Παρασκευή 17 Νοεμβρίου 2017
Thalamic volume reduction in drug-naive patients with new-onset genetic generalized epilepsy
Summary
Objective
Patients with genetic generalized epilepsy (GGE) have subtle morphologic abnormalities of the brain revealed with magnetic resonance imaging (MRI), particularly in the thalamus. However, it is unclear whether morphologic abnormalities of the brain in GGE are a consequence of repeated seizures over the duration of the disease, or are a consequence of treatment with antiepileptic drugs (AEDs), or are independent of these factors. Therefore, we measured brain morphometry in a cohort of AED-naive patients with GGE at disease onset. We hypothesize that drug-naive patients at disease onset have gray matter changes compared to age-matched healthy controls.
Methods
We performed quantitative measures of gray matter volume in the thalamus, putamen, caudate, pallidum, hippocampus, precuneus, prefrontal cortex, precentral cortex, and cingulate in 29 AED-naive patients with new-onset GGE and compared them to 32 age-matched healthy controls. We subsequently compared the shape of any brain structures found to differ in gray matter volume between the groups.
Results
The thalamus was the only structure to show reduced gray matter volume in AED-naive patients with new-onset GGE compared to healthy controls. Shape analysis revealed that the thalamus showed deflation, which was not uniformly distributed, but particularly affected a circumferential strip involving anterior, superior, posterior, and inferior regions with sparing of medial and lateral regions.
Significance
Structural abnormalities in the thalamus are present at the initial onset of GGE in AED-naive patients, suggesting that thalamic structural abnormality is an intrinsic feature of GGE and not a consequence of AEDs or disease duration.
http://ift.tt/2j63lNt
Prevalence of health services usage and associated factors in the Amazon region of Brazil: a population-based cross-sectional study
Objectives
To estimate the prevalence of healthcare use and associated factors in the Manaus metropolitan region and to describe the reasons for lack of access.
DesignCross-sectional population-based study.
SettingA survey conducted between May and August of 2015 in eight cities from Manaus metropolitan region, Amazonas, Brazil.
Participants4001 adults ≥18 years of age.
Primary outcomes measuresPhysician visits, dentist visits and hospitalisations in the last 12 months were the primary outcomes. Associated factors were investigated through the calculation of prevalence ratio (PR) obtained by hierarchical Poisson regression modelling.
Results4001 adults were included in the study, 53% of whom were women. The self-reported prevalence of medical visits was 77% (95% CI 75% to 77%); dentist visits, 36% (95% CI 34% to 37%) and hospital admission, 7% (95% CI 6% to 7%). Physician visits were higher in women PR=1.18 (95% CI 1.14 to 1.23), the elderly PR=1.18 (95% CI 1.10 to 1.26) and people with health insurance PR=1.14 (95% CI 1.10 to 1.19). Dentist visits declined with older age PR=0.38 (95% CI 0.30 to 0.49), lower education level PR=0.62 (95% CI 0.51 to 0.74) and lower economic class PR=0.65 (95% CI 0.57 to 0.75). Hospitalisations were found to be twice as frequent for women than for men and three times as frequent among those who reported very poor health status. Among the individuals who did not receive medical attention in the previous 2 weeks, 58% reported lack of facilities or appointment unavailable and 14% reported lack of doctors.
ConclusionWhile more than half visited the doctor in the last year, a lower proportion of people with socioeconomic inequities visited the dentist. Organisational and service policies are needed to increase equity in health services in the region.
http://ift.tt/2issL8H
The association between gastro-oesophageal reflux disease and subsequent rheumatoid arthritis occurrence: a nested case-control study from Taiwan
Objective
Gastro-oesophageal reflux disease (GORD) is a common comorbidity among patients with rheumatoid arthritis (RA). While GORD has been attributed to the antirheumatic medications, no studies of human cohorts have investigated a link between GORD and RA. This study investigates whether GORD is associated with a subsequent RA diagnosis over a 5-year follow-up using a population-based dataset.
SettingTaiwan
ParticipantsWe used data from the Taiwan Longitudinal Health Insurance Database. The study group consisted of 13 645 patients with an ambulatory claim showing a GORD diagnosis. We used propensity score matching to select 13 645 comparison patients (one per study patient with GORD).
InterventionWe tracked each patient's claims over a 5-year period to identify those who subsequently received a diagnosis of RA. Cox proportional hazard (PH) regression modelling was used for analysis.
ResultsOver 5-year follow-up, RA incidence rate per 1000 person-years was 2.81 among patients with GORD and 0.84 among the comparison group. Cox PH modelling showed that GORD was independently associated with a 2.84-fold increased risk of RA (95% CI 2.09 to 3.85) over 5-year follow-up, after adjusting for the number of ambulatory care visits within the year following the index date (to mitigate surveillance bias).
ConclusionsWe observed that GORD might associate with subsequent RA occurrence. Because current treatment guidelines for RA emphasise early diagnosis and prompt treatment, the observed association between GORD and RA may help acquaint clinicians to patients with GORD with higher RA risk and facilitate early diagnosis and treatment.
http://ift.tt/2iszWxI
Physical activity in former elite cricketers and strategies for promoting physical activity after retirement from cricket: a qualitative study
Objectives
The health benefits of professional sport dissipate after retirement unless an active lifestyle is adopted, yet reasons for adopting an active or inactive lifestyle after retirement from sport are poorly understood. Elite cricket is all-encompassing, requiring a high volume of activity and unique physical demands. We aimed to identify influences on physical activity behaviours in active and insufficiently active former elite cricketers and provide practical strategies for promoting physical activity after cricket retirement.
Design18 audio-recorded semistructured telephone interviews were performed. An inductive thematic approach was used and coding was iterative and data-driven facilitated by NVivo software. Themes were compared between sufficiently active and insufficiently active participants.
SettingAll participants formerly played professional cricket in the UK.
ParticipantsParticipants were male, mean age 57±11 (range 34–77) years, participated in professional cricket for 12±7 seasons and retired on average 23±9 years previously. Ten participants (56%) were classified as sufficiently active according to the UK Physical Activity Guidelines (moderate-intensity activity ≥150 min per week or vigorous-intensity activity ≥75 min per week). Eight participants did not meet these guidelines and were classified as insufficiently active.
ResultsKey physical activity influences were time constraints, habit formation, intrinsic and extrinsic motivation, physical activity preferences, pain/physical impairment and cricket coaching. Recommendations for optimising physical activity across the lifespan after cricket retirement included; prioritise physical activity, establish a physical activity plan prior to cricket retirement and don't take a break from physical activity, evaluate sources of physical activity motivation and incorporate into a physical activity plan, find multiple forms of satisfying physical activity that can be adapted to accommodate fluctuations in physical capabilities across the lifespan and coach cricket.
ConclusionsPhysically active and less active retired cricketers shared contrasting attributes that informed recommendations for promoting a sustainable, physically active lifestyle after retirement from professional cricket.
http://ift.tt/2isQ1mM
Interpretation of health news items reported with or without spin: protocol for a prospective meta-analysis of 16 randomised controlled trials
Introduction
We aim to compare the interpretation of health news items reported with or without spin. 'Spin' is defined as a misrepresentation of study results, regardless of motive (intentionally or unintentionally) that overemphasises the beneficial effects of the intervention and overstates safety compared with that shown by the results.
Methods and analysisWe have planned a series of 16 randomised controlled trials (RCTs) to perform a prospective meta-analysis. We will select a sample of health news items reporting the results of four types of study designs, evaluating the effect of pharmacological treatment and containing the highest amount of spin in the headline and text. News items reporting four types of studies will be included: (1) preclinical studies; (2) phase I/II (non-randomised) trials; (3) RCTs and (4) observational studies. We will rewrite the selected news items and remove the spin. The original news and rewritten news will be appraised by four types of populations: (1) French-speaking patients; (2) French-speaking general public; (3) English-speaking patients and (4) English-speaking general public. Each RCT will explore the interpretation of news items reporting one of the four study designs by each type of population and will include a sample size of 300 participants. The primary outcome will be participants' interpretation of the benefit of treatment after reading the news items: (What do you think is the probability that treatment X would be beneficial to patients? (scale, 0 (very unlikely) to 10 (very likely)).
This study will evaluate the impact of spin on the interpretation of health news reporting results of studies by patients and the general public.
Ethics and disseminationThis study has obtained ethics approval from the Institutional Review Board of the Institut national de la santé et de la recherche médicale (INSERM) (registration no: IRB00003888). The description of all the steps and the results of this prospective meta-analysis will be available online and will be disseminated as a published article. On the completion of this study, the results will be sent to all participants.
PROSPERO registration numberCRD42017058941.
http://ift.tt/2APZ48f
Effect of ephedrine and phenylephrine on brain oxygenation and microcirculation in anaesthetised patients with cerebral tumours: study protocol for a randomised controlled trial
Introduction
During brain tumour surgery, vasopressor drugs are commonly administered to increase mean arterial blood pressure with the aim of maintaining sufficient cerebral perfusion pressure. Studies of the commonly used vasopressors show that brain oxygen saturation is reduced after phenylephrine administration, but unaltered by ephedrine administration. These findings may be explained by different effects of phenylephrine and ephedrine on the cerebral microcirculation, in particular the capillary transit-time heterogeneity, which determines oxygen extraction efficacy. We hypothesised that phenylephrine is associated with an increase in capillary transit-time heterogeneity and a reduction in cerebral metabolic rate of oxygen compared with ephedrine. Using MRI and positron emission tomography (PET) as measurements in anaesthetised patients with brain tumours, this study will examine whether phenylephrine administration elevates capillary transit-time heterogeneity more than ephedrine, thereby reducing brain oxygenation.
Methods and analysisThis is a double-blind, randomised clinical trial including 48 patients scheduled for surgical brain tumour removal. Prior to imaging and surgery, anaesthetised patients will be randomised to receive either phenylephrine or ephedrine infusion until mean arterial blood pressure increases to above 60 mm Hg or 20% above baseline. Twenty-four patients were allocated to MRI and another 24 patients to PET examination. MRI measurements include cerebral blood flow, capillary transit-time heterogeneity, cerebral blood volume, blood mean transit time, and calculated oxygen extraction fraction and cerebral metabolic rate of oxygen for negligible tissue oxygen extraction. PET measurements include cerebral metabolic rate of oxygen, cerebral blood flow and oxygen extraction fraction. Surgery is initiated after MRI/PET measurements and subdural intracranial pressure is measured.
Ethics and disseminationThis study was approved by the Central Denmark Region Committee on Health Research Ethics (12 June 2015; 1-10-72-116-15). Results will be disseminated via peer-reviewed publication and presentation at international conferences.
Trial registration numberNCT02713087; Pre-results. 2015-001359-60; Pre-results.
http://ift.tt/2itmJVd
Early vasopressor use following traumatic injury: a systematic review
Objectives
Current guidelines suggest limiting the use of vasopressors following traumatic injury; however, wide variations in practice exist. Although excessive vasoconstriction may be harmful, these agents may help reduce administration of potentially harmful resuscitation fluids. This systematic review aims to compare early vasopressor use to standard resuscitation in adults with trauma-induced shock.
DesignSystematic review.
Data sourcesWe searched MEDLINE, EMBASE, ClinicalTrials.gov and the Central Register of Controlled Trials from inception until October 2016, as well as the proceedings of 10 relevant international conferences from 2005 to 2016.
Eligibility criteria for selecting studiesRandomised controlled trials and controlled observational studies that compared the early vasopressor use with standard resuscitation in adults with acute traumatic injury.
ResultsOf 8001 citations, we retrieved 18 full-text articles and included 6 studies (1 randomised controlled trial and 5 observational studies), including 2 published exclusively in abstract form. Across observational studies, vasopressor use was associated with increased short-term mortality, with unadjusted risk ratios ranging from 2.31 to 7.39. However, the risk of bias was considered high in these observational studies because patients who received vasopressors were systematically sicker than patients treated without vasopressors. One clinical trial (n=78) was too imprecise to yield meaningful results. Two clinical trials are currently ongoing. No study measured long-term quality of life or cognitive function.
ConclusionsExisting data on the effects of vasopressors following traumatic injury are of very low quality according to the Grading of Recommendations, Assessment, Development and Evaluation methodology. With emerging evidence of harm associated with aggressive fluid resuscitation and, in selected subgroups of patients, with permissive hypotension, the alternatives to vasopressor therapy are limited. Observational data showing that vasopressors are part of usual care would provide a strong justification for high-quality clinical trials of early vasopressor use during trauma resuscitation.
Trial registration numberhttp://ift.tt/2is2Vl1
Subclinical Propionibacterium acnes infection estimation in the intervertebral disc (SPInE-ID): protocol for a prospective cohort
Introduction
Low back pain and vertebral endplate abnormalities are common conditions within the population. Subclinical infection caused by indolent pathogens can potentially lead to these findings, with differentiation between them notably challenging from a clinical perspective. Progressive infection of the intervertebral disc has been extensively associated with increasing low back pain, with Propionibacterium acnes specifically implicated with in relation to sciatica. The main purpose of this study is to identify if the presence of an infective pathogen within the intervertebral disc is primary or is a result of intraoperative contamination, and whether this correlates to low back pain.
Methods and analysisAn open prospective cohort study will be performed. Subjects included within the study will be between the ages of 18 and 65 years and have a diagnosis of lumbar disc herniation requiring open decompression surgery. Excised herniated disc fragments, muscle and ligamentum flavum samples will be collected during surgery and sent to microbiology for tissue culture and pathogen identification. Score questionnaires for pain, functionality and quality of life will be given preoperatively and at 1, 3, 6 and 12 months postoperatively. A MRI will be performed 12 months after surgery for analysis of Modic changes and baseline comparison. The primary endpoint is the rate of disc infection in patients with symptomatic degenerative disc disease. The secondary endpoints will be performance scores, Modic incidence and volume.
Ethics and disseminationThis study was approved by our Institutional Review Board and was only initiated after it (CAAE 65102617.2.0000.0071). Patients agreeing to participate will sign an informed consent form before entering the study. Results will be published in a peer reviewed medical journal irrespective of study findings. If shown to be the case, this would have profound effects on the way physicians treat chronic low back pain, even impacting health costs.
Trials registration numberNCT0315876; Pre-results.
http://ift.tt/2APYQhp
Contribution of short sleep duration to ethnic differences in cardiovascular disease: results from a cohort study in the Netherlands
Objectives
We analysed association between short sleep duration and prevalence of cardiovascular disease (CVD) in a multiethnic population living in the Netherlands, and the contribution of short sleep to the observed ethnic differences in the prevalence of CVD, independent of CVD risk factors.
Methods20 730 participants (aged 18–71 years) of the HELIUS (Healthy Life in an Urban Setting) Study were investigated. Self-reported sleep duration was classified as: short (<7 hours/night) and healthy (7–9 hours/night). Prevalence of CVD was assessed using the Rose Questionnaire on angina pectoris, intermittent claudication and possible myocardial infarction. Association of short sleep duration with prevalent CVD and the contribution of short sleep to the observed ethnic differences in the prevalence of CVD were analysed using adjusted prevalence ratio(s) (PRs) with 95% CI.
ResultsResults indicate that short sleep was associated with CVD among all ethnic groups with PRs ranging from 1.41 (95% CI 1.21 to 1.65) in Moroccans to 1.62 (95% CI 1.20 to 2.18) in Dutch after adjustment for age, sex and conventional CVD risk factors. The independent contributions of short sleep (in percentage) to ethnic differences in CVD compared with Dutch were 10%, 15%, 15%, 5% and 5% in South-Asian Surinamese, African-Surinamese, Ghanaian, Turkish and Moroccan, respectively.
ConclusionShort sleep contributed to ethnic differences in CVD independent of well-known CVD risk factors particularly in Surinamese and Ghanaian groups. Reducing sleep deprivation may be a relevant entry point for reducing increased CVD risks among the various ethnic minority groups.
http://ift.tt/2AR0MpP
Protocol of the sepsivit study: a prospective observational study to determine whether continuous heart rate variability measurement during the first 48 hours of hospitalisation provides an early warning for deterioration in patients presenting with infection or sepsis to the emergency department of a Dutch academic teaching hospital
Introduction
One in five patients with sepsis deteriorates within 48 hours after hospital admission. Regrettably, a clear tool for the early detection of deterioration is still lacking. The SepsiVit study aims to determine whether continuous heart rate variability (HRV) measurement can provide an early warning for deterioration in patients presenting with suspected infection or sepsis to the emergency department (ED).
Methods and analysisThe protocol of a prospective observational study in the ED. We will include 171 adult medical patients presenting with suspected infection or sepsis and at least two systemic inflammatory response syndrome criteria. Patients with known pregnancy, cardiac transplantation or not admitted to our hospital are excluded.
High sample frequency ECG signals (500 Hz), respiratory rate, blood pressure and peripheral oxygen saturation will be recorded continuously during the first 48 hours of hospitalisation using a bedside patient monitor (Philips IntelliVue MP70). Primary endpoint is patient deterioration, defined as the development of organ dysfunction, unplanned intensive care unit admission or in-hospital mortality. The ECG data will be used for offline HRV analysis. We will compare the HRV between two groups (deterioration/no deterioration) and analyse whether HRV provides an early warning for deterioration. Furthermore, we will create a multivariate predictive model for deterioration based on heart rate, respiratory rate and HRV. As planned secondary analyses, we (1) perform a subgroup analysis for patients with pneumosepsis and urosepsis and (2) determine whether HRV using lower sample frequencies (1 Hz or less) suffices to predict deterioration.
Ethics and disseminationThe Institutional Review Board of the University Medical Center Groningen granted a waiver for the study (METc 2015/164). Results will be disseminated through international peer-reviewed publications and conference presentations. A lay summary of the results will be provided to the study participants.
Trial registration numberhttp://ift.tt/2ARrWgv
Exploring the effects of transfers and readmissions on trends in population counts of hospital admissions for coronary heart disease: a Western Australian data linkage study
Objectives
To develop a method for categorising coronary heart disease (CHD) subtype in linked data accounting for different CHD diagnoses across records, and to compare hospital admission numbers and ratios of unlinked versus linked data for each CHD subtype over time, and across age groups and sex.
DesignCohort study.
Data sourcePerson-linked hospital administrative data covering all admissions for CHD in Western Australia from 1988 to 2013.
Main outcomeRatios of (1) unlinked admission counts to contiguous admission (CA) counts (accounting for transfers), and (2) 28-day episode counts (accounting for transfers and readmissions) to CA counts stratified by CHD subtype, sex and age group.
ResultsIn all CHD subtypes, the ratios changed in a linear or quadratic fashion over time and the coefficients of the trend term differed across CHD subtypes. Furthermore, for many CHD subtypes the ratios also differed by age group and sex. For example, in women aged 35–54 years, the ratio of unlinked to CA counts for non-ST elevation myocardial infarction admissions in 2000 was 1.10, and this increased in a linear fashion to 1.30 in 2013, representing an annual increase of 0.0148.
ConclusionThe use of unlinked counts in epidemiological estimates of CHD hospitalisations overestimates CHD counts. The CA and 28-day episode counts are more aligned with epidemiological studies of CHD. The degree of overestimation of counts using only unlinked counts varies in a complex manner with CHD subtype, time, sex and age group, and it is not possible to apply a simple correction factor to counts obtained from unlinked data.
http://ift.tt/2ARpc2B
The physical and mental health problems of refugee and migrant fathers: findings from an Australian population-based study of children and their families
Objectives
The aim of this study was to report on the physical and mental health of migrant and refugee fathers participating in a population-based study of Australian children and their families.
DesignCross-sectional survey data drawn from a population-based longitudinal study when children were aged 4–5 years.
SettingPopulation-based study of Australian children and their families.
Participants8137 fathers participated in the study when their children were aged 4–5 years. There were 131 (1.6%) fathers of likely refugee background, 872 (10.7%) fathers who migrated from English-speaking countries, 1005 (12.4%) fathers who migrated from non-English-speaking countries and 6129 (75.3%) Australian-born fathers.
Primary outcome measuresFathers' psychological distress was assessed using the self-report Kessler-6. Information pertaining to physical health conditions, global or overall health, alcohol and tobacco use, and body mass index status was obtained.
ResultsCompared with Australian-born fathers, fathers of likely refugee background (adjusted OR(aOR) 3.17, 95% CI 2.13 to 4.74) and fathers from non-English-speaking countries (aOR 1.79, 95%CI 1.51 to 2.13) had higher odds of psychological distress. Refugee fathers were more likely to report fair to poor overall health (aOR 1.95, 95% CI 1.06 to 3.60) and being underweight (aOR 3.49, 95% CI 1.57 to 7.74) compared with Australian-born fathers. Refugee fathers and those from non-English-speaking countries were less likely to report light (aOR 0.25, 95% CI 0.15 to 0.43, and aOR 0.30, 95% CI 0.24 to 0.37, respectively) and moderate to harmful alcohol use (aOR 0.04, 95% CI 0.10 to 0.17, and aOR 0.14, 95% CI 0.10 to 0.19, respectively) than Australian-born fathers. Finally, fathers from non-English-speaking and English-speaking countries were less likely to be overweight (aOR 0.62, 95% CI 0.51 to 0.75, and aOR 0.84, 95% CI 0.68 to 1.03, respectively) and obese (aOR 0.43, 95% CI 0.32 to 0.58, and aOR 0.77, 95% CI 0.61 to 0.98, respectively) than Australian-born fathers.
ConclusionFathers of refugee background experience poorer mental health and poorer general health than Australian-born fathers. Fathers who have migrated from non-English-speaking countries also report greater psychological distress than Australian-born fathers. This underscores the need for primary healthcare services to tailor efforts to reduce disparities in health outcomes for refugee populations that may be vulnerable due to circumstances and sequelae of forced migration and to recognise the additional psychological stresses that may accompany fatherhood following migration from non-English-speaking countries. It is important to note that refugee and migrant fathers report less alcohol use and are less likely to be overweight and obese than Australian-born fathers.
http://ift.tt/2AQcPnf
Systematic review of disparities in surgical care for Māori in New Zealand
Background
Health equity for Indigenous peoples in the context of surgery has recently become topical amongst surgeons in Australasia. Health inequities are amongst the most consistent and compelling disparities between Māori and New Zealand Europeans (NZE) in New Zealand (NZ). We aimed to investigate where ethnic disparities in surgical care may occur and highlight some of the potential contributing factors, over all surgical specialties, between Māori and NZE adults in NZ.
Methods
A systematic review was performed in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement. A series of electronic searches were performed in Medline, Embase, PubMed and CINAHL.
Results
Ten studies met the inclusion criteria. All studies employed a range of indicators for surgical care including receipt of surgery following diagnosis, delays to treatment and post-operative morbidity and mortality. Disparities in the receipt of surgical treatment for several cancers were observed for Māori and remained after adjustment for socioeconomic variables and extent of disease. Māori were more likely to experience delays in treatment and referral to other medical specialties involved in their care.
Conclusion
Despite the significant variation in the types of diseases, procedures and indicators of surgical care of the included studies, consistent findings are that disparities in different aspects of surgical care exist between Māori and NZE in NZ. This review highlights the need to better quantify the important issue of health equity for Māori in surgery given the lack of studies over the majority of surgical specialties.
http://ift.tt/2APQ038
Suspended animation: the past, present and future of major cardiothoracic trauma
About 50% of the trauma victims die at the scene mostly because of exsanguinating haemorrhage. Most trials of resuscitation fail in face of the ongoing bleeding. Ongoing research/studies to save these victims by inducing rapid hypothermia using cardiopulmonary bypass as an emergency initial measure along with delayed resuscitation show improved outcomes. A comprehensive review of this research and analysis of studies showed that rapid induction of hypothermia within 5 min of cardiac arrest is associated with better survival and improved neurological outcome. This led us to conclude that suspended animation is a lifesaving modality for the treatment of trauma victims, otherwise hurtling towards certain death. This should be integrated into regular clinical practice. The US Food and Drug Administration has given its approval for clinical trials on such an intervention.
http://ift.tt/2ir2Xtl
Pretreatment advanced lung cancer inflammation index (ALI) for predicting early progression in nivolumab-treated patients with advanced non–small cell lung cancer
Abstract
Programmed death-ligand 1 (PD-L1) expression status is inadequate for indicating nivolumab in patients with non–small cell lung cancer (NSCLC). Because the baseline advanced lung cancer inflammation index (ALI) is reportedly associated with patient outcomes, we investigated whether the pretreatment ALI is prognostic in NSCLC patients treated with nivolumab. We retrospectively reviewed the medical records of all patients treated with nivolumab for advanced NSCLC between December 2015 and May 2016 at three Japanese institutes. Multivariate logistic regression and Cox proportional hazards models were used to assess the impact of the pretreatment ALI (and other inflammation-related parameters) on progression-free survival (PFS) and early progression (i.e., within 8 weeks after starting nivolumab). A total of 201 patients were analyzed; their median age was 68 years (range, 27–87 years), 67% were men, and 24% had an Eastern Cooperative Oncology Group (ECOG) performance status of 2 or higher. An ECOG performance status ≥2, serum albumin <3.7 g/dL, neutrophil-to-lymphocyte ratio ≥4, and ALI <18 were significantly associated with poor PFS and early progression on univariate analysis. Multivariate analyses revealed that pretreatment ALI <18 was independently associated with inferior PFS (median, 1.4 vs. 3.7 months, P < 0.001) and a higher likelihood of early progression (odds ratio, 2.76; 95% confidence interval 1.44–5.34; P = 0.002). The pretreatment ALI was found to be a significant independent predictor of early progression in patients with advanced NSCLC receiving nivolumab, and may help identify patients likely to benefit from continued nivolumab treatment in routine clinical practice.
Pretreatment ALI was a significant independent predictor of early progression in advanced NSCLC patients receiving nivolumab. This may be useful for clinical decision making by identifying patients who may benefit from continued nivolumab treatment.
http://ift.tt/2jye4Ei
Effect of Transfusion on Mortality and Other Adverse Events Among Critically Ill Septic Patients: An Observational Study Using a Marginal Structural Cox Model*
Objectives: RBC transfusion is often required in patients with sepsis. However, adverse events have been associated with RBC transfusion, raising safety concerns. A randomized controlled trial validated the 7 g/dL threshold, but previously transfused patients were excluded. Cohort studies led to conflicting results and did not handle time-dependent covariates and history of treatment. Additional data are thus warranted to guide patient's management. Design: To estimate the effect of one or more RBC within 1 day on three major outcomes (mortality, ICU-acquired infections, and severe hypoxemia) at day 30, we used marginal structural models. A trajectory modeling, based on hematocrit evolution pattern, allowed identification of subgroups. Secondary analyses were performed into each of them. Setting: A prospective French multicenter database. Patients: Patients with sepsis at admission. Patients with hemorrhagic shock at admission were excluded. Interventions: None. Measurements and Main Results: Overall, in our cohort of 6,016 patients, RBC transfusion was not associated with death (hazard ratio, 1.07; 95% CI, 0.88–1.30; p = 0.52). However, RBC transfusion was associated with increased occurrence of ICU-acquired infections (hazard ratio, 2.77; 95% CI, 2.33–3.28; phttp://ift.tt/2hKaXsl
Effects of High-Flow Nasal Cannula on the Work of Breathing in Patients Recovering From Acute Respiratory Failure*
Objectives: High-flow nasal cannula is increasingly used in the management of respiratory failure. However, little is known about its impact on respiratory effort, which could explain part of the benefits in terms of comfort and efficiency. This study was designed to assess the effects of high-flow nasal cannula on indexes of respiratory effort (i.e., esophageal pressure variations, esophageal pressure-time product/min, and work of breathing/min) in adults. Design: A randomized controlled crossover study was conducted in 12 patients with moderate respiratory distress (i.e., after partial recovery from an acute episode, allowing physiologic measurements). Setting: Institut Universitaire de Cardiologie et de Pneumologie de Québec, QC, Canada. Subjects: Twelve adult patients with respiratory distress symptoms were enrolled in this study. Interventions: Four experimental conditions were evaluated: baseline with conventional oxygen therapy and high-flow nasal cannula at 20, 40, and 60 L/min. The primary outcomes were the indexes of respiratory effort (i.e., esophageal pressure variations, esophageal pressure-time product/min, and work of breathing/min). Secondary outcomes included tidal volume, respiratory rate, minute volume, dynamic lung compliance, inspiratory resistance, and blood gases. Measurements and Main Results: Esophageal pressure variations decreased from 9.8 (5.8–14.6) cm H2O at baseline to 4.9 (2.1–9.1) cm H2O at 60 L/min (p = 0.035). Esophageal pressure-time product/min decreased from 165 (126–179) to 72 (54–137) cm H2O • s/min, respectively (p = 0.033). Work of breathing/min decreased from 4.3 (3.5–6.3) to 2.1 (1.5–5.0) J/min, respectively (p = 0.031). Respiratory pattern variables and capillary blood gases were not significantly modified between experimental conditions. Dynamic lung compliance increased from 38 (24–64) mL/cm H2O at baseline to 59 (43–175) mL/cm H2O at 60 L/min (p = 0.007), and inspiratory resistance decreased from 9.6 (5.5–13.4) to 5.0 (1.0–9.1) cm H2O/L/s, respectively (p = 0.07). Conclusions: High-flow nasal cannula, when set at 60 L/min, significantly reduces the indexes of respiratory effort in adult patients recovering from acute respiratory failure. This effect is associated with an improvement in respiratory mechanics.http://ift.tt/2jzoljB
The Epidemiology of Chronic Critical Illness After Severe Traumatic Injury at Two Level–One Trauma Centers*
Objective: To determine the incidence and risk factors of chronic critical illness after severe blunt trauma. Design: Prospective observational cohort study (NCT01810328). Setting: Two level–one trauma centers in the United States. Patients: One hundred thirty-five adult blunt trauma patients with hemorrhagic shock who survived beyond 48 hours after injury. Interventions: None. Measurements and Main Results: Chronic critical illness was defined as an ICU stay lasting 14 days or more with evidence of persistent organ dysfunction. Three subjects (2%) died within the first 7 days, 107 (79%) exhibited rapid recovery and 25 (19%) progressed to chronic critical illness. Patients who developed chronic critical illness were older (55 vs 44-year-old; p = 0.01), had more severe shock (base deficit, –9.2 vs –5.5; p = 0.005), greater organ failure severity (Denver multiple organ failure score, 3.5 ± 2.4 vs 0.8 ± 1.1; phttp://ift.tt/2AbZadW
Effects of Hyperoxia During Resuscitation From Hemorrhagic Shock in Swine With Preexisting Coronary Artery Disease
Objectives: Investigation of the effects of hyperoxia during resuscitation from hemorrhagic shock in swine with preexisting coronary artery disease. Design: Prospective, controlled, randomized trial. Setting: University animal research laboratory. Subjects: Nineteen hypercholesterolemic pigs with preexisting coronary artery disease. Interventions: Anesthetized, mechanically ventilated, and surgically instrumented pigs underwent 3 hours of hemorrhagic shock (removal of 30% of the calculated blood volume and subsequent titration of mean arterial blood pressure ≈40 mm Hg). Postshock resuscitation (48 hr) comprised retransfusion of shed blood, crystalloids (balanced electrolyte solution), and norepinephrine support. Pigs were randomly assigned to "control" (FIO2 0.3, adjusted for arterial oxygen saturation ≥ 90%) and "hyperoxia" (FIO2 1.0 for 24 hr) groups. Measurements and Main Results: Before, at the end of shock and every 12 hours of resuscitation, datasets comprising hemodynamics, calorimetry, blood gases, cytokines, and cardiac and renal function were recorded. Postmortem, organs were sampled for immunohistochemistry, western blotting, and mitochondrial high-resolution respirometry. Survival rates were 50% and 89% in the control and hyperoxia groups, respectively (p = 0.077). Apart from higher relaxation constant τ at 24 hours, hyperoxia did not affect cardiac function. However, troponin values were lower (2.2 [0.9–6.2] vs 6.9 [4.8–9.8] ng/mL; phttp://ift.tt/2jE2XtP
Serial Daily Organ Failure Assessment Beyond ICU Day 5 Does Not Independently Add Precision to ICU Risk-of-Death Prediction
Objectives: To identify circumstances in which repeated measures of organ failure would improve mortality prediction in ICU patients. Design: Retrospective cohort study, with external validation in a deidentified ICU database. Setting: Eleven ICUs in three university hospitals within an academic healthcare system in 2014. Patients: Adults (18 yr old or older) who satisfied the following criteria: 1) two of four systemic inflammatory response syndrome criteria plus an ordered blood culture, all within 24 hours of hospital admission; and 2) ICU admission for at least 2 calendar days, within 72 hours of emergency department presentation. Intervention: None Measurements and Main Results: Data were collected until death, ICU discharge, or the seventh ICU day, whichever came first. The highest Sequential Organ Failure Assessment score from the ICU admission day (ICU day 1) was included in a multivariable model controlling for other covariates. The worst Sequential Organ Failure Assessment scores from the first 7 days after ICU admission were incrementally added and retained if they obtained statistical significance (phttp://ift.tt/2AbYVj2
Emotional Impact of End-of-Life Decisions on Professional Relationships in the ICU: An Obstacle to Collegiality?*
Objectives: End-of-life decisions are not only common in the ICU but also frequently elicit strong feelings among health professionals. Even though we seek to develop more collegial interprofessional approaches to care and health decision-making, there are many barriers to successfully managing complex decisions. The aim of this study is to better understand how emotions influence the end-of-life decision-making process among professionals working in ICU. Design: Qualitative study with clinical interviews. All interviews were transcribed verbatim and analyzed thematically using interpretative phenomenological analysis. Setting: Two independent ICUs at the "Centre Hospitalier de l'Université de Montréal." Subjects: Ten physicians and 10 nurses. Interventions: None. Measurements and Main Results: During the end-of-life decision-making process, families and patients restructure the decision-making frame by introducing a strong emotional dimension. This results in the emergence of new challenges quite different from the immediacy often associated with intensive care. In response to changes in decision frames, physicians rely on their relationship with the patient's family to assist with advanced care decisions. Nurses, however, draw on their relationship and proximity to the patient to denounce therapeutic obstinacy. Conclusions: Our study suggests that during the end-of-life decision-making process, nurses' feelings toward their patients and physicians' feelings toward their patients' families influence the decisions they make. Although these emotional dimensions allow nurses and physicians to act in a manner that is consistent with their professional ethics, the professionals themselves seem to have a poor understanding of these dimensions and often overlook them, thus hindering collegial decisions.http://ift.tt/2A91a74
Time Course of Septic Shock in Immunocompromised and Nonimmunocompromised Patients
Objectives: To address the impact of underlying immune conditions on the course of septic shock with respect to both mortality and the development of acute infectious and noninfectious complications. Design: An 8-year (2008–2015) monocenter retrospective study. Setting: A medical ICU in a tertiary care center. Patients: Patients diagnosed for septic shock within the first 48 hours of ICU admission were included. Patients were classified in four subgroups with respect to their immune status: nonimmunocompromised and immunocompromised distributed into hematologic or solid malignancies and nonmalignant immunosuppression. Outcomes were in-hospital death and the development of ischemic and hemorrhagic complications and ICU-acquired infections. The determinants of death and complications were addressed by multivariate competing risk analysis. Interventions: None. Measurements and Main Results: Eight hundred one patients were included. Among them, 305 (38%) were immunocompromised, distributed into solid tumors (122), hematologic malignancies (106), and nonmalignant immunosuppression (77). The overall 3-day, in-ICU, and in-hospital mortality rates were 14.1%, 37.3%, and 41.3%, respectively. Patients with solid tumors displayed increased in-hospital mortality (cause-specific hazard, 2.20 [95% CI, 1.64–2.96]; phttp://ift.tt/2A917bo
Sepsis Reduces Bone Strength Before Morphologic Changes Are Identifiable
Objectives: Survivors of critical illness have an increased prevalence of bone fractures. However, early changes in bone strength, and their relationship to structural changes, have not been described. We aimed to characterize early changes in bone functional properties in critical illness and their relationship to changes in bone structure, using a sepsis rodent model. Design: Experimental study. Setting: Animal research laboratory. Subjects: Adult Sprague-Dawley rats. Interventions: Forty Sprague-Dawley rats were randomized to cecal ligation and puncture or sham surgery. Twenty rodents (10 cecal ligation and puncture, 10 sham) were killed at 24 hours, and 20 more at 96 hours. Measurements and Main Results: Femoral bones were harvested for strength testing, microCT imaging, histologic analysis, and multifrequency scanning probe microscopy. Fracture loads at the femoral neck were significantly reduced for cecal ligation and puncture–exposed rodents at 24 hours (83.39 ± 10.1 vs 103.1 ± 17.6 N; p = 0.014) and 96 hours (81.60 ± 14.2 vs 95.66 ± 14.3 N; p = 0.047). Using multifrequency scanning probe microscopy, collagen elastic modulus was lower in cecal ligation and puncture–exposed rats at 24 hours (1.37 ± 0.2 vs 6.13 ± 0.3 GPa; p = 0.001) and 96 hours (5.57 ± 0.5 vs 6.13 ± 0.3 GPa; p = 0.006). Bone mineral elastic modulus was similar at 24 hours but reduced in cecal ligation and puncture–exposed rodents at 96 hours (75.34 ± 13.2 vs 134.4 ± 8.2 GPa; phttp://ift.tt/2hKaRkt
Pediatric Sepsis Endotypes Among Adults With Sepsis
Objectives: Recent transcriptomic studies describe two subgroups of adults with sepsis differentiated by a sepsis response signature. The implied biology and related clinical associations are comparable with recently reported pediatric sepsis endotypes, labeled "A" and "B." We classified adults with sepsis using the pediatric endotyping strategy and the sepsis response signature and determined how endotype assignment, sepsis response signature membership, and age interact with respect to mortality. Design: Retrospective analysis of publically available transcriptomic data representing critically ill adults with sepsis from which the sepsis response signature groups were derived and validated. Setting: Multiple ICUs. Patients: Adults with sepsis. Interventions: None. Measurements and Main Results: Transcriptomic data were conormalized into a single dataset yielding 549 unique cases with sepsis response signature assignments. Each subject was assigned to endotype A or B using the expression data for the 100 endotyping genes. There were 163 subjects (30%) assigned to endotype A and 386 to endotype B. There was a weak, positive correlation between endotype assignment and sepsis response signature membership. Mortality rates were similar between patients assigned endotype A and those assigned endotype B. A multivariable logistic regression model fit to endotype assignment, sepsis response signature membership, age, and the respective two-way interactions revealed that endotype A, sepsis response signature 1 membership, older age, and the interactions between them were associated with mortality. Subjects coassigned to endotype A, and sepsis response signature 1 had the highest mortality. Conclusions: Combining the pediatric endotyping strategy with sepsis response signature membership might provide complementary, age-dependent, biological, and prognostic information.http://ift.tt/2AQWVsQ
Racial Differences in Palliative Care Use After Stroke in Majority-White, Minority-Serving, and Racially Integrated U.S. Hospitals
Objectives: Racial/ethnic differences in palliative care resource use after stroke have been recognized, but it is unclear whether patient or hospital characteristics drive this disparity. We sought to determine whether palliative care use after intracerebral hemorrhage and ischemic stroke differs between hospitals serving varying proportions of minority patients. Design: Population-based cross-sectional study. Setting: Inpatient hospital admissions from the Nationwide Inpatient Sample between 2007 and 2011. Patients: A total of 46,735 intracerebral hemorrhage and 331,521 ischemic stroke cases. Interventions: Palliative care use. Measurements and Main Results: Intracerebral hemorrhage and ischemic stroke admissions were identified from the Nationwide Inpatient Sample between 2007 and 2011. Hospitals were categorized based on the percentage of ethnic minority stroke patients ( 50% minorities ["minority hospitals"]). Logistic regression was used to evaluate the association between race/ethnicity and palliative care use within and between the different hospital strata. Stroke patients receiving care in minority hospitals had lower odds of palliative care compared with those treated in white hospitals, regardless of individual patient race/ethnicity (adjusted odds ratio, 0.65; 95% CI, 0.50–0.84 for intracerebral hemorrhage and odds ratio, 0.62; 95% CI, 0.50–0.77 for ischemic stroke). Ethnic minorities had a lower likelihood of receiving palliative care compared with whites in any hospital stratum, but the odds of palliative care for both white and minority intracerebral hemorrhage patients was lower in minority compared with white hospitals (odds ratio, 0.66; 95% CI, 0.50–0.87 for white and odds ratio, 0.64; 95% CI, 0.46–0.88 for minority patients). Similar results were observed in ischemic stroke. Conclusions: The odds of receiving palliative care for both white and minority stroke patients is lower in minority compared with white hospitals, suggesting system-level factors as a major contributor to explain race disparities in palliative care use after stroke.http://ift.tt/2A90QFo
Expanding the neurodevelopmental phenotype of PURA syndrome
PURA syndrome is a recently described developmental encephalopathy presenting with neonatal hypotonia, feeding difficulties, global developmental delay, severe intellectual disability, and frequent apnea and epilepsy. We describe 18 new individuals with heterozygous sequence variations in PURA. A neuromotor disorder starting with neonatal hyptonia, but ultimately allowing delayed progression to walking, was present in nearly all individuals. Congenital apnea was present in 56% during infancy, but all cases in this cohort resolved during the first year of life. Feeding difficulties were frequently reported, with gastrostomy tube placement required in 28%. Epilepsy was present in 50% of the subjects, including infantile spasms and Lennox–Gastaut syndrome. Skeletal complications were found in 39%. Disorders of gastrointestinal motility and nystagmus were also recurrent features. Autism was diagnosed in one individual, potentially expanding the neurodevelopmental phenotype associated with this syndrome. However, we did not find additional PURA sequence variations in a cohort of 120 subjects with autism. We also present the first neuropathologic studies of PURA syndrome, and describe chronic inflammatory changes around the arterioles within the deep white matter. We did not find significant correlations between mutational class and severity, nor between location of the sequence variation in PUR repeat domains. Further studies are required in larger cohorts of subjects with PURA syndrome to clarify these genotype–phenotype associations.
http://ift.tt/2AY39YG
Unique association of hypochondroplasia with craniosynostosis and cleft palate in a Mexican family
Hypochondroplasia (HCH) is a skeletal dysplasia caused by an abnormal function of the fibroblast growth factor receptor 3. Although believed to be relatively common, its prevalence and phenotype are not well established owing to its clinical, radiological, and genetic heterogeneity. Here we report on a molecularly proven HCH family with an affected father and two children. The siblings (male and female) with HCH also had craniosynostosis and cleft palate, respectively. The present report supports the conclusion that the full clinical spectrum of HCH is not completely delineated. It also suggests that secondary, as yet unknown, modifying factors can influence the final phenotype.
http://ift.tt/2ySx57d
p.Arg69Trp in RNASEH2C is a founder variant in three Indian families with Aicardi–Goutières syndrome
Aicardi–Goutières syndrome is an early-onset severe neurological disorder characterized by intracranial calcification, white matter abnormalities, hepatosplenomegaly, cerebrospinal fluid lymphocytosis, and elevated interferon-α levels, thus mimicking congenital viral infections. It is a genetically heterogeneous condition and autosomal recessive and autosomal dominant forms with variations in seven genes known till date. Variations in RNASEH2C cause an autosomal recessive form of AGS. Here we report three Indian families with variant, c.205C>T (NM_032193.3, p.Arg69Trp) in RNASEH2C gene identified by whole-exome sequencing and targeted molecular testing of the variant. Review of literature and our data suggest this is likely to be a founder variant in Asians and it would be a good initial variant to screen in patients with Aicardi–Goutières syndrome in Indians.
http://ift.tt/2AXWden
A model to characterize psychopathological features in adults with Prader-Willi syndrome
High prevalence of behavioral and psychiatric disorders in adults with Prader-Willi Syndrome (PWS) has been reported in last few years. However, data are confusing and often contradictory. In this article, we propose a model to achieve a better understanding of the psychopathological features in adults with PWS. The study is based on clinical observations of 150 adult inpatients, males and females. Non-parametric statistics were performed to analyse the association of psychopathological profiles with genotype, gender and age. We propose a model of psychiatric disorders in adults with PWS based on cognitive, emotional and behavioural issues. This model defines four psychopathological profiles: Basic, Impulsive, Compulsive, and Psychotic. The Basic profile is defined by traits and symptoms that are present in varying degrees in all persons with PWS. In our cohort, this Basic profile corresponds to 55% of the patients. The rest show, in addition to these characteristics, salient features of impulsivity (Impulsive profile, 19%), compulsivity (Compulsive profile, 7%), or psychosis (Psychotic profile, 19%). The analysis of factors associated with different profiles reveals an effect of genotype on Basic and Psychotic profiles (Deletion: 70% Basic, 9% Psychotic; Non-deletion: 23% Basic, 43% Psychotic) and a positive correlation between male sex and impulsivity, unmediated by sex hormone treatment. This is a clinical study, based on observation proposing an original model to understand the psychiatric and behavioural disorders in adults with PWS. Further studies are needed in order to test the validity of this model.
http://ift.tt/2ySm99J
The Influence of Genetic Stability on Aspergillus fumigatus Virulence and Azole Resistance
Genetic stability is extremely important for the survival of every living organism and a very complex set of genes have evolved to cope with DNA repair upon DNA damage. Here, we investigated the Aspergillus fumigatus AtmA (Ataxia-telangiectasia mutated) and AtrA kinases and how they impact virulence and the evolution of azole resistance. We demonstrated that A. fumigatus atmA and atrA null mutants are haploid and have a discrete chromosomal polymorphism. The atmA and atrA strains are sensitive to several DNA damaging agents but surprisingly both strains were more resistant than the wild-type strain to paraquat, menadione, and hydrogen peroxide. The atmA and atrA genes showed synthetic lethality emphasizing the cooperation between both enzymes and their consequent redundancy. The lack of atmA and atrA does not cause any significant virulence reduction in A. fumigatus in a neutropenic murine model of invasive pulmonary aspergillosis and in the invertebrate alternative model Galleria mellonela. Wild-type, atmA and atrA populations that were previously transferred 10 times in minimal medium in the absence of voriconazole have not shown any significant changes in drug resistance acquisition. In contrast, atmA and atrA populations similarly evolved in the presence of a subinhibitory concentration of voriconazole showed about 5 to 10-fold increase when compared to the original MIC values. There are discrete alterations in the voriconazole target Cyp51A/Erg11A or cyp51/erg11 and/or Cdr1B efflux transporter overexpression that do not seem to be the main mechanisms to explain voriconazole resistance in these evolved populations. Taken together, these results suggest that genetic instability caused by atmA and atrA mutations can confer an adaptive advantage mainly in the intensity of voriconazole resistance acquisition.
http://ift.tt/2iscPDn
Rapid and Efficient CRISPR/Cas9-Based Mating-Type Switching of Saccharomyces cerevisiae
Rapid and highly efficient mating-type switching of Saccharomyces cerevisiae enables a wide variety of genetic manipulations such as the construction of strains, for instance isogenic haploid pairs of both mating-types, diploids and polyploids. We used the CRISPR/Cas9 system to generate a double-strand break (DSB) at the MAT locus, and in a single co-transformation, both haploid and diploid cells were switched to the specified mating-type at ~80% efficiency. The mating-type of strains carrying either rod or ring chromosome III were switched, including those lacking HMLα and HMRa cryptic mating loci. Furthermore, we transplanted the synthetic yeast chromosome V to build a haploid poly-synthetic chromosome strain by using this method together with an endoreduplication intercross strategy. The CRISPR/Cas9 mating-type switching method will be useful in building the complete synthetic yeast (Sc2.0) genome. Importantly, it is a generally useful method to build polyploids of a defined genotype and generally expedites strain construction, for example in the construction of fully a/a/a/a isogenic tetraploids.
http://ift.tt/2iscJM1
Co-occurring Alterations Affect Outcomes in EGFR-Mutant Lung Cancer [Research Watch]
Sequencing cfDNA from 1,122 patients with EGFR-mutant lung cancer reveals co-occurring alterations.
http://ift.tt/2yUVB7Q
Inflammation-Induced IgA+ Cells Promote Hepatocellular Tumorigenesis [Research Watch]
Chronic inflammation may promote hepatocellular carcinoma by suppressing cytotoxic T-cell activity.
http://ift.tt/2AULfpP
The Active Conformation of Integrin {beta}7 May Be a Multiple Myeloma Target [Research Watch]
CAR T cells targeting active integrin β7 have cytotoxic activity against multiple myeloma (MM) cells.
http://ift.tt/2yUVvx0
High BCAT1 Expression Mimics IDH Mutations in Acute Myeloid Leukemia [Research Watch]
High BCAT1 expression is linked to shorter survival in patients with IDH– and TET2–wild-type AML.
http://ift.tt/2AUL7GR
The extracellular membrane-proximal domain of membrane-bound IgE restricts B cell activation by limiting B cell antigen receptor surface expression
Abstract
Immunoglobulin E (IgE) antibodies are key mediators of allergic reactions. Due to their potentially harmful anaphylactic properties their production is tightly regulated. The membrane-bound isoform of IgE (mIgE), which is an integral component of the B cell antigen receptor, has been shown to be critical for the regulation of IgE responses in mice. In primate species including humans, mIgE can be expressed in two isoforms that are produced by alternative splicing of the primary ε Ig heavy chain transcript, and differ in the absence or presence of an extracellular membrane-proximal domain (EMPD) consisting of 52 amino acids. However, the function of the EMPD remains unclear. Here, we demonstrate that the EMPD restricts surface expression of mIgE-containing BCRs in human and murine B cells. The EMPD does not interfere with BCR assembly but acts as an autonomous endoplasmic reticulum retention domain. Limited surface expression of EMPD-containing mIgE-BCRs caused impaired activation of intracellular signaling cascades and hence represents a regulatory mechanism that may control the production of potentially anaphylactic IgE antibodies in primate species.
This article is protected by copyright. All rights reserved
http://ift.tt/2mBTgwW
Influence of Enzalutamide on Cabazitaxel Pharmacokinetics; a Drug-Drug Interaction Study in Metastatic Castration Resistant Prostate Cancer (mCRPC) Patients
Purpose: In ongoing clinical research on metastatic castration-resistant prostate cancer (mCRPC) treatment, the potential enhanced efficacy of the combination of taxanes with AR-targeted agents, i.e. enzalutamide and abiraterone, is currently being explored. Since enzalutamide induces the CYP3A4 enzyme and taxanes are metabolized by this enzyme, a potential drug-drug interaction needs to be investigated. Design: Therefore, we performed a pharmacokinetic cross-over study in mCRPC patients who were scheduled for treatment with cabazitaxel Q3W (25 mg/m2). Patients were studied for three consecutive cabazitaxel cycles. Enzalutamide (160 mg QD) was administered concomitantly after the first cabazitaxel cycle, during 6 weeks. Primary endpoint was the difference in mean area under the curve (AUC) between the first (cabazitaxel monotherapy) and third cabazitaxel cycle, when enzalutamide was added. Results: A potential clinically relevant 22% (95%CI: 9-34%, p=0.005) reduction in cabazitaxel exposure was found with concomitant enzalutamide use. The geometric mean AUC0-24h of cabazitaxel was 181 ng*h/mL (95%CI 150-219 ng*h/mL) in cycle 3 and 234 ng*h/mL (95%CI 209-261 ng*h/mL) in cycle 1 This combination did not result in excessive toxicity, while PSA response was promising. Conclusions: We found a significant decrease in cabazitaxel exposure when combined with enzalutamide. In an era of clinical trials on combination strategies for mCRPC, it is important to be aware of clinically relevant drug-drug interactions. Since recent study results support the use of a lower standard cabazitaxel dose of 20 mg/m2, the clinical relevance of this interaction may be substantial, since the addition of enzalutamide may result in sub-therapeutic cabazitaxel exposure.
http://ift.tt/2Ab8ZsK
Interferon- 2; signaling in melanocytes and melanoma cells regulates expression of CTLA-4
CTLA-4 is a cell surface receptor on T cells that functions as an immune checkpoint molecule to enforce tolerance to cognate antigens. Anti-CTLA-4 immunotherapy is highly effective at reactivating T cell responses against melanoma, which is postulated to be due to targeting CTLA-4 on T cells. Here we report that CTLA-4 is also highly expressed by most human melanoma cell lines, as well as in normal human melanocytes. Interferon-gamma (IFNG) signaling activated the expression of the human CTLA-4 gene in a melanocyte and melanoma cell-specific manner. Mechanistically, IFNG activated CTLA-4 expression through JAK1/2-dependent phosphorylation of STAT1, which bound a specific gamma-activated sequence (GAS) site on the CTLA-4 promoter, thereby licensing CBP/p300-mediated histone acetylation and local chromatin opening. In melanoma cell lines, elevated baseline expression relied upon constitutive activation of the MAPK pathway. Notably, RNA-seq analyses of melanoma specimens obtained from patients who had received anti-CTLA-4 immunotherapy (ipilimumab) showed upregulation of an IFNG-response gene expression signature, including CTLA-4 itself, which correlated significantly with durable response. Taken together, our results raise the possibility that CTLA-4 targeting on melanoma cells may contribute to the clinical immunobiology of anti-CTLA-4 responses.
http://ift.tt/2zLT4QX
Predictors of early-onset post-ischemic stroke depression: a cross-sectional study
Post-stroke depression (PSD) seriously affects the rehabilitation of nerve function and quality of life. However, the pathogenesis of PSD is still not clear. This study aimed to investigate the demographic, cl...
http://ift.tt/2zc0duv
Recent advances in inflammasome biology
David E Place | Thirumala-Devi Kanneganti
http://ift.tt/2jAeLgA
Type I interferon-mediated autoinflammation and autoimmunity
Stefanie Kretschmer | Min Ae Lee-Kirsch
http://ift.tt/2hI9aUN
Mechanisms of propofol attenuation of ketamine-induced neonatal brain injury
OBJECTIVE: We studied the mechanisms of protective effects of propofol on ketamine-induced damage to neonatal cognitive function.
MATERIALS AND METHODS: We utilized a rat model of ketamine anaesthesia. Eighty neonatal rats (7 days after birth) were divided into four groups: normal saline group, ketamine group, and low- and high-dose propofol combined with ketamine groups. Six hours after anaesthesia, we obtained hippocampal tissue, and quantified apoptotic index and total protein concentration, and assessed global proteomics changes induced by two tested drugs. The latter changes were documented by two-dimensional electrophoresis and matrix-assisted laser desorption/ ionization time of flight mass spectrometry. To evaluate cognitive functions, water maze test was applied after animals grew for 21 days. We further repeated proteomics studies at 21 days post-anaesthesia.
RESULTS: Ketamine markedly up-regulated apoptotic index and decreased total protein concentration. Propofol dose-dependently reverted these adverse changes. Six hours post-anaesthesia, combined propofol and ketamine administration up-regulated the following proteins in the hippocampus: PD1A3, NDUFB10, HSPA8, ATP5JD, and PSMA1. Furthermore, the following proteins were down-regulated: PPIA, PKM2, GFAP, NSE, PPIA, PKM2, and GFAP. After 21 days, animals treated with ketamine showed marked disturbances in cognitive function as demonstrated by increased time of the water maze test, whereas propofol diminished these changes. In addition, expression of proteins largely normalized in propofol-treated animals, with only two up-regulated proteins (FUBP3 and PRDX5) and three down-regulated proteins (GAPDH, AKR1A1, and VCP).
CONCLUSIONS: Adverse effects of ketamine on cognitive function are reverted by propofol, also through beneficial effects on protein expression in the hippocampus.
L'articolo Mechanisms of propofol attenuation of ketamine-induced neonatal brain injury sembra essere il primo su European Review.
http://ift.tt/1ZA4IWo
Natural History of Infantile-Onset Spinal Muscular Atrophy
Abstract
Objective: Infantile-onset spinal muscular atrophy (SMA) is the most common genetic cause of infant mortality, typically resulting in death prior to age 2. Clinical trials in this population require an understanding of disease progression and identification of meaningful biomarkers to hasten therapeutic development and predict outcomes.
Methods: A longitudinal, multi-center, prospective natural history study enrolled 26 SMA infants, and 27 control infants less than six months of age. Recruitment occurred at 14 centers over 21 months within the NINDS-sponsored NeuroNEXT Network. Infant motor function scales (TIMPSI, CHOP-INTEND and AIMS) and putative physiologic and molecular biomarkers were assessed prior to 6 months of age and at 6, 9, 12, 18 and 24-months with progression, correlations between motor function and biomarkers and hazard ratios were analyzed.
Results: Motor function scores (MFS) and CMAP decreased rapidly in SMA infants, whereas MFS in all healthy infants rapidly increased. Correlations were identified between TIMPSI and CMAP in SMA infants. TIMPSI at first study visit was associated with risk of combined endpoint of death or permanent invasive ventilation in SMA infants. Post hoc analysis of survival to combined endpoint in SMA infants with 2 copies of SMN2 indicated a median age of 8 months at death (95%CI: 6,17).
Interpretation: These data of SMA and control outcome measures delineates meaningful change in clinical trials in infantile-onset SMA. The power and utility of NeuroNEXT to provide "real world", prospective natural history data sets to accelerate public and private drug development programs for rare disease is demonstrated. This article is protected by copyright. All rights reserved.
http://ift.tt/2A8O89E
Mitochondrial DNA changes in pedunculopontine cholinergic neurons in Parkinson's
ABSTRACT
In Parkinson's disease (PD), mitochondrial dysfunction associates with nigral dopaminergic neuronal loss. Cholinergic neuronal loss co-occurs, particularly within a brainstem structure, the pedunculopontine nucleus (PPN). We isolated single cholinergic neurons from post-mortem PPNs of aged controls and PD patients. Mitochondrial DNA (mtDNA) copy number and mtDNA deletions were increased significantly in PD patients compared to controls. Furthermore, compared to controls the PD patients had significantly more PPN cholinergic neurons containing mtDNA deletion levels exceeding 60%, a level associated with deleterious effects on oxidative phosphorylation. The current results differ from studies reporting mtDNA depletion in nigral dopaminergic neurons of PD patients. This article is protected by copyright. All rights reserved.
http://ift.tt/2zNpxGu
The analysis of novel microRNA mimic sequences in cancer cells reveals lack of specificity in stem-loop RT-qPCR-based microRNA detection
MicroRNAs are frequently downregulated in cancer, and restoring expression has tumour suppressive activity in tumour cells. Our recent phase I clinical trial investigated microRNA-based therapy in patients wit...
http://ift.tt/2AacxeU
Associations Between Nucleus Size, and Immunohistochemical Galectin-3, Cytokeratine-19 and Hbme-1 Markers in Thyroid Papillary Carcinoma: A Morphometric Analyze
Abstract
This study aimed to evaluate the morphometric measurements in cases with papillary thyroid carcinoma, and determine a cut-off value to support diagnosis. Fifty cases with a diagnosis of papillary thyroid carcinoma (PTC) were included in the study with their Galectine-3, CK-19 and HBME-1 immunohistochemical staining results. Demographic and clinical data gathered from pathology reports, which included demographic information such as patients' sex, age, macroscopic tumor size, number of tumor focuses; prognostic parameters such as lenfovascular invasion, perineural invasion, thyroid capsule invasion; and results of immunohistochemical CK- 19, Galectin-3 and HBME-1 staining. Longest nuclear diameters of 150 tumor cells and 150 normal thyrocytes of each case were manually measured in an image analysis software, and mean longest nuclear diameters (MLND-TC and MLND-NC), and also tumor cell/normal cell longest nuclear diameter ratio (TC/NC-LNDR) were calculated. MLND-TC was higher than MLND-NC. The cases with higher MLND-TC had increased risk of capsule invasion in case of a negative staining with Galectine-3, HBME-1, or CK-19. When TC/NC-LNDR was high, number of tumor focus tended to be multiple and lymphovascular invasion risk was also increased. Subtypes of PTC were not differed regarding staining patterns. And finally, increased TC/NC-LNDR was associated with increased risk of having poor prognostic factors. The results of this study suggest that MLND-NC, MLND-TC, and TC/NCLNDR are valuable and easy-to-use measures, which can assist routine histology practice.
http://ift.tt/2zMiVs0
Role of Urine Drug Testing in the Current Opioid Epidemic
While the evidence for urine drug testing for patients on chronic opioid therapy is weak, the guidelines created by numerous medical societies and state and federal regulatory agencies recommend that it be included as one of the tools used to monitor patients for compliance with chronic opioid therapy. To get the most comprehensive results, clinicians should order both an immunoassay screen and confirmatory urine drug test. The immunoassay screen, which can be performed as an in-office point-of-care test or as a laboratory-based test, is a cheap and convenient study to order. Limitations of an immunoassay screen, however, include having a high threshold of detectability and only providing qualitative information about a select number of drug classes. Because of these restrictions, clinicians should understand that immunoassay screens have high false-positive and false-negative rates. Despite these limitations, though, the results can assist the clinician with making preliminary treatment decisions. In comparison, a confirmatory urine drug test, which can only be performed as a laboratory-based test, has a lower threshold of detectability and provides both qualitative and quantitative information. A urine drug test's greater degree of specificity allows for a relatively low false-negative and false-positive rate in contrast to an immunoassay screen. Like any other diagnostic test, an immunoassay screen and a confirmatory urine drug test both possess limitations. Clinicians must keep this in mind when interpreting an unexpected test result and consult with their laboratory when in doubt about the meaning of the test result to avoid making erroneous decisions that negatively impact both the patient and clinician.http://ift.tt/2APFEjU
General Anesthesia Imposes Negative Effects on Heart Rate and Blood Pressure Regulation in Patients With a History of Head and Neck Radiation Therapy
BACKGROUND: Head and neck radiation therapy (HNRT) impairs baroreflex sensitivity, and it may potentiate the effects of anesthetics on heart rate (HR) and blood pressure (BP) regulation. Currently, the impacts of HNRT on HR and BP under anesthesia remain unclear. METHODS: In this study, 472 patients with primary oral cavity or oropharyngeal cancer at all stages were examined. Half of the patients underwent HNRT plus surgery. The other half underwent surgery only and was matched with the treatment patients according to age, sex, and body mass index at a 1:1 ratio. The HRs and BPs in the 2 groups during anesthetic induction, skin incision, and emergence were compared retrospectively. A multivariable model of repeated measures with unstructured covariance structure was used to examine the associations of HNRT with intraoperative HRs and BPs after adjusting for baseline HR and BP, time, use of β-blockers, history of chemotherapy, and American Society of Anesthesiologists physical status score. BPs and HRs were collected every 5 minutes. The baseline HR and BP measurements were not included in the outcome vector and were only used as adjustment for baselines. RESULTS: Compared with corresponding baseline values in controls, the baseline HR was significantly higher (P = .0012) and the baseline systolic BP was lower (Phttp://ift.tt/2isjyx8
Noninfectious Fever in the Near-Term Pregnant Rat Induces Fetal Brain Inflammation: A Model for the Consequences of Epidural-Associated Maternal Fever
BACKGROUND: Women laboring with epidural analgesia experience fever much more frequently than do women who chose other forms of analgesia, and maternal intrapartum fever is associated with numerous adverse consequences, including brain injury in the fetus. We developed a model of noninfectious inflammatory fever in the near-term pregnant rat to simulate the pathophysiology of epidural-associated fever and hypothesized that it would produce fetal brain inflammation. METHODS: Twenty-four pregnant Sprague-Dawley rats were studied at 20 days gestation (term: 22 days). Dams were treated by injection of rat recombinant interleukin (IL)-6 or vehicle at 90-minute intervals, and temperature was monitored every 30 minutes. Eight hours after the first treatment, dams were delivered of fetuses and then killed. Maternal IL-6 was measured at delivery. Fetal brains (n = 24) were processed and stained for ED-1/CD68, a marker for activated microglia, and cell counts in the lateral septal and hippocampal brain regions were measured. Fetal brains were also stained for cyclooxygenase-2 (COX-2), a downstream marker of neuroinflammation. Eight fetal brains were further analyzed for quantitative forebrain COX-2 by Western blotting compared to a β-actin standard. Maternal temperature and IL-6 levels were compared between treatments, as were cell counts, COX-2 staining, and COX-2 levels by Mann-Whitney U test, repeated-measures analysis of variance, or Fisher exact test, as appropriate. RESULTS: Injection of rat IL-6 at 90-minute intervals produced an elevation of maternal temperature compared to vehicle (Phttp://ift.tt/2AQIq8x
Effect of an Intravenous Dexamethasone Added to Caudal Local Anesthetics to Improve Postoperative Pain: A Systematic Review and Meta-analysis With Trial Sequential Analysis
BACKGROUND: Caudal anesthesia has been used for postoperative pain control in pediatric surgical patients, but the duration of the analgesic effect is occasionally unsatisfactory. Intravenous steroids have been shown to be effective for postsurgical pain management after certain surgeries. The aim of this meta-analysis with trial sequential analysis (TSA) was to evaluate the analgesic effect of steroids in patients administered with caudal anesthesia. METHODS: This study was a systematic review and meta-analysis. A search of published literature was conducted in the MEDLINE, EMBASE, Web of Science, and Cochrane Central Register of Controlled Trials databases and in trial registration sites. Randomized controlled trials that compared intravenous steroids with a placebo in pediatric patients who had received caudal anesthesia for surgery were included in the study. The primary outcomes from the present meta-analysis were the analgesic duration and the number of patients who required rescue analgesics. The analgesic duration and incidence of rescue use were summarized using mean difference or risk ratio with a 97.5% confidence interval (CI), respectively. If the 97.5% CI of the mean difference or risk ratio included a value of 0 or 1, respectively, we considered the difference not to be significant. We used the random effects model to combine the results. Heterogeneity was quantified with the I2 statistic. The quality of the trials was evaluated using the Cochrane methodology. Moreover, a TSA with a risk of type 1 error of 2.5% and power of 90% was performed. We established the minimum clinically meaningful difference of analgesic duration as 3 hours. The target sample size for meta-analysis was also calculated in the TSA. We also assessed adverse events. RESULTS: Six trials with 424 patients were included; 211 patients received intravenous steroids. All trials compared dexamethasone of at least 0.5 mg/kg dose with a placebo. Dexamethasone prolonged the duration of caudal analgesia (mean difference, 244 minutes; 97.5% CI, 188–300). Heterogeneity was considerable with an I2 value of 94.8%. Quality of evidence was very low. The TSA suggested that only 17.0% of the target sample size had been reached, but the cumulative Z score crossed the trial sequential monitoring boundary to indicate a benefit. Rescue use was reported in 4 studies with 260 patients. Rescue use was not significantly reduced in the dexamethasone group (risk ratio, 0.53; 97.5% CI, 0.09–3.30; I2, 98.7%). No increase in adverse events was reported. CONCLUSIONS: Intravenous dexamethasone prolongs the analgesic duration of caudal anesthesia. Trials to investigate the effectiveness of a lower dose of the dexamethasone in prolonging analgesic effects would be of interest. Further trials with a low risk of bias are necessary.http://ift.tt/2AQtKpO
Opioid Prescribing for the Treatment of Acute Pain in Children on Hospital Discharge
BACKGROUND: The epidemic of nonmedical use of prescription opioids has been fueled by the availability of legitimately prescribed unconsumed opioids. The aim of this study was to better understand the contribution of prescriptions written for pediatric patients to this problem by quantifying how much opioid is dispensed and consumed to manage pain after hospital discharge, and whether leftover opioid is appropriately disposed of. Our secondary aim was to explore the association of patient factors with opioid dispensing, consumption, and medication remaining on completion of therapy. METHODS: Using a scripted 10-minute interview, parents of 343 pediatric inpatients (98% postoperative) treated at a university children's hospital were questioned within 48 hours and 10 to 14 days after discharge to determine amount of opioid prescribed and consumed, duration of treatment, and disposition of unconsumed opioid. Multivariable linear regression was used to examine predictors of opioid prescribing, consumption, and doses remaining. RESULTS: Median number of opioid doses dispensed was 43 (interquartile range, 30–85 doses), and median duration of therapy was 4 days (interquartile range, 1–8 days). Children who underwent orthopedic or Nuss surgery consumed 25.42 (95% confidence interval, 19.16–31.68) more doses than those who underwent other types of surgery (Phttp://ift.tt/2ishuVI
Health care workers’ knowledge, attitudes and practices on tuberculosis infection control, Nepal
Infection control remains a key challenge for Tuberculosis (TB) control program with an increased risk of TB transmission among health care workers (HCWs), especially in settings with inadequate TB infection c...
http://ift.tt/2yRLEYL
Using Integrative Medicine in Pain Management: An Evaluation of Current Evidence
Complementary medicine therapies are frequently used to treat pain conditions such as headaches and neck, back, and joint pain. Chronic pain, described as pain lasting longer than 3–6 months, can be a debilitating condition that has a significant socioeconomic impact. Pharmacologic approaches are often used for alleviating chronic pain, but recently there has been a reluctance to prescribe opioids for chronic noncancer pain because of concerns about tolerance, dependence, and addiction. As a result, there has been increased interest in integrative medicine strategies to help manage pain and to reduce reliance on prescription opioids to manage pain. This article offers a brief critical review of integrative medical therapies used to treat chronic pain, including nutritional supplements, yoga, relaxation, tai chi, massage, spinal manipulation, and acupuncture. The goal of this article is to identify those treatments that show evidence of efficacy and to identify gaps in the literature where additional studies and controlled trials are needed. An electronic search of the databases of PubMed, The Cochrane Library, EMBASE, PsycINFO, and Science Citation Index Expanded was conducted. Overall, weak positive evidence was found for yoga, relaxation, tai chi, massage, and manipulation. Strong evidence for acupuncture as a complementary treatment for chronic pain that has been shown to decrease the usage of opioids was found. Few studies were found in which integrative medicine approaches were used to address opioid misuse and abuse among chronic pain patients. Additional controlled trials to address the use of integrative medicine approaches in pain management are needed.http://ift.tt/2j2Sfc8
Massive Transfusion Protocols: When to Turn On, and Off, the Fire Hose
No abstract availablehttp://ift.tt/2j4NJd1
Initiation and Termination of Massive Transfusion Protocols: Current Strategies and Future Prospects
The advent of massive transfusion protocols (MTP) has had a significant positive impact on hemorrhaging trauma patient morbidity and mortality. Nevertheless, societal MTP guidelines and individual MTPs at academic institutions continue to circulate opposing recommendations on topics critical to MTPs. This narrative review discusses up-to-date information on 2 such topics, the initiation and termination of an MTP. The discussion for each begins with a review of the recommendations and supporting literature presented by MTP guidelines from 3 prominent societies, the American Society of Anesthesiologists, the American College of Surgeons, and the task force for Advanced Bleeding Care in Trauma. This is followed by an in-depth analysis of the main components within those recommendations. Societal recommendations on MTP initiation in hemorrhaging trauma patients emphasize the use of retrospectively validated massive transfusion (MT) prediction score, specifically, the Assessment of Blood Consumption and Trauma-Associated Severe Hemorrhage scores. Validation studies have shown that both scoring systems perform similarly. Both scores reliably identify patients that will not require an MT, while simultaneously overpredicting MT requirements. However, each scoring system has its unique advantages and disadvantages, and this review discusses how specific aspects of each scoring system can affect widespread applicability and statistical performance. In addition, we discuss the often overlooked topic of initiating MT in nontrauma patients and the specific tools physicians have to guide the MT initiation decision in this unique setting. Despite the serious complications that can arise with transfusion of large volumes of blood products, there is considerably less research pertinent to the topic of MTP termination. Societal recommendations on MTP termination emphasize applying clinical reasoning to identify patients who have bleeding source control and are adequately resuscitated. This review, however, focuses primarily on the recommendations presented by the Advanced Bleeding Care in Trauma's MTP guidelines that call for prompt termination of the algorithm-guided model of resuscitation and rapidly transitioning into a resuscitation model guided by laboratory test results. We also discuss the evidence in support of laboratory result–guided resuscitation and how recent literature on viscoelastic hemostatic assays, although limited, highlights the potential to achieve additional benefits from this method of resuscitation.http://ift.tt/2j3f27K
TSPO imaging using the novel PET ligand [ 18 F]GE-180: quantification approaches in patients with multiple sclerosis
Abstract
Background
PET ligands targeting the translocator protein (TSPO) represent promising tools to visualise neuroinflammation. Here, we analysed parameters obtained in dynamic and static PET images using the novel TSPO ligand [18F]GE-180 in patients with relapsing remitting multiple sclerosis (RRMS) and an approach for semi-quantitative assessment of this disease in clinical routine.
Seventeen dynamic [18F]GE-180 PET scans of RRMS patients were evaluated (90 min). A pseudo-reference region (PRR) was defined after identification of the least disease-affected brain area by voxel-based comparison with six healthy controls (HC) and upon exclusion of voxels suspected of being affected in static 60–90 min p.i. images. Standardised uptake value ratios (SUVR) obtained from static images normalised to PRR were correlated to the distribution volume ratios (DVR) derived from dynamic data with Logan reference tissue model.
Results
Group comparison with HC revealed white matter and thalamus as most affected regions. Fewest differences were found in grey matter, and normalisation to frontal cortex (FC) yielded the greatest reduction in variability of healthy grey and white matter. Hence, FC corrected for affected voxels was chosen as PRR, leading to time-activity curves of FC which were congruent to HC data (SUV60–90 0.37, U test P = 0.42). SUVR showed a very strong correlation with DVR (Pearson ρ > 0.9). Focal MS lesions exhibited a high SUVR (range, 1.3–3.2).
Conclusions
This comparison with parameters from dynamic data suggests that SUVR normalised to corrected frontal cortex as PRR is suitable for the quantification of [18F]GE-180 uptake in lesions and different brain regions of RRMS patients. This efficient diagnostic protocol based on static [18F]GE-180 PET scans acquired 60–90 min p.i. allows the semi-quantitative assessment of neuroinflammation in RRMS patients in clinical routine.
http://ift.tt/2mBsCnL
Understanding the molecular basis of acute myeloid leukemias: where are we now?
International Journal of Hematologic Oncology, Volume 6, Issue 2, Page 43-53, November 2017.
http://ift.tt/2zcQd4c
Chronic lymphocytic leukemia: “The times they are a-changin”
International Journal of Hematologic Oncology, Volume 6, Issue 2, Page 27-29, November 2017.
http://ift.tt/2myZLAu
The influence of antiretroviral therapy on clinical aspects of HIV-related lymphoma
International Journal of Hematologic Oncology, Volume 6, Issue 2, Page 35-38, November 2017.
http://ift.tt/2zcq0CM
Editor of Biometrika
Professor Anthony C. Davison has announced his wish to retire as Editor of Biometrika on 31 December 2017, when he will have completed 10 years' service.
http://ift.tt/2zRaut6
http://ift.tt/2zRaut6
On two-stage estimation of structural instrumental variable models
Summary
Two-stage least squares estimation is popular for structural equation models with unmeasured confounders. In such models, both the outcome and the exposure are assumed to follow linear models conditional on the measured confounders and instrumental variable, which is related to the outcome only via its relation with the exposure. We consider data where both the outcome and the exposure may be incompletely observed, with particular attention to the case where both are censored event times. A general class of two-stage minimum distance estimators is proposed that separately fits linear models for the outcome and exposure and then uses a minimum distance criterion based on the reduced-form model for the outcome to estimate the regression parameters of interest. An optimal minimum distance estimator is identified which may be superior to the usual two-stage least squares estimator with fully observed data. Simulation studies demonstrate that the proposed methods perform well with realistic sample sizes. Their practical utility is illustrated in a study of the comparative effectiveness of colon cancer treatments, where the effect of chemotherapy on censored survival times may be confounded with patient status.http://ift.tt/2j5ppb1
Doubly robust nonparametric inference on the average treatment effect
Summary
Doubly robust estimators are widely used to draw inference about the average effect of a treatment. Such estimators are consistent for the effect of interest if either one of two nuisance parameters is consistently estimated. However, if flexible, data-adaptive estimators of these nuisance parameters are used, double robustness does not readily extend to inference. We present a general theoretical study of the behaviour of doubly robust estimators of an average treatment effect when one of the nuisance parameters is inconsistently estimated. We contrast different methods for constructing such estimators and investigate the extent to which they may be modified to also allow doubly robust inference. We find that while targeted minimum loss-based estimation can be used to solve this problem very naturally, common alternative frameworks appear to be inappropriate for this purpose. We provide a theoretical study and a numerical evaluation of the alternatives considered. Our simulations highlight the need for and usefulness of these approaches in practice, while our theoretical developments have broad implications for the construction of estimators that permit doubly robust inference in other problems.http://ift.tt/2zPJI4f
Blocking strategies and stability of particle Gibbs samplers
Summary
Sampling from the posterior probability distribution of the latent states of a hidden Markov model is nontrivial even in the context of Markov chain Monte Carlo. To address this, Andrieu et al. (2010) proposed a way of using a particle filter to construct a Markov kernel that leaves the posterior distribution invariant. Recent theoretical results have established the uniform ergodicity of this Markov kernel and shown that the mixing rate does not deteriorate provided the number of particles grows at least linearly with the number of latent states. However, this gives rise to a cost per application of the kernel that is quadratic in the number of latent states, which can be prohibitive for long observation sequences. Using blocking strategies, we devise samplers that have a stable mixing rate for a cost per iteration that is linear in the number of latent states and which are easily parallelizable.http://ift.tt/2j5asFZ
Differential network analysis via lasso penalized D-trace loss
Summary
Biological networks often change under different environmental and genetic conditions. In this paper, we model network change as the difference of two precision matrices and propose a novel loss function called the D-trace loss, which allows us to directly estimate the precision matrix difference without attempting to estimate the precision matrices themselves. Under a new irrepresentability condition, we show that the D-trace loss function with the lasso penalty can yield consistent estimators in high-dimensional settings if the difference network is sparse. A very efficient algorithm is developed based on the alternating direction method of multipliers to minimize the penalized loss function. Simulation studies and a real-data analysis show that the proposed method outperforms other methods.http://ift.tt/2j5arBV
A $C_p$ criterion for semiparametric causal inference
Summary
For marginal structural models, which play an important role in causal inference, we consider a model selection problem within a semiparametric framework using inverse-probability-weighted estimation or doubly robust estimation. In this framework, the modelling target is a potential outcome that may be missing, so there is no classical information criterion. We define a mean squared error for treating the potential outcome and derive an asymptotic unbiased estimator as a $C_{p}$ criterion using an ignorable treatment assignment condition. Simulation shows that the proposed criterion outperforms a conventional one by providing smaller squared errors and higher frequencies of selecting the true model in all the settings considered. Moreover, in a real-data analysis we found a clear difference between the two criteria.http://ift.tt/2zPG4Hz
Optimal designs for active controlled dose-finding trials with efficacy-toxicity outcomes
Summary
We derive optimal designs to estimate efficacy and toxicity in active controlled dose-finding trials when the bivariate continuous outcomes are described using nonlinear regression models. We determine upper bounds on the required number of different doses and provide conditions under which the boundary points of the design space are included in the optimal design. We provide an analytical description of minimally supported optimal designs and show that they do not depend on the correlation between the bivariate outcomes.http://ift.tt/2j5aq0P
Partition-based ultrahigh-dimensional variable screening
Summary
Traditional variable selection methods are compromised by overlooking useful information on covariates with similar functionality or spatial proximity, and by treating each covariate independently. Leveraging prior grouping information on covariates, we propose partition-based screening methods for ultrahigh-dimensional variables in the framework of generalized linear models. We show that partition-based screening exhibits the sure screening property with a vanishing false selection rate, and we propose a data-driven partition screening framework with unavailable or unreliable prior knowledge on covariate grouping and investigate its theoretical properties. We consider two special cases: correlation-guided partitioning and spatial location-guided partitioning. In the absence of a single partition, we propose a theoretically justified strategy for combining statistics from various partitioning methods. The utility of the proposed methods is demonstrated via simulation and analysis of functional neuroimaging data.http://ift.tt/2zPJmdV
Robust rank estimation for transformation models with random effects
Summary
Semiparametric transformation models with random effects are useful in analysing recurrent and clustered data. With specified error and random effect distributions, Zeng & Lin (2007a) proved that nonparametric maximum likelihood estimators are semiparametric efficient. In this paper we consider a more general class of transformation models with random effects, under which an unknown monotonic transformation of the response is linearly related to the covariates and the random effects with unspecified error and random effect distributions. This includes many popular models. We propose an estimator based on the maximum rank correlation, which relies on symmetry of the random effect distribution, and establish its consistency and asymptotic normality. A random weighting resampling scheme is employed for inference. The proposed method can be extended to censored and clustered data. Numerical studies demonstrate that the proposed method performs well in practical situations. Application of the method is illustrated with the Framingham cholesterol data.http://ift.tt/2j5aoWL
Distribution-free tests of independence in high dimensions
Summary
We consider the testing of mutual independence among all entries in a $d$-dimensional random vector based on $n$ independent observations. We study two families of distribution-free test statistics, which include Kendall's tau and Spearman's rho as important examples. We show that under the null hypothesis the test statistics of these two families converge weakly to Gumbel distributions, and we propose tests that control the Type I error in the high-dimensional setting where $d >n$. We further show that the two tests are rate-optimal in terms of power against sparse alternatives and that they outperform competitors in simulations, especially when $d$ is large.http://ift.tt/2j5anSH
Principal component analysis and the locus of the Fréchet mean in the space of phylogenetic trees
Summary
Evolutionary relationships are represented by phylogenetic trees, and a phylogenetic analysis of gene sequences typically produces a collection of these trees, one for each gene in the analysis. Analysis of samples of trees is difficult due to the multi-dimensionality of the space of possible trees. In Euclidean spaces, principal component analysis is a popular method of reducing high-dimensional data to a low-dimensional representation that preserves much of the sample's structure. However, the space of all phylogenetic trees on a fixed set of species does not form a Euclidean vector space, and methods adapted to tree space are needed. Previous work introduced the notion of a principal geodesic in this space, analogous to the first principal component. Here we propose a geometric object for tree space similar to the $k$th principal component in Euclidean space: the locus of the weighted Fréchet mean of $k+1$ vertex trees when the weights vary over the $k$-simplex. We establish some basic properties of these objects, in particular showing that they have dimension $k$, and propose algorithms for projection onto these surfaces and for finding the principal locus associated with a sample of trees. Simulation studies demonstrate that these algorithms perform well, and analyses of two datasets, containing Apicomplexa and African coelacanth genomes respectively, reveal important structure from the second principal components.http://ift.tt/2zPJgmz
Estimating network edge probabilities by neighbourhood smoothing
Summary
The estimation of probabilities of network edges from the observed adjacency matrix has important applications to the prediction of missing links and to network denoising. It is usually addressed by estimating the graphon, a function that determines the matrix of edge probabilities, but this is ill-defined without strong assumptions on the network structure. Here we propose a novel computationally efficient method, based on neighbourhood smoothing, to estimate the expectation of the adjacency matrix directly, without making the structural assumptions that graphon estimation requires. The neighbourhood smoothing method requires little tuning, has a competitive mean squared error rate and outperforms many benchmark methods for link prediction in simulated and real networks.http://ift.tt/2j5phs3
Semiparametric analysis of complex polygenic gene-environment interactions in case-control studies
Summary
Many methods have recently been proposed for efficient analysis of case-control studies of gene-environment interactions using a retrospective likelihood framework that exploits the natural assumption of gene-environment independence in the underlying population. However, for polygenic modelling of gene-environment interactions, which is a topic of increasing scientific interest, applications of retrospective methods have been limited due to a requirement in the literature for parametric modelling of the distribution of the genetic factors. We propose a general, computationally simple, semiparametric method for analysis of case-control studies that allows exploitation of the assumption of gene-environment independence without any further parametric modelling assumptions about the marginal distributions of any of the two sets of factors. The method relies on the key observation that an underlying efficient profile likelihood depends on the distribution of genetic factors only through certain expectation terms that can be evaluated empirically. We develop asymptotic inferential theory for the estimator and evaluate its numerical performance via simulation studies. An application of the method is presented.http://ift.tt/2zPJfiv
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Αλέξανδρος Γ. Σφακιανάκης Medicine by Alexandros G. Sfakianakis,Anapafseos 5 Agios Nikolaos 72100 Crete Greece,00302841026182,0030693260717...
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heory of COVID-19 pathogenesis Publication date: November 2020Source: Medical Hypotheses, Volume 144Author(s): Yuichiro J. Suzuki ScienceD...
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