Search

Purpose To characterize a novel neurodevelopmental syndrome due to loss-of-function (LoF) variants in Ankyrin 2 (ANK2), and to explore the effects on neuronal network dynamics and homeostatic plasticity in human-induced pluripotent stem cell-derived neurons. Methods We collected clinical and molecular data of 12 individuals with heterozygous de novo LoF variants in ANK2. We generated a heterozygous LoF allele of ANK2 using CRISPR/Cas9 in human-induced pluripotent stem cells (hiPSCs). HiPSCs were differentiated into excitatory neurons, and we measured their spontaneous electrophysiological responses using micro-electrode arrays (MEAs). We also characterized their somatodendritic morphology and axon initial segment (AIS) structure and plasticity. Results We found a broad neurodevelopmental disorder (NDD), comprising intellectual disability, autism spectrum disorders and early onset epilepsy. Using MEAs, we found that hiPSC-derived neurons with heterozygous LoF of ANK2 show a hyperactive and desynchronized neuronal network. ANK2-deficient neurons also showed increased somatodendritic structures and altered AIS structure of which its plasticity is impaired upon activity-dependent modulation. Conclusions Phenotypic characterization of patients with de novo ANK2 LoF variants defines a novel NDD with early onset epilepsy. Our functional in vitro data of ANK2-deficient human neurons show a specific neuronal phenotype in which reduced ANKB expression leads to hyperactive and desynchronized neuronal network activity, increased somatodendritic complexity and AIS structure and impaired activity-dependent plasticity of the AIS.

Introduction: Emerging evidence suggests that Chemotherapy (CT) treated breast cancer survivors (BCS) who have “risk variants” in genes may be more susceptible to cognitive impairment (CI) and/or poor cardiac phenotypes. The objective of this preliminary study was to examine whether there is a relationship between genetic variants and objective/subjective cognitive or cardiac phenotypes. Methods and Analysis: BCS were recruited from Moffitt Cancer Center, Morsani College of Medicine, AdventHealth Tampa and Sarasota Memorial Hospital. Genomic DNA were collected at baseline for genotyping analysis. A total of 16 single nucleotide polymorphisms (SNPs) from 14 genes involved in cognitive or cardiac function were evaluated. Three genetic models (additive, dominant, and recessive) were used to test correlation coefficients between genetic variants and objective/subjective measures of cognitive functioning and cardiac outcomes (heart rate, diastolic blood pressure, systolic blood pressure, respiration rate, and oxygen saturation). Results: BCS (207 participants) with a mean age of 56 enrolled in this study. The majority were non-Hispanic white (73.7%), married (63.1%), and received both CT and radiation treatment (77.3%). Three SNPs in genes related to cognitive functioning (rs429358 in APOE, rs1800497 in ANKK1, rs10119 in TOMM40) emerged with the most consistent significant relationship with cognitive outcomes. Among five candidate SNPs related to cardiac functioning, rs8055236 in CDH13 and rs1801133 in MTHER emerged with potential significant relationships with cardiac phenotype. Conclusions: These preliminary results provide initial targets to further examine whether BCS with specific genetic profiles may preferentially benefit from interventions designed to improve cognitive and cardiac functioning following CT.

Abstract: Cancer involves the uncontrolled division of cells resulting in abnormal cell growth due to various gene mutations and is considered the second major cause of death. Due to drug resistance to current anticancer drugs, cancer incidence is rising, and seeking effective treatment is a major concern. Natural products are prospective to yield unique molecules, as nature is a leading source of various drug molecules due to plenty of pharmacologically active molecules. Thymoquinone, a bioactive constituent obtained from Nigella sativa L., has drawn considerable attention among researchers in recent years due to its anticancer potential involving various molecular targets, including initiation of apoptosis initiation, arrest of cell cycle and generation of ROS, besides targeting multiple kinases such as tyrosine kinase, MAPK, and Janus kinase. The current review summarizes the thymoquinone chemistry, sources and anticancer potential involving various molecular targets.

Bone indexes including trabecular bone score (TBS) and bone mineral density (BMD) have been shown to be associated with wide spectrum of variables including physical activity, vitamin D, liver enzymes, biochemical measurements, mental and sleep disorders, and quality of life. Here we aimed to determine the most important factors related to TBS and BMD in SUVINA dataset.Data were extracted from the Survey of Ultraviolet Intake by Nutritional Approach (SUVINA study) including all 306 subjects entered this survey. All the available parameters in the SUVINA database were included the analysis. XGBoost modeler software was used to define the most important features associated with bone indexes including TBS and BMD in various sites.Applying XGBoost modeling for 4 bone indexes indicated that this algorithm could identify the most important variables in relation to bone indexes with an accuracy of 92%, 93%, 90% and 90% respectively for TBS T-score, lumbar Z-score, neck of femur Z-score and Radius Z-score. Serum vitamin D, pro-oxidant-oxidant balance (PAB) and physical activity level (PAL) were the most important factors related to bone indices in different sites of the body.Our findings indicated that XGBoost could identify the most important variables with an accuracy ofgt;90% for TBS and BMD. The most important features associated with bone indexes were serum vitamin D, PAB and PAL.

Background: Curcumin, a hydrophobic polyphenolic compound present in Curcuma longa Linn. (Turmeric), has been used to improve various neurodegenerative conditions, including Amyotrophic lateral sclerosis, multiple sclerosis, Parkinson's disease, Prion disease, stroke, anxiety, depression, and ageing. However, the Blood-Brain Barrier (BBB) impedes the delivery of curcumin to the brain, limiting its therapeutic potential. Objective/Aim: This review summarises the recent advances towards the therapeutic efficacy of curcumin along with various novel strategies to overcome its poor bioavailability across the bloodbrain barrier. Methods: The data for the compilation of this review work were searched in PubMed Scopus, Google Scholar, and Science Direct. Result: The review also summarises the numerous toxicological studies and the role of curcumin in CNS disorders. Conclusion: The review also summarises the numerous toxicological studies and the role of curcumin in CNS disorders.

Preclinical studies have demonstrated a complex cross-talk between Notch and estrogen signaling in ERα-positive breast cancer. Gamma-secretase inhibitors (GSIs) are investigational agents that block the cleavage and activation of Notch receptors. In animal models of endocrine-resistant breast cancer, combinations of tamoxifen and GSIs produce additive or synergistic efficacy, while decreasing the intestinal toxicity of GSIs. However, results of a clinical trial of a GSI-endocrine therapy combination in the metastatic setting have not been published to date, nor had the safety of such combinations been investigated with longer term treatment. We conducted a phase 1b dose escalation trial (NCT01149356) of GSI RO4929097 with exemestane in patients with ERα+, metastatic breast cancer (MBC) Study objectives: to determine the safety, tolerability and maximum tolerated dose (MTD) or recommended phase 2 dose (RP2D) of RO4929097 when administered in combination with exemestane in patients with estrogen receptor positive metastatic breast cancer Results: We enrolled 15 patients with MBC. Of 14 evaluable patients, one had a partial response, 6 had stable disease and 7 progressive disease. Twenty % of patients had stable disease for ≥ 6 months. Common toxicities included nausea (73.3%), anorexia (60%), hyperglycemia (53.3%), hypophosphatemia (46.7%), fatigue (66.7%) and cough (33.0%). Grade 3 toxicities were uncommon, and included hypophosphatemia (13%) and rash (6.3%). Rash was the only DLT observed at 140 mg/d. Results suggest a possible recommended phase 2 dose of 90 mg/d. Ten patients with evaluable archival tissue showed expression of PKCα, which correlated with expression of Notch4. Mammospheres from a PKCα-expressing, endocrine-resistant T47D cell line were inhibited by a GSI-fulvestrant combination Conclusions: Our data indicate that combinations including endocrine therapy and Notch inhibitors deserve further investigation in endocrine-resistant ERα-positive breast cancer.

PURPOSE: Most studies of adherence to treatment for breast cancer have focused on early-stage patients. Findings from these studies may not generalize to patients with metastatic breast cancer (MBC). The objective of this study was to identify barriers and facilitators of adherence to cyclin-dependent kinase 4/6 (CDK4/6) inhibitors among patients with MBC, guided by the Social Ecologic Model (SEM). METHODS: Patients with MBC (N=25), their caregivers (N=9), and oncology providers (N=13) completed semi-structured qualitative interviews exploring their experiences with CDK4/6 inhibitors. Interviews were audio recorded, transcribed verbatim, and analyzed by three raters using a combined deductive and inductive approach. RESULTS: Qualitative analysis identified barriers and facilitators of adherence at each SEM level. Intrapersonal and interpersonal factors were most frequently discussed. Intrapersonal factors included knowledge/beliefs about CDK4/6 inhibitors, side effects, and establishing a routine. Interpersonal factors included effective communication with/coordination by the care team, support from family and friends, and information from other patients with MBC. Although less frequently discussed, policy factors (i.e., cost of CDK4/6 inhibitors) were of great concern to patients, caregivers, and providers. CONCLUSION: Barriers to adherence to CDK4/6 inhibitors exist at multiple levels. Our results underscore the potential value of a multilevel intervention (e.g., patient education, evidence-based strategies for symptom management, tips for open and assertive communication with providers, information about financial resources/support available, etc.) to support adherence in this population.

Background: Amyotrophic lateral sclerosis (ALS) is a motor neuron disease (MND) that typically causes death within 3-5 years after diagnosis. Regardless of the substantial scientific knowledge accrued from more than a century ago, truly effective therapeutic strategies remain distant. Various conventional drugs are being used but are having several adverse effects. Objective/Aim: The current study aims to thoroughly review plant-derived compounds with well-defined ALS activities and their structure-activity relationships. Moreover, the review also focuses on complex genetics, clinical trials, and the use of natural products that might decrypt the future and novel therapeutics in ALS. Methods: The collection of data for the compilation of this review work was searched in PubMed Scopus, Google Scholar, and Science Direct. Results: Results showed that phytochemicals like-Ginkgolides, Protopanaxatriol, Genistein, epigallocatechingallate, resveratrol, cassoside, and others possess Amyotrophic lateral sclerosis (ALS) activity by various mechanisms. Conclusion: These plant-derived compounds may be considered as supplements to conventional (ALS). Moreover, further preclinical and clinical studies are required to understand the structure-activity relationships, metabolism, absorption, and mechanisms of plant-derived natural agents.

Background Multiple sclerosis is a chronic and disabling neurological disease among young people. One of the major complaints in patients with multiple sclerosis (PWMS) is falling. There are a number of factors that risk factors for falling, including balance disorder and spasticity. Core stability (CS) exercises such as trunk muscle strengthening exercises can improve balance and mobility and reduce falling. Dynamic neuromuscular stabilization (DNS) exercise is a new functional rehabilitation strategy that optimizes motor function based on the principles of developmental kinesiology. This trial will evaluate the effectiveness of DNS in comparison to CS on balance, spasticity, and falling in PWMS. Methods A total of 64 PWMS, between 30 and 50 years old and expanded disability status scale (EDSS) between 2 to 5, will be recruited from neurophysiotherapy clinic, Faculty of Rehabilitation Sciences, Iran University of Medical Sciences to participate in this 2-armed parallel study. Participants will be randomly divided into two groups to receive CS exercise or DNS exercise. All participants will receive exercise treatment for 15 sessions during a period of 5 weeks (3 sessions per week). Primary outcome measures will be balance. Falling rate, fear of falling, patient mobility, as well as spasticity, will be measured as secondary outcomes. All outcome measures will be measured at baseline, the day after the completion of the 15th session, and after 17 weeks. Discussion Dynamic neurostabilization exercises utilize the subconscious stimulation of special zones to reflexively mediate the diaphragm and other core stabilization muscles, which is extremely effective for individuals with reduced somatosensory or movement awareness. Findings from the proposed study are expected to benefit the knowledge base of the physiotherapist, and it can be a good alternative for the rehabilitation program and even reduce medication use in patients with multiple sclerosis. These exercises are easy to understand and applicable for these patients and their partners as well. Trial registration The trial was registered in the Iran registry organization with code IRCT20140222016680N5 and was approved on April 7th, 2020. Address: IRCT administration team, Central Library Building, Iran University Campus, Hemmat Freeway, next to Milad tower, Tehran, Iran. postal code:14496-14535.

To evaluate the diagnostic yield of the first 8 hours of video-EEG (vEEG) monitoring in detecting Psychogenic Non-Epileptic Seizures (PNES) during the Epilepsy Monitoring Unit (EMU) admission. We performed a retrospective chart review of patients ages ≥4 years who were admitted to the EMU between 2011 and 2018 (n = 616). We calculated the proportion of patients diagnosed with PNES within the first 8 hours of EEG recording and studied the associated risk factors for patients diagnosed with PNES and patients with epileptic seizures (ES). Out of the total 616 patients, 24% (149) patients had an EMU diagnosis of PNES. Of these, 44.3% had at least one typical event within the first 8 hours of vEEG monitoring. A higher incidence was seen within the pediatric subgroup (54.8% had an event within 8 hours). A diagnosis of chronic pain disorder was more common with PNES compared to ES (48.3% versus 16.5%, p < 0.001). A suspicion for PNES documented during an office visit was noted in a high proportion of patients (68.5%) who eventually had a PNES event during EMU. Our study suggests that in a well-selected group of patients (such as a high suspicion of PNES during a physician/neurology office visit), an outpatient 8-hour vEEG could open new avenues for a prompt diagnosis. This could especially be beneficial in hospital settings where there is either a lack of an EMU or a delay in admission to the EMU.

Aim There is an urgent need to set up a useful biomarker for ovarian cancer. Galectin-1 is a promising carbohydrate-binding protein which plays a remarkable role in various malignancies yet its clinical significance is questionable. In this study, we have tested the clinical implications of serum Galectin-1 levels in patients with ovarian tumours. Main methods Serum Galectin-1 levels were quantified in 84 newly diagnosed ovarian tumour patients and 20 healthy controls by Enzyme Linked Immuno Sorbent Assay during the course of the disease. Therefore the samples were taken at diagnosis, after surgery and after chemotherapy. Key findings The Galectin-1 levels were found to be associated with various variables of Ovarian Cancer patients. The levels were found to be prominently high in postmenopausal patients. Galectin-1 levels were raised in epithelial ovarian tumours with significantly high levels in serous subtype. A decrease in Galectin-1 levels post-surgical intervention and after receiving chemotherapy was found. Galectin-1 levels evidently distinguished between normal, benign, malignant and metastatic cases as compared to CA125 levels. Galectin-1 demonstrated to be a better biomarker than CA125 according to the Receiver Operating Characteristic (ROC) curve analysis. Significance The study emphasizes that serum Galectin-1 may serve as a better surrogate biomarker in Ovarian Cancer for early detection, discriminating between malignant and benign abdominal masses and monitoring the progression of the disease and response to treatment.

Peripheral arterial disease is a major health problem, and in about 1% to 2% of patients, the disease progresses to critical limb ischaemia (CLI), also known as critical limb-threatening ischaemia. In a substantial number of individuals with CLI, no effective treatment options other than amputation are available, with around a quarter of these patients requiring a major amputation during the following year. This is the second update of a review first published in 2011.To evaluate the benefits and harms of local intramuscular transplantation of autologous adult bone marrow mononuclear cells (BMMNCs) as a treatment for CLI.We used standard, extensive Cochrane search methods. The latest search date was 8 November 2021.We included all randomised controlled trials (RCTs) of CLI in which participants were randomly allocated to intramuscular administration of autologous adult BMMNCs or control (either no intervention, conventional conservative therapy, or placebo).We used standard Cochrane methods. Our primary outcomes of interest were all-cause mortality, pain, and amputation. Our secondary outcomes were angiographic analysis, ankle-brachial index (ABI), pain-free walking distance, side effects and complications. We assessed the certainty of the evidence using the GRADE approach.We included four RCTs involving a total of 176 participants with a clinical diagnosis of CLI. Participants were randomised to receive either intramuscular cell implantation of BMMNCs or control. The control arms varied between studies, and included conventional therapy, diluted autologous peripheral blood, and saline. There was no clear evidence of an effect on mortality related to the administration of BMMNCs compared to control (risk ratio (RR) 1.00, 95% confidence interval (CI) 0.15 to 6.63; 3 studies, 123 participants; very low-certainty evidence). All trials assessed changes in pain severity, but the trials used different forms of pain assessment tools, so we were unable to pool data. Three studies individually reported that no differences in pain reduction were observed between the BMMNC and control groups. One study reported that reduction in rest pain was greater in the BMMNC group compared to the control group (very low-certainty evidence). All four trials reported the rate of amputation at the end of the study period. We are uncertain if amputations were reduced in the BMMNC group compared to the control group, as a possible small effect (RR 0.52, 95% CI 0.27 to 0.99; 4 studies, 176 participants; very low-certainty evidence) was lost after undertaking sensitivity analysis (RR 0.52, 95% CI 0.19 to 1.39; 2 studies, 89 participants). None of the included studies reported any angiographic analysis. Ankle-brachial index was reported differently by each study, so we were not able to pool the data. Three studies reported no changes between groups, and one study reported greater improvement in ABI (as haemodynamic improvement) in the BMMNC group compared to the control group (very low-certainty evidence). One study reported pain-free walking distance, finding no clear difference between BMMNC and control groups (low-certainty evidence). We pooled the data for side effects reported during the follow-up, and this did not show any clear difference between BMMNC and control groups (RR 2.13, 95% CI 0.50 to 8.97; 4 studies, 176 participants; very low-certainty evidence). We downgraded the certainty of the evidence due to the concerns about risk of bias, imprecision, and inconsistency.We identified a small number of studies that met our inclusion criteria, and these differed in the controls they used and how they measured important outcomes. Limited data from these trials provide very low- to low-certainty evidence, and we are unable to draw conclusions to support the use of local intramuscular transplantation of BMMNC for improving clinical outcomes in people with CLI. Evidence from larger RCTs is needed in order to provide adequate statistical power to assess the role of this procedure.

Background: Genus Berberis (family Berberidaceae), which contains about 650 species and 17 genera worldwide, has been used in folklore and various traditional medicine systems. Berberis Linn. is the most established group among genera with around 450-500 species across the world. This comprehensive review will not only help researchers for further evaluation but also provide substantial information for future exploitation of species to develop novel herbal formulations. Objective: The present review is focussed to summarize and collect the updated review of information of Genus Berberis species reported to date regarding their ethnomedicinal information, chemical constituents, traditional/folklore use, and reported pharmacological activities on more than 40 species of Berberis. Conclusion: A comprehensive survey of the literature reveals that various species of the genus possess various phytoconstituents mainly alkaloids, flavonoid based compounds isolated from different parts of a plant with a wide range of pharmacological activities. So far, many pharmacological activities like anti-cancer, anti-hyperlipidemic, hepatoprotective, immunomodulatory, anti-inflammatory both in vitro & in vivo and clinical study of different extracts/isolated compounds of different species of Berberis have been reported, proving their importance as a medicinal plant and claiming their traditional use.

Background Allergen immunotherapy (AIT) is a promising treatment for allergic disease that induces immunological tolerance through the administration of specific allergens. The study of AIT is in its early stage and its clinical effects are not well elucidated. The present study was aimed at determining the effect of AIT on pulmonary function and serum variables of mild allergic asthma patients. Methods A total of 80 patients with mild allergic asthma were recruited for the study. Allergen Specific Immunotherapy was administered in the form of Sublingual Immunotherapy and consisted of a build up phase followed by a maintenance phase (six months each respectively). Total serum IgE and vitamin D levels were quantified by ELISA. The percent eosinophill count was determined by cell analyzers. Pulmonary function test was performed at the baseline and after the end of study period. Subjective symptom score was recorded in the form of asthma control questionnaire score. Results There was a significant increase in the pre FEV1% and pre FEV1/FVC post AIT administration. A significant decrease in the total serum IgE was found post AIT. A decrease in Asthma control Questionnaire (ACQ) scores indicated an improvement in clinical symptoms. Besides there was a significant effect on ICS discontinuation after AIT. Conclusion The study supports SLIT as an effective treatment for Immunomodulation in mild allergic asthmatics besides it gives us significant information regarding the safety and efficacy of SLIT in such patients.

Anxiety is among the most debilitating nonmotor symptoms of Parkinson's disease (PD). This study aimed to determine how PD patients with low and high levels of anxiety (LA-PD and HA-PD, respectively) compare with age- and sex-matched controls at the level of motor control of reach-to-grasp movements during single- and dual-task conditions with varying complexity. Reach-to-grasp movement kinematics were assessed in 20 LA-PD, 20 HA-PD, and 20 sex- and age-matched healthy controls under single- as well as easy and difficult dual-task conditions. Assessment of PD patients was performed during both the on- and off-drug phases. The results obtained during dual-task conditions reveal deficits in both reach and grasp components for all three groups (e.g., decreased peak velocity and delayed maximum hand opening). However, these deficits were significantly greater in the PD groups, especially in the HA-PD group. Although dopaminergic medication improved reach kinematics, it had no effect on grasp kinematics. The results of our study indicated that high levels of anxiety may enhance the inefficiency of upper limb motor control in PD patients, especially during high demanding cognitive conditions, and should, therefore, be considered in the assessment and planning of interventions for upper limb function in these patients.

Tuberculosis is a respiratory disease that is treatable with antibiotics. An increasing prevalence of resistance means that to ensure a good treatment outcome it is desirable to test the susceptibility of each infection to different antibiotics. Conventionally, this is done by culturing a clinical sample and then exposing aliquots to a panel of antibiotics, each being present at a pre-determined concentration, thereby determining if the sample isresistant or susceptible to each sample. The minimum inhibitory concentration (MIC) of a drug is the lowestconcentration that inhibits growth and is a more useful quantity but requires each sample to be tested at a range ofconcentrations for each drug. Using 96-well broth micro dilution plates with each well containing a lyophilised pre-determined amount of an antibiotic is a convenient and cost-effective way to measure the MICs of several drugs at once for a clinical sample. Although accurate, this is still an expensive and slow process that requires highly-skilled and experienced laboratory scientists. Here we show that, through the BashTheBug project hosted on the Zooniverse citizen science platform, a crowd of volunteers can reproducibly and accurately determine the MICs for 13 drugs and that simply taking the median or mode of 11-17 independent classifications is sufficient. There is therefore a potential role for crowds to support (but not supplant) the role of experts in antibiotic susceptibility testing.Tuberculosis is a bacterial respiratory infection that kills about 1.4 million people worldwide each year. While antibiotics can cure the condition, the bacterium responsible for this disease

The Comprehensive Resistance Prediction for Tuberculosis: an International Consortium (CRyPTIC) presents here a data compendium of 12,289 Mycobacterium tuberculosis global clinical isolates, all of which have undergone whole-genome sequencing and have had their minimum inhibitory concentrations to 13 antitubercular drugs measured in a single assay. It is the largest matched phenotypic and genotypic dataset for M. tuberculosis to date. Here, we provide a summary detailing the breadth of data collected, along with a description of how the isolates were selected, collected, and uniformly processed in CRyPTIC partner laboratories across 23 countries. The compendium contains 6,814 isolates resistant to at least 1 drug, including 2,129 samples that fully satisfy the clinical definitions of rifampicin resistant (RR), multidrug resistant (MDR), pre-extensively drug resistant (pre-XDR), or extensively drug resistant (XDR). The data are enriched for rare resistance-associated variants, and the current limits of genotypic prediction of resistance status (sensitive/resistant) are presented by using a genetic mutation catalogue, along with the presence of suspected resistance-conferring mutations for isolates resistant to the newly introduced drugs bedaquiline, clofazimine, delamanid, and linezolid. Finally, a case study of rifampicin monoresistance demonstrates how this compendium could be used to advance our genetic understanding of rare resistance phenotypes. The data compendium is fully open source and it is hoped that it will facilitate and inspire future research for years to come.

Burn injury results in a triad of inter-related adaptive responses: a systemic inflammatory response, a stress response, and a consequent hypermetabolic state which supports the former two. These pathological responses extend beyond the site of injury to affect distant organs and influence long-term outcomes in the patient. Animal models have proven valuable in advancing our understanding of mechanisms underlying the multifactorial manifestations of burn injury. While rodent models have been unprecedented in providing insights into signaling pathways, metabolic responses, protein turnover, cellular and molecular changes; small animal models do not replicate hypermetabolism, hyperinflammation, and wound healing after a burn injury as seen in humans. Herein, we provide a concise review of preferred large animal models utilized to understand burn pathophysiology based on organ systems and associated dysfunction. Additionally, we present a detailed protocol of contact burn injury in the Yorkshire pig model with a focus on preoperative care, anesthesia, analgesia, wound excision and grafting, dressing application, and frequency of dressing changes.

In January 2020, with support from the U.S. Department of Homeland Security (DHS), CDC instituted an enhanced entry risk assessment and management (screening) program for air passengers arriving from certain countries with widespread, sustained transmission of SARS-CoV-2, the virus that causes coronavirus disease 2019 (COVID-19). The objectives of the screening program were to reduce the importation of COVID-19 cases into the United States and slow subsequent spread within states. Screening aimed to identify travelers with COVID-19-like illness or who had a known exposure to a person with COVID-19 and separate them from others. Screening also aimed to inform all screened travelers about self-monitoring and other recommendations to prevent disease spread and obtain their contact information to share with public health authorities in destination states. CDC delegated postarrival management of crew members to airline occupational health programs by issuing joint guidance with the Federal Aviation Administration.* During January 17-September 13, 2020, a total of 766,044 travelers were screened, 298 (0.04%) of whom met criteria for public health assessment; 35 (0.005%) were tested for SARS-CoV-2, and nine (0.001%) had a positive test result. CDC shared contact information with states for approximately 68% of screened travelers because of data collection challenges and some states' opting out of receiving data. The low case detection rate of this resource-intensive program highlighted the need for fundamental change in the U.S. border health strategy. Because SARS-CoV-2 infection and transmission can occur in the absence of symptoms and because the symptoms of COVID-19 are nonspecific, symptom-based screening programs are ineffective for case detection. Since the screening program ended on September 14, 2020, efforts to reduce COVID-19 importation have focused on enhancing communications with travelers to promote recommended preventive measures, reinforcing mechanisms to refer overtly ill travelers to CDC, and enhancing public health response capacity at ports of entry. More efficient collection of contact information for international air passengers before arrival and real-time transfer of data to U.S. health departments would facilitate timely postarrival public health management, including contact tracing, when indicated. Incorporating health attestations, predeparture and postarrival testing, and a period of limited movement after higher-risk travel, might reduce risk for transmission during travel and translocation of SARS-CoV-2 between geographic areas and help guide more individualized postarrival recommendations.

Transdermal route has been an ever sought-after means of drug administration, regarded as being the most convenient and patient compliant. However, skin poses a great barrier to the entry of the external particles including bacteria, viruses, allergens, and drugs as well (mostly hydrophilic or high molecular weight drugs), consequent to its complex structure and composition. Among the various means of enhancing drug permeation through the skin, e.g. chemical permeation enhancers, electroporation, thermophoresis, etc. drug delivery through nanoparticles has been of great interest. Current literature reports a vast number of nanoparticles that have been implicated for drug delivery through the skin. However, a precise account of critical factors involved in drug delivery and mechanisms concerning the permeation of nanoparticles through the skin is necessary. The purpose of this review is to enumerate the factors crucial in governing the prospect of drug delivery through skin and classify the skin permeation mechanisms of nanoparticles. Among the various mechanisms discussed are the ones governed by principles of kinetics, osmotic gradient, adhesion, hydration, diffusion, occlusion, electrostatic interaction, thermodynamics, etc. Among the most common factors affecting skin permeation of nanoparticles that are discussed include size, shape, surface charge density, composition of nanoparticles, mechanical stress, pH, etc.

Pexidartinib is approved for treatment of adults with symptomatic tenosynovial giant cell tumor. In vitro data showed pexidartinib's potential to inhibit and induce cytochrome P450 (CYP) 3A, inhibit CYP2C9, CYP2C19 and P‐glycoprotein (P‐gp). Herein, 2 open‐label, single‐sequence, crossover studies evaluated the drug‐drug interaction potential of pexidartinib on CYP enzymes (CYP2C9, CYP2C19, and CYP3A) and P‐gp. Thirty‐two subjects received single oral doses of midazolam (CYP3A substrate) and tolbutamide (CYP2C9 substrate) alone and after single and multiple oral doses of pexidartinib. Twenty subjects received single oral doses of omeprazole (CYP2C19 substrate) and digoxin (P‐gp substrate) alone or with pexidartinib. Analysis of variance was conducted to determine the effect of pexidartinib on various substrates’ pharmacokinetics. No drug‐drug interaction was concluded if the 90% confidence interval of the ratio of test to reference was within the range 80% to 125%. Coadministration of single and multiple doses of pexidartinib resulted in 21% and 52% decreases, respectively, in the area under the plasma concentration–time curve from time zero to the last measurable time point (AUClast) of midazolam, whereas AUClast values of tolbutamide increased 15% and 36%, respectively. Omeprazole exposure decreased on concurrent administration with pexidartinib, the metabolite‐to‐parent ratio was similar following omeprazole administration alone vs coadministration with pexidartinib; pexidartinib did not affect CYP2C19‐mediated metabolism. Maximum plasma concentrations of digoxin slightly increased (32%) with pexidartinib coadministration; no significant effect on digoxin AUClast. These results indicate that pexidartinib is a moderate inducer of CYP3A and a weak inhibitor of CYP2C9 and does not significantly affect CYP2C19‐mediated metabolism or P‐gp transport.

To determine prevalence of, seroprevalence of, and potential exposure to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) among a cohort of evacuees returning to the United States from Wuhan, China, in January 2020, we conducted a cross-sectional study of quarantined evacuees from 1 repatriation flight. Overall, 193 of 195 evacuees completed exposure surveys and submitted upper respiratory or serum specimens or both at arrival in the United States. Nearly all evacuees had taken preventive measures to limit potential exposure while in Wuhan, and none had detectable SARS-CoV-2 in upper respiratory tract specimens, suggesting the absence of asymptomatic respiratory shedding among this group at the time of testing. Evidence of antibodies to SARS-CoV-2 was detected in 1 evacuee, who reported experiencing no symptoms or high-risk exposures in the previous 2 months. These findings demonstrated that this group of evacuees posed a low risk of introducing SARS-CoV-2 to the United States.

Objectives To examine the association between maternal body dissatisfaction and mother's (mis)perception of their infant's weight classification among families from low-income households. Methods Mother-infant dyads were recruited during well-child visits from two urban primary care clinics. Maternal body dissatisfaction was measured using the Stunkard Figure Rating Scale. Perception of infant weight was assessed using a 5-point Likert scale. Infant weight-for-length (WFL) percentiles were calculated using WHO growth charts. Associations between maternal body dissatisfaction score and mother's (mis)perception of their infant's weight classification were examined using logistic regression allowing for non-linear associations via restricted cubic splines. Results Mothers (n=180) were 26.6 ± 5.1 years old and 72% Black; infants were 8.8 ± 2.1 months old. Mean infant WFL percentile was 64 ± 26. On average, mothers wanted to be one body figure smaller than their perceived current body size. Most mothers (82%) accurately perceived their infant's weight classification while few overestimated (7%) or underestimated (11%) their child's weight category. The probability of mothers misperceiving their infant's weight classification increased as maternal body dissatisfaction increased in either extreme in unadjusted (p Conclusions Increased maternal body dissatisfaction may be associated with mother's misperception of infant weight classification. Future studies should examine this relationship in a heterogeneous population.

Goals We aimed to investigate the mortality and hospital utilization outcomes of hospitalized nonalcoholic steatohepatitis (NASH) patients with and without kidney failure in a nationwide cohort. Background NASH is a common medical condition associated with significant morbidity and mortality. A paucity of data exists regarding the impact of kidney failure (defined as acute and chronic kidney failure) on outcomes of NASH hospitalizations. Materials and methods We conducted a retrospective cohort study using the 2016 Nationwide Inpatient Sample dataset of adult patients hospitalized for NASH, stratified for the presence of renal failure. The primary outcome was inpatient mortality, predictors were analyzed using multivariate logistic regression. Secondary outcomes were the length of stay and mean total hospitalization charges. Results The overall sample included 7,135,090 patients. Among 6855 patients admitted for NASH, 598 or 8.7% had comorbid kidney failure. After multivariate regression analysis, NASH patients with renal failure had increased in-hospital mortality [odds ratio=28.72, 95% confidence interval (CI): 8.99-91.73], length of stay (β=3.02, 95% CI: 2.54-3.5), total hospital charges (β=$37,045, 95% CI: $31,756.18-$42,335.62). Positive predictors of mortality in the renal failure group were Charlson Comorbidity Index ≥3 [adjusted odds ratio (aOR)=3.46, 95% CI: 1.04-11.51], variceal bleeding (aOR=3.02, 95% CI: 1.06-8.61), and hepatic encephalopathy (aOR=26.38, 95% CI: 1.29-540.56). Predictors of decreased mortality were Medicaid (aOR=0.047, 95% CI: 0.28-0.79) and private insurance (aOR=0.56, 95% CI: 0.38-0.83). Conclusions The prevalence of renal failure in NASH hospitalizations is associated with markedly increased mortality, hospital costs, and length of stay. As a result, clinicians should be vigilant in treating kidney failure in this population.

On December 31, 2019, Chinese health officials reported a cluster of cases of acute respiratory illness in persons associated with the Hunan seafood and animal market in the city of Wuhan, Hubei Province, in central China. On January 7, 2020, Chinese health officials confirmed that a novel coronavirus (2019-nCoV) was associated with this initial cluster (1). As of February 4, 2020, a total of 20,471 confirmed cases, including 2,788 (13.6%) with severe illness,* and 425 deaths (2.1%) had been reported by the National Health Commission of China (2). Cases have also been reported in 26 locations outside of mainland China, including documentation of some person-to-person transmission and one death (2). As of February 4, 11 cases had been reported in the United States. On January 30, the World Health Organization (WHO) Director-General declared that the 2019-nCoV outbreak constitutes a Public Health Emergency of International Concern.† On January 31, the U.S. Department of Health and Human Services (HHS) Secretary declared a U.S. public health emergency to respond to 2019-nCoV.§ Also on January 31, the president of the United States signed a "Proclamation on Suspension of Entry as Immigrants and Nonimmigrants of Persons who Pose a Risk of Transmitting 2019 Novel Coronavirus," which limits entry into the United States of persons who traveled to mainland China to U.S. citizens and lawful permanent residents and their families (3). CDC, multiple other federal agencies, state and local health departments, and other partners are implementing aggressive measures to slow transmission of 2019-nCoV in the United States (4,5). These measures require the identification of cases and their contacts in the United States and the appropriate assessment and care of travelers arriving from mainland China to the United States. These measures are being implemented in anticipation of additional 2019-nCoV cases in the United States. Although these measures might not prevent the eventual establishment of ongoing, widespread transmission of the virus in the United States, they are being implemented to 1) slow the spread of illness; 2) provide time to better prepare health care systems and the general public to be ready if widespread transmission with substantial associated illness occurs; and 3) better characterize 2019-nCoV infection to guide public health recommendations and the development of medical countermeasures including diagnostics, therapeutics, and vaccines. Public health authorities are monitoring the situation closely. As more is learned about this novel virus and this outbreak, CDC will rapidly incorporate new knowledge into guidance for action by CDC and state and local health departments.

On August 1, 2018, the Democratic Republic of the Congo (DRC) declared its 10th Ebola virus disease (Ebola) outbreak in an area with a high volume of cross-border population movement to and from neighboring countries. The World Health Organization (WHO) designated Rwanda, South Sudan, and Uganda as the highest priority countries for Ebola preparedness because of the high risk for cross-border spread from DRC (1). Countries might base their disease case definitions on global standards; however, historical context and perceived risk often affect why countries modify and adapt definitions over time, moving toward or away from regional harmonization. Discordance in case definitions among countries might reduce the effectiveness of cross-border initiatives during outbreaks with high risk for regional spread. CDC worked with the ministries of health (MOHs) in DRC, Rwanda, South Sudan, and Uganda to collect MOH-approved Ebola case definitions used during the first 6 months of the outbreak to assess concordance (i.e., commonality in category case definitions) among countries. Changes in MOH-approved Ebola case definitions were analyzed, referencing the WHO standard case definition, and concordance among the four countries for Ebola case categories (i.e., community alert, suspected, probable, confirmed, and case contact) was assessed at three dates (2). The number of country-level revisions ranged from two to four, with all countries revising Ebola definitions by February 2019 after a December 2018 peak in incidence in DRC. Case definition complexity increased over time; all countries included more criteria per category than the WHO standard definition did, except for the "case contact" and "confirmed" categories. Low case definition concordance and lack of awareness of regional differences by national-level health officials could reduce effectiveness of cross-border communication and collaboration. Working toward regional harmonization or considering systematic approaches to addressing country-level differences might increase efficiency in cross-border information sharing.

Parental feeding styles, including the emotional environment parents create to modify a child's eating behaviors, have been associated with measures of adiposity in cross-sectional studies. The longitudinal relation between parental feeding styles in early infancy and adiposity in later infancy/toddlerhood are scant and have shown mixed results, particularly in families from low-income households.This study examined the relation between parental feeding styles and infant BMI z-score trajectories between 6 and 18 mo in families from low-income households.Parent-infant dyads were recruited during the infant's 6-, 9-, or 12-mo well-child visit. Feeding styles were assessed using the Infant Feeding Style Questionnaire (IFSQ). Infant anthropometrics from birth through 18 mo were extracted from the electronic medical record. BMI z-score slopes were estimated for each infant between 0-6 mo and 6-18 mo. Associations between feeding styles and BMI z-score slopes were examined using mixed models controlling for demographic, clinical, and feeding covariates.The final analytic sample included 198 dyads (69% Black; median infant age: 9.0 mo; IQR: 6.8-10.3 mo). The predominant parent feeding styles included the following: laissez-faire (30%), restrictive (28%), responsive (23%), and pressuring (19%). In adjusted models, the predominant feeding style at enrollment was associated with the BMI z-score slope between 6 and 18 mo, with the responsive feeding style exhibiting a steeper increase in BMI z-score than other feeding styles. Infant feeding style was not associated with BMI z-score slope between birth and 6 mo of age. Infants of parents who exhibited restrictive feeding styles were more likely to have a BMI ≥85th percentile at their last measurement.The predominant parent feeding style during infancy in a low-income population was associated with infant BMI z-score between 6 and 18 mo of age, but not earlier. Further studies are needed to better understand how predictive factors collectively contribute to BMI increase in the first 2 y.

Background Organic cation transporter 1 primarily governs the action of metformin in the liver. There are considerable inter-individual variations in metformin response. In light of this, it is crucial to obtain a greater understanding of the influence of OCT1 expression or polymorphism in the context of variable responses elicited by metformin treatment. Results We observed that the variable response to metformin in the responders and non-responders is independent of isoform variation and mRNA expression of OCT-1. We also observed an insignificant difference in the serum metformin levels of the patient groups. Further, molecular docking provided us with an insight into the hotspot regions of OCT-1 for metformin binding. Genotyping of these regions revealed SNPs 156T>C and 1222A>G in both the groups, while as 181C>T and 1201G>A were found only in non-responders. The 181T>C and 1222A>G changes were further found to alter OCT-1 structure in silico and affect metformin transport in vitro which was illustrated by their effect on the activation of AMPK, the marker for metformin activity. Conclusion Taken together, our results corroborate the role of OCT-1 in the transport of metformin and also point at OCT1 genetic variations possibly affecting the transport of metformin into the cells and hence its subsequent action in responders and non-responders.

Abstract: Heterocyclic compounds are that type of substances that are deeply intertwined with biological processes. Heterocycles are found in about 90% of commercially available medicines. In medicinal chemistry, finding new synthetic molecules with drug-like characteristics is a regular problem, which triggered the development of pharmacological molecules, the majority of which are based on N-heterocyclic motifs. Among the heterocycles, the pyrrole scaffold is the most commonly found heterocycle in both natural and synthetic bioactive compounds. Pyrrole has a fivemembered heterocyclic ring with a plethora of pharmacophores, resulting in a library of different lead compounds. Pyrrole derivatives are physiologically active heterocyclic compounds that can be used as scaffolds for antibacterial, antiviral, anticancer, antitubercular, anti-inflammatory, and as enzyme inhibitors. On account of their extensive pharmacological profile, pyrrole and its various synthetic derivatives have drawn much attention from researchers to explore it for the benefit of humankind. This review presents an overview of recent developments in the pyrrole derivatives against multiple therapeutic targets.

Assessing parental readiness to change their child's lifestyle behaviors can be used as a guide for counseling during well-child appointments. The aim of our study was to determine if parental readiness to change pre-visit was associated with plan adherence post-visit in a predominantly low-income population. Parents (n=178) self-identified readiness to change on a Likert scale and subsequently received counseling. Multivariate logistic regression was used to evaluate associations between readiness to change and plan adherence. There was no association between readiness to change and self-reported follow-through with nutrition plans (AOR at 3 months: 1.5 [0.52; 4.18]; p=.5). The ready-to-change group reported higher, albeit non-significant, follow-through with activity plans at three months (AOR 3.6 [0.82; 15.96]; p=.09). Providers should engage all parent/child dyads in behavior modification for nutrition and activity regardless of parents' pre-visit readiness to change.

Drug susceptibility testing ofM. tuberculosisis rooted in a binary susceptible/resistant paradigm. While there are considerable advantages in measuring the minimum inhibitory concentrations (MICs) of a panel of drugs for an isolate, it is necessary to measure the epidemiological cut-off values (ECOFF/ECVs) to permit comparison with qualitative data. Here we present ECOFF/ECVs for 13 anti-tuberculosis compounds, including bedaquiline and delamanid, derived from 20 637 clinical isolates collected by 14 laboratories based in 11 countries on five continents. Each isolate was incubated for 14 days on a dry 96-well broth microdilution plate and then read. Resistance to most of the drugs due to prior exposure is expected and the MIC distributions for many of the compounds are complex, and therefore aphenotypicallywild-type population could not be defined. Since a majority of samples also underwent genetic sequencing, we defined agenotypicallywild-type population and measured the MIC of the 99th percentile by direct measurement andviafitting a Gaussian using interval regression. The proposed ECOFF/ECVs were then validated by comparing with the MIC distributions of high-confidence genetic variants that confer resistance and with qualitative drug susceptibility tests obtainedviathe Mycobacterial Growth Indicator Tube (MGIT) system or Microscopic-Observation Drug Susceptibility (MODS) assay. These ECOFF/ECVs will inform and encourage the more widespread adoption of broth microdilution: this is a cheap culture-based method that tests the susceptibility of 12–14 antibiotics on a single 96-well plate and so could help personalise the treatment of tuberculosis.

BackgroundThe gap between knowledge and practice, along with postponing or not implementing research findings in practice and policy-making, is one of the reasons for low-quality services. Hence, this study aimed at presenting a model of knowledge implementation in health system management in Iran.MethodsThe present two-phase study was first performed qualitatively using a directive content analysis approach based on the Promoting Action on Research Implementation in Health Services (PARIHS) model. The researchers extracted the barriers and facilitators by conducting semi-structured individual interviews. Then, in a three-stage Delphi study, 25 health experts determined the barrier removal strategies. Data were analysed using MAXQDA10 software.Results The content analysis of the interviews led to the emergence of 1212 codes under three categories of evidence, context and facilitation. The findings indicate that health managers make fewer decisions based on research findings. Instead, they make decisions regarding the experiences of service providers and organization data. In addition to the subcategories in the PARIHS model, the researchers extracted political, social and administrative factors under the context category. The relationships between the features of evidence, context, facilitation, barriers and strategies were presented in the final model.Conclusion The presented model comprehensively emphasizes the evidence resources, context preparation, and facilitation of the knowledge implementation process.

Hypoxia, a driver of tumor growth and metastasis, regulates angiogenic pathways that are targets for vessel normalization and ovarian cancer management. However, toxicities and resistance to anti-angiogenics can limit their use making identification of new targets vital. Inhibin, a heteromeric TGFβ ligand, is a contextual regulator of tumor progression acting as an early tumor suppressor, yet also an established biomarker for ovarian cancers. Here, we find that hypoxia increases inhibin levels in ovarian cancer cell lines, xenograft tumors, and patients. Inhibin is regulated primarily through HIF-1, shifting the balance under hypoxia from activins to inhibins. Hypoxia regulated inhibin promotes tumor growth, endothelial cell invasion and permeability. Targeting inhibin in vivo through knockdown and anti-inhibin strategies robustly reduces permeability in vivo and alters the balance of pro and anti-angiogenic mechanisms resulting in vascular normalization. Mechanistically, inhibin regulates permeability by increasing VE-cadherin internalization via ACVRL1 and CD105, a receptor complex that we find to be stabilized directly by inhibin. Our findings demonstrate direct roles for inhibins in vascular normalization via TGF-β receptors providing new insights into the therapeutic significance of inhibins as a strategy to normalize the tumor vasculature in ovarian cancer.

Abstract: Flavonoids, a class of polyphenolic secondary metabolites, are present in fruits, vegetables, beverages such as wine and tea abundantly. Flavonoids exhibit a diverse array of pharmacological activities, including anticancer activity, and are toxic to cancer cells but not harmful to healthy cells. Besides, humans and animals cannot synthesize flavonoids, which leads to a dramatic increase in the consumption of plant flavonoids. Flavonoids consist of a 15- carbon skeleton in C6-C3-C6 rings with divergent substitution patterns to form a series of compounds. Due to their multi-faceted mechanism of action by modulating various signaling pathways associated with apoptosis, cellular proliferation, inflammation, differentiation, metastasis, angiogenesis, they interrupt the initiation, promotion, and progression of cancer. The present review highlights the Structural Activity Relationship (SAR) of flavonoids and recent insights on the progress of natural flavonoids and their synthetic analogs as prospective drug candidates against cancer, along with molecular mechanisms of action.

Allergen immunotherapy (AIT) is the only disease-modifying treatment for allergic disorders that induces immunological tolerance through administration of specific allergens. Studies on AIT for subcutaneous route are in abundance; however, the efficacy of AIT in tablet form through sublingual route has not been well elucidated. The present prospective, parallel-group, controlled study sought to compare the efficacy of sublingual immunotherapy (SLIT) tablets with pharmacotherapy (PT) in 332 house dust mite (HDM)-specific allergic asthma and/or rhinitis patients over a period of 3 years. Patients were followed up for a 6-month run-in period and then randomly stratified as those who would receive SLIT, SLIT in addition to PT (SLIT+PT), and PT alone. AIT was administered in the form of sublingual tablets. Symptom and medication scores were measured every 3 months. In vitro evaluation of serum total and HDM specific immunoglobulin E (HDM sIgE) levels was carried out every 3 months, whereas in vivo skin prick test was performed annually for 3 years. Our study demonstrated sustained clinical improvement, reduction in inhaled corticosteroid (ICS) dose and duration as well as prevention from development of neosensitization to other aero allergens in HDM-allergic asthmatics and/or rhinitis patients treated with 3 years SLIT. Despite a remarkable clinical improvement with AIT, we observed that SLIT did not significantly change the skin reactivity to HDM at 3 years and there was no significant change in the ratio of serum total and HDM sIgE. Given the immune and disease modifying effects of AIT in allergic diseases, the present study supports the notion of its sublingual mode being an effective long-term immunomodulator in HDM-sensitized nasobronchial allergies.

Worldwide, breast cancer has an eminent morbidity and mortality rate, as it is a neoplastic disease among females. The query of the prospective danger of bovine leukemia virus (BLV) to humans is an old but exceedingly topical focus of scientific debate. The objective of the current study was to determine the possible relationship between BLV and breast cancer. A total of 2710 formalin-fixed paraffin-embedded (FFPE) breast cancer samples were selected regardless of the age, ethnicity, or municipality origin of the subjects. The presence of BLV in human breast cancer was determined through nested PCR by amplifying tax and gag genes followed by partial sequencing. Homology was confirmed by using the online BLAST Tool. BLV genes were found to be positive in 26.8% (728/2710) of the samples from breast cancer patients and 10% (10/80) of the samples without cancer (negative control). The results indicated a correlation between the presence of the BLV gene and breast cancer (odds ratio = 0.3889; confidence interval = 1,18; p = 0.0029). The current findings suggest a possible link between BLV and human breast carcinoma. Therefore, screening cattle herds and milk products is suggested to reduce the viral transmission risk to humans.

Triple-negative breast cancer (TNBC) has few therapeutic targets, making nonspecific chemotherapy the main treatment. Therapies enhancing cancer cell sensitivity to cytotoxic agents could significantly improve patient outcomes. A BCL2-associated agonist of cell death (BAD) pathway gene expression signature (BPGES) was derived using principal component analysis (PCA) and evaluated for associations with the TNBC phenotype and clinical outcomes. Immunohistochemistry was used to determine the relative expression levels of phospho-BAD isoforms in tumour samples. Cell survival assays evaluated the effects of BAD pathway inhibition on chemo-sensitivity. BPGES score was associated with TNBC status and overall survival (OS) in breast cancer samples of the Moffitt Total Cancer Care dataset and The Cancer Genome Atlas (TCGA). TNBC tumours were enriched for the expression of phospho-BAD isoforms. Further, the BPGES was associated with TNBC status in breast cancer cell lines of the Cancer Cell Line Encyclopedia (CCLE). Targeted inhibition of kinases known to phosphorylate BAD protein resulted in increased sensitivity to platinum agents in TNBC cell lines compared to non-TNBC cell lines. The BAD pathway is associated with triple-negative status and OS. TNBC tumours were enriched for the expression of phosphorylated BAD protein compared to non-TNBC tumours. These findings suggest that the BAD pathway it is an important determinant of TNBC clinical outcomes.

A hallmark after burn is the stress and inflammatory-induced hypermetabolic response. Recently, we and others found that browning of white adipose tissue (WAT) is a critical component of this complex detrimental response. Although browning and inflammation have been independently delineated to occur after injury, their interaction is currently not well defined. One of the master regulators of inflammation and adipose tissue remodeling after burns is nucleotide-binding and oligomerization domain, leucine rich repeat and pyrin domain containing 3 (NLRP3) inflammasome. The aim of this this study was to determine whether NLRP3 modulates and activates WAT browning after burn. To obtain molecular and mechanistic insights, we used an NLRP3 knockout (NLRP3−/−) murine burn model. We demonstrated that genetic deletion of NLRP3 promoted persistent and augmented browning in adipocytes, evidenced by increased gene expression of peroxisome proliferator-activated receptor γ and CIDEA at 3 days (5.74 vs. 0.29, P < 0.05; 26.0 vs. 0.71, P < 0.05) and uncoupling protein 1 ( UCP1) and PGC1α at 7 days (7,406 vs. 3,894, P < 0.05; 20.6 vs. 2.52, P < 0.01) and enhanced UCP1 staining and multilocularity. Additionally, the main regulator of postburn WAT browning, IL-6, was elevated in the plasma acutely after burn in NLRP3−/− compared with wild-type counterparts (478.9 vs. 67.1 pg/mL, P < 0.05 at 3 days). These results suggest that NLRP3 has antibrowning effects and that blocking NLRP3 increases thermogenesis and augments browning via increased levels of IL-6. Our findings provide insights into targeting innate inflammatory systems for regulation of adaptive thermogenesis, a critical response after burns and other hypermetabolic conditions.