Decompressive craniectomy plus best medical treatment versus best medical treatment alone for spontaneous severe deep supratentorial intracerebral haemorrhage: a randomised controlled clinical trial.

BACKGROUND: It is unknown whether decompressive craniectomy improves clinical outcome for people with spontaneous severe deep intracerebral haemorrhage. The SWITCH trial aimed to assess whether decompressive craniectomy plus best medical treatment in these patients improves outcome at 6 months compared to best medical treatment alone. METHODS: In this multicentre, randomised, open-label, assessor-blinded trial conducted in 42 stroke centres in Austria, Belgium, Finland, France, Germany, the Netherlands, Spain, Sweden, and Switzerland, adults (18-75 years) with a severe intracerebral haemorrhage involving the basal ganglia or thalamus were randomly assigned to receive either decompressive craniectomy plus best medical treatment or best medical treatment alone. The primary outcome was a score of 5-6 on the modified Rankin Scale (mRS) at 180 days, analysed in the intention-to-treat population. This trial is registered with ClincalTrials.gov, NCT02258919, and is completed. FINDINGS: SWITCH had to be stopped early due to lack of funding. Between Oct 6, 2014, and April 4, 2023, 201 individuals were randomly assigned and 197 gave delayed informed consent (96 decompressive craniectomy plus best medical treatment, 101 best medical treatment). 63 (32%) were women and 134 (68%) men, the median age was 61 years (IQR 51-68), and the median haematoma volume 57 mL (IQR 44-74). 42 (44%) of 95 participants assigned to decompressive craniectomy plus best medical treatment and 55 (58%) assigned to best medical treatment alone had an mRS of 5-6 at 180 days (adjusted risk ratio [aRR] 0·77, 95% CI 0·59 to 1·01, adjusted risk difference [aRD] -13%, 95% CI -26 to 0, p=0·057). In the per-protocol analysis, 36 (47%) of 77 participants in the decompressive craniectomy plus best medical treatment group and 44 (60%) of 73 in the best medical treatment alone group had an mRS of 5-6 (aRR 0·76, 95% CI 0·58 to 1·00, aRD -15%, 95% CI -28 to 0). Severe adverse events occurred in 42 (41%) of 103 participants receiving decompressive craniectomy plus best medical treatment and 41 (44%) of 94 receiving best medical treatment. INTERPRETATION: SWITCH provides weak evidence that decompressive craniectomy plus best medical treatment might be superior to best medical treatment alone in people with severe deep intracerebral haemorrhage. The results do not apply to intracerebral haemorrhage in other locations, and survival is associated with severe disability in both groups. FUNDING: Swiss National Science Foundation, Swiss Heart Foundation, Inselspital Stiftung, and Boehringer Ingelheim.

Magnetic resonance imaging to monitor disease activity in giant cell arteritis treated with ultra-short glucocorticoids and tocilizumab.

OBJECTIVES: MRI is well established for diagnosing GCA. Its role in monitoring disease activity has yet to be determined. We investigated vascular and musculoskeletal inflammation using MRI in the patients of the GUSTO trial to assess the utility of MRI in monitoring disease activity. METHODS: Eighteen patients with newly diagnosed GCA received 500 mg methylprednisolone intravenously for 3 consecutive days followed by tocilizumab monotherapy from day 3 until week 52. Cranial, thoracic and abdominal MRI exams were performed at baseline (active, new-onset disease), and at weeks 24, 52 (remission on-treatment), and 104 (remission off-treatment). MRI findings typical for PMR as well as extent and severity of vasculitic disease were rated. RESULTS: In total, 673 vascular segments and 943 musculoskeletal regions in 55 thoracic/abdominal MRI and 490 vascular segments in 49 cranial MRI scans of 18 patients were analysed. Vasculitic vessels were still detectable in one in four cranial segments at week 24. At weeks 52 and 104, no cranial vascular segment showed a vasculitic manifestation. Large vessels, except for the ascending aorta, and PMR displayed little or no decrease in inflammatory findings over time. CONCLUSION: Vasculitic manifestations in the cranial vessels normalised after 52 weeks of treatment, whereas large vessel and PMR findings persisted despite lasting full remission. The dynamics of cranial vessel signals suggest that MRI of these arteries might qualify as a potential diagnostic tool for monitoring disease activity and for detecting relapse after 52 weeks of treatment.

Musculoskeletal magnetic resonance imaging findings support a common spectrum of giant cell arteritis and polymyalgia rheumatica.

OBJECTIVES: To investigate the proportion and distribution of contrast enhancement (CE) of musculoskeletal structures with MRI of the thorax/abdomen/pelvis in giant cell arteritis (GCA). METHODS: CE at 34 musculoskeletal sites was rated with a 4-point ordinal scale. Patients were divided into groups with/without glucocorticoid (GC) treatment and with/without symptoms of polymyalgia rheumatica (PMR). Two composite scores were created: an MRI-score, including seven sites and a Limited-MRI-score, including four sites. RESULTS: Retrospectively, 90 consecutive patients with GCA were included. The population included 54 and 36 patients with and without PMR symptoms, respectively, and 45 (50%) patients were receiving GCs at the time of MRI. CE was found in 90.7% of lumbar spines, 87.5% of the pelvis, 82.2% of shoulder girdles and in 95.6% at any site in patients without GCs. The proportion of patients without and with GCs with at least moderate enhancement was 91.1%/75.6% at ≥ 1-3, 75.6%/51.1% at ≥ 4-6 and 64.4%/28.9% at ≥ 7-9 sites. The mean difference between the proportion of pathological CE in patients with and without GCs was 27.4% for synovial sites and 18.3% for periarticular/musculotendinous sites. Both composite scores captured substantial differences between groups, correlation was very strong between scores. CONCLUSIONS: MRI shows CE of musculoskeletal structures typical of PMR in most patients with GCA, supporting the concept of "GCA-PMR Spectrum Disease". Changes are more frequent at periarticular/musculotendinous sites and in the presence of PMR symptoms. A clear response to GCs is evident, less so for periarticular/musculotendinous sites.

Time to Treatment With Intravenous Thrombolysis Before Thrombectomy and Functional Outcomes in Acute Ischemic Stroke: A Meta-Analysis.

Importance: The benefit of intravenous thrombolysis (IVT) for acute ischemic stroke declines with longer time from symptom onset, but it is not known whether a similar time dependency exists for IVT followed by thrombectomy. Objective: To determine whether the benefit associated with IVT plus thrombectomy vs thrombectomy alone decreases with treatment time from symptom onset. Design, Setting, and Participants: Individual participant data meta-analysis from 6 randomized clinical trials comparing IVT plus thrombectomy vs thrombectomy alone. Enrollment was between January 2017 and July 2021 at 190 sites in 15 countries. All participants were eligible for IVT and thrombectomy and presented directly at thrombectomy-capable stroke centers (n = 2334). For this meta-analysis, only patients with an anterior circulation large-vessel occlusion were included (n = 2313). Exposure: Interval from stroke symptom onset to expected administration of IVT and treatment with IVT plus thrombectomy vs thrombectomy alone. Main Outcomes and Measures: The primary outcome analysis tested whether the association between the allocated treatment (IVT plus thrombectomy vs thrombectomy alone) and disability at 90 days (7-level modified Rankin Scale [mRS] score range, 0 [no symptoms] to 6 [death]; minimal clinically important difference for the rates of mRS scores of 0-2: 1.3%) varied with times from symptom onset to expected administration of IVT. Results: In 2313 participants (1160 in IVT plus thrombectomy group vs 1153 in thrombectomy alone group; median age, 71 [IQR, 62 to 78] years; 44.3% were female), the median time from symptom onset to expected administration of IVT was 2 hours 28 minutes (IQR, 1 hour 46 minutes to 3 hours 17 minutes). There was a statistically significant interaction between the time from symptom onset to expected administration of IVT and the association of allocated treatment with functional outcomes (ratio of adjusted common odds ratio [OR] per 1-hour delay, 0.84 [95% CI, 0.72 to 0.97], P = .02 for interaction). The benefit of IVT plus thrombectomy decreased with longer times from symptom onset to expected administration of IVT (adjusted common OR for a 1-step mRS score shift toward improvement, 1.49 [95% CI, 1.13 to 1.96] at 1 hour, 1.25 [95% CI, 1.04 to 1.49] at 2 hours, and 1.04 [95% CI, 0.88 to 1.23] at 3 hours). For a mRS score of 0, 1, or 2, the predicted absolute risk difference was 9% (95% CI, 3% to 16%) at 1 hour, 5% (95% CI, 1% to 9%) at 2 hours, and 1% (95% CI, -3% to 5%) at 3 hours. After 2 hours 20 minutes, the benefit associated with IVT plus thrombectomy was not statistically significant and the point estimate crossed the null association at 3 hours 14 minutes. Conclusions and Relevance: In patients presenting at thrombectomy-capable stroke centers, the benefit associated with IVT plus thrombectomy vs thrombectomy alone was time dependent and statistically significant only if the time from symptom onset to expected administration of IVT was short.

Thrombectomy alone versus intravenous alteplase plus thrombectomy in patients with stroke: an open-label, blinded-outcome, randomised non-inferiority trial.

BACKGROUND: Whether thrombectomy alone is equally as effective as intravenous alteplase plus thrombectomy remains controversial. We aimed to determine whether thrombectomy alone would be non-inferior to intravenous alteplase plus thrombectomy in patients presenting with acute ischaemic stroke. METHODS: In this multicentre, randomised, open-label, blinded-outcome trial in Europe and Canada, we recruited patients with stroke due to large vessel occlusion confirmed with CT or magnetic resonance angiography admitted to endovascular centres. Patients were randomly assigned (1:1) via a centralised web server using a deterministic minimisation method to receive stent-retriever thrombectomy alone or intravenous alteplase plus stent-retriever thrombectomy. In both groups, thrombectomy was initiated as fast as possible with any commercially available Solitaire stent-retriever revascularisation device (Medtronic, Irvine, CA, USA). In the combined treatment group, intravenous alteplase (0·9 mg/kg bodyweight, maximum dose 90 mg per patient) was administered as early as possible after randomisation for 60 min with 10% of the calculated dose given as an initial bolus. Personnel assessing the primary outcome were masked to group allocation; patients and treating physicians were not. The primary binary outcome was a score of 2 or less on the modified Rankin scale at 90 days. We assessed the non-inferiority of thrombectomy alone versus intravenous alteplase plus thrombectomy in all randomly assigned and consenting patients using the one-sided lower 95% confidence limit of the Mantel-Haenszel risk difference, with a prespecified non-inferiority margin of 12%. The main safety endpoint was symptomatic intracranial haemorrhage assessed in all randomly assigned and consenting participants. This trial is registered with ClinicalTrials.gov, NCT03192332, and is closed to new participants. FINDINGS: Between Nov 29, 2017, and May 7, 2021, 5215 patients were screened and 423 were randomly assigned, of whom 408 (201 thrombectomy alone, 207 intravenous alteplase plus thrombectomy) were included in the primary efficacy analysis. A modified Rankin scale score of 0-2 at 90 days was reached by 114 (57%) of 201 patients assigned to thrombectomy alone and 135 (65%) of 207 patients assigned to intravenous alteplase plus thrombectomy (adjusted risk difference -7·3%, 95% CI -16·6 to 2·1, lower limit of one-sided 95% CI -15·1%, crossing the non-inferiority margin of -12%). Symptomatic intracranial haemorrhage occurred in five (2%) of 201 patients undergoing thrombectomy alone and seven (3%) of 202 patients receiving intravenous alteplase plus thrombectomy (risk difference -1·0%, 95% CI -4·8 to 2·7). Successful reperfusion was less common in patients assigned to thrombectomy alone (182 [91%] of 201 vs 199 [96%] of 207, risk difference -5·1%, 95% CI -10·2 to 0·0, p=0·047). INTERPRETATION: Thrombectomy alone was not shown to be non-inferior to intravenous alteplase plus thrombectomy and resulted in decreased reperfusion rates. These results do not support omitting intravenous alteplase before thrombectomy in eligible patients. FUNDING: Medtronic and University Hospital Bern.

Diffusion-weighted magnetic resonance imaging for the diagnosis of giant cell arteritis - a comparison with T1-weighted black-blood imaging.

OBJECTIVES: To investigate the diagnostic performance of diffusion-weighted imaging (DWI) of the superficial cranial arteries in the diagnosis of giant cell arteritis (GCA). METHODS: Retrospectively, 156 patients with clinically suspected GCA were included. A new 4-point ordinal DWI rating scale was developed. A post-contrast, fat-suppressed, T1-weighted "black-blood" sequence (T1-BB) was rated for comparison. Ten arterial segments were assessed: common superficial temporal arteries, temporal and parietal branches, occipital and posterior auricular arteries bilaterally. The expert clinical diagnosis after ≥ 6 months of follow-up was the diagnostic reference standard. Diagnostic accuracy was evaluated for different rating methods. RESULTS: The study cohort consisted of 87 patients with and 69 without GCA. For DWI, the area under the curve was 0.90. For a cut-off of ≥ 2 consecutive pathological slices, DWI showed a sensitivity of 75.9%, a specificity of 94.2% and a positive likelihood ratio of 13.09. With a cut-off of ≥ 3 consecutive pathological slices, sensitivity was 70.1%, specificity was 98.6%, and the positive likelihood ratio was 48.38. For the T1-BB, values were 88.5%, 88.4% and 7.63, respectively. The inter-rater analysis for DWI with a cut-off of ≥ 2 pathological slices showed a kappa of 1.00 on the patient level and 0.85 on the arterial segment level. For the T1-BB the kappa was 0.78 and 0.79, respectively. CONCLUSION: DWI of the superficial cranial arteries demonstrates a good diagnostic accuracy and reliability for the diagnosis of GCA. DWI is widely available and can be used immediately in clinical practice for patients with suspected GCA.

Annual incidence and severity of acute episodes in hereditary thrombotic thrombocytopenic purpura.

Hereditary thrombotic thrombocytopenic purpura (hTTP) is a rare thrombotic microangiopathy characterized by severe congenital ADAMTS13 deficiency and recurring acute episodes causing morbidity and premature death. Information on the annual incidence and severity of acute episodes in patients with hTTP is largely lacking. This study reports prospective data on 87 patients from the Hereditary TTP Registry (clinicaltrials.gov #NCT01257269) for survival, frequency, and severity of acute episodes from enrollment until December 2019. The 87 patients, followed up for a median of 4.2 years (range, 0.01-15 years), had a median age at overt disease onset and at clinical diagnosis of 4.6 years and 18 years (range, 0.0-70 years for both), respectively. Forty-three patients received regular plasma prophylaxis, whereas 22 did not, and treatment changed over time or was unknown in the remaining 22. Forty-three patients experienced 131 acute episodes, of which 91 (69%) occurred in patients receiving regular prophylaxis. This resulted in an annual incidence of acute episodes of 0.36 (95% confidence interval [CI], 0.29-0.44) with regular plasma treatment and of 0.41 (95% CI, 0.30-0.56) without regular plasma treatment. More than one-third of acute episodes (n = 51) were documented in children <10 years of age at enrollment and were often triggered by infections. Their annual incidence of acute episodes was significantly higher than in patients aged >40 years (1.18 [95% CI, 0.88-1.55] vs 0.14 [95% CI, 0.08-0.23]). The prophylactic plasma infusion regimens used were insufficient to prevent acute episodes in many patients. Such regimens are burdensome, and caregivers, patients, and their guardians are reluctant to start regular plasma infusions, from which children particularly would benefit.

The Early HOSPITAL Score to Predict 30-Day Readmission Soon After Hospitalization: a Prospective Multicenter Study.

BACKGROUND: The simplified HOSPITAL score is an easy-to-use prediction model to identify patients at high risk of 30-day readmission before hospital discharge. An earlier stratification of this risk would allow more preparation time for transitional care interventions. OBJECTIVE: To assess whether the simplified HOSPITAL score would perform similarly by using hemoglobin and sodium level at the time of admission instead of discharge. DESIGN: Prospective national multicentric cohort study. PARTICIPANTS: In total, 934 consecutively discharged medical inpatients from internal general services. MAIN MEASURES: We measured the composite of the first unplanned readmission or death within 30 days after discharge of index admission and compared the performance of the simplified score with lab at discharge (simplified HOSPITAL score) and lab at admission (early HOSPITAL score) according to their discriminatory power (Area Under the Receiver Operating characteristic Curve (AUROC)) and the Net Reclassification Improvement (NRI). KEY RESULTS: During the study period, a total of 3239 patients were screened and 934 included. In total, 122 (13.2%) of them had a 30-day unplanned readmission or death. The simplified and the early versions of the HOSPITAL score both showed very good accuracy (Brier score 0.11, 95%CI 0.10-0.13). Their AUROC were 0.66 (95%CI 0.60-0.71), and 0.66 (95%CI 0.61-0.71), respectively, without a statistical difference (p value 0.79). Compared with the model at discharge, the model with lab at admission showed improvement in classification based on the continuous NRI (0.28; 95%CI 0.08 to 0.48; p value 0.004). CONCLUSION: The early HOSPITAL score performs, at least similarly, in identifying patients at high risk for 30-day unplanned readmission and allows a readmission risk stratification early during the hospital stay. Therefore, this new version offers a timely preparation of transition care interventions to the patients who may benefit the most.

Quantitative ultrasound to monitor the vascular response to tocilizumab in giant cell arteritis.

OBJECTIVES: To characterize the effect of ultra-short glucocorticoids followed by Tocilizumab monotherapy on the intima-media thickness (IMT) in GCA. METHODS: Eighteen GCA patients received 500 mg for 3 consecutive days (total of 1500mg) i.v. methylprednisolone on days 0-2, followed by i.v. Tocilizumab (8 mg/kg) on day 3 and thereafter weekly s.c. Tocilizumab injections (162 mg) over 52 weeks. US of temporal (TAs), axillary (AAs) and subclavian (SAs) arteries was performed at baseline, on days 2-3, and at weeks 4, 8, 12, 24 and 52. The largest IMT of all segments and IMT at landmarks of AA/SA were recorded. IMT was scaled by mean normal values and averaged. Each segment was classified according to diagnostic cut-offs. RESULTS: Of the 18 GCA patients, 16 patients had TA and 6 had extracranial large artery involvement. The IMT showed a sharp decline on day 2/3 in the TAs and AAs/SAs. In TAs, this was followed by an increase to baseline levels at week 4 and a subsequent slow decrease, which was paralleled by decreasing symptoms and achievement of clinical remission. The AAs/SAs showed a new signal of vasculitis at week 4 in three patients, with an IMT increase up to week 8. CONCLUSION: Glucocorticoid pulse therapy induced a transient decrease of the IMT in TAs and AAs/SAs. Tocilizumab monotherapy resulted in a slow and steady decrease in IMT of the TAs and a smaller and delayed effect on the AAs/SAs. The data strongly support a remission-inducing effect of Tocilizumab and argue the case for US having an important role in monitoring disease activity in GCA. TRIAL REGISTRATION: ClinicalTrials.gov, www.clinicaltrials.gov, NCT03745586.

Treatment for gastrointestinal and pancreatic neuroendocrine tumours: a network meta-analysis.

BACKGROUND: Several available therapies for neuroendocrine tumours (NETs) have demonstrated efficacy in randomised controlled trials. However, translation of these results into improved care faces several challenges, as a direct comparison of the most pertinent therapies is incomplete. OBJECTIVES: To evaluate the safety and efficacy of therapies for NETs, to guide clinical decision-making, and to provide estimates of relative efficiency of the different treatment options (including placebo) and rank the treatments according to their efficiency based on a network meta-analysis. SEARCH METHODS: We identified studies through systematic searches of the following bibliographic databases: the Cochrane Central Register of Controlled Trials (CENTRAL) in the Cochrane Library; MEDLINE (Ovid); and Embase from January 1947 to December 2020. In addition, we checked trial registries for ongoing or unpublished eligible trials and manually searched for abstracts from scientific and clinical meetings. SELECTION CRITERIA: We evaluated randomised controlled trials (RCTs) comparing two or more therapies in people with NETs (primarily gastrointestinal and pancreatic). DATA COLLECTION AND ANALYSIS: Two review authors independently selected studies and extracted data to a pre-designed data extraction form. Multi-arm studies were included in the network meta-analysis using the R-package netmeta. We separately analysed two different outcomes (disease control and progression-free survival) and two types of NET (gastrointestinal and pancreatic NET) in four network meta-analyses. A frequentist approach was used to compare the efficacy of therapies. MAIN RESULTS: We identified 55 studies in 90 records in the qualitative analysis, reporting 39 primary RCTs and 16 subgroup analyses. We included 22 RCTs, with 4299 participants, that reported disease control and/or progression-free survival in the network meta-analysis. Precision-of-treatment estimates and estimated heterogeneity were limited, although the risk of bias was predominantly low. The network meta-analysis of progression-free survival found nine therapies for pancreatic NETs: everolimus (hazard ratio [HR], 0.36 [95% CI, 0.28 to 0.46]), interferon plus somatostatin analogue (HR, 0.34 [95% CI, 0.14 to 0.80]), everolimus plus somatostatin analogue (HR, 0.38 [95% CI, 0.26 to 0.57]), bevacizumab plus somatostatin analogue (HR, 0.36 [95% CI, 0.15 to 0.89]), interferon (HR, 0.41 [95% CI, 0.18 to 0.94]), sunitinib (HR, 0.42 [95% CI, 0.26 to 0.67]), everolimus plus bevacizumab plus somatostatin analogue (HR, 0.48 [95% CI, 0.28 to 0.83]), surufatinib (HR, 0.49 [95% CI, 0.32 to 0.76]), and somatostatin analogue (HR, 0.51 [95% CI, 0.34 to 0.77]); and six therapies for gastrointestinal NETs: 177-Lu-DOTATATE plus somatostatin analogue (HR, 0.07 [95% CI, 0.02 to 0.26]), everolimus plus somatostatin analogue (HR, 0.12 [95%CI, 0.03 to 0.54]), bevacizumab plus somatostatin analogue (HR, 0.18 [95% CI, 0.04 to 0.94]), interferon plus somatostatin analogue (HR, 0.23 [95% CI, 0.06 to 0.93]), surufatinib (HR, 0.33 [95%CI, 0.12 to 0.88]), and somatostatin analogue (HR, 0.34 [95% CI, 0.16 to 0.76]), with higher efficacy than placebo. Besides everolimus for pancreatic NETs, the results suggested an overall superiority of combination therapies, including somatostatin analogues. The results indicate that NET therapies have a broad range of risk for adverse events and effects on quality of life, but these were reported inconsistently. Evidence from this network meta-analysis (and underlying RCTs) does not support any particular therapy (or combinations of therapies) with respect to patient-centred outcomes (e.g. overall survival and quality of life). AUTHORS' CONCLUSIONS: The findings from this study suggest that a range of efficient therapies with different safety profiles is available for people with NETs.

Cervical cancer risk in women living with HIV across four continents: A multicohort study.

We compared invasive cervical cancer (ICC) incidence rates in Europe, South Africa, Latin and North America among women living with HIV who initiated antiretroviral therapy (ART) between 1996 and 2014. We analyzed cohort data from the International Epidemiology Databases to Evaluate AIDS (IeDEA) and the Collaboration of Observational HIV Epidemiological Research in Europe (COHERE) in EuroCoord. We used flexible parametric survival models to determine regional ICC rates and risk factors for incident ICC. We included 64,231 women from 45 countries. During 320,141 person-years (pys), 356 incident ICC cases were diagnosed (Europe 164, South Africa 156, North America 19 and Latin America 17). Raw ICC incidence rates per 100,000 pys were 447 in South Africa (95% confidence interval [CI]: 382-523), 136 in Latin America (95% CI: 85-219), 76 in North America (95% CI: 48-119) and 66 in Europe (95% CI: 57-77). Compared to European women ICC rates at 5 years after ART initiation were more than double in Latin America (adjusted hazard ratio [aHR]: 2.43, 95% CI: 1.27-4.68) and 11 times higher in South Africa (aHR: 10.66, 95% CI: 6.73-16.88), but similar in North America (aHR: 0.79, 95% CI: 0.37-1.71). Overall, ICC rates increased with age (>50 years vs. 16-30 years, aHR: 1.57, 95% CI: 1.03-2.40) and lower CD4 cell counts at ART initiation (per 100 cell/µl decrease, aHR: 1.25, 95% CI: 1.15-1.36). Improving access to early ART initiation and effective cervical cancer screening in women living with HIV should be key parts of global efforts to reduce cancer-related health inequities.

Emergency front of neck access in children: a new learning approach in a rabbit model.

BACKGROUND: Cannot intubate-cannot ventilate situations in healthy children are uncommon but are often associated with poor outcome. Several airway management algorithms suggest emergency tracheal access. Little agreement exists on how to perform emergency front of the neck access (eFONA) in children <8 yr. We studied the learning curves of clinicians performing simulated paediatric eFONA. METHODS: After watching an instructional video, 50 physicians, from five medical specialties, performed 10 emergency tracheotomies on rabbit cadavers. We analysed their learning curves relative to performance time and concurring injuries. RESULTS: With an overall success rate of 94%, performance time decreased from 107 s (standard deviation [sd], 45) to 55 s (sd 17) over 10 attempts. The learning curve was steep between the first and the fourth attempts with an 11% decrease in performance time (95% confidence interval [CI], 9-13%; P<0.001) per attempt and then flattened to a 4% (95% CI, 3-5%; P<0.001) decrease per attempt between the fourth and the tenth attempt. Age, years of clinical experience, and sex showed a significant effect on the learning curve, whereas medical specialty and adult eFONA experience did not. The 58% (95% CI, 44-72%) probability for severe injury during the first attempt decreased to 14% (95% CI, 8-20%) at the second attempt. Men were more likely to cause minor injuries than women (P<0.001). CONCLUSIONS: Irrespective of medical specialty, paediatric clinicians acquired the eFONA technique within four attempts and were on average able to establish an airway in <1 min when performing emergency tracheotomy on a paediatric airway simulator. CLINICAL TRIAL REGISTRATION: NCT03576352.

The skill of tracheal intubation with rigid scopes - a randomised controlled trial comparing learning curves in 740 intubations.

BACKGROUND: Rigid scopes are successfully used for management of difficult airways, but learning curves have not been established. METHODS: This randomised controlled trial was performed at the University Hospital Bern in Switzerland to establish learning curves for the rigid scopes Bonfils and SensaScope and to assess their performance. Fifteen consultant anaesthetists and 15 anaesthesia registrars performed a total of 740 intubations (10 to 20 intubations with each device per physician) in adult patients without predictors of a difficult airway under general anaesthesia. According to randomisation, physicians intubated the patient's trachea with either the Bonfils or the SensaScope. A maximum of three intubation attempts was allowed. Primary outcome was overall time to successful intubation. Secondary outcome parameters included first attempt success, first attempt success within 60 s, failures and adverse events. RESULTS: A clear learning effect was demonstrated: Over 20 trials, intubations became 2.5-times quicker and first attempt intubation success probability increased by 21-28 percentage points. Fourteen and 20 trials were needed with the Bonfils and the SensaScope, respectively, to reach a 90% first attempt success probability. Intubation times were 23% longer (geometric mean ratio 1.23, 95% confidence interval 1.12-1.36, p < 0.001) and first attempt success was less likely (odds ratio 0.64, 95% confidence interval 0.45-0.92, p = 0.016) with the SensaScope. Consultants showed a tendency for a better first attempt success compared to registrars. Overall, 23 intubations (10 Bonfils, 13 SensaScope) failed. Adverse events were rare and did not differ between devices. CONCLUSIONS: A clear learning effect was demonstrated for both rigid scopes. Fourteen intubations with the Bonfils and 20 intubations with the SensaScope were required to reach a 90% first attempt success probability. Learning of the technique seemed more complex with the SensaScope compared to the Bonfils. TRIAL REGISTRATION: Current Controlled Trials, ISRCTN14429285 . Registered 28 September 2011, retrospectively registered.

Effect of CIMicifuga racemosa on metaBOLIC parameters in women with menopausal symptoms: a retrospective observational study (CIMBOLIC).

PURPOSE: To compare the influence of Cimicifuga racemosa extract (CR, Ze 450) and menopausal hormone therapy (MHT) on metabolic parameters and body weight in symptomatic menopausal women. METHODS: In this monocentric retrospective cohort study, women over 40 years old with a first consultation between 2009 and 2016 were screened. Included in the final analysis were women treated with either MHT or CR and having at least one follow-up consultation. Metabolic serum parameters (lipids, glucose, insulin, and HOMA-IR), body weight, and menopausal symptoms [Menopause Rating Scale (MRS)-II] were the main outcome measures. Statistical analysis by uni- and multi-variable linear mixed-effects regression models assuming a linear effect of time. RESULTS: 174 women were included in the final analysis (CR n = 32, MHT n = 142). There was no difference between the groups regarding baseline characteristics (age, BMI, serum metabolic parameters, hormones, and blood pressure) and total MRS-II score, while reproductive stage differed significantly with more postmenopausal women treated with CR (83%) than MHT (55%) (p = 0.038). Median follow-up time was 12 months. In both groups, metabolic serum parameters and body weight did not change over the follow-up period, while total and MRS-II subscores improved. CONCLUSION: Menopausal symptoms improved significantly in both groups (MHT and CR), while serum metabolic parameters and body weight did not change in MHT- or CR-treated women.

Effect of Biomechanical Footwear on Knee Pain in People With Knee Osteoarthritis: The BIOTOK Randomized Clinical Trial.

IMPORTANCE: Individually calibrated biomechanical footwear therapy may improve pain and physical function in people with symptomatic knee osteoarthritis, but the benefits of this therapy are unclear. OBJECTIVE: To assess the effect of a biomechanical footwear therapy vs control footwear over 24 weeks of follow-up. DESIGN, SETTING, AND PARTICIPANTS: Randomized clinical trial conducted at a Swiss university hospital. Participants (N = 220) with symptomatic, radiologically confirmed knee osteoarthritis were recruited between April 20, 2015, and January 10, 2017. The last participant visit occurred on August 15, 2017. INTERVENTIONS: Participants were randomized to biomechanical footwear involving shoes with individually adjustable external convex pods attached to the outsole (n = 111) or to control footwear (n = 109) that had visible outsole pods that were not adjustable and did not create a convex walking surface. MAIN OUTCOMES AND MEASURES: The primary outcome was knee pain at 24 weeks of follow-up assessed with the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) pain subscore standardized to range from 0 (no symptoms) to 10 (extreme symptoms). The secondary outcomes included WOMAC physical function and stiffness subscores and the WOMAC global score, all ranging from 0 (no symptoms) to 10 (extreme symptoms) at 24 weeks of follow-up, and serious adverse events. RESULTS: Among the 220 randomized participants (mean age, 65.2 years [SD, 9.3 years]; 104 women [47.3%]), 219 received the allocated treatment and 213 (96.8%) completed follow-up. At 24 weeks of follow-up, the mean standardized WOMAC pain subscore improved from 4.3 to 1.3 in the biomechanical footwear group and from 4.0 to 2.6 in the control footwear group (between-group difference in scores at 24 weeks of follow-up, -1.3 [95% CI, -1.8 to -0.9]; P < .001). The results were consistent for WOMAC physical function subscore (between-group difference, -1.1 [95% CI, -1.5 to -0.7]), WOMAC stiffness subscore (between-group difference, -1.4 [95% CI, -1.9 to -0.9]), and WOMAC global score (between-group difference, -1.2 [95% CI, -1.6 to -0.8]) at 24 weeks of follow-up. Three serious adverse events occurred in the biomechanical footwear group compared with 9 in the control footwear group (2.7% vs 8.3%, respectively); none were related to treatment. CONCLUSIONS AND RELEVANCE: Among participants with knee pain from osteoarthritis, use of biomechanical footwear compared with control footwear resulted in an improvement in pain at 24 weeks of follow-up that was statistically significant but of uncertain clinical importance. Further research would be needed to assess long-term efficacy and safety, as well as replication, before reaching conclusions about the clinical value of this device. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT02363712.

The International Hereditary Thrombotic Thrombocytopenic Purpura Registry: key findings at enrollment until 2017.

Congenital thrombotic thrombocytopenic purpura is an autosomal recessive inherited disease with a clinically heterogeneous course and an incompletely understood genotype-phenotype correlation. In 2006, the Hereditary TTP Registry started recruitment for a study which aimed to improve the understanding of this ultra-rare disease. The objective of this study is to present characteristics of the cohort until the end of 2017 and to explore the relationship between overt disease onset and ADAMTS13 activity with emphasis on the recurring ADAMTS13 c.4143_4144dupA mutation. Diagnosis of congenital thrombotic thrombocytopenic purpura was confirmed by severely deficient ADAMTS13 activity (≤10% of normal) in the absence of a functional inhibitor and the presence of ADAMTS13 mutations on both alleles. By the end of 2017, 123 confirmed patients had been enrolled from Europe (n=55), Asia (n=52, 90% from Japan), the Americas (n=14), and Africa (n=2). First recognized disease manifestation occurred from around birth up to the age of 70 years. Of the 98 different ADAMTS13 mutations detected, c.4143_4144dupA (exon 29; p.Glu1382Argfs*6) was the most frequent mutation, present on 60 of 246 alleles. We found a larger proportion of compound heterozygous than homozygous carriers of ADAMTS13 c.4143_4144dupA with overt disease onset at < 3 months of age (50% vs 37%), despite the fact that ADAMTS13 activity was <1% in 18 of 20 homozygous, but in only 8 of 14 compound heterozygous carriers. An evaluation of overt disease onset in all patients with an available sensitive ADAMTS13 activity assay (n=97) shows that residual ADAMTS13 activity is not the only determinant of age at first disease manifestation. Registered at clinicaltrials.gov identifier NCT01257269.

Magnetic resonance angiography in giant cell arteritis: results of a randomized controlled trial of tocilizumab in giant cell arteritis.

Objective: To analyse magnetic resonance angiographic (MRA) vessel wall signals from a randomized controlled trial of tocilizumab (TCZ) to treat GCA. Methods: Participants were assigned in a 2:1 ratio to receive either TCZ + glucocorticoids (GCs) or placebo + GC infusions at 4-week intervals for 52 weeks. GCs were started at 1 mg/kg/day, then tapered to 0.1 mg/kg/day at week 12 and thereafter down to zero. Patients with initial positive MRA findings underwent control MRA at weeks 12 and 52. Vessel wall signals were scored from 0 (normal) to 3 (intense late enhancement). Outcomes were the number of patients with complete MRA remission at weeks 12 and 52, and changes in vasculitis score, vessel anatomy and atherosclerosis. Results: Of the 30 randomized participants, nine TCZ and two placebo patients had no vessel wall enhancement on initial MRA. At week 12, MRAs were performed in nine TCZ and four placebo patients (nine and three in clinical remission, respectively). Three (33%) TCZ patients showed normalization of vessel wall signals compared with one (25%) placebo patient. At week 52, there was additional MRA improvement in some TCZ patients, but one-third showed persistent or increased late vessel wall enhancement. There was no formation of aneurysms or stenosis and no increase in atherosclerosis. Conclusions: Although TCZ resulted in complete clinical and laboratory remission of GCA over 52 weeks, MRA signals in vessel walls normalized in only one-third of patients. Whether these signals are of prognostic importance remains to be determined.

Tocilizumab for induction and maintenance of remission in giant cell arteritis: a phase 2, randomised, double-blind, placebo-controlled trial.

BACKGROUND: Giant cell arteritis is an immune-mediated disease of medium and large-sized arteries that affects mostly people older than 50 years of age. Treatment with glucocorticoids is the gold-standard and prevents severe vascular complications but is associated with substantial morbidity and mortality. Tocilizumab, a humanised monoclonal antibody against the interleukin-6 receptor, has been associated with rapid induction and maintenance of remission in patients with giant cell arteritis. We therefore aimed to study the efficacy and safety of tocilizumab in the first randomised clinical trial in patients with newly diagnosed or recurrent giant cell arteritis. METHODS: In this single centre, phase 2, randomised, double-blind, placebo-controlled trial, we recruited patients aged 50 years and older from University Hospital Bern, Switzerland, who met the 1990 American College of Rheumatology criteria for giant cell arteritis. Patients with new-onset or relapsing disease were randomly assigned (2:1) to receive either tocilizumab (8 mg/kg) or placebo intravenously. 13 infusions were given in 4 week intervals until week 52. Both groups received oral prednisolone, starting at 1 mg/kg per day and tapered down to 0 mg according to a standard reduction scheme defined in the study protocol. Allocation to treatment groups was done using a central computerised randomisation procedure with a permuted block design and a block size of three, and concealed using central randomisation generated by the clinical trials unit. Patients, investigators, and study personnel were masked to treatment assignment. The primary outcome was the proportion of patients who achieved complete remission of disease at a prednisolone dose of 0·1 mg/kg per day at week 12. All analyses were intention to treat. This trial is registered with ClinicalTrials.gov, number NCT01450137. RESULTS: Between March 3, 2012, and Sept 9, 2014, 20 patients were randomly assigned to receive tocilizumab and prednisolone, and ten patients to receive placebo and glucocorticoid; 16 (80%) and seven (70%) patients, respectively, had new-onset giant cell arteritis. 17 (85%) of 20 patients given tocilizumab and four (40%) of ten patients given placebo reached complete remission by week 12 (risk difference 45%, 95% CI 11-79; p=0·0301). Relapse-free survival was achieved in 17 (85%) patients in the tocilizumab group and two (20%) in the placebo group by week 52 (risk difference 65%, 95% CI 36-94; p=0·0010). The mean survival-time difference to stop glucocorticoids was 12 weeks in favour of tocilizumab (95% CI 7-17; p<0·0001), leading to a cumulative prednisolone dose of 43 mg/kg in the tocilizumab group versus 110 mg/kg in the placebo group (p=0·0005) after 52 weeks. Seven (35%) patients in the tocilizumab group and five (50%) in the placebo group had serious adverse events. INTERPRETATION: Our findings show, for the first time in a trial setting, the efficacy of tocilizumab in the induction and maintenance of remission in patients with giant cell arteritis. FUNDING: Roche and the University of Bern.

A randomized controlled pilot study to evaluate the effect of an enteral formulation designed to improve gastrointestinal tolerance in the critically ill patient-the SPIRIT trial.

BACKGROUND: Diarrhea is frequent in patients in intensive care units (ICU) and is associated with discomfort and complications and may increase the length of stay and nursing workload. METHODS: This was a prospective, double-blind, randomized, controlled single-center pilot study to assess the incidence and frequency of diarrhea and the respective effects of a modified enteral diet (intervention: Peptamen® AF, rich in proteins, medium chain triglycerides and fish oil) compared to a standard diet (control: Isosource® Energy) in 90 randomized adult patients (intervention, n = 46; control, n = 44) with an ICU stay ≥5 days and tube feeding ≥3 days. Tube feeding was initiated within 72 h of ICU admission and continued up to 10 days. The caloric goal was adjusted to needs by indirect calorimetry. Gastrointestinal function, nutritional intake, and nursing workload were recorded. Follow-up was until 28 days after randomization. RESULTS: Median age was 63.3 (interquartile range (IQR) 51.0-73.2) years and Simplified Acute Physiology Score (SAPS) II was 61.0 (IQR 47.8-74). Time to reach caloric goal (intervention: 2.2 (0.8-3.7) days (median, IQR); control: 2.0 (1.3-2.7) days; p = 0.16), length of time on study nutrition (intervention: 5.0 (3.6-6.4) days; control: 7.0 (5.3-8.7) days; p = 0.26), and calorie intake (intervention: 18.0 (12.5-20.9) kcal/kg/day; control 19.7 (17.3-23.1) kcal/kg/day; p = 0.08) did not differ between groups, with a higher protein intake for Peptamen® group (1.13 (0.78-1.31) g/kg/day vs 0.80 (0.70-0.94); p < 0.001). No difference in diarrhea incidence (intervention group: 29 (64%); control group: 31 (70%); p = 0.652), use of fecal collectors (23 (51%) vs. 24 (55%); p = 0.83), or diarrhea-free days (161 (64%) vs 196 (68%); p = 0.65) was found. Nursing workload and cost for diarrhea care were not different between the groups. In a post-hoc analysis, adjusted for treatment group, age, sex, and SAPS II score, diarrhea was associated with length of mechanical ventilation (9.5 (6.0-13.1) vs. 3.9 (3.2-4.6) days; p = 0.006) and length of ICU stay (11.0 (8.9-13.1) vs. 5.0 (3.8-6.2) days; p = 0.001). CONCLUSIONS: In this pilot study, we found a high incidence of diarrhea, which was not attenuated by Peptamen® AF. Patients with diarrhea stayed longer in the ICU. TRIAL REGISTRATION: ClinicalTrials.gov identifier, NCT01581957 . Registered on 18 April 2012.

Ultrasound intima-media thickness cut-off values for the diagnosis of giant cell arteritis using a dual clinical and MRI reference standard and cardiovascular risk stratification.

Objectives: To derive segmental cut-off values and measures of diagnostic accuracy for the intima-media thickness of compressed temporal artery segments for the diagnosis of giant cell arteritis (GCA) on the patient level. To examine the influence of cardiovascular risk. Methods: Retrospectively, patients evaluated for GCA with an ultrasound of the temporal arteries and an MRI of the head, including a T1-fatsat-black blood (T1-BB) sequence, were identified and classified based on cardiovascular risk and a dual reference standard of T1-BB on the segmental level and the clinical diagnosis on the patient level. Intima-media thickness of the common superficial temporal artery (CSTA), frontal and parietal branches (FB, PB) were measured by compression technique. Statistically and clinically optimal (specificity of approx. 90% for the patient level) cut-offs were derived. Diagnostic accuracy was evaluated on the patient level. Results: The population consisted of 144 patients, 74 (51.4%) with and 70 (48.6%) without GCA. The statistically optimal cut-offs were 0.86 mm, 0.68 mm and 0.67 mm for the CSTA, the FB and PB, respectively. On the patient level sensitivity and specificity were 86.5 and 81.4%. Clinically optimal cut-offs were 1.01 mm, 0.82 mm and 0.69 mm and showed a sensitivity of 79.7% and a specificity of 90.0%. For patients without high cardiovascular risk, statistically optimal cut-offs showed a sensitivity of 89.6% and a specificity of 90.5%. Conclusion: Newly derived ultrasound intima-media thickness cut-offs with a dual reference standard show high diagnostic accuracy on the patient level for the diagnosis of GCA, particularly in patients without high cardiovascular risk.