«The Broken Years»: War Crimes and the laws of war under the impact of the First World War

When the First World War began, the international co-operation of legal academics, which had been a characteristic of the late 19th and early 20th century came to a halt. In the context of the atrocities in Belgium as well as Serbia academics on both sides became involved in the propaganda campaigns of the belligerents on both sides. Not many of them were able to divest themselves. The presentation will claim that as a consequence the time between the First World War and the beginning of the Second can be characterized as «Broken Years» not only in regard to war veterans (Gammage 1974), but also in regard to the international academic discourse on issues of war crimes and the laws of war. This shall be substantiated by a look at academic activities in the interwar period within the International Law Association, the Institut de Droit International, the Interparliamentary Union, the Association Internationale de Droit Pénal and the Internationale Kriminalistische Vereinigung.

Self-etch primers and conventional acid-etch technique for orthodontic bonding: a systematic review and meta-analysis

The use of self-etch primers has increased steadily because of their time savings and greater simplicity; however, overall benefits and potential disadvantages and harms have not been assessed systematically. In this study, we reviewed randomized controlled trials to assess the risk of attachment failure, bonding time, and demineralization adjacent to attachments between 1-stage (self-etch) and 2-stage (acid etch) bonding in orthodontic patients over a minimum follow-up period of 12 months.

Epoetin and Darbepoetin for Managing Anemia in Patients Undergoing Cancer Treatment: Comparative Effectiveness Update

Objectives: To update the 2006 systematic review of the comparative benefits and harms of erythropoiesis-stimulating agent (ESA) strategies and non-ESA strategies to manage anemia in patients undergoing chemotherapy and/or radiation for malignancy (excluding myelodysplastic syndrome and acute leukemia), including the impact of alternative thresholds for initiating treatment and optimal duration of therapy. Data sources: Literature searches were updated in electronic databases (n=3), conference proceedings (n=3), and Food and Drug Administration transcripts. Multiple sources (n=13) were searched for potential gray literature. A primary source for current survival evidence was a recently published individual patient data meta-analysis. In that meta-analysis, patient data were obtained from investigators for studies enrolling more than 50 patients per arm. Because those data constitute the most currently available data for this update, as well as the source for on-study (active treatment) mortality data, we limited inclusion in the current report to studies enrolling more than 50 patients per arm to avoid potential differential endpoint ascertainment in smaller studies. Review methods: Title and abstract screening was performed by one or two (to resolve uncertainty) reviewers; potentially included publications were reviewed in full text. Two or three (to resolve disagreements) reviewers assessed trial quality. Results were independently verified and pooled for outcomes of interest. The balance of benefits and harms was examined in a decision model. Results: We evaluated evidence from 5 trials directly comparing darbepoetin with epoetin, 41 trials comparing epoetin with control, and 8 trials comparing darbepoetin with control; 5 trials evaluated early versus late (delay until Hb ≤9 to 11 g/dL) treatment. Trials varied according to duration, tumor types, cancer therapy, trial quality, iron supplementation, baseline hemoglobin, ESA dosing frequency (and therefore amount per dose), and dose escalation. ESAs decreased the risk of transfusion (pooled relative risk [RR], 0.58; 95% confidence interval [CI], 0.53 to 0.64; I2 = 51%; 38 trials) without evidence of meaningful difference between epoetin and darbepoetin. Thromboembolic event rates were higher in ESA-treated patients (pooled RR, 1.51; 95% CI, 1.30 to 1.74; I2 = 0%; 37 trials) without difference between epoetin and darbepoetin. In 14 trials reporting the Functional Assessment of Cancer Therapy (FACT)-Fatigue subscale, the most common patient-reported outcome, scores decreased by −0.6 in control arms (95% CI, −6.4 to 5.2; I2 = 0%) and increased by 2.1 in ESA arms (95% CI, −3.9 to 8.1; I2 = 0%). There were fewer thromboembolic and on-study mortality adverse events when ESA treatment was delayed until baseline Hb was less than 10 g/dL, in keeping with current treatment practice, but the difference in effect from early treatment was not significant, and the evidence was limited and insufficient for conclusions. No evidence informed optimal duration of therapy. Mortality was increased during the on-study period (pooled hazard ratio [HR], 1.17; 95% CI, 1.04 to 1.31; I2 = 0%; 37 trials). There was one additional death for every 59 treated patients when the control arm on-study mortality was 10 percent and one additional death for every 588 treated patients when the control-arm on-study mortality was 1 percent. A cohort decision model yielded a consistent result—greater loss of life-years when control arm on-study mortality was higher. There was no discernible increase in mortality with ESA use over the longest available followup (pooled HR, 1.04; 95% CI, 0.99 to 1.10; I2 = 38%; 44 trials), but many trials did not include an overall survival endpoint and potential time-dependent confounding was not considered. Conclusions: Results of this update were consistent with the 2006 review. ESAs reduced the need for transfusions and increased the risk of thromboembolism. FACT-Fatigue scores were better with ESA use but the magnitude was less than the minimal clinically important difference. An increase in mortality accompanied the use of ESAs. An important unanswered question is whether dosing practices and overall ESA exposure might influence harms.

Prophylactic antibiotics or G(M)-CSF for the prevention of infections and improvement of survival in cancer patients receiving myelotoxic chemotherapy.

BACKGROUND Febrile neutropenia (FN) and other infectious complications are some of the most serious treatment-related toxicities of chemotherapy for cancer, with a mortality rate of 2% to 21%. The two main types of prophylactic regimens are granulocyte (macrophage) colony-stimulating factors (G(M)-CSF) and antibiotics, frequently quinolones or cotrimoxazole. Current guidelines recommend the use of colony-stimulating factors when the risk of febrile neutropenia is above 20%, but they do not mention the use of antibiotics. However, both regimens have been shown to reduce the incidence of infections. Since no systematic review has compared the two regimens, a systematic review was undertaken. OBJECTIVES To compare the efficacy and safety of G(M)-CSF compared to antibiotics in cancer patients receiving myelotoxic chemotherapy. SEARCH METHODS We searched The Cochrane Library, MEDLINE, EMBASE, databases of ongoing trials, and conference proceedings of the American Society of Clinical Oncology and the American Society of Hematology (1980 to December 2015). We planned to include both full-text and abstract publications. Two review authors independently screened search results. SELECTION CRITERIA We included randomised controlled trials (RCTs) comparing prophylaxis with G(M)-CSF versus antibiotics for the prevention of infection in cancer patients of all ages receiving chemotherapy. All study arms had to receive identical chemotherapy regimes and other supportive care. We included full-text, abstracts, and unpublished data if sufficient information on study design, participant characteristics, interventions and outcomes was available. We excluded cross-over trials, quasi-randomised trials and post-hoc retrospective trials. DATA COLLECTION AND ANALYSIS Two review authors independently screened the results of the search strategies, extracted data, assessed risk of bias, and analysed data according to standard Cochrane methods. We did final interpretation together with an experienced clinician. MAIN RESULTS In this updated review, we included no new randomised controlled trials. We included two trials in the review, one with 40 breast cancer patients receiving high-dose chemotherapy and G-CSF compared to antibiotics, a second one evaluating 155 patients with small-cell lung cancer receiving GM-CSF or antibiotics.We judge the overall risk of bias as high in the G-CSF trial, as neither patients nor physicians were blinded and not all included patients were analysed as randomised (7 out of 40 patients). We considered the overall risk of bias in the GM-CSF to be moderate, because of the risk of performance bias (neither patients nor personnel were blinded), but low risk of selection and attrition bias.For the trial comparing G-CSF to antibiotics, all cause mortality was not reported. There was no evidence of a difference for infection-related mortality, with zero events in each arm. Microbiologically or clinically documented infections, severe infections, quality of life, and adverse events were not reported. There was no evidence of a difference in frequency of febrile neutropenia (risk ratio (RR) 1.22; 95% confidence interval (CI) 0.53 to 2.84). The quality of the evidence for the two reported outcomes, infection-related mortality and frequency of febrile neutropenia, was very low, due to the low number of patients evaluated (high imprecision) and the high risk of bias.There was no evidence of a difference in terms of median survival time in the trial comparing GM-CSF and antibiotics. Two-year survival times were 6% (0 to 12%) in both arms (high imprecision, low quality of evidence). There were four toxic deaths in the GM-CSF arm and three in the antibiotics arm (3.8%), without evidence of a difference (RR 1.32; 95% CI 0.30 to 5.69; P = 0.71; low quality of evidence). There were 28% grade III or IV infections in the GM-CSF arm and 18% in the antibiotics arm, without any evidence of a difference (RR 1.55; 95% CI 0.86 to 2.80; P = 0.15, low quality of evidence). There were 5 episodes out of 360 cycles of grade IV infections in the GM-CSF arm and 3 episodes out of 334 cycles in the cotrimoxazole arm (0.8%), with no evidence of a difference (RR 1.55; 95% CI 0.37 to 6.42; P = 0.55; low quality of evidence). There was no significant difference between the two arms for non-haematological toxicities like diarrhoea, stomatitis, infections, neurologic, respiratory, or cardiac adverse events. Grade III and IV thrombopenia occurred significantly more frequently in the GM-CSF arm (60.8%) compared to the antibiotics arm (28.9%); (RR 2.10; 95% CI 1.41 to 3.12; P = 0.0002; low quality of evidence). Neither infection-related mortality, incidence of febrile neutropenia, nor quality of life were reported in this trial. AUTHORS' CONCLUSIONS As we only found two small trials with 195 patients altogether, no conclusion for clinical practice is possible. More trials are necessary to assess the benefits and harms of G(M)-CSF compared to antibiotics for infection prevention in cancer patients receiving chemotherapy.

Applicability of DNA Analysis on Adhesive Tape in Forensic Casework

Adhesive tape is commonly used in crimes and is often the subject of forensic evaluation. DNA analysis of adhesive tape can provide DNA profiles of suspects. The object of this study was to evaluate the applicability of DNA analysis on adhesive tape samples in forensic casework. We retrospectively reviewed all cases involving adhesive tape or similar items received by our institute for DNA analysis during the past 11 years. From 100 forensic cases reviewed, 150 adhesive tape samples were examined. A total of 98 DNA profiles were obtained from these samples. Sixty-two of the profiles provided feasible case-relevant information. In conclusion, DNA profiling of adhesive tape samples can be useful in a variety of forensic cases.

Effectiveness of chlamydia screening: systematic review

BACKGROUND: Screening programmes are promoted to control transmission of and prevent female reproductive tract morbidity caused by genital chlamydia. The objective of this study was to examine the effectiveness of register-based and opportunistic chlamydia screening interventions. METHODS: We searched seven electronic databases (Cinahl, Cochrane Controlled Trials Register, DARE, Embase, Medline, PsycINFO and SIGLE) without language restrictions from January 1990 to October 2007 and reference lists of retrieved articles to identify studies published before 1990. We included studies examining primary outcomes (pelvic inflammatory disease, ectopic pregnancy, infertility, adverse pregnancy outcomes, neonatal infection, chlamydia prevalence) and harms of chlamydia screening in men and non-pregnant and pregnant women. We extracted data in duplicate and synthesized the data narratively or used random effects meta-analysis, where appropriate. RESULTS: We included six systematic reviews, five randomized trials, one non-randomized comparative study and one time trend study. Five reviews recommended screening of women at high risk of chlamydia. Two randomized trials found that register-based screening of women at high risk of chlamydia and of female and male high school students reduced the incidence of pelvic inflammatory disease in women at 1 year. Methodological inadequacies could have overestimated the observed benefits. One randomized trial showed that opportunistic screening in women undergoing surgical termination of pregnancy reduced post-abortal rates of pelvic inflammatory disease compared with no screening. We found no randomized trials showing a benefit of opportunistic screening in other populations, no trial examining the effects of more than one screening round and no trials examining the harms of chlamydia screening. CONCLUSION: There is an absence of evidence supporting opportunistic chlamydia screening in the general population younger than 25 years, the most commonly recommended approach. Equipoise remains, so high-quality randomized trials of multiple rounds of screening with biological outcome measures are still needed to determine the balance of benefits and harms of chlamydia screening.

Systemic prokinetic pharmacologic treatment for postoperative adynamic ileus following abdominal surgery in adults

BACKGROUND: Postoperative adynamic bowel atony interferes with recovery following abdominal surgery. Prokinetic pharmacologic drugs are widely used to accelerate postoperative recovery. OBJECTIVES: To evaluate the benefits and harms of systemic acting prokinetic drugs to treat postoperative adynamic ileus in patients undergoing abdominal surgery. SEARCH STRATEGY: Trials were identified by computerised searches of the Cochrane Central Register of Controlled Trials, MEDLINE, EMBASE, and the Cochrane Colorectal Cancer Group specialised register. The reference lists of included trials and review articles were tracked and authors contacted. SELECTION CRITERIA: Randomised controlled parallel-group trials (RCT) comparing the effect of systemically acting prokinetic drugs against placebo or no intervention. DATA COLLECTION AND ANALYSIS: Four reviewers independently extracted the data and assessed trial quality. Trial authors were contacted for additional information if needed. MAIN RESULTS: Thirty-nine RCTs met the inclusion criteria contributing a total of 4615 participants. Most trials enrolled a small number of patients and showed moderate to poor (reporting of) methodological quality, in particular regarding allocation concealment and intention-to-treat analysis. Fifteen systemic acting prokinetic drugs were investigated and ten comparisons could be summarized. Six RCTs support the effect of Alvimopan, a novel peripheral mu receptor antagonist. However, the trials do not meet reporting guidelines and the drug is still in an investigational stage. Erythromycin showed homogenous and consistent absence of effect across all included trials and outcomes. The evidence is insufficient to recommend the use of cholecystokinin-like drugs, cisapride, dopamine-antagonists, propranolol or vasopressin. Effects are either inconsistent across outcomes, or trials are too small and often of poor methodological quality. Cisapride has been withdrawn from the market due to adverse cardiac events in many countries. Intravenous lidocaine and neostigmine might show a potential effect, but more evidence on clinically relevant outcomes is needed. Heterogeneity among included trials was seen in 10 comparisons. No major adverse drug effects were evident. AUTHORS' CONCLUSIONS: Alvimopan may prove to be beneficial but proper judgement needs adherence to reporting standards. Further trials are needed on intravenous lidocaine and neostigmine. The remaining drugs can not be recommended due to lack of evidence or absence of effect.

[Primary ciliary dyskinesia (Pcd) in Austria]

INTRODUCTION: Primary ciliary dyskinesia (PCD) is a rare hereditary recessive disease with symptoms of recurrent pneumonia, chronic bronchitis, bronchiectasis, and chronic sinusitis. Chronic rhinitis is often the presenting symptom in newborns and infants. Approximately half of the patients show visceral mirror image arrangements (situs inversus). In this study, we aimed 1) to determine the number of paediatric PCD patients in Austria, 2) to show the diagnostic and therapeutic modalities used in the clinical centres and 3) to describe symptoms of children with PCD. PATIENTS, MATERIAL AND METHODS: For the first two aims, we analysed data from a questionnaire survey of the European Respiratory Society (ERS) task force on Primary Ciliary Dyskinesia in children. All paediatric respiratory units in Austria received a questionnaire. Symptoms of PCD patients from Vienna Children's University Hospital (aim 3) were extracted from case histories. RESULTS: In 13 Austrian clinics 48 patients with PCD (36 aged from 0-19 years) were identified. The prevalence of reported cases (aged 0-19 yrs) in Austria was 1:48000. Median age at diagnosis was 4.8 years (IQR 0.3-8.2), lower in children with situs inversus compared to those without (3.1 vs. 8.1 yrs, p = 0.067). In 2005-2006, the saccharine test was still the most commonly used screening test for PCD in Austria (45%). Confirmation of the diagnosis was usually by electron microscopy (73%). All clinics treated exacerbations immediately with antibiotics, 73% prescribed airway clearance therapy routinely to all patients. Other therapies and diagnostic tests were applied very inconsistently across Austrian hospitals. All PCD patients from Vienna (n = 13) had increased upper and lower respiratory secretions, most had recurring airway infections (n = 12), bronchiectasis (n = 7) and bronchitis (n = 7). CONCLUSION: Diagnosis and therapy of PCD in Austria are inhomogeneous. Prospective studies are needed to learn more about the course of the disease and to evaluate benefits and harms of different treatment strategies.

Mammografie-Screening

Nur wenige Vorsorgeuntersuchungen sind so umfassend in randomisiert-kon- trollierten Studien (RCTs) untersucht worden wie das Screening auf Brustkrebs mit Hilfe der Mammografie. Es liegen derzeit acht große randomisiert-kontrol- lierte Studien und mehrere Meta-Analysen vor. Letztere kommen mehrheitlich zum Schluss, dass sich die Brustkrebssterblichkeit durch Mammografie-Screening um etwa 20 % senken lässt. Dies bedeutet im Schweizer Kontext, dass etwa 1 von 1'000 Frauen weniger an Brustkrebs stirbt, wenn Frauen ab dem 50. Lebensjahr zehn Jahre lang gescreent werden. Andererseits führt das Screening auch zu Überdiagnosen und Übertherapien. So nimmt die Zahl der Brustkrebsdiagnosen um etwa 20 % zu, was zu einer entsprechenden Zunahme an chirurgischen Ein- griffen, Strahlen- und Chemotherapien führt. Über zehn Jahre gerechnet, erhal- ten etwa 4 von 1'000 Frauen eine Brustkrebsdiagnose, die sie ohne Screening nicht erhalten hätten. Etwa 200 von 1'000 Frauen sind im Verlaufe von zehn Jahren (fünf Screening-Runden) mit abklärungsbedürftigen Befunden konfron- tiert, wobei es sich dabei mehrheitlich um falsch positive Befunde handelt. Gleichzeitig werden auch mit einem Screening-Programm 20 bis 30 % der Brust- krebse nicht im Screening erfasst. Die Information der Bevölkerung bezüglich des Mammografie-Screenings ist derzeit noch mangelhaft. Dies führt dazu, dass der mögliche Nutzen von den betroffenen Frauen überschätzt und der Schaden unterschätzt wird. Die Aufklärung der Bevölkerung im Hinblick auf Nutzen und Risiken des Mammografie-Screenings muss daher verbessert werden, denn Frau- en haben einen Anspruch auf evidenzbasierte Informationen und eine „infor- mierte Entscheidung“.

Somatostatin-based radiopeptide therapy with [177Lu-DOTA]-TOC versus [90Y-DOTA]-TOC in neuroendocrine tumours

PURPOSE Somatostatin-based radiopeptide treatment is generally performed using the β-emitting radionuclides (90)Y or (177)Lu. The present study aimed at comparing benefits and harms of both therapeutic approaches. METHODS In a comparative cohort study, patients with advanced neuroendocrine tumours underwent repeated cycles of [(90)Y-DOTA]-TOC or [(177)Lu-DOTA]-TOC until progression of disease or permanent adverse events. Multivariable Cox regression and competing risks regression were employed to examine predictors of survival and adverse events for both treatment groups. RESULTS Overall, 910 patients underwent 1,804 cycles of [(90)Y-DOTA]-TOC and 141 patients underwent 259 cycles of [(177)Lu-DOTA]-TOC. The median survival after [(177)Lu-DOTA]-TOC and after [(90)Y-DOTA]-TOC was comparable (45.5 months versus 35.9 months, hazard ratio 0.91, 95% confidence interval 0.63-1.30, p = 0.49). Subgroup analyses revealed a significantly longer survival for [(177)Lu-DOTA]-TOC over [(90)Y-DOTA]-TOC in patients with low tumour uptake, solitary lesions and extra-hepatic lesions. The rate of severe transient haematotoxicities was lower after [(177)Lu-DOTA]-TOC treatment (1.4 vs 10.1%, p = 0.001), while the rate of severe permanent renal toxicities was similar in both treatment groups (9.2 vs 7.8%, p = 0.32). CONCLUSION The present results revealed no difference in median overall survival after [(177)Lu-DOTA]-TOC and [(90)Y-DOTA]-TOC. Furthermore, [(177)Lu-DOTA]-TOC was less haematotoxic than [(90)Y-DOTA]-TOC.

Perioperative use of crystalloids in patients undergoing open radical cystectomy: balanced Ringer's maleate versus a glucose 5%/potassium-based balanced solution: study protocol for a randomized controlled trial

BACKGROUND The optimal crystalloid solution to use perioperatively in patients undergoing open radical cystectomy remains unclear. Many of the fluids used for intravenous hydration contain supraphysiologic concentrations of chloride, which can induce hyperchloremia and metabolic acidosis, resulting in renal vasoconstriction and decreased renal function. In addition, patients receiving less fluid and less sodium show faster recovery of gastrointestinal (GI) function after colonic surgery. METHODS AND DESIGN This is an investigator-initiated, single-center, randomized, controlled, parallel group trial with assessor-blinded outcome assessment, in the Department of Urology, University Hospital Bern, Switzerland. The study will involve 44 patients with bladder cancer scheduled for radical cystectomy and urinary diversion. The primary outcome is the duration between the end of surgery and the return of the GI function (first defecation). Secondary outcomes are fluid balance (body weight difference postoperatively versus preoperatively) and the incidence of kidney function disorders according to the Risk-Injury-Failure-Loss-End Stage Renal Disease (RIFLE classification). An equal number of patients are allocated to receive Ringerfundin® solution or a glucose/potassium-based balanced crystalloid solution as baseline infusion during the entire time that intravenous administration of fluid is necessary during the perioperative period. The randomized crystalloid solution is infused at a rate of 1 ml/kg/h until the bladder has been removed, followed by 3 ml/kg/h until the end of surgery. Postoperative hydration is identical in both groups and consists of 1,500 ml of the randomized crystalloid solution per 24 hours. Postoperative patient care is identical in both groups; patients are allowed to drink clear fluids immediately after surgery, and liquid diet is started on postoperative day 1, as well as active mobilization and the use of chewing gum. Body weight is measured daily in the morning. Time of first flatus and first defecation are recorded. DISCUSSION This trial assesses the benefits and harms of two different balanced crystalloid solutions for perioperative fluid management in patients undergoing open radical cystectomy with urinary diversion, with regard to return of GI function and effects on postoperative renal function. TRIAL REGISTRATION Current Controlled Trials ISRCTN32976792 (registered on November 21 2013).

Corticosteroid treatment for community-acquired pneumonia--the STEP trial: study protocol for a randomized controlled trial

BACKGROUND Community-acquired pneumonia (CAP) is the third-leading infectious cause of death worldwide. The standard treatment of CAP has not changed for the past fifty years and its mortality and morbidity remain high despite adequate antimicrobial treatment. Systemic corticosteroids have anti-inflammatory effects and are therefore discussed as adjunct treatment for CAP. Available studies show controversial results, and the question about benefits and harms of adjunct corticosteroid therapy has not been conclusively resolved, particularly in the non-critical care setting. METHODS/DESIGN This randomized multicenter study compares a treatment with 7 days of prednisone 50 mg with placebo in adult patients hospitalized with CAP independent of severity. Patients are screened and enrolled within the first 36 hours of presentation after written informed consent is obtained. The primary endpoint will be time to clinical stability, which is assessed every 12 hours during hospitalization. Secondary endpoints will be, among others, all-cause mortality within 30 and 180 days, ICU stay, duration of antibiotic treatment, disease activity scores, side effects and complications, value of adrenal function testing and prognostic hormonal and inflammatory biomarkers to predict outcome and treatment response to corticosteroids. Eight hundred included patients will provide an 85% power for the intention-to-treat analysis of the primary endpoint. DISCUSSION This largest to date double-blind placebo-controlled multicenter trial investigates the effect of adjunct glucocorticoids in 800 patients with CAP requiring hospitalization. It aims to give conclusive answers about benefits and risks of corticosteroid treatment in CAP. The inclusion of less severe CAP patients will be expected to lead to a relatively low mortality rate and survival benefit might not be shown. However, our study has adequate power for the clinically relevant endpoint of clinical stability. Due to discontinuing glucocorticoids without tapering after seven days, we limit duration of glucocorticoid exposition, which may reduce possible side effects. TRIAL REGISTRATION 7 September 2009 on ClinicalTrials.gov: NCT00973154.

Intra-articular corticosteroid for knee osteoarthritis.

BACKGROUND Knee osteoarthritis is a leading cause of chronic pain, disability, and decreased quality of life. Despite the long-standing use of intra-articular corticosteroids, there is an ongoing debate about their benefits and safety. This is an update of a Cochrane review first published in 2005. OBJECTIVES To determine the benefits and harms of intra-articular corticosteroids compared with sham or no intervention in people with knee osteoarthritis in terms of pain, physical function, quality of life, and safety. SEARCH METHODS We searched the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, and EMBASE (from inception to 3 February 2015), checked trial registers, conference proceedings, reference lists, and contacted authors. SELECTION CRITERIA We included randomised or quasi-randomised controlled trials that compared intra-articular corticosteroids with sham injection or no treatment in people with knee osteoarthritis. We applied no language restrictions. DATA COLLECTION AND ANALYSIS We calculated standardised mean differences (SMDs) and 95% confidence intervals (CI) for pain, function, quality of life, joint space narrowing, and risk ratios (RRs) for safety outcomes. We combined trials using an inverse-variance random-effects meta-analysis. MAIN RESULTS We identified 27 trials (13 new studies) with 1767 participants in this update. We graded the quality of the evidence as 'low' for all outcomes because treatment effect estimates were inconsistent with great variation across trials, pooled estimates were imprecise and did not rule out relevant or irrelevant clinical effects, and because most trials had a high or unclear risk of bias. Intra-articular corticosteroids appeared to be more beneficial in pain reduction than control interventions (SMD -0.40, 95% CI -0.58 to -0.22), which corresponds to a difference in pain scores of 1.0 cm on a 10-cm visual analogue scale between corticosteroids and sham injection and translates into a number needed to treat for an additional beneficial outcome (NNTB) of 8 (95% CI 6 to 13). An I(2) statistic of 68% indicated considerable between-trial heterogeneity. A visual inspection of the funnel plot suggested some asymmetry (asymmetry coefficient -1.21, 95%CI -3.58 to 1.17). When stratifying results according to length of follow-up, benefits were moderate at 1 to 2 weeks after end of treatment (SMD -0.48, 95% CI -0.70 to -0.27), small to moderate at 4 to 6 weeks (SMD -0.41, 95% CI -0.61 to -0.21), small at 13 weeks (SMD -0.22, 95% CI -0.44 to 0.00), and no evidence of an effect at 26 weeks (SMD -0.07, 95% CI -0.25 to 0.11). An I(2) statistic of ≥ 63% indicated a moderate to large degree of between-trial heterogeneity up to 13 weeks after end of treatment (P for heterogeneity≤0.001), and an I(2) of 0% indicated low heterogeneity at 26 weeks (P=0.43). There was evidence of lower treatment effects in trials that randomised on average at least 50 participants per group (P=0.05) or at least 100 participants per group (P=0.013), in trials that used concomittant viscosupplementation (P=0.08), and in trials that used concomitant joint lavage (P≤0.001).Corticosteroids appeared to be more effective in function improvement than control interventions (SMD -0.33, 95% CI -0.56 to -0.09), which corresponds to a difference in functions scores of -0.7 units on standardised Western Ontario and McMaster Universities Arthritis Index (WOMAC) disability scale ranging from 0 to 10 and translates into a NNTB of 10 (95% CI 7 to 33). An I(2) statistic of 69% indicated a moderate to large degree of between-trial heterogeneity. A visual inspection of the funnel plot suggested asymmetry (asymmetry coefficient -4.07, 95% CI -8.08 to -0.05). When stratifying results according to length of follow-up, benefits were small to moderate at 1 to 2 weeks after end of treatment (SMD -0.43, 95% CI -0.72 to -0.14), small to moderate at 4 to 6 weeks (SMD -0.36, 95% CI -0.63 to -0.09), and no evidence of an effect at 13 weeks (SMD -0.13, 95% CI -0.37 to 0.10) or at 26 weeks (SMD 0.06, 95% CI -0.16 to 0.28). An I(2) statistic of ≥ 62% indicated a moderate to large degree of between-trial heterogeneity up to 13 weeks after end of treatment (P for heterogeneity≤0.004), and an I(2) of 0% indicated low heterogeneity at 26 weeks (P=0.52). We found evidence of lower treatment effects in trials that randomised on average at least 50 participants per group (P=0.023), in unpublished trials (P=0.023), in trials that used non-intervention controls (P=0.031), and in trials that used concomitant viscosupplementation (P=0.06).Participants on corticosteroids were 11% less likely to experience adverse events, but confidence intervals included the null effect (RR 0.89, 95% CI 0.64 to 1.23, I(2)=0%). Participants on corticosteroids were 67% less likely to withdraw because of adverse events, but confidence intervals were wide and included the null effect (RR 0.33, 95% CI 0.05 to 2.07, I(2)=0%). Participants on corticosteroids were 27% less likely to experience any serious adverse event, but confidence intervals were wide and included the null effect (RR 0.63, 95% CI 0.15 to 2.67, I(2)=0%).We found no evidence of an effect of corticosteroids on quality of life compared to control (SMD -0.01, 95% CI -0.30 to 0.28, I(2)=0%). There was also no evidence of an effect of corticosteroids on joint space narrowing compared to control interventions (SMD -0.02, 95% CI -0.49 to 0.46). AUTHORS' CONCLUSIONS Whether there are clinically important benefits of intra-articular corticosteroids after one to six weeks remains unclear in view of the overall quality of the evidence, considerable heterogeneity between trials, and evidence of small-study effects. A single trial included in this review described adequate measures to minimise biases and did not find any benefit of intra-articular corticosteroids.In this update of the systematic review and meta-analysis, we found most of the identified trials that compared intra-articular corticosteroids with sham or non-intervention control small and hampered by low methodological quality. An analysis of multiple time points suggested that effects decrease over time, and our analysis provided no evidence that an effect remains six months after a corticosteroid injection.

Towards tailored radiopeptide therapy.

PURPOSE Somatostatin receptor-targeted radiopeptide therapy is commonly performed using single radioisotopes. We evaluated the benefits and harms of combining radioisotopes in radiopeptide therapy in patients with neuroendocrine tumor. METHODS Using multivariable-adjusted survival analyses and competing risk analyses we evaluated outcomes in patients with neuroendocrine tumor receiving (90)Y-DOTATOC, (177)Lu-DOTATOC or their combination. RESULTS (90)Y-DOTATOC plus (177)Lu-DOTATOC treatment was associated with longer survival than (90)Y-DOTATOC (66.1 vs. 47.5 months; n = 1,358; p < 0.001) or (177)Lu-DOTATOC alone (66.1 vs. 45.5 months; n = 390; p < 0.001). (177)Lu-DOTATOC was associated with longer survival than (90)Y-DOTATOC in patients with solitary lesions (HR 0.3, range 0.1 - 0.7; n = 153; p = 0.005), extrahepatic metastases (HR 0.5, range 0.3 - 0.9; n = 256; p = 0.029) and metastases with low uptake (HR 0.1, range 0.05 - 0.4; n = 113; p = 0.001). (90)Y-DOTATOC induced higher hematotoxicity rates than combined treatment (9.5% vs. 4.0%, p = 0.005) or (177)Lu-DOTATOC (9.5 vs. 1.4%, p = 0.002). Renal toxicity was similar among the treatments. CONCLUSIONS Using (90)Y and (177)Lu might facilitate tailoring radiopeptide therapy and improve survival in patients with neuroendocrine tumors.