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Background: Clinical trials investigating acetabular fractures are heterogeneous in their investigated outcomes and their corresponding measurements. Standardization may facilitate comparability and pooling of research results, which would lead to an increase in knowledge about the optimal treatment of acetabular fractures, resulting in long-term evidence-based treatment decisions and improvements in patient care. The aim of this systematic review is to identify the reported outcomes and their measurements from studies on treatments for acetabular fractures to develop a core outcome set which contains the most relevant outcome measures to be included in future studies. Methods: Studies published in English and German including patients aged 16 years and older, with a surgically treated acetabular fracture, will be included. Studies with nonsurgical treatment, pathologic fractures, polytraumatized patients, and patients younger than 16 years of age will be excluded because other outcomes may be of interest in these cases. Any prospective and retrospective study will be included. Systematic reviews will be excluded, but their included studies will be screened for eligibility. The literature will be searched on MEDLINE, CENTRAL, Web of Science, ClinicalTrials.gov, and WHO ICTRP. Risk of selective reporting of outcomes will be assessed using the Outcome Reporting Bias in Trials classification system. Heterogeneously defined outcomes that measure the same outcome will be grouped and subsequently categorized into outcome domains using the taxonomy of the Core Outcome Measures in Effectiveness Trials Initiative. Discussion: It is expected that a high number of studies will be included, and many outcomes will be identified using different definitions and measurement instruments. A limitation of this systematic review is that only previously investigated outcomes will be detected, thus disregarding potentially relevant outcomes. Systematic review registration: PROSPERO CRD42022357644 [ABSTRACT FROM AUTHOR]

Aims: Previous trials on the effectiveness of genotype‐guided warfarin dosing vs. conventional dosing have been inconclusive. We conducted a systematic review and meta‐analysis of randomized trials comparing genotype‐guided to conventional dosing strategies. Methods: PubMed and the Cochrane Library were searched up to 23 October 2017. Results: A total of 76 and 94 entries were retrieved were retrieved from PubMed and the Cochrane Library, respectively. A total of 2626 subjects in the genotype‐guided dosing (mean age 63.3 ± 5.8 years; 46% male) and 2604 subjects in the conventional dosing (mean age 64.7 ± 6.1 years; 46% male) groups (mean follow‐up duration 64 days) from 18 trials were included. Compared with conventional dosing, genotype‐guided dosing significantly shortened the time to first therapeutic international normalized ratio (INR) (mean difference 2.6 days, standard error 0.3 days; P < 0.0001; I2 0%) and time to first stable INR (mean difference 5.9 days, standard error 2.0 days; P < 0.01; I2 94%). Genotype‐guided dosing also increased the time in therapeutic range (mean difference 3.1%, standard error 1.2%; P < 0.01; I2 80%) and reduced the risks of both excessive anticoagulation, defined as INR ≥4 [risk ratio (RR) 0.87; 95% confidence interval (CI) 0.78, 0.98; P < 0.05; I2: 0%), and bleeding (RR 0.82; 95% CI 0.69, 0.98; P < 0.05; I2 31%). No difference in thromboembolism (RR 0.84; 95% CI 0.56, 1.26; P = 0.40; I2 0%) or mortality (RR 1.16; 95% CI 0.46, 2.91; P = 0.76; I2 0%) was observed between the two groups. Conclusions: Genotype‐guided warfarin dosing offers better safety with less bleeding compared with conventional dosing strategies. No significant benefit on thromboembolism or mortality was evident. [ABSTRACT FROM AUTHOR]

Aims: The subcutaneous implantable cardioverter defibrillator (S-ICD) was introduced to overcome complications related to transvenous leads. Adoption of the S-ICD requires implanters to learn a new implantation technique. The aim of this study was to assess the learning curve for S-ICD implanters with respect to implant-related complications, procedure time, and inappropriate shocks (IASs).Methods and Results: In a pooled cohort from two clinical S-ICD databases, the IDE Trial and the EFFORTLESS Registry, complications, IASs at 180 days follow-up and implant procedure duration were assessed. Patients were grouped in quartiles based on experience of the implanter and Kaplan-Meier estimates of complication and IAS rates were calculated. A total of 882 patients implanted in 61 centres by 107 implanters with a median of 4 implants (IQR 1,8) were analysed. There were a total of 59 patients with complications and 48 patients with IAS. The complication rate decreased significantly from 9.8% in Quartile 1 (least experience) to 5.4% in Quartile 4 (most experience) (P = 0.02) and non-significantly for IAS from 7.9 to 4.8% (P = 0.10). Multivariable analysis demonstrated a hazard ratio of 0.78 (P = 0.045) for complications and 1.01 (P = 0.958) for IAS. Dual-zone programming increased with experience of the individual implanter (P < 0.001), which reduced IAS significantly in the multivariable model (HR 0.44, P = 0.01). Procedure time decreased from 75 to 65 min (P < 0.001). The complication rate and procedure time stabilized after Quartile 2 (>13 implants).Conclusion: There is a short and significant learning curve associated with physicians adopting the S-ICD. Performance stabilizes after 13 implants. [ABSTRACT FROM AUTHOR]

Purpose: To describe the clinical features and outcomes of estrogen receptor negative (ER-) and progesterone receptor positive (PgR+) breast cancer. Methods: We retrospectively reviewed a well-characterized database of sequential patients diagnosed with early stage invasive breast carcinoma. Outcomes of interest were time to relapse (TTR) and overall survival (OS). Multivariable Cox proportional hazards analysis was conducted to assess the association of ER-/PgR+ with TTR and OS in comparison to ER+ and to ER- and PgR negative (ER-/PgR-) tumors irrespective of HER2 status. ER and PgR expression was conservatively defined as 10% or greater staining of cancer cells. Results: 815 patients were followed for a median of 40.5 months; 56 patients (7%) had ER-/PgR+, 624 (77%) had ER+ and 136 (17%) had ER-/PgR- phenotypes. Compared with ER+ tumors, ER-/PgR+ tumors were associated with younger age (50 versus 59 years, p=0.03), high grade (50% versus 24%, p<0.001) and more frequent HER2 overexpression/amplification (43% versus 14%, p<0.001). TTR for ER-/PgR+ was intermediate between ER+ and ER-/PgR- tumors, but was not significantly different from ER+ tumors. Recurrences in the ER-/PgR+ and ER-/PgR- groups occurred early in follow-up while in ER+ tumors recurrences continued to occur over the duration of follow-up. OS of ER-/PgR+ was similar to ER+ tumors and better than that of ER-/PgR- tumors. Conclusions: The ER-/PgR+ phenotype is associated with higher grade with HER2 overexpression/amplification and occurs more commonly in younger women. Risk of relapse and death more closely resembles ER+ than ER-/PgR- tumors suggesting this phenotype represents a group of more aggressive hormone receptor positive tumors. [ABSTRACT FROM AUTHOR]

Introduction:Previous small-molecule antiangiogenics have compromised chemotherapy dose intensity in breast cancer. We present a phase I trial of a novel selective agent, nintedanib, plus standard chemotherapy in early breast cancer.Methods:Her-2-negative breast cancer patients with tumours larger than 2 cm were eligible for dose-escalation trial (classic 3+3 method).Results:The recommended phase II dose (RP2D) was 150 mg BID of nintedanib combined with standard dose of weekly paclitaxel followed by adriamycin plus cyclophosphamide. The dose-limiting toxicity was transaminase elevation. At the RP2D, the dose intensity was ∼100%. The pathologic complete response was 50%.Conclusions:The combination allows the delivery of full-dose intensity, while efficacy seems promising. [ABSTRACT FROM AUTHOR]

Background There is growing interest in conducting clinical and cluster randomized trials through electronic health records. This paper reports on the methodological issues identified during the implementation of two cluster randomized trials using the electronic health records of the Clinical Practice Research Datalink (CPRD). Methods Two trials were completed in primary care: one aimed to reduce inappropriate antibiotic prescribing for acute respiratory infection; the other aimed to increase physician adherence with secondary prevention interventions after first stroke. The paper draws on documentary records and trial datasets to report on the methodological experience with respect to research ethics and research governance approval, general practice recruitment and allocation, sample size calculation and power, intervention implementation, and trial analysis. Results We obtained research governance approvals from more than 150 primary care organizations in England, Wales, and Scotland. There were 104 CPRD general practices recruited to the antibiotic trial and 106 to the stroke trial, with the target number of practices being recruited within six months. Interventions were installed into practice information systems remotely over the internet. The mean number of participants per practice was 5,588 in the antibiotic trial and 110 in the stroke trial, with the coefficient of variation of practice sizes being 0.53 and 0.56 respectively. Outcome measures showed substantial correlations between the 12 months before, and after intervention, with coefficients ranging from 0.42 for diastolic blood pressure to 0.91 for proportion of consultations with antibiotics prescribed, defining practice and participant eligibility for analysis requires careful consideration. Conclusions Cluster randomized trials may be performed efficiently in large samples from UK general practices using the electronic health records of a primary care database. The geographical dispersal of trial sites presents a difficulty for research governance approval and intervention implementation. Pretrial data analyses should inform trial design and analysis plans. [ABSTRACT FROM AUTHOR]

Background Hypertension is the leading global risk factor for mortality. Hypertension treatment and control rates are low worldwide, and delays in seeking care are associated with increased mortality. Thus, a critical component of hypertension management is to optimize linkage and retention to care. Methods/Design This study investigates whether community health workers, equipped with a tailored behavioral communication strategy and smartphone technology, can increase linkage and retention of hypertensive individuals to a hypertension care program and significantly reduce blood pressure among them. The study will be conducted in the Kosirai and Turbo Divisions of western Kenya. An initial phase of qualitative inquiry will assess facilitators and barriers of linkage and retention to care using a modified Health Belief Model as a conceptual framework. Subsequently, we will conduct a cluster randomized controlled trial with three arms: 1) usual care (community health workers with the standard level of hypertension care training); 2) community health workers with an additional tailored behavioral communication strategy; and 3) community health workers with a tailored behavioral communication strategy who are also equipped with smartphone technology. The co-primary outcome measures are: 1) linkage to hypertension care, and 2) one-year change in systolic blood pressure among hypertensive individuals. Cost-effectiveness analysis will be conducted in terms of costs per unit decrease in blood pressure and costs per disability-adjusted life year gained. Discussion This study will provide evidence regarding the effectiveness and cost-effectiveness of strategies to optimize linkage and retention to hypertension care that can be applicable to non-communicable disease management in low- and middle-income countries. Trial registration This trial is registered with www.clinicaltrials.gov (NCT01844596) on 30 April 2013. [ABSTRACT FROM AUTHOR]

The prevalence of diabetes mellitus is rising globally, and it induces a substantial public health burden to the healthcare systems. Its optimal control is one of the most significant challenges faced by physicians and policy-makers. Whereas some of the established oral hypoglycaemic drug classes like biguanide, sulphonylureas, thiazolidinediones have been extensively used, the newer agents like dipeptidyl peptidase-4 (DPP-4) inhibitors and the human glucagon-like peptide-1 (GLP-1) analogues have recently emerged as suitable options due to their similar efficacy and favorable side effect profiles. These agents are widely recognized alternatives to the traditional oral hypoglycaemic agents or insulin, especially in conditions where they are contraindicated or unacceptable to patients. Many studies which evaluated their clinical effects, either alone or as add-on agents, were conducted in Western countries. There exist few reviews on their effectiveness in the Asia-Pacific region. The purpose of this systematic review is to address the comparative effectiveness of these new classes of medications as add-on therapies to sulphonylurea drugs among diabetic patients in the Asia-Pacific countries. We conducted a thorough literature search of the MEDLINE and EMBASE from the inception of these databases to August 2013, supplemented by an additional manual search using reference lists from research studies, meta-analyses and review articles as retrieved by the electronic databases. A total of nine randomized controlled trials were identified and described in this article. It was found that DPP-4 inhibitors and GLP-1 analogues were in general effective as add-on therapies to existing sulphonylurea therapies, achieving HbA1c reductions by a magnitude of 0.59–0.90% and 0.77–1.62%, respectively. Few adverse events including hypoglycaemic attacks were reported. Therefore, these two new drug classes represent novel therapies with great potential to be major therapeutic options. Future larger-scale research should be conducted among other Asia-Pacific region to evaluate their efficacy in other ethnic groups. [ABSTRACT FROM AUTHOR]

Background A healthy diet is associated with reduced risk of diabetes, cardiovascular disease and cancer. The study aimed to evaluate the cost-effectiveness of a universal strategy to promote healthy diet through brief intervention in primary care. Methods The research was informed by a systematic review of randomised trials which found that brief interventions in primary care may be associated with a 0.5 portion per day increase in fruit and vegetable consumption. A Markov model that included five long-term conditions (diabetes, coronary heart disease, stroke, colorectal cancer and depression) was developed. Empirical data from a large cohort of United Kingdom-based participants sampled from the Clinical Practice Research Datalink populated the model. Simulations compared an intervention promoting healthy diet over 5 years in healthy adults, and standard care in which there was no intervention. The annual cost of intervention, in the base case, was one family practice consultation per participant year. Health service costs were included and the model adopted a lifetime perspective. The primary outcome was net health benefit in quality adjusted life years (QALYs). Results A cohort of 262,704 healthy participants entered the model. Intervention was associated with an increase in life years lived free from physical disease of 41.9 (95% confidence interval - 17.4 to 101.0) per 1,000 participants entering the model (probability of increase 88.0%). New incidences of disease states were reduced by 28.4 (18.7 to 75.8) per 1,000, probability reduced 84.6%. Discounted incremental QALYs were 4.3 (-8.8 to 18.0) per 1,000, while incremental costs were £139,755 (£60,466 to 220,059) per 1,000. Net health benefits at £30,000 per QALY were -0.32 (-13.8 to 13.5) QALYs per 1,000 participants (probability cost-effective 47.9%). When the intervention was restricted to adults aged 50 to 74 years, net health benefits were 2.94 (-21.3 to 26.4) QALYs per 1000, probability increased 59.0%. Conclusions A universal strategy to promote healthy diet through brief intervention in primary care is unlikely to be cost-effective, even when delivered at low unit cost. A targeted strategy aimed at older individuals at higher risk of disease might be more cost-effective. More effective dietary change interventions are needed. [ABSTRACT FROM AUTHOR]

Background: We evaluated BCR-ABL1 kinetics in patients treated with nilotinib and analyzed whether a dynamic model of changes in BCR-ABL1 levels over time could be used to predict long-term responses. Methods: Patients from the nilotinib registration trial (CAMN107A2101; registered at www.clinicaltrials.gov as NCT00109707) who had imatinib-resistant or -intolerant Philadelphia chromosome-positive (Ph+) chronic myeloid leukemia (CML) in chronic phase (CP) or accelerated phase with BCR-ABL1 > 10% (on the international scale [IS]) at baseline and, in the first 6 months, had at least three BCR-ABL1 transcript measurements and an average daily dose of at least 720 mg were included in this analysis (N = 123). Results: More than half of patients (65/123; 53%) had a slow monophasic response and the remainder (58/123; 47%) had a biphasic response, in which patients had a rapid initial decrease in BCR-ABL1 transcripts followed by a more gradual response. The biphasic response type strongly correlated with improved event-free survival (EFS). Data in the first 6 months of follow-up were sufficient to predict EFS at 24 months. Conclusions: Unlike newly diagnosed patients with Ph+ CML-CP-in whom the majority had a biphasic response-approximately half of patients with imatinib-resistant or -intolerant CML had a slower, monophasic response. Second-line patients who did have a biphasic response had an EFS outlook similar to that of newly diagnosed patients treated with imatinib. Our model was comparable to using BCR-ABL1 (IS) ⩽ 10% at 6 months as a threshold for predicting EFS. [ABSTRACT FROM AUTHOR]

AIMS To assess and compare the mechanisms of central nervous system (CNS) penetration of antimuscarinic overactive bladder (OAB) agents. METHODS Physical properties were computed or compiled from the literature. Rats were administered 5-hydroxymethyl tolterodine (HMT), darifenacin, oxybutynin, solifenacin, tolterodine or trospium subcutaneously. At 1 h postdose, plasma, brain and cerebrospinal fluid (CSF) concentrations were determined using LC-MS/MS assays. Brain and plasma protein binding were determined in vitro. Permeability in the presence and absence of the efflux transporter P-glycoprotein (P-gp) was assessed in RRCK and MDCK-MDR1 transwell assays. RESULTS Oxybutynin displayed extensive CNS penetration, with brain : plasma ratios (B : P), unbound brain : unbound plasma ratios (Kp,free) and CSF : free plasma ratios each >1. Tolterodine (B : P = 2.95, Kp,free = 0.23 and CSF : free plasma = 0.16) and solifenacin (B : P = 3.04, Kp,free = 0.28 and CSF : free plasma = 1.41) showed significant CNS penetration but with some restriction from CNS as indicated by Kp,free values significantly <1. 5-HMT, darifenacin and trospium displayed much lower B : P (0.03-0.16), Kp,free (0.01-0.04) and CSF : free plasma (0.004-0.06), consistent with poor CNS penetration. Permeability in RRCK cells was low for trospium (0.63 × 10-6 cm s-1), moderate for 5-HMT (11.7 × 10-6 cm s-1) and high for darifenacin, solifenacin, tolterodine and oxybutynin (21.5-38.2 × 10-6 cm s-1). In MDCK-MDR1 cells 5-HMT, darifenacin and trospium, were P-gp substrates, whereas oxybutynin, solifenacin and tolterodine were not P-gp substrates. CONCLUSIONS Brain penetration was low for antimuscarinics that are P-gp substrates (5-HMT, darifenacin and trospium), and significant for those that are not P-gp substrates (oxybutynin, solifenacin and tolterodine).CNS adverse events reported in randomized controlled clinical trials show general alignment with the preclinical data described in this study. [ABSTRACT FROM AUTHOR]

Boron neutron capture therapy (BNCT) provides highly targeted delivery of radiation through the limited spatial distribution of its effects. This translational research/phase I clinical trial investigates whether BNCT might be developed as a treatment option for squamous cell carcinoma of head and neck (SCCHN) relying upon preferential uptake of the two compounds, sodium mercaptoundecahydro- closo-dodecaborate (BSH) or L- para-boronophenylalanine (BPA) in the tumour. Before planned tumour resection, three patients received BSH and three patients received BPA. The 10B-concentration in tissues and blood was measured with prompt gamma ray spectroscopy. Adverse effects from compounds did not occur. After BPA infusion the 10B-concentration ratio of tumour/blood was 4.0 ± 1.7. 10B-concentration ratios of tumour/normal tissue were 1.3 ± 0.5 for skin, 2.1 ± 1.2 for muscle and 1.4 ± 0.01 for mucosa. After BSH infusion the 10B-concentration ratio of tumour/blood was 1.2 ± 0.4. 10B-concentration ratios of tumour/normal tissue were 3.6 ± 0.6 for muscle, 2.5 ± 1.0 for lymph nodes, 1.4 ± 0.5 for skin and 1.0 ± 0.3 for mucosa. BPA and BSH deliver 10B to SCCHN to an extent that might allow effective BNCT treatment. Mucosa and skin are the most relevant organs at risk. [ABSTRACT FROM AUTHOR]

Dose escalation is often used in depressed patients who fail to respond to standard doses of selective serotonin reuptake inhibitors, but clinical efficacy is equivocal. We aimed to reassess the efficacy of paroxetine dose escalation and quantify whether paroxetine dose escalation increases occupancy of the serotonin transporter (SERT) more than placebo dose escalation in a randomized controlled trial. We recruited 107 nonpsychotic, unipolar depressed outpatients (18–70 years; Hamilton Depression Rating Scale (HDRS17) >18) from primary care and psychiatric outpatient departments. After 6 weeks, open-label paroxetine 20 mg per day (T0), nonresponding patients (HDRS17 decrease <50%; n=60) were randomized to double-blind paroxetine (30–50 mg per day as tolerable) or placebo dose escalation (paroxetine 20 mg per day+placebo). Patients were followed until 6 weeks after randomization (T1). Forty-nine patients, drug free at study entry, underwent single-photon emission-computed tomography (SPECT) scanning before treatment and were scanned repeatedly at T0 and T1. Paroxetine serum concentrations and SERT occupancy were determined at T0 and T1 (n=32). We terminated the dose-escalation trial after an interim analysis. Thirty nonresponding patients were randomized to paroxetine (46.7±5.5 mg per day), 27 to placebo dose escalation. Response rates were 10/30 (33.3%) and 10/27 (37.0%), respectively. Repeated measurement analyses showed no significant effect for treatment (p=0.88, exceeding a priori stopping rules for futility (p>0.5)). Overall dropout was higher for placebo (26.7%) than paroxetine (3.3%; p=0.03). Paroxetine dose escalation increased paroxetine serum concentrations (p<0.001). SPECT measurements (12 patients randomized to paroxetine (46.9±4.8 mg) and 14 to placebo dose escalation) showed no significant increase of midbrain SERT occupancy (2.5±26.4%, paroxetine; 3.1±25.8% placebo; p=0.687) nor in diencephalon (p=0.529). Paroxetine dose escalation in depressed patients has no clinical benefit over placebo dose escalation. This is explained by the absence of significant increases of SERT occupancy by paroxetine dose escalation, despite increased paroxetine serum concentrations (ISRCTN44111488).Neuropsychopharmacology (2009) 34, 999–1010; doi:10.1038/npp.2008.148; published online 1 October 2008 [ABSTRACT FROM AUTHOR]

Background: In a substantial proportion of depressed patients, stressful life events play a role in triggering the evolution of the illness. Exposure to stress has effects on different levels in laboratory animals as well and for the rat it has been shown that chronic mild stress (CMS) can cause antidepressant-reversible depressive-like effects. The adoption of the model to the mouse seems to be problematic, depending on the strain used and behavioural endpoint defined. Our aim was to evaluate the applicability of CMS to mice in order to induce behavioural alterations suggested to reflect depression-like symptoms. Methodology/Principal Findings: A weekly CMS protocol was applied to male mice of different mouse strains (D2Ola, BL/6J and BL/6N) and its impact on stress-sensitive behavioural measures (anhedonia-, anxiety- and depression-related parameters) and body weight was assessed. Overnight illumination as commonly used stressor in CMS protocols was particularly investigated in terms of its effect on general activity and subsequently derived saccharin intake. CMS application yielded strain-dependent behavioural and physiological responses including 'paradox' anxiolytic-like effects. Overnight illumination was found to be sufficient to mimic anhedonic-like behaviour in BL/6J mice when being applied as sole stressor. Conclusions/Significance: The CMS procedure induced some behavioural changes that are compatible with the common expectations, i.e. 'anhedonic' behaviour, but in parallel behavioural alterations were observed which would be described as 'anomalous' (e.g. decreased anxiety). The results suggest that a shift in the pattern of circadian activity has a particular high impact on the anhedonic profile. Changes in activity in response to novelty seem to drive the 'anomalous' behavioural alterations as well. [ABSTRACT FROM AUTHOR]

Meshed, split-thickness skin grafts, especially when required to be widely spread, do not obtain immediate biologic closure. In patients with burns that cover a large percentage of the body surface area, this leaves the patient at risk for metabolic problems and life-threatening infection. Objective: The purpose of this study was to determine whether amnion-derived cellular cytokine solution could improve epithelialization kinetics and accelerate closure of meshed skin graft interstices. Methods: Human meshed, split-thickness skin grafts were explanted to athymic "nude" rats and treated with 3 different regimens of amnion-derived cellular cytokine solution (groups I, II, and III) or normal saline (group IV) as a control. Serial wound tracings of unepithelialized interstitial wound areas were compared over time. Two different preparations of amnion-derived cellular cytokine solution were also compared with one another, one containing animal components and the other free of animal components. Results: Only 67.03% of interstices in control animals closed by day 9. This compared with 92.2% closure for group I, 83.72% for group II, and 90.64% for group III. Interstices in all 3 groups treated with amnion-derived cellular cytokine solution (with or without animal-derived components) closed faster statistically than in the control animals (P < .05). There were no statistical differences among the 3 amnion-derived cellular cytokine solution-treated groups. Conclusions: These data suggest that epithelialization kinetics and interstitial closure of meshed skin grafts can be accelerated with the use of amnion-derived cellular cytokine solution, a physiologic cocktail of cytokines, and provide support for a future clinical trial. [ABSTRACT FROM AUTHOR]

Background: Pulmonary arterial hypertension restricts the ability of patients to perform routine physical activities. As part of pulmonary arterial hypertension treatment, inhaled iloprost can be administered via a nebulizer that tracks inhalation behavior. Pulmonary arterial hypertension treatment is guided by intermittent clinical measurements, such as 6-minute walk distance, assessed during regular physician visits. Continuous digital monitoring of physical activity may facilitate more complete assessment of the impact of pulmonary arterial hypertension on daily life. Physical activity tracking with a wearable has not yet been assessed with simultaneous tracking of pulmonary arterial hypertension medication intake.Objective: We aimed to digitally track the physical parameters of patients with pulmonary arterial hypertension who were starting treatment with iloprost using a Breelib nebulizer. The primary objective was to investigate correlations between changes in digital physical activity measures and changes in traditional clinical measures and health-related quality of life over 3 months. Secondary objectives were to evaluate inhalation behavior, adverse events, and changes in heart rate and sleep quality.Methods: We conducted a prospective, multicenter observational study of adults with pulmonary arterial hypertension in World Health Organization functional class III who were adding inhaled iloprost to existing pulmonary arterial hypertension therapy. Daily distance walked, step count, number of standing-up events, heart rate, and 6-minute walk distance were digitally captured using smartwatch (Apple Watch Series 2) and smartphone (iPhone 6S) apps during a 3-month observation period (which began when iloprost treatment began). Before and at the end of the observation period (within 2 weeks), we also evaluated 6-minute walk distance, Borg dyspnea, functional class, B-type natriuretic peptide (or N-terminal pro-B-type natriuretic peptide) levels, health-related quality of life (EQ-5D questionnaire), and sleep quality (Pittsburgh Sleep Quality Index).Results: Of 31 patients, 18 were included in the full analysis (observation period: median 91.5 days, IQR 88.0 to 92.0). Changes from baseline in traditional and digital 6-minute walk distance were moderately correlated (r=0.57). Physical activity (daily distance walked: median 0.4 km, IQR -0.2 to 1.9; daily step count: median 591, IQR -509 to 2413) and clinical measures (traditional 6-minute walk distance: median 26 m, IQR 0 to 40) changed concordantly from baseline to the end of the observation period. Health-related quality of life showed little change. Total sleep score and resting heart rate slightly decreased. Distance walked and step count showed short-term increases after each iloprost inhalation. No new safety signals were identified (safety analysis set: n=30).Conclusions: Our results suggest that despite challenges, parallel monitoring of physical activity, heart rate, and iloprost inhalation is feasible in patients with pulmonary arterial hypertension and may complement traditional measures in guiding treatment; however, the sample size of this study limits generalizability.Trial Registration: ClinicalTrials.gov NCT03293407; https://clinicaltrials.gov/ct2/show/NCT03293407.International Registered Report Identifier (irrid): RR2-10.2196/12144. [ABSTRACT FROM AUTHOR]

Nifurtimox and benznidazole are the front-line drugs used to treat Chagas disease, the most important parasitic infection in the Americas. These agents function as prodrugs and must be activated within the parasite to have trypanocidal effects. Despite >40 years of research, the mechanism(s) of action and resistance have remained elusive. Here, we report that in trypanosomes, both drugs are activated by a NADH-dependent, mitochondrially localized, bacterial-like, type I nitroreductase (NTR), and that down-regulation of this explains how resistance may emerge. Loss of a single copy of this gene in Trypanosoma cruzi, either through in vitro drug selection or by targeted gene deletion, is sufficient to cause significant cross-resistance to a wide range of nitroheterocyclic drugs. In Trypanosoma brucei, loss of a single NTR allele confers similar cross-resistance without affecting growth rate or the ability to establish an infection. This potential for drug resistance by a simple mechanism has important implications, because nifurtimox is currently undergoing phase Ill clinical trials against African trypanosomiasis. [ABSTRACT FROM AUTHOR]

Objectives. New onset heart failure (HF) has been associated with the use of TNF-α antagonists etanercept and infliximab based upon spontaneous adverse event reports. HF clinical trials of these agents were stopped early due to futility or worsening of existing HF. A potential association between etanercept and infliximab and new onset HF has been studied minimally at a population level. [ABSTRACT FROM PUBLISHER]

Outcome measures of venous ulcer healing are not uniformly accepted. Stringent criteria of 100% closure fail to provide information of healing over the entire span of repair. Wound-healing trajectories (plot of percentage of wound closure versus time of wound treatment) were constructed for 232 patients treated in eight clinical trials at two independent wound care/research centres. Trajectories were constructed for ulcers that totally healed (100% closure) and those that did not (<100% closure) over a 20-week period. Kaplan–Meier survival plots determined the percentage of patients achieving total healing versus time of treatment. The wound-healing trajectories were almost identical for patients achieving complete ulcer healing, as were the trajectories for patients with less than 100% closure. The trajectories for the ulcers healing completely were significantly different from those with <100% closure. Only 60% of all patients achieved 100% closure by 20 weeks. Using linear regression, it was predicted that it would take 31 weeks for all patients to achieve total healing. Total healing is an inadequate outcome measure for healing of venous stasis ulcers. Clinical trials using this measure would require excessive time periods. As wound-healing trajectories for patients treated at two centres mimic one another, shifting the wound-healing trajectory from one of impaired healing to one of a more ideal healing course may be considered a better outcome measure for determining healing of venous stasis ulcers. [ABSTRACT FROM AUTHOR]

Background: It is estimated that 2.5 million people in the United States have venous ulcers. Standard care for ulcers includes compression, debridement of necrotic tissue, treatment of edema, and control of infection. There has been a search for additional therapeutic compounds and/or devices to enhance ulcer healing beyond that provided by standard care. A previous phase 2a clinical trial suggested repifermin (KGF-2) might enhance ulcer healing. Materials and Methods: A randomized, double-blinded, parallel group, multicenter clinical trial was conducted to evaluate the safety and efficacy of topical repifermin treatment, for up to 26 weeks, in the healing of chronic venous ulcers in 352 patients. Results: The percent of ulcers achieving 100% closure by 20 weeks was not significantly different in ulcers treated with 60 µg/cm² or 120 µg/cm² of repifermin compared with placebo treatment. Similarly, there was no difference in total healing among the 3 treatment groups at 26 weeks or at 16 weeks. Time to closure was also statistically identical for the 3 treatment groups. Safety analyses showed that topical repifermin is well-tolerated. Conclusion: Healing of chronic venous ulcers is not enhanced by the addition of topical repifermin (KGF-2) to standardized care. [ABSTRACT FROM AUTHOR]

To compare the antileukemic efficacy of idarubicin and mitoxantrone in elderly patients with acute myeloid leukemia (AML) and to evaluate the feasibility of autologous transplantation using PBSC after consolidation in those with a good performance status, 160 patients (median age 69 years), with AML at diagnosis, 118 of them with de novo AML and 42 with AML secondary to myelodysplastic syndrome or toxic exposure (sAML), received induction treatment with idarubicin, 8 mg/m2/day or mitoxantrone, 7 mg/m2/day, on days 1, 3, and 5, both combined with VP-16, 100 mg/m2/day on days 1 to 3 and cytarabine (araC), 100 mg/m2/day, on days 1 to 7. G-CSF, 5 microg/kg/day, was administered after chemotherapy in patients aged more than 70 years. Patients in complete remission (CR) received one course of consolidation using the same schedule as for induction except the araC administration was shortened to 5 days. Some patients younger than 70 years were then scheduled for autologous stem cell harvest on days 5 to 7 of G-CSF, 5 microg/kg/day, initiated after hematopoietic recovery from consolidation. Autologous transplantation was performed following an additional chemotherapy conditioning. Ninety-five patients (59%) achieved CR, without significant difference between the idarubicin (56% CR) and mitoxantrone (63% CR) group. There was also no significant difference in CR rate between de novo AML (63%) and secondary AML (55%) (P = 0.12). Patients aged < 70 years had 67% CR, while patients aged > or = 70 years had 49% (P = 0.02). There was no significant difference in the duration of aplasia between the two arms. Median time to neutrophil recovery was 22 days in patients who received G-CSF following induction and 27 days in patients who did not (P = 0.006). Severe extrahematologic toxicities of induction did not differ between the two arms and included sepsis (39%), diarrhea (13%), hyperbilirubinemia (8%), hemorrhage (6%) and vomiting (6%). Overall, 14 patients (9%), died from toxicity of induction. First consolidation was administered in 74 patients of whom seven (9%) died from toxicity. Nineteen patients have received transplantation. Median time to recovery of neutrophils > 0.5 x 10(9)/l was 13 days and of platelets > 50 x 10(9)/l 43 days following consolidation. There were two toxic deaths. Median disease-free survival and survival from time of achieving CR of non transplanted patients are 6 and 7 months respectively without difference between the two arms. Fourteen transplanted patients relapsed at a median of 5 months post-transplant. We conclude that this regimen is well tolerated and has a good efficacy to induce CR, without a significant difference in efficacy and toxicity between idarubicin and mitoxantrone. Intensive postinduction, including transplantation, is feasible; however, this procedure did not seem to prevent early relapse in the majority of patients. Neither the high rate of CR nor consolidation nor transplant procedure in a selected group of patients did translate into improved DFS and/or survival. [ABSTRACT FROM AUTHOR]

The protozoan parasite Trypanosoma cruzi causes Chagas disease, an important public health problem throughout Latin America. Current therapeutic options are characterised by limited efficacy, long treatment regimens and frequent toxic side-effects. Advances in this area have been compromised by gaps in our knowledge of disease pathogenesis, parasite biology and drug activity. Nevertheless, several factors have come together to create a more optimistic scenario. Drug-based research has become more systematic, with increased collaborations between the academic and commercial sectors, often within the framework of not-for-profit consortia. High-throughput screening of compound libraries is being widely applied, and new technical advances are helping to streamline the drug development pipeline. In addition, drug repurposing and optimisation of current treatment regimens, informed by laboratory research, are providing a basis for new clinical trials. Here, we will provide an overview of the current status of Chagas disease drug development, highlight those areas where progress can be expected, and describe how fundamental research is helping to underpin the process. [ABSTRACT FROM AUTHOR]

Background/aims: Use of electronic health records and information technology to deliver more efficient clinical trials is attracting the attention of research funders and researchers. We report on methodological issues and data quality for a comparison of 'automated' and manual (or 'in-practice') methods for recruitment and randomisation in a large randomised controlled trial, with individual patient allocation in primary care.Methods: We conducted a three-arm randomised controlled trial in primary care to evaluate interventions to improve the uptake of invited NHS health checks for cardiovascular risk assessment. Eligible participants were identified using a borough-wide health check management information system. An in-practice recruitment and randomisation method used at 12 general practices required the research team to complete monthly visits to each general practice. For the fully automated method, employed for six general practices, randomisation of eligible participants was performed automatically and remotely using a bespoke algorithm embedded in the health check management information system.Results: There were 8588 and 4093 participants recruited for the manual and automated methods, respectively. The in-practice method was ready for implementation 3 months sooner than the automated method and the in-practice method allowed for full control and documentation of the randomisation procedure. However the in-practice approach was labour intensive and the requirement for participant records to be stored locally resulted in the loss of data for 10 practice months. No records for participants allocated using the automated method were lost. A fixed-effects meta-analysis showed that effect estimates for the primary outcome were consistent for the two allocation methods.Conclusions: This trial demonstrated the feasibility of automated recruitment and randomisation methods into a randomised controlled trial performed in primary care. Future research should explore the application of these techniques in other clinical contexts and health care settings.Trial Registration: Current Controlled Trials, ID: ISRCTN42856343 . Registered on 21 March 2013. [ABSTRACT FROM AUTHOR]

Purpose Aspergillosis is uncommon in HIV patients and has been mostly reported in patients with CD4<50/µL. Data on risk factors and prognosis are scarce. We reviewed 19 cases of aspergillosis diagnosed in our HIV cohort. Methods In the Brussels Saint-Pierre HIV cohort, 19 patients were diagnosed with aspergillosis between 1998 and 2012 (0.87/1000 patient/year of follow-up). We analyzed retrospectively and described localization and invasiveness of aspergillosis, risk factors, treatment and outcome of these patients. Results Patients were mostly African (74%) and mean age was 40 years (22-60). Clinical presentation were 10 invasive aspergillosis (IA) (53%), 6 pulmonary aspergilloma (31%) and 3 sinus fungal ball (16%). The global mortality was 42%. IA was proven for 3 patients, probable for 4 patients and possible for 3 patients according to IDSA definitions. Risk factors for IA included CD4<200/µL (70%; 40%<50 CD4/µL), corticotherapy (50%), neutropenia (20%), intravenous drug use (20%), cirrhosis (20%). IA arose in the time course of septic shock in 30% and opportunistic infections occurred concomitantly in 40%. Seven patients out of 10 with IA died including 3 patients before antifungal therapy. The 3 survivors recovered without relapse. Four patients were treated with voriconazole, 2 with itraconazole, 2 with liposomal amphotericine, 1 with caspofungine, and 2 with bitherapy. Among patients with aspergilloma (n=6), the major associated risk factor was tuberculosis sequelae (80%). Two patients were successfully treated with surgery and voriconazole, 1 died from massive hemoptysis, 2 were lost to follow-up, 1 is currently asymptomatic without treatment. Among patients with sinus fungal ball (n=3), all recovered without relapse with surgical treatment associated with voriconazole for one. Conclusion Incidence of aspergillosis in HIV patients remains low but in accordance to previous reports, mortality of IA is high (70%). CD4<200 is the most common risk factor (70%) but 80% of patients who died had other risk factors, mostly corticotherapy. IA is often concomitant with other infectious diseases (40% with other opportunistic infections and 30% in the time course of septic shock), which can potentially delay diagnosis. Prognosis of pulmonary aspergilloma and sinus fungal ball is better. [ABSTRACT FROM AUTHOR]

Purpose of the study Fever of unknown origin (FUO) is a challenging clinical entity in HIV patients. FDG-PET/CT is well validated in the work-up of FUO in HIV-negative patients but in HIV viremic patients, metabolism of HIV reactive lymph nodes could decrease its specificity. We prospectively evaluated the usefulness of FDG-PET/CT in FUO in HIV-positive patients and in particular whether HIV viremia impacts on FDG-PET/CT performance. Methods FDG-PET/CT was performed in 20 HIV patients with FUO and compared with FDG-PET/CT in 10 HIV viremic patients without FUO. Final diagnosis for FUO was based on histopathology, microbiology, or clinical and imaging follow-up. Mode of diagnosis, accordance of FDG-PET/CT with final diagnosis, localization of invasive diagnosis procedures was recorded in order to assess usefulness of FDG-PET/CT. Results FDG-PET/CT showed a different pattern in FUO and asymptomatic viremic patients. Reactive HIV lymph nodes in asymptomatic viremic patients were mostly peripheral with mean SUVmax of 6.5. In patients with FUO and underlying focal pathologies, hypermetabolic lymph nodes were central with mean SUVmax of 11.6. Presence of central lymph nodes with high FDG uptake in had a 100% specificity for focal pathology, even in viremic patients and absence of these had 100% negative predictive value. Lymph node biopsy in central hypermetabolic areas allowed identifying underlying disease in all FUO patients. For peripheral lymph nodes, a ROC curve was built in order to define the best cut-off of SUVmax for biopsy: SUVmax of 6-8 showed a sensitivity of 62.5% and specificity of 75%. Lymph nodes with SUVmax<4 had sensitivity of 0%. Conclusions FDG-PET/CT contributed to the diagnosis or exclusion of a focal etiology of the febrile state in 80% of HIV patients with FUO. Although number of patients was small, we could highlight several clear-cut features to help interpreting FDG-PET/CT in HIV patients with FUO. As in HIV-negative patients, we showed the usefulness of FDG-PET/CT in FUO in HIV patients even if they are viremic. [ABSTRACT FROM AUTHOR]

Background: The subcutaneous (S) implantable cardioverter-defibrillator (ICD) is safe and effective for sudden cardiac death prevention. However, patients in previous S-ICD studies had fewer comorbidities, had less left ventricular dysfunction, and received more inappropriate shocks (IAS) than in typical transvenous ICD trials. The UNTOUCHED trial (Understanding Outcomes With the S-ICD in Primary Prevention Patients With Low Ejection Fraction) was designed to evaluate the IAS rate in a more typical, contemporary ICD patient population implanted with the S-ICD using standardized programming and enhanced discrimination algorithms.Methods: Primary prevention patients with left ventricular ejection fraction ≤35% and no pacing indications were included. Generation 2 or 3 S-ICD devices were implanted and programmed with rate-based therapy delivery for rates ≥250 beats per minute and morphology discrimination for rates ≥200 and <250 beats per minute. Patients were followed for 18 months. The primary end point was the IAS-free rate compared with a 91.6% performance goal, derived from the results for the ICD-only patients in the MADIT-RIT study (Multicenter Automatic Defibrillator Implantation Trial-Reduce Inappropriate Therapy). Kaplan-Meier analyses were performed to evaluate event-free rates for IAS, all-cause shock, and complications. Multivariable proportional hazard analysis was performed to determine predictors of end points.Results: S-ICD implant was attempted in 1116 patients, and 1111 patients were included in postimplant follow-up analysis. The cohort had a mean age of 55.8±12.4 years, 25.6% were women, 23.4% were Black, 53.5% had ischemic heart disease, 87.7% had symptomatic heart failure, and the mean left ventricular ejection fraction was 26.4±5.8%. Eighteen-month freedom from IAS was 95.9% (lower confidence limit, 94.8%). Predictors of reduced incidence of IAS were implanting the most recent generation of device, using the 3-incision technique, no history of atrial fibrillation, and ischemic cause. The 18-month all-cause shock-free rate was 90.6% (lower confidence limit, 89.0%), meeting the prespecified performance goal of 85.8%. Conversion success rate for appropriate, discrete episodes was 98.4%. Complication-free rate at 18 months was 92.7%.Conclusions: This study demonstrates high efficacy and safety with contemporary S-ICD devices and programming despite the relatively high incidence of comorbidities in comparison with earlier S-ICD trials. The inappropriate shock rate (3.1% at 1 year) is the lowest reported for the S-ICD and lower than many transvenous ICD studies using contemporary programming to reduce IAS. Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT02433379. [ABSTRACT FROM AUTHOR]

Background: Clinical trials show benefit from lowering systolic blood pressure (SBP) in people ≥80 years of age, but nonrandomized epidemiological studies suggest lower SBP may be associated with higher mortality. This study aimed to evaluate associations of SBP with all-cause mortality by frailty category >80 years of age and to evaluate SBP trajectories before death.Methods: A population-based cohort study was conducted using electronic health records of 144 403 participants ≥80 years of age registered with family practices in the United Kingdom from 2001 to 2014. Participants were followed for ≤5 years. Clinical records of SBP were analyzed. Frailty status was classified using the e-Frailty Index into the categories of fit, mild, moderate, and severe. All-cause mortality was evaluated by frailty status and mean SBP in Cox proportional-hazards models. SBP trajectories were evaluated using person months as observations, with mean SBP and antihypertensive treatment status estimated for each person month. Fractional polynomial models were used to estimate SBP trajectories over 5 years before death.Results: During follow-up, 51 808 deaths occurred. Mortality rates increased with frailty level and were greatest at SBP <110 mm Hg. In fit women, mortality was 7.7 per 100 person years at SBP 120 to 139 mm Hg, 15.2 at SBP 110 to 119 mm Hg, and 22.7 at SBP <110 mm Hg. For women with severe frailty, rates were 16.8, 25.2, and 39.6, respectively. SBP trajectories showed an accelerated decline in the last 2 years of life. The relative odds of SBP <120 mm Hg were higher in the last 3 months of life than 5 years previously in both treated (odds ratio, 6.06; 95% confidence interval, 5.40-6.81) and untreated (odds ratio, 6.31; 95% confidence interval, 5.30-7.52) patients. There was no evidence of intensification of antihypertensive therapy in the final 2 years of life.Conclusions: A terminal decline of SBP in the final 2 years of life suggests that nonrandomized epidemiological associations of low SBP with higher mortality may be accounted for by reverse causation if participants with lower blood pressure values are closer, on average, to the end of life. [ABSTRACT FROM AUTHOR]

The sequence of alterations occurring in recurrent erythema multiforme was studied with clinical observations, 1-μm tissue sections, and immunofluorescence techniques. Lesions evolved through 3 stages: an initial red papule, a vesicle surmounting a red papule, and a target (iris) lesion, Focal endothelial cell swelling was present in clinically normal skin, In the red papule, endothelial cytoplasmic swelling, vacuolization, and nuclear hypertrophy with luminal obliteration of superficial venules developed. These venular alterations were more marked with endothelial cell necrosis, and involved deeper venules as well in vesicular and target lesions. Lymphocytes surrounded the venules and infiltrated the lower epidermis in the red papule and the vesicular lesions. Venular damage was correlated with the degree of infiltration by lymphocytes, apparently the primary effector cell, suggesting the venule as a primary target of injury. Hypogranulated basophils were noted around venules in vesicular and target lesions. Fibrin deposits were identified within and interstitially beneath the yes ides. The presence of lymphocytes, basophils, and interstitial fibrin deposition is similar to the changes of cutaneous delayed-type hypersensitivity and suggests a role for cell-mediated immunity in the pathogenesis of erythema multiforme. [ABSTRACT FROM AUTHOR]