Impairing the BET family coactivator BRD4 with small-molecule inhibitors (BETi) showed encouraging preclinical activity in treating acute myeloid leukemia (AML). However, dose-limiting toxicities and ...limited clinical activity dampened the enthusiasm for BETi as a single agent. BETi resistance in AML myeloblasts was found to correlate with maintaining mitochondrial respiration, suggesting that identifying the metabolic pathway sustaining mitochondrial integrity could help develop approaches to improve BETi efficacy. Herein, we demonstrated that mitochondria-associated lactate dehydrogenase allows AML myeloblasts to utilize lactate as a metabolic bypass to fuel mitochondrial respiration and maintain cellular viability. Pharmacologically and genetically impairing lactate utilization rendered resistant myeloblasts susceptible to BET inhibition. Low-dose combinations of BETi and oxamate, a lactate dehydrogenase inhibitor, reduced in vivo expansion of BETi-resistant AML in cell line and patient-derived murine models. These results elucidate how AML myeloblasts metabolically adapt to BETi by consuming lactate and demonstrate that combining BETi with inhibitors of lactate utilization may be useful in AML treatment.
Lactate utilization allows AML myeloblasts to maintain metabolic integrity and circumvent antileukemic therapy, which supports testing of lactate utilization inhibitors in clinical settings to overcome BET inhibitor resistance in AML. See related commentary by Boët and Sarry, p. 950.
There is substantial evidence documenting the effects of behavioural interventions on weight loss (WL). However, behavioural approaches to initial WL are followed by some degree of longer-term weight ...regain, and large trials focusing on evidence-based approaches to weight loss maintenance (WLM) have generally only demonstrated small beneficial effects. The current state-of-the-art in behavioural interventions for WL and WLM raises questions of (i) how we define the relationship between WL and WLM, (ii) how energy balance (EB) systems respond to WL and influence behaviours that primarily drive weight regain, (iii) how intervention content, mode of delivery and intensity should be targeted to keep weight off, (iv) which mechanisms of action in complex interventions may prevent weight regain and (v) how to design studies and interventions to maximise effective longer-term weight management. In considering these issues a writing team within the NoHoW Consortium was convened to elaborate a position statement, and behaviour change and obesity experts were invited to discuss these positions and to refine them. At present the evidence suggests that developing the skills to self-manage EB behaviours leads to more effective WLM. However, the effects of behaviour change interventions for WL and WLM are still relatively modest and our understanding of the factors that disrupt and undermine self-management of eating and physical activity is limited. These factors include physiological resistance to weight loss, gradual compensatory changes in eating and physical activity and reactive processes related to stress, emotions, rewards and desires that meet psychological needs. Better matching of evidence-based intervention content to quantitatively tracked EB behaviours and the specific needs of individuals may improve outcomes. Improving objective longitudinal tracking of energy intake and energy expenditure over time would provide a quantitative framework in which to understand the dynamics of behaviour change, mechanisms of action of behaviour change interventions and user engagement with intervention components to potentially improve weight management intervention design and evaluation.
Background
Venous leg ulcers (VLUs) are a common type of complex wound that have a negative impact on people's lives and incur high costs for health services and society. It has been suggested that ...prolonged high levels of protease activity in the later stages of the healing of chronic wounds may be associated with delayed healing. Protease modulating treatments have been developed which seek to modulate protease activity and thereby promote healing in chronic wounds.
Objectives
To determine whether protease activity is an independent prognostic factor for the healing of venous leg ulcers.
Search methods
In February 2018, we searched the following databases: Cochrane Central Register of Controlled Trials (CENTRAL), Ovid MEDLINE, Ovid Embase and CINAHL.
Selection criteria
We included prospective and retrospective longitudinal studies with any follow‐up period that recruited people with VLUs and investigated whether protease activity in wound fluid was associated with future healing of VLUs. We included randomised controlled trials (RCTs) analysed as cohort studies, provided interventions were taken into account in the analysis, and case‐control studies if there were no available cohort studies. We also included prediction model studies provided they reported separately associations of individual prognostic factors (protease activity) with healing. Studies of any type of protease or combination of proteases were eligible, including proteases from bacteria, and the prognostic factor could be examined as a continuous or categorical variable; any cut‐off point was permitted. The primary outcomes were time to healing (survival analysis) and the proportion of people with ulcers completely healed; the secondary outcome was change in ulcer size/rate of wound closure. We extracted unadjusted (simple) and adjusted (multivariable) associations between the prognostic factor and healing.
Data collection and analysis
Two review authors independently assessed studies for inclusion at each stage, and undertook data extraction, assessment of risk of bias and GRADE assessment. We collected association statistics where available. No study reported adjusted analyses: instead we collected unadjusted results or calculated association measures from raw data. We calculated risk ratios when both outcome and prognostic factor were dichotomous variables. When the prognostic factor was reported as continuous data and healing outcomes were dichotomous, we either performed regression analysis or analysed the impact of healing on protease levels, analysing as the standardised mean difference. When both prognostic factor and outcome were continuous data, we reported correlation coefficients or calculated them from individual participant data.
We displayed all results on forest plots to give an overall visual representation. We planned to conduct meta‐analyses where this was appropriate, otherwise we summarised narratively.
Main results
We included 19 studies comprising 21 cohorts involving 646 participants. Only 11 studies (13 cohorts, 522 participants) had data available for analysis. Of these, five were prospective cohort studies, four were RCTs and two had a type of case‐control design. Follow‐up time ranged from four to 36 weeks. Studies covered 10 different matrix metalloproteases (MMPs) and two serine proteases (human neutrophil elastase and urokinase‐type plasminogen activators). Two studies recorded complete healing as an outcome; other studies recorded partial healing measures. There was clinical and methodological heterogeneity across studies; for example, in the definition of healing, the type of protease and its measurement, the distribution of active and bound protease species, the types of treatment and the reporting of results. Therefore, meta‐analysis was not performed. No study had conducted multivariable analyses and all included evidence was of very low certainty because of the lack of adjustment for confounders, the high risk of bias for all studies except one, imprecision around the measures of association and inconsistency in the direction of association. Collectively the research indicated complete uncertainty as to the association between protease activity and VLU healing.
Authors' conclusions
This review identified very low validity evidence regarding any association between protease activity and VLU healing and there is complete uncertainty regarding the relationship. The review offers information for both future research and systematic review methodology.
Background
The current global pandemic has created unprecedented challenges in the blood supply network. Given the recent shortages, there must be a civilian plan for massively bleeding patients when ...there are no blood products on the shelf. Recognizing that the time to death in bleeding patients is less than 2 h, timely resupply from unaffected locations is not possible. One solution is to transfuse emergency untested whole blood (EUWB), similar to the extensive military experience fine‐tuned over the last 19 years. While this concept is anathema in current civilian transfusion practice, it seems prudent to have a vetted plan in place.
Methods and Materials
During the early stages of the 2020 global pandemic, a multidisciplinary and international group of clinicians with broad experience in transfusion medicine communicated routinely. The result is a planning document that provides both background information and a high‐level guide on how to emergently deliver EUWB for patients who would otherwise die of hemorrhage.
Results and Conclusions
Similar plans have been utilized in remote locations, both on the battlefield and in civilian practice. The proposed recommendations are designed to provide high‐level guidance for experienced blood bankers, transfusion experts, clinicians, and health authorities. Like with all emergency preparedness, it is always better to have a well‐thought‐out and trained plan in place, rather than trying to develop a hasty plan in the midst of a disaster. We need to prevent the potential for empty shelves and bleeding patients dying for lack of blood.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
The evidence for the lifesaving benefits of prehospital transfusions is increasing. As such, emergency medical services (EMS) might increasingly become interested in providing this important ...intervention. While a few EMS and air medical agencies have been providing exclusively red blood cell (RBC) transfusions to their patients for many years, transfusing plasma in addition to the RBCs, or simply using low titer group O whole blood (LTOWB) in place of two separate components, will be a novel experience for many services. The recommendations presented in this document were created by the Trauma, Hemostasis and Oxygenation Research (THOR)-AABB (formerly known as the American Association of Blood Banks) Working Party, and they are intended to provide a framework for implementing prehospital blood transfusion programs in line with the best available evidence. These recommendations cover all aspects of such a program including storing, transporting, and transfusing blood products in the prehospital phase of hemorrhagic resuscitation.
Patients with coeliac disease (CD) commonly report a variety of adverse symptoms to gluten, but descriptions of the symptomatic response in the literature may have been confounded by the presence of ...food components such as fermentable carbohydrates (FODMAPs) causing symptoms of irritable bowel syndrome independent of gluten. In recent unmasked and masked low FODMAP gluten challenge studies in small groups of treated CD patients, nausea and vomiting were shown to be the key symptoms associated with serum interleukin (IL)-2 release. Our objective was to utilise a large and diverse cohort of people with CD undertaking a standardised gluten food challenge to characterise the demographic, genetic and clinical factors influencing the severity and timing of acute gluten reactions and IL-2 production.
A total of 295 adults treated for CD were observed for 6 h after an unmasked food challenge consisting of 10 g vital wheat gluten (low in FODMAPs) in 100 ml water. Assessments included patient-reported outcomes, serum IL-2 and adverse events. Responses were analysed according to patient characteristics, HLA-DQ genotype, duodenal histology and response to a second gluten challenge.
Peak symptom severity was at 3 h (median severity 5/10). Peak IL-2 was at 4 h (median 4 pg/ml, range undetectable to 1028 pg/ml). Older age, older age at diagnosis, HLA-DQ2.5 positivity and homozygosity for HLA-DQB1*02 were each significantly associated with IL-2 elevations after gluten. Patients positive for HLA-DQ2.5, DQ8, DQ2.2 or DQ7 showed elevated IL-2 after gluten. Patient factors were not significantly associated with severity of digestive symptoms, but symptoms were correlated to one another and serum IL-2. Gluten challenge after 5 months caused more vomiting and higher IL-2 levels, but responses correlated with the first.
Gluten-induced symptoms and cytokine release is common in adults with treated CD. Age, genetics and previous response to gluten predict these acute reactions to gluten challenge. Structured symptom assessment and serum IL-2 after standardised gluten challenge may inform on patient diagnosis, the role of gluten in symptomatology and the need for adjunctive treatment.
ClinicalTrials.gov , NCT03644069 Registered 21 May 2018.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Background
Coronavirus has serially overtaken our metropolitan hospitals. At peak, patients with acute respiratory distress syndrome may outnumber mechanical ventilators. In our Miami Hospital ...System, COVID‐19 cases have multiplied for 4 weeks and elective surgery has been suspended.
Methods
An Otolaryngologic Triage Committee was created to appropriately allocate resources to patients. Hospital ethicists provided support. Our tumor conference screened patients for nonsurgical options. Patients were tested twice for coronavirus before performing urgent contaminated operations. N95 masks and protective equipment were conserved when possible. Patients with low‐grade cancers were advised to delay surgery, and other difficult decisions were made.
Results
Hundreds of surgeries were canceled. Sixty‐five cases screened over 3 weeks are tabulated. Physicians and patients expressed discomfort regarding perceived deviations from standards, but risk of COVID‐19 exposure tempered these discussions.
Conclusions
We describe the use of actively managed surgical triage to fairly balance our patient's health with public health concerns.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
Smooth pursuit eye movements have been investigated as a diagnostic tool for mild traumatic brain injury (mTBI). However, the degree to which smooth pursuit differentiates mTBI patients from healthy ...controls (i.e. its diagnostic performance) is only moderate. Our goal was to establish if simultaneous performance of smooth pursuit and a working memory task increased the diagnostic performance of pursuit metrics following mTBI. We integrated an n-back task with two levels of working memory load into a pursuit target, and tested single- and dual-task pursuit in mTBI patients and healthy controls. We assessed pursuit using measures of velocity accuracy, positional accuracy and positional variability. The mTBI group had higher pursuit variability than the control group in all conditions. Performing a concurrent 1-back task decreased pursuit variability for both the mTBI and control groups. Performing a concurrent 2-back task produced differential effects between the groups: Pursuit variability was significantly decreased in the control group, but not in the mTBI group. Diagnostic indices were improved when pursuit was combined with the 2-back task, and increased by 20% for the most sensitive variable. Smooth pursuit with simultaneous working memory load may be a superior diagnostic tool for mTBI than measuring smooth pursuit alone.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
Over the last several decades, transoral resection techniques for treatment of supraglottic lesions have become increasingly favored to reduce the need for either open transcervical resection or ...primary chemoradiation. Transoral robotic surgery (TORS) offers advantages in visualization, dissection control, and access to remove bulky tumors en bloc. However, the management of the airway for these cases tends to vary, without clear guidelines as to when a tracheostomy is necessary.
A retrospective review of all patients who underwent transoral robotic supraglottic partial laryngectomy at a large academic center from May 2005 through December 2016 was performed. Airway management was examined, specifically as it pertains to whether a tracheostomy was performed at the time of surgery or otherwise. Demographic and tumor characteristics were also evaluated.
Sixty-three patients were included. Forty (63%) were male, the average age at surgery was 63.6, and the majority (90.5%) underwent resection for squamous cell carcinoma of the supraglottis. Thirty-nine patients (62%) underwent the procedure with standard endotracheal intubation using a wire-reinforced tube. Of these, four patients required subsequent tracheostomy- 2 for laryngeal edema postoperatively, one for airway management during a postoperative bleeding event, and one for laryngeal edema following initiation of adjuvant chemoradiation. Twenty patients (32%) underwent tracheostomy at the time of transoral resection for airway management, 17 of whom were decannulated an average of 12.2 weeks following surgery. Those who underwent tracheostomy at the time of surgery had a higher percentage of tumors involving multiple supraglottic subsites (
= 0.031), 85 vs. 54% in the group who did not undergo tracheostomy. No difference in age, BMI, clinical T-stage, or clinical N stage was found between the two groups.
Performing a tracheostomy at the time of surgery should be considered for those patients with more extensive malignant disease (≥T2 tumors). While avoiding tracheostomy is often preferred by the patient, the maintenance of the patent airway peri-operatively should be first priority when considering airway management. Furthermore, as the majority of those patients receiving tracheostomy are decannulated within 4 months of surgery, the tracheostomy could be considered a short-term adjunct to the procedure.
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