Summary Background Immobilisation predicts adverse outcomes in patients in the surgical intensive care unit (SICU). Attempts to mobilise critically ill patients early after surgery are frequently ...restricted, but we tested whether early mobilisation leads to improved mobility, decreased SICU length of stay, and increased functional independence of patients at hospital discharge. Methods We did a multicentre, international, parallel-group, assessor-blinded, randomised controlled trial in SICUs of five university hospitals in Austria (n=1), Germany (n=1), and the USA (n=3). Eligible patients (aged 18 years or older, who had been mechanically ventilated for <48 h, and were expected to require mechanical ventilation for ≥24 h) were randomly assigned (1:1) by use of a stratified block randomisation via restricted web platform to standard of care (control) or early, goal-directed mobilisation using an inter-professional approach of closed-loop communication and the SICU optimal mobilisation score (SOMS) algorithm (intervention), which describes patients’ mobilisation capacity on a numerical rating scale ranging from 0 (no mobilisation) to 4 (ambulation). We had three main outcomes hierarchically tested in a prespecified order: the mean SOMS level patients achieved during their SICU stay (primary outcome), and patient's length of stay on SICU and the mini-modified functional independence measure score (mmFIM) at hospital discharge (both secondary outcomes). This trial is registered with ClinicalTrials.gov ( NCT01363102 ). Findings Between July 1, 2011, and Nov 4, 2015, we randomly assigned 200 patients to receive standard treatment (control; n=96) or intervention (n=104). Intention-to-treat analysis showed that the intervention improved the mobilisation level (mean achieved SOMS 2·2 SD 1·0 in intervention group vs 1·5 0·8 in control group, p<0·0001), decreased SICU length of stay (mean 7 days SD 5–12 in intervention group vs 10 days 6–15 in control group, p=0·0054), and improved functional mobility at hospital discharge (mmFIM score 8 4–8 in intervention group vs 5 2–8 in control group, p=0·0002). More adverse events were reported in the intervention group (25 cases 2·8%) than in the control group (ten cases 0·8%); no serious adverse events were observed. Before hospital discharge 25 patients died (17 16% in the intervention group, eight 8% in the control group). 3 months after hospital discharge 36 patients died (21 22% in the intervention group, 15 17% in the control group). Interpretation Early, goal-directed mobilisation improved patient mobilisation throughout SICU admission, shortened patient length of stay in the SICU, and improved patients’ functional mobility at hospital discharge. Funding Jeffrey and Judy Buzen.
Background A pilot study using a novel high-sensitivity cardiac troponin I (hs-cTnI) assay suggested that cTnI might be released into blood during exercise-induced myocardial ischemia. We ...investigated the potential clinical value of this signal. Methods We included 819 patients with suspected exercise-induced myocardial ischemia referred for rest/bicycle myocardial perfusion single-photon emission computed tomography. The treating cardiologist used all available clinical information to quantify clinical judgment regarding the presence of myocardial ischemia using a visual analog scale twice: prior and after stress testing. High-sensitivity cTnI measurements were obtained before, immediately after peak stress, and 2 hours after stress testing in a blinded manner. Myocardial ischemia was adjudicated using perfusion single-photon emission computed tomography and coronary angiography findings. Results Exercise-induced myocardial ischemia was detected in 278 (34%) patients. High-sensitivity cTnI levels were significantly higher at all time points in patients with myocardial ischemia as compared with those without ( P < .001 for all). Combining clinical judgment prior exercise testing with baseline hs-cTnI levels increased diagnostic accuracy as quantified by the area under the receiver operating characteristics curve (AUC) from 0.672 to 0.757 ( P < .001). Combining clinical judgment after exercise testing (AUC 0.704) with baseline or poststress hs-cTnI levels also increased the diagnostic accuracy (AUC 0.761-0.771, P < .001 for all). In contrast, exercise-induced changes in hs-cTnI during exercise did not seem useful, as they were small and similar in patients with or without myocardial ischemia. Conclusions High-sensitivity cTnI concentrations at rest and after exercise, but not its exercise-induced changes, provide substantial incremental value to clinical judgment including exercise electrocardiography regarding the presence of myocardial ischemia.
Summary Background Plasmodium falciparum sporozite (PfSPZ) Vaccine is a metabolically active, non-replicating, whole malaria sporozoite vaccine that has been reported to be safe and protective ...against P falciparum controlled human malaria infection in malaria-naive individuals. We aimed to assess the safety and protective efficacy of PfSPZ Vaccine against naturally acquired P falciparum in malaria-experienced adults in Mali. Methods After an open-label dose-escalation study in a pilot safety cohort, we did a double-blind, randomised, placebo-controlled trial based in Donéguébougou and surrounding villages in Mali. We recruited 18–35-year-old healthy adults who were randomly assigned (1:1) in a double-blind manner, with stratification by village and block randomisation, to receive either five doses of 2·7 × 105 PfSPZ or normal saline at days 0, 28, 56, 84, and 140 during the dry season (January to July inclusive). Participants and investigators were masked to group assignments, which were unmasked at the final study visit, 6 months after receipt of the last vaccination. Participants received combined artemether and lumefantrine (four tablets, each containing 20 mg artemether and 120 mg lumefantrine, given twice per day over 3 days for a total of six doses) to eliminate P falciparum before the first and last vaccinations. We collected blood smears every 2 weeks and during any illness for 24 weeks after the fifth vaccination. The primary outcome was the safety and tolerability of the vaccine, assessed as local and systemic reactogenicity and adverse events. The sample size was calculated for the exploratory efficacy endpoint of time to first P falciparum infection beginning 28 days after the fifth vaccination. The safety analysis included all participants who received at least one dose of investigational product, whereas the efficacy analyses included only participants who received all five vaccinations. This trial is registered at ClinicalTrials.gov , number NCT01988636. Findings Between Jan 18 and Feb 24, 2014, we enrolled 93 participants into the main study cohort with 46 participants assigned PfSPZ Vaccine and 47 assigned placebo, all of whom were evaluable for safety. We detected no significant differences in local or systemic adverse events or laboratory abnormalities between the PfSPZ Vaccine and placebo groups, and only grade 1 (mild) local or systemic adverse events occurred in both groups. The most common solicited systemic adverse event in the vaccine and placebo groups was headache (three 7% people in the vaccine group vs four 9% in the placebo group) followed by fatigue (one 2% person in the placebo group), fever (one 2% person in the placebo group), and myalgia (one 2% person in each group). The exploratory efficacy analysis included 41 participants from the vaccine group and 40 from the placebo group. Of these participants, 37 (93%) from the placebo group and 27 (66%) from the vaccine group developed P falciparum infection. The hazard ratio for vaccine efficacy was 0·517 (95% CI 0·313–0·856) by time-to-infection analysis (log-rank p=0·01), and 0·712 (0·528–0·918) by proportional analysis (p=0·006). Interpretation PfSPZ Vaccine was well tolerated and safe. PfSPZ Vaccine showed significant protection in African adults against P falciparum infection throughout an entire malaria season. Funding US National Institutes of Health Intramural Research Program, Sanaria.
Summary Background TDP-43 is a major component of the ubiquitinated inclusions that characterise amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD) with ubiquitin ...inclusions (FTLD-U). TDP-43 is an RNA-binding and DNA-binding protein that has many functions and is encoded by the TAR DNA-binding protein gene ( TARDBP ) on chromosome 1. Our aim was to investigate whether TARDBP is a candidate disease gene for familial ALS that is not associated with mutations in superoxide dismutase 1 ( SOD1 ). Methods TARDBP was sequenced in 259 patients with ALS, FTLD, or both. We used TaqMan-based SNP genotyping to screen for the identified variants in control groups matched to two kindreds of patients for age and ethnic origin. Additional clinical, genetic, and pathological assessments were made in these two families. Findings We identified two variants in TARDBP , which would encode Gly290Ala and Gly298Ser forms of TDP-43, in two kindreds with familial ALS. The variants seem to be pathogenic because they co-segregated with disease in both families, were absent in controls, and were associated with TDP-43 neuropathology in both members of one of these families for whom CNS tissue was available. Interpretation The Gly290Ala and Gly298Ser mutations are located in the glycine-rich domain of TDP-43, which regulates gene expression and mediates protein–protein interactions such as those with heterogeneous ribonucleoproteins. Owing to the varied and important cellular functions of TDP-43, these mutations might cause neurodegeneration through both gains and losses of function. The finding of pathogenic mutations in TARDBP implicates TDP-43 as an active mediator of neurodegeneration in TDP-43 proteinopathies, a class of disorder that includes ALS and FTLD-U. Funding National Institutes of Health (AG10124, AG17586, AG005136-22, PO1 AG14382), Department of Veterans Affairs, Friedrich-Baur Stiftung (0017/2007), US Public Health Service, ALS Association, and Fundació ‘la Caixa’.
Background In patients with Marfan syndrome, the complications of aortic degeneration, including dissection, aneurysm, and rupture represent the main cause of mortality. Although contemporary ...management of ascending aortic disease requires open surgical reconstruction, endovascular repair is now available for management of descending thoracic and abdominal aortic pathology (ie, thoracic endovascular aortic repair TEVAR, endovascular aneurysm repair EVAR). The short- and long-term benefit of endovascular repair in Marfan patients remains largely unproven. We examine our outcomes after EVAR in this patient population. Methods All patients with a diagnosis of Marfan syndrome who were treated with TEVAR/EVAR were evaluated in a retrospective review. Perioperative, procedure-specific and patient covariate data were aggregated. Primary endpoints were overall mortality and procedural success as divided into three categories: (1) successful therapy, (2) primary failure, or (3) secondary failure. Results Between 2000 and June 2010, 16 patients were identified as having undergone 19 TEVAR/EVAR procedures. These included three emergent operations (two for acute dissection/malperfusion and one for anastomotic disruption early after open repair). All 16 patients had previously undergone at least one (range, 1-5) open operation of the ascending aorta or arch at a time interval from 33 years to 1 week prior to the index endovascular repair. During a median follow-up of 9.3 months (range, 0-46 months), there were four deaths (25%). Six patients (38%) had successful endovascular interventions. Despite early success, there was one death in this group at 1 month postintervention. Seven patients (44%) experienced primary treatment failure with five undergoing open conversion and one undergoing left subclavian coil embolization (the seventh was lost to follow-up and presented 4 months later in cardiac arrest and expired without repair). There were three deaths in the primary treatment failure group. Two patients experienced secondary treatment failure. One underwent the index TEVAR for acute dissection with malperfusion and required a subsequent TEVAR for more distal aortic pathology. He is stable without disease progression. The other patient underwent open conversion after a second EVAR with four-vessel “chimney” stent grafts and is stable with his entire native aorta having been replaced. Conclusions Aortic disease associated with Marfan syndrome is a complex clinical problem and many patients require remedial procedures. Endovascular therapy can provide a useful adjunct or bridge to open surgical treatment in selected patients. However, failure of endovascular therapy is common, and its use should be judicious with close follow-up to avoid delay if open surgical repair is required.
To determine whether vitrectomy surgery rates have changed over the past decade and factors affecting the odds of undergoing this procedure.
Retrospective, longitudinal cohort study.
All enrollees 21 ...years of age or older between 2001 and 2012 in a United States managed care network.
Claims data from a managed care network were analyzed to identify all enrollees who underwent 1 vitrectomy or more each year from 2001 through 2012. Rates of vitrectomy per 1000 enrollees were computed each year from 2001 through 2012 for the entire group and separately for patients with and without diabetes mellitus. Multivariate logistic regression assessed factors affecting the odds of undergoing vitrectomy surgery.
Annual rates of vitrectomy surgery from 2001 through 2012 and odds ratios (ORs) of undergoing a vitrectomy with 95% confidence intervals (CIs).
Among the 11 161 907 eligible enrollees, 40 892 (0.4%) underwent vitrectomy over the 12-year period. The average age of those undergoing vitrectomy was 57±13 years. Overall vitrectomy rates increased 31% from 2001 to 2012 (from 1.47 to 1.92 per 1000 patients). During this same period, the vitrectomy rate among persons with diabetes mellitus decreased by 43% (from 5.84 to 3.31 per 1000 patients with diabetes). Women had 24% decreased odds of undergoing vitrectomy (adjusted odds ratio OR, 0.76; 95% confidence interval CI, 0.72-0.79). The odds of undergoing a vitrectomy were 17% greater for black persons (adjusted OR, 1.17; 95% CI, 1.07-1.27) and 7% higher for persons with diabetes (adjusted OR, 1.07; 95% CI, 1.01-1.14).
Overall, we observed an increase in the vitrectomy rates per 1000 enrollees in this large managed care network over the course of the past decade. However, among persons with diabetes mellitus, vitrectomy rates declined substantially over this period. These changes may be explained, in part, by advances in surgical instrumentation and imaging methods to detect retinal diseases changing indications for surgery, improvements in diabetes care, and alternative treatment options for managing retinal conditions. These results may be useful for future planning of manpower needs and highlight the need for aggressive prevention of complications in black persons with diabetes.
To investigate motion artifacts, image quality, and practical differences in electrocardiographic (ECG)-gated versus non-ECG-gated high-pitch dual-source computed tomography angiography (CTA) of the ...whole aorta.
Two groups, each including 40 patients, underwent either ECG-gated or non-ECG-gated high-pitch dual-source CTA of the whole aorta. The aortic annulus, aortic valve, coronary ostia, and the presence of motion artifacts of the thoracic aorta as well as vascular contrast down to the femoral arteries were independently assessed by two readers. Additional objective parameters including image noise and signal-to-noise ratio were analyzed.
Subjective and objective scoring revealed no presence of motional artifacts regardless of whether the ECG-gated or the non-ECG-gated protocol was used (P > 0.1). Image acquisition parameters (examination length, examination duration, radiation dose) were comparable between the two groups without significant differences. The aortic annulus, aortic valve, and coronary ostia were reliably evaluable in all patients. Vascular contrast was rated excellent in both groups.
High-pitch dual-source CTA of the whole aorta is a robust and dose-efficient examination strategy for the evaluation of aortic pathologies whether or not ECG gating is used.
Summary Background Streptococcus pneumoniae is a leading cause of bacterial pneumonia, meningitis, and sepsis in children worldwide. However, many countries lack national estimates of disease burden. ...Effective interventions are available, including pneumococcal conjugate vaccine and case management. To support local and global policy decisions on pneumococcal disease prevention and treatment, we estimated country-specific incidence of serious cases and deaths in children younger than 5 years. Methods We measured the burden of pneumococcal pneumonia by applying the proportion of pneumonia cases caused by S pneumoniae derived from efficacy estimates from vaccine trials to WHO country-specific estimates of all-cause pneumonia cases and deaths. We also estimated burden of meningitis and non-pneumonia, non-meningitis invasive disease using disease incidence and case-fatality data from a systematic literature review. When high-quality data were available from a country, these were used for national estimates. Otherwise, estimates were based on data from neighbouring countries with similar child mortality. Estimates were adjusted for HIV prevalence and access to care and, when applicable, use of vaccine against Haemophilus influenzae type b. Findings In 2000, about 14·5 million episodes of serious pneumococcal disease (uncertainty range 11·1–18·0 million) were estimated to occur. Pneumococcal disease caused about 826 000 deaths (582 000–926 000) in children aged 1–59 months, of which 91 000 (63 000–102 000) were in HIV-positive and 735 000 (519 000–825 000) in HIV-negative children. Of the deaths in HIV-negative children, over 61% (449 000 316 000–501 000) occurred in ten African and Asian countries. Interpretation S pneumoniae causes around 11% (8–12%) of all deaths in children aged 1–59 months (excluding pneumococcal deaths in HIV-positive children). Achievement of the UN Millennium Development Goal 4 for child mortality reduction can be accelerated by prevention and treatment of pneumococcal disease, especially in regions of the world with the greatest burden. Funding GAVI Alliance and the Vaccine Fund.
Background Combined pulmonary fibrosis and emphysema (CPFE) is increasingly recognized, but its prevalence and prognosis remain unclear. We sought to determine the prevalence, clinical features, and ...prognosis of CPFE in idiopathic pulmonary fibrosis (IPF), using a standardized and reproducible definition. Methods Patients with IPF were identified from two ongoing cohorts. Two radiologists scored emphysema and fibrosis severity on high-resolution CT (HRCT) scans. CPFE was defined as ≥ 10% emphysema on HRCT scan. Clinical characteristics and outcomes of patients with CPFE and IPF and those with non-CPFE IPF were compared with unadjusted analysis and then analysis after adjustment for HRCT fibrosis score. Mortality was compared using competing risks regression to handle lung transplantation. Sensitivity analyses were performed using Cox proportional hazards, including time to death (transplantation censored) and time to death or transplant. Results CPFE criteria were met in 29 of 365 patients with IPF (8%), with high agreement between radiologists (κ = 0.74). Patients with CPFE had less fibrosis on HRCT scans and higher FVC, but greater oxygen requirements ( P ≤ .01 for all comparisons). Findings were maintained with adjustment for fibrosis severity. Inhaled therapies for COPD were used by 53% of patients with CPFE. There was no significant difference in mortality comparing patients with CPFE and IPF to those with non-CPFE IPF (hazard ratio, 1.14; 95% CI, 0.61-2.13; P = .69). Conclusions CPFE was identified in 8% of patients with IPF and is a distinct, clinical phenotype with potential therapies that remain underutilized. Patients with CPFE and IPF and those with non-CPFE IPF have similar mortality.
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