereas in DIC there is a global deficiency of coagulation factors. Severe hypofibrinogenaemia (<1 g/l) that persists despite FFP replacement may be treated with fibrinogen concentrate or cryoprecipitate. In cases of DIC where thrombosis predominates, such as arterial or venous thromboembolism, severe purpura fulminans associated with acral ischemia or vascular skin infarction, therapeutic doses of heparin should be considered. In these patients where there is perceived to be a co-existing high risk of bleeding there may be benefits in using continuous infusion unfractionated heparin (UFH) due to its short half-life and reversibility. Weight adjusted doses (e.g. 10 mu/kg/h) may be used without the intention of prolonging the APTT ratio to 1.5-2.5 times the control. Monitoring the APTT in these cases may be complicated and clinical observation for signs of bleeding is important. In critically ill, non-bleeding patients with DIC, prophylaxis for venous thromboembolism with prophylactic doses of heparin or low molecular weight heparin is recommended. Consider treating patients with severe sepsis and DIC with recombinant human activated protein C (continuous infusion, 24 microg/kg/h for 4 d). Patients at high risk of bleeding should not be given recombinant human activated protein C. Current manufacturers guidance advises against using this product in patients with platelet counts of <30 x 10(9)/l. In the event of invasive procedures, administration of recombinant human activated protein C should be discontinued shortly before the intervention (elimination half-life approximately 20 min) and may be resumed a few hours later, dependent on the clinical situation. In the absence of further prospective evidence from randomised controlled trials confirming a beneficial effect of antithrombin concentrate on clinically relevant endpoints in patients with DIC and not receiving heparin, administration of antithrombin cannot be recommended. In general, patients with DIC should not be treated with antifibrinolytic agents. Patients with DIC that is characterised by a primary hyperfibrinolytic state and who present with severe bleeding could be treated with lysine analogues, such as tranexamic acid (e.g. 1 g every 8 h).

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.

2 Adverse effects: Clinical outcomes from RCTs of interventions to reduce unnecessary antibiotic use, Outcome 5 Length of stay, all RCTs with results of cluster RCTs adjusted by inflation factor. . . . . . Analysis 2.6. Comparison 2 Adverse effects: Clinical outcomes from RCTs of interventions to reduce unnecessary antibiotic use, Outcome 6 Length of stay, low or medium 'Risk of bias' RCTs only. . . . . . . . . . . . . .

BACKGROUND: The incidence of human papillomavirus (HPV)-positive oropharyngeal cancer, a disease affecting younger patients, is rapidly increasing. Cetuximab, an epidermal growth factor receptor inhibitor, has been proposed for treatment de-escalation in this setting to reduce the toxicity of standard cisplatin treatment, but no randomised evidence exists for the efficacy of this strategy. METHODS: ). The primary outcome was overall severe (grade 3-5) toxicity events at 24 months from the end of treatment. The primary outcome was assessed by intention-to-treat and per-protocol analyses. This trial is registered with the ISRCTN registry, number ISRCTN33522080. FINDINGS: Between Nov 12, 2012, and Oct 1, 2016, 334 patients were recruited (166 in the cisplatin group and 168 in the cetuximab group). Overall (acute and late) severe (grade 3-5) toxicity did not differ significantly between treatment groups at 24 months (mean number of events per patient 4·8 [95% CI 4·2-5·4] with cisplatin vs 4·8 [4·2-5·4] with cetuximab; p=0·98). At 24 months, overall all-grade toxicity did not differ significantly either (mean number of events per patient 29·2 [95% CI 27·3-31·0] with cisplatin vs 30·1 [28·3-31·9] with cetuximab; p=0·49). However, there was a significant difference between cisplatin and cetuximab in 2-year overall survival (97·5% vs 89·4%, hazard ratio 5·0 [95% CI 1·7-14·7]; p=0·001) and 2-year recurrence (6·0% vs 16·1%, 3·4 [1·6-7·2]; p=0·0007). INTERPRETATION: Compared with the standard cisplatin regimen, cetuximab showed no benefit in terms of reduced toxicity, but instead showed significant detriment in terms of tumour control. Cisplatin and radiotherapy should be used as the standard of care for HPV-positive low-risk patients who are able to tolerate cisplatin. FUNDING: Cancer Research UK.

BACKGROUND: The administration of growth hormone can attenuate the catabolic response to injury, surgery, and sepsis. However, the effect of high doses of growth hormone on the length of stay in intensive care and in the hospital, the duration of mechanical ventilation, and the outcome in critically ill adults who are hospitalized for long periods is not known. METHODS: We carried out two prospective, multicenter, double-blind, randomized, placebo-controlled trials in parallel involving 247 Finnish patients and 285 patients in other European countries who had been in an intensive care unit for 5 to 7 days and who were expected to require intensive care for at least 10 days. The patients had had cardiac surgery, abdominal surgery, multiple trauma, or acute respiratory failure. The patients received either growth hormone (mean [+/-SD] daily dose, 0.10 +/- 0.02 mg per kilogram of body weight) or placebo until discharge from intensive care or for a maximum of 21 days. RESULTS: The in-hospital mortality rate was higher in the patients who received growth hormone than in those who did not (P<0.001 for both studies). In the Finnish study, the mortality rate was 39 percent in the growth hormone group, as compared with 20 percent in the placebo group. The respective rates in the multinational study were 44 percent and 18 percent. The relative risk of death for patients receiving growth hormone was 1.9 (95 percent confidence interval, 1.3 to 2.9) in the Finnish study and 2.4 (95 percent confidence interval, 1.6 to 3.5) in the multinational study. Among the survivors, the length of stay in intensive care and in the hospital and the duration of mechanical ventilation were prolonged in the growth hormone group. CONCLUSIONS: In patients with prolonged critical illness, high doses of growth hormone are associated with increased morbidity and mortality.

CONTEXT: Extracorporeal membrane oxygenation (ECMO) can support gas exchange in patients with severe acute respiratory distress syndrome (ARDS), but its role has remained controversial. ECMO was used to treat patients with ARDS during the 2009 influenza A(H1N1) pandemic. OBJECTIVE: To compare the hospital mortality of patients with H1N1-related ARDS referred, accepted, and transferred for ECMO with matched patients who were not referred for ECMO. DESIGN, SETTING, AND PATIENTS: A cohort study in which ECMO-referred patients were defined as all patients with H1N1-related ARDS who were referred, accepted, and transferred to 1 of the 4 adult ECMO centers in the United Kingdom during the H1N1 pandemic in winter 2009-2010. The ECMO-referred patients and the non-ECMO-referred patients were matched using data from a concurrent, longitudinal cohort study (Swine Flu Triage study) of critically ill patients with suspected or confirmed H1N1. Detailed demographic, physiological, and comorbidity data were used in 3 different matching techniques (individual matching, propensity score matching, and GenMatch matching). MAIN OUTCOME MEASURE: Survival to hospital discharge analyzed according to the intention-to-treat principle. RESULTS: Of 80 ECMO-referred patients, 69 received ECMO (86.3%) and 22 died (27.5%) prior to discharge from the hospital. From a pool of 1756 patients, there were 59 matched pairs of ECMO-referred patients and non-ECMO-referred patients identified using individual matching, 75 matched pairs identified using propensity score matching, and 75 matched pairs identified using GenMatch matching. The hospital mortality rate was 23.7% for ECMO-referred patients vs 52.5% for non-ECMO-referred patients (relative risk [RR], 0.45 [95% CI, 0.26-0.79]; P = .006) when individual matching was used; 24.0% vs 46.7%, respectively (RR, 0.51 [95% CI, 0.31-0.81]; P = .008) when propensity score matching was used; and 24.0% vs 50.7%, respectively (RR, 0.47 [95% CI, 0.31-0.72]; P = .001) when GenMatch matching was used. The results were robust to sensitivity analyses, including amending the inclusion criteria and restricting the location where the non-ECMO-referred patients were treated. CONCLUSION: For patients with H1N1-related ARDS, referral and transfer to an ECMO center was associated with lower hospital mortality compared with matched non-ECMO-referred patients.

BACKGROUND: It is unclear whether patients with early-stage Hodgkin's lymphoma and negative findings on positron-emission tomography (PET) after three cycles of chemotherapy with doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD) require radiotherapy. METHODS: Patients with newly diagnosed stage IA or stage IIA Hodgkin's lymphoma received three cycles of ABVD and then underwent PET scanning. Patients with negative PET findings were randomly assigned to receive involved-field radiotherapy or no further treatment; patients with positive PET findings received a fourth cycle of ABVD and radiotherapy. This trial assessing the noninferiority of no further treatment was designed to exclude a difference in the 3-year progression-free survival rate of 7 or more percentage points from the assumed 95% progression-free survival rate in the radiotherapy group. RESULTS: A total of 602 patients (53.3% male; median age, 34 years) were recruited, and 571 patients underwent PET scanning. The PET findings were negative in 426 of these patients (74.6%), 420 of whom were randomly assigned to a study group (209 to the radiotherapy group and 211 to no further therapy). At a median of 60 months of follow-up, there had been 8 instances of disease progression in the radiotherapy group, and 8 patients had died (3 with disease progression, 1 of whom died from Hodgkin's lymphoma); there had been 20 instances of disease progression in the group with no further therapy, and 4 patients had died (2 with disease progression and none from Hodgkin's lymphoma). In the radiotherapy group, 5 of the deaths occurred in patients who received no radiotherapy. The 3-year progression-free survival rate was 94.6% (95% confidence interval [CI], 91.5 to 97.7) in the radiotherapy group and 90.8% (95% CI, 86.9 to 94.8) in the group that received no further therapy, with an absolute risk difference of -3.8 percentage points (95% CI, -8.8 to 1.3). CONCLUSIONS: The results of this study did not show the noninferiority of the strategy of no further treatment after chemotherapy with regard to progression-free survival. Nevertheless, patients in this study with early-stage Hodgkin's lymphoma and negative PET findings after three cycles of ABVD had a very good prognosis either with or without consolidation radiotherapy. (Funded by Leukaemia and Lymphoma Research and others; RAPID ClinicalTrials.gov number, NCT00943423.).

A complete understanding of how exposure to environmental substances promotes cancer formation is lacking. More than 70 years ago, tumorigenesis was proposed to occur in a two-step process: an initiating step that induces mutations in healthy cells, followed by a promoter step that triggers cancer development1. Here we propose that environmental particulate matter measuring ≤2.5 μm (PM2.5), known to be associated with lung cancer risk, promotes lung cancer by acting on cells that harbour pre-existing oncogenic mutations in healthy lung tissue. Focusing on EGFR-driven lung cancer, which is more common in never-smokers or light smokers, we found a significant association between PM2.5 levels and the incidence of lung cancer for 32,957 EGFR-driven lung cancer cases in four within-country cohorts. Functional mouse models revealed that air pollutants cause an influx of macrophages into the lung and release of interleukin-1β. This process results in a progenitor-like cell state within EGFR mutant lung alveolar type II epithelial cells that fuels tumorigenesis. Ultradeep mutational profiling of histologically normal lung tissue from 295 individuals across 3 clinical cohorts revealed oncogenic EGFR and KRAS driver mutations in 18% and 53% of healthy tissue samples, respectively. These findings collectively support a tumour-promoting role for PM2.5 air pollutants and provide impetus for public health policy initiatives to address air pollution to reduce disease burden. Combination of epidemiology, preclinical models and ultradeep DNA profiling of clinical cohorts unpicks the inflammatory mechanism by which air pollution promotes lung cancer

OBJECTIVES: For effective health care provision, knowledge of disease prevalence is paramount. There has been no systematic endeavour to establish continent-based AS estimates, however, prevalence is thought to vary by country and background HLA-B27 prevalence. This study aimed to estimate AS prevalence worldwide and to calculate the expected number of cases. METHODS: A systematic literature search was conducted. Prevalence data were extracted and used to calculate the mean prevalence by continent and the expected number of cases based on country-specific prevalence (or, if missing, the prevalence from neighbouring countries). A second estimate was made using the prevalence from countries with similar HLA-B27 prevalences if a country-specific prevalence estimate was not available. RESULTS: The mean AS prevalence per 10,000 (from 36 eligible studies) was 23.8 in Europe, 16.7 in Asia, 31.9 in North America, 10.2 in Latin America and 7.4 in Africa. Additional estimates, weighted by study size, were calculated as 18.6, 18.0 and 12.2 for Europe, Asia and Latin America, respectively. There were sufficient studies to estimate the number of cases in Europe and Asia, calculated to be 1.30-1.56 million and 4.63-4.98 million, respectively. CONCLUSION: This study represents the first systematic attempt to collate estimates of AS prevalence into a single continent-based estimate. In addition, the number of expected cases in Europe and Asia was estimated. Through reviewing the current literature, it is apparent that the continuing conduct of epidemiological studies of AS prevalence is of great importance, particularly as diagnostic capabilities improve and with the recent development of the criteria for axial SpA.

Of the 131 studies on monotherapy or combination therapy assessed, 56 studies on the different forms of phototherapy fulfilled the criteria for inclusion in the guidelines. Approximately three-quarters of all patients treated with phototherapy attained at least a PASI 75 response after 4 to 6 weeks, and clearance was frequently achieved (levels of evidence 2 and 3). Phototherapy represents a safe and very effective treatment option for moderate to severe forms of psoriasis vulgaris. The onset of clinical effects occurs within 2 weeks. Of the unwanted side effects, UV erythema from overexposure is by far the most common and is observed frequently. With repeated or long-term use, the consequences of high, cumulative UV doses (such as premature aging of the skin) must be taken into consideration. In addition, carcinogenic risk is associated with oral PUVA and is probable for local PUVA and UVB. The practicability of the therapy is limited by spatial, financial, human, and time constraints on the part of the physician, as well as by the amount of time required by the patient. From the perspective of the cost-bearing institution, phototherapy has a good cost-benefit ratio. However, the potentially significant costs for, and time required of, the patient must be considered.

BACKGROUND: The COVID-19 pandemic has placed unprecedented strain on health-care systems. Frailty is being used in clinical decision making for patients with COVID-19, yet the prevalence and effect of frailty in people with COVID-19 is not known. In the COVID-19 in Older PEople (COPE) study we aimed to establish the prevalence of frailty in patients with COVID-19 who were admitted to hospital and investigate its association with mortality and duration of hospital stay. METHODS: This was an observational cohort study conducted at ten hospitals in the UK and one in Italy. All adults (≥18 years) admitted to participating hospitals with COVID-19 were included. Patients with incomplete hospital records were excluded. The study analysed routinely generated hospital data for patients with COVID-19. Frailty was assessed by specialist COVID-19 teams using the clinical frailty scale (CFS) and patients were grouped according to their score (1-2=fit; 3-4=vulnerable, but not frail; 5-6=initial signs of frailty but with some degree of independence; and 7-9=severe or very severe frailty). The primary outcome was in-hospital mortality (time from hospital admission to mortality and day-7 mortality). FINDINGS: Between Feb 27, and April 28, 2020, we enrolled 1564 patients with COVID-19. The median age was 74 years (IQR 61-83); 903 (57·7%) were men and 661 (42·3%) were women; 425 (27·2%) had died at data cutoff (April 28, 2020). 772 (49·4%) were classed as frail (CFS 5-8) and 27 (1·7%) were classed as terminally ill (CFS 9). Compared with CFS 1-2, the adjusted hazard ratios for time from hospital admission to death were 1·55 (95% CI 1·00-2·41) for CFS 3-4, 1·83 (1·15-2·91) for CFS 5-6, and 2·39 (1·50-3·81) for CFS 7-9, and adjusted odds ratios for day-7 mortality were 1·22 (95% CI 0·63-2·38) for CFS 3-4, 1·62 (0·81-3·26) for CFS 5-6, and 3·12 (1·56-6·24) for CFS 7-9. INTERPRETATION: In a large population of patients admitted to hospital with COVID-19, disease outcomes were better predicted by frailty than either age or comorbidity. Our results support the use of CFS to inform decision making about medical care in adult patients admitted to hospital with COVID-19. FUNDING: None.

BACKGROUND: Treatments for open-angle glaucoma aim to prevent vision loss through lowering of intraocular pressure, but to our knowledge no placebo-controlled trials have assessed visual function preservation, and the observation periods of previous (unmasked) trials have typically been at least 5 years. We assessed vision preservation in patients given latanoprost compared with those given placebo. METHODS: In this randomised, triple-masked, placebo-controlled trial, we enrolled patients with newly diagnosed open-angle glaucoma at ten UK centres (tertiary referral centres, teaching hospitals, and district general hospitals). Eligible patients were randomly allocated (1:1) with a website-generated randomisation schedule, stratified by centre and with a permuted block design, to receive either latanoprost 0·005% (intervention group) or placebo (control group) eye drops. Drops were administered from identical bottles, once a day, to both eyes. The primary outcome was time to visual field deterioration within 24 months. Analyses were done in all individuals with follow-up data. The Data and Safety Monitoring Committee (DSMC) recommended stopping the trial on Jan 6, 2011 (last patient visit July, 2011), after an interim analysis, and suggested a change in primary outcome from the difference in proportions of patients with incident progression between groups to time to visual field deterioration within 24 months. This trial is registered, number ISRCTN96423140. FINDINGS: We enrolled 516 individuals between Dec 1, 2006, and March 16, 2010. Baseline mean intraocular pressure was 19·6 mm Hg (SD 4·6) in 258 patients in the latanoprost group and 20·1 mm Hg (4·8) in 258 controls. At 24 months, mean reduction in intraocular pressure was 3·8 mm Hg (4·0) in 231 patients assessed in the latanoprost group and 0·9 mm Hg (3·8) in 230 patients assessed in the placebo group. Visual field preservation was significantly longer in the latanoprost group than in the placebo group: adjusted hazard ratio (HR) 0·44 (95% CI 0·28-0·69; p=0·0003). We noted 18 serious adverse events, none attributable to the study drug. INTERPRETATION: This is the first randomised placebo-controlled trial to show preservation of the visual field with an intraocular-pressure-lowering drug in patients with open-angle glaucoma. The study design enabled significant differences in vision to be assessed in a relatively short observation period. FUNDING: Pfizer, UK National Institute for Health Research Biomedical Research Centre.

BACKGROUND: Anti-glomerular basement membrane (GBM) antibody disease is an autoantibody-mediated disorder that usually presents as rapidly progressive glomerulonephritis, often with pulmonary hemorrhage (the Goodpasture syndrome). It is reported that patients with severe renal failure do not generally recover renal function. OBJECTIVE: To examine the long-term outcome of severe anti-GBM antibody disease. DESIGN: Retrospective review of patients treated for confirmed anti-GBM antibody disease over 25 years. SETTING: A tertiary referral center in the United Kingdom. PATIENTS: 71 treated patients with anti-GBM antibody disease. INTERVENTION: All patients received plasma exchange, prednisolone, and cyclophosphamide. MEASUREMENTS: Patient and renal survival, renal histology, and antibody levels. RESULTS: Patients who presented with a creatinine concentration less than 500 micromol/L (5.7 mg/dL) (n = 19) had 100% patient survival and 95% renal survival at 1 year and 84% patient survival and 74% renal survival at last follow-up. In patients who presented with a creatinine concentration of 500 micromol/L or more (>/=5.7 mg/dL) (n = 13) but did not require immediate dialysis, patient and renal survival were 83% and 82% at 1 year and 62% and 69% at last follow-up. In patients who presented with dialysis-dependent renal failure (n = 39), patient and renal survival were 65% and 8% at 1 year and 36% and 5% at last follow-up. All patients who required immediate dialysis and had 100% crescents on renal biopsy remained dialysis dependent. CONCLUSIONS: Patients with the Goodpasture syndrome and severe renal failure should be considered for urgent immunosuppression therapy, including plasma exchange, to maximize the chance of renal recovery. Patients needing immediate dialysis are less likely to recover.