Effectiveness of anti-obesity medications approved for long-term use in a multidisciplinary weight management program: a multi-center clinical experience.

BACKGROUND AND AIMS: Randomized clinical trials have proven the efficacy and safety of Food and Drug Administration (FDA) approved anti-obesity medications (AOMs) for long-term use. It is unclear whether these outcomes can be replicated in real-world clinical practice where clinical complexities arise. The aim of this study was to evaluate the effectiveness and side effects of these medications in real-world multidisciplinary clinical practice settings. METHODS: We reviewed the electronic medical records (EMR) of patients with obesity who were prescribed an FDA-approved AOM for long-term use in academic and community multidisciplinary weight loss programs between January 2016 and January 2020. INTERVENTION: We assessed percentage total body weight loss (%TBWL), metabolic outcomes, and side effect profile up to 24 months after AOM initiation. RESULTS: The full cohort consisted of 304 patients (76% women, 95.2% White, median age of 50 years old [IQR, 39-58]). The median follow-up time was 9.1 months [IQR, 4.2-14.1] with a median number of 3 visits [IQR, 2-4]. The most prescribed medication was phentermine/topiramate extended-release (ER) (51%), followed by liraglutide (26.3%), bupropion/naltrexone sustained-release (SR) (16.5%), and lorcaserin (6.2%). %TBWL was 5.0%, 6.8%, 9.3%, 10.3%, and 10.5% at 3, 6, 12, 18, and 24 months. 60.2% of the entire cohort achieved at least 5% TBWL. Overall, phentermine/topiramate-ER had the most robust weight loss response during follow-up, with the highest %TBWL at 12 months of 12.0%. Adverse events were reported in 22.4% of patients. Only 9% of patients discontinued the medication due to side effects. CONCLUSIONS: AOMs resulted in significant long-term weight loss, that was comparable to outcomes previously reported in clinical trials.

American Association of Clinical Endocrinology Clinical Practice Guideline: Developing a Diabetes Mellitus Comprehensive Care Plan-2022 Update.

OBJECTIVE: The objective of this clinical practice guideline is to provide updated and new evidence-based recommendations for the comprehensive care of persons with diabetes mellitus to clinicians, diabetes-care teams, other health care professionals and stakeholders, and individuals with diabetes and their caregivers. METHODS: The American Association of Clinical Endocrinology selected a task force of medical experts and staff who updated and assessed clinical questions and recommendations from the prior 2015 version of this guideline and conducted literature searches for relevant scientific papers published from January 1, 2015, through May 15, 2022. Selected studies from results of literature searches composed the evidence base to update 2015 recommendations as well as to develop new recommendations based on review of clinical evidence, current practice, expertise, and consensus, according to established American Association of Clinical Endocrinology protocol for guideline development. RESULTS: This guideline includes 170 updated and new evidence-based clinical practice recommendations for the comprehensive care of persons with diabetes. Recommendations are divided into four sections: (1) screening, diagnosis, glycemic targets, and glycemic monitoring; (2) comorbidities and complications, including obesity and management with lifestyle, nutrition, and bariatric surgery, hypertension, dyslipidemia, retinopathy, neuropathy, diabetic kidney disease, and cardiovascular disease; (3) management of prediabetes, type 2 diabetes with antihyperglycemic pharmacotherapy and glycemic targets, type 1 diabetes with insulin therapy, hypoglycemia, hospitalized persons, and women with diabetes in pregnancy; (4) education and new topics regarding diabetes and infertility, nutritional supplements, secondary diabetes, social determinants of health, and virtual care, as well as updated recommendations on cancer risk, nonpharmacologic components of pediatric care plans, depression, education and team approach, occupational risk, role of sleep medicine, and vaccinations in persons with diabetes. CONCLUSIONS: This updated clinical practice guideline provides evidence-based recommendations to assist with person-centered, team-based clinical decision-making to improve the care of persons with diabetes mellitus.

Atypical Salmonella enterica Serovars in Murine and Human Macrophage Infection Models.

Nontyphoidal Salmonella species are globally disseminated pathogens and are the predominant cause of gastroenteritis. The pathogenesis of salmonellosis has been extensively studied using in vivo murine models and cell lines, typically challenged with Salmonella enterica serovar Typhimurium. Although S. enterica serovars Enteritidis and Typhimurium are responsible for most of the human infections reported to the Centers for Disease Control and Prevention (CDC), several other serovars also contribute to clinical cases of salmonellosis. Despite their epidemiological importance, little is known about their infection phenotypes. Here, we report the virulence characteristics and genomes of 10 atypical S. enterica serovars linked to multistate foodborne outbreaks in the United States. We show that the murine RAW 264.7 macrophage model of infection is unsuitable for inferring human-relevant differences in nontyphoidal Salmonella infections, whereas differentiated human THP-1 macrophages allowed these isolates to be further characterized in a more human-relevant context.

Yersinia canariae sp. nov., isolated from a human yersiniosis case.

A Gram-negative rod from the Yersinia genus was isolated from a clinical case of yersiniosis in the United Kingdom. Long read sequencing data from an Oxford Nanopore Technologies (ONT) MinION in conjunction with Illumina HiSeq reads were used to generate a finished quality genome of this strain. Overall Genome Related Index (OGRI) of the strain was used to determine that it was a novel species within Yersinia, despite biochemical similarities to Yersinia enterocolitica. The 16S ribosomal RNA gene accessions are MN434982-MN434987 and the accession number for the complete and closed chromosome is CP043727. The type strain is SRR7544370T (=NCTC 14382T/=LMG 31573T).

Covid-19 & Obesity: Beyond Bmi.

The pandemic of novel coronavirus disease 2019 (COVID-19) has triggered an international crisis resulting in excess morbidity and mortality with adverse societal, economic, and geopolitical consequences. Like other disease states, there are patient characteristics that impact clinical risk and determine the spectrum of severity. Obesity, or adiposity-based chronic disease, has emerged as an important risk factor for morbidity and mortality due to COVID-19. It is imperative to further stratify risk in patients with obesity to determine optimal mitigation and perhaps therapeutic preparedness strategies. We suspect that insulin resistance is an important pathophysiologic cause of poor outcomes in patients with obesity and COVID-19 independent of body mass index. This explains the association of type 2 diabetes mellitus (T2DM), hypertension (HTN), and cardiovascular disease with poor outcomes since insulin resistance is the main driver of both dysglycemia-based chronic disease and cardiometabolic-based chronic disease towards end-stage disease manifestations. Staging the severity of adiposity-related disease in a "complication-centric" manner (HTN, dyslipidemia, metabolic syndrome, T2DM, obstructive sleep apnea, etc.) among different ethnic groups in patients with COVID-19 should help predict the adverse risk of adiposity on patient health in a pragmatic and actionable manner during this pandemic.

AMERICAN ASSOCIATION OF CLINICAL ENDOCRINOLOGISTS/AMERICAN COLLEGE OF ENDOCRINOLOGY CLINICAL PRACTICE GUIDELINES FOR THE DIAGNOSIS AND TREATMENT OF POSTMENOPAUSAL OSTEOPOROSIS-2020 UPDATE.

Objective: The development of these guidelines is sponsored by the American Association of Clinical Endocrinologists (AACE) Board of Directors and American College of Endocrinology (ACE) Board of Trustees and adheres with published AACE protocols for the standardized production of clinical practice guidelines (CPGs). Methods: Recommendations are based on diligent reviews of the clinical evidence with transparent incorporation of subjective factors, according to established AACE/ACE guidelines for guidelines protocols. Results: The Executive Summary of this 2020 updated guideline contains 52 recommendations: 21 Grade A (40%), 24 Grade B (46%), 7 Grade C (14%), and no Grade D (0%). These detailed, evidence-based recommendations allow for nuance-based clinical decision-making that addresses multiple aspects of real-world care of patients. The evidence base presented in the subsequent Appendix provides relevant supporting information for the Executive Summary recommendations. This update contains 368 citations: 123 (33.5%) evidence level (EL) 1 (highest), 132 (36%) EL 2 (intermediate), 20 (5.5%) EL 3 (weak), and 93 (25%) EL 4 (lowest). New or updated topics in this CPG include: clarification of the diagnosis of osteoporosis, stratification of the patient according to high-risk and very-high-risk features, a new dual-action therapy option, and transitions from therapeutic options. Conclusion: This guideline is a practical tool for endocrinologists, physicians in general, regulatory bodies, health-related organizations, and interested laypersons regarding the diagnosis, evaluation, and treatment of post-menopausal osteoporosis. Abbreviations: 25(OH)D = 25-hydroxyvitamin D; AACE = American Association of Clinical Endocrinologists; ACE = American College of Endocrinology; AFF = atypical femoral fracture; ASBMR = American Society for Bone and Mineral Research; BEL = best evidence level; BMD = bone mineral density; BTM = bone turnover marker; CI = confidence interval; CPG = clinical practice guideline; CTX = C-terminal telopeptide type-I collagen; DXA = dual-energy X-ray absorptiometry; EL = evidence level; FDA = U.S. Food and Drug Administration; FRAX® = Fracture Risk Assessment Tool; GI = gastrointestinal; HORIZON = Health Outcomes and Reduced Incidence with Zoledronic acid ONce yearly Pivotal Fracture Trial (zoledronic acid and zoledronate are equivalent terms); ISCD = International Society for Clinical Densitometry; IU = international units; IV = intravenous; LSC = least significant change; NOF = National Osteoporosis Foundation; ONJ = osteonecrosis of the jaw; PINP = serum amino-terminal propeptide of type-I collagen; PTH = parathyroid hormone; R = recommendation; ROI = region of interest; RR = relative risk; SD = standard deviation; TBS = trabecular bone score; VFA = vertebral fracture assessment; WHO = World Health Organization.

AMERICAN ASSOCIATION OF CLINICAL ENDOCRINOLOGISTS/AMERICAN COLLEGE OF ENDOCRINOLOGY CLINICAL PRACTICE GUIDELINES FOR THE DIAGNOSIS AND TREATMENT OF POSTMENOPAUSAL OSTEOPOROSIS- 2020 UPDATE EXECUTIVE SUMMARY.

Objective: The development of these guidelines is sponsored by the American Association of Clinical Endocrinologists (AACE) Board of Directors and American College of Endocrinology (ACE) Board of Trustees and adheres with published AACE protocols for the standardized production of clinical practice guidelines (CPGs). Methods: Recommendations are based on diligent reviews of the clinical evidence with transparent incorporation of subjective factors, according to established AACE/ACE guidelines for guidelines protocols. Results: The Executive Summary of this 2020 updated guideline contains 52 recommendations: 21 Grade A (40%), 24 Grade B (46%), 7 Grade C (14%), and no Grade D (0%). These detailed, evidence-based recommendations allow for nuance-based clinical decision-making that addresses multiple aspects of real-world care of patients. The evidence base presented in the subsequent Appendix provides relevant supporting information for the Executive Summary recommendations. This update contains 368 citations: 123 (33.5%) evidence level (EL) 1 (highest), 132 (36%) EL 2 (intermediate), 20 (5.5%) EL 3 (weak), and 93 (25%) EL 4 (lowest). New or updated topics in this CPG include: clarification of the diagnosis of osteoporosis, stratification of the patient according to high-risk and very-high-risk features, a new dual-action therapy option, and transitions from therapeutic options. Conclusion: This guideline is a practical tool for endocrinologists, physicians in general, regulatory bodies, health-related organizations, and interested laypersons regarding the diagnosis, evaluation, and treatment of post-menopausal osteoporosis.

Yersinia hibernica sp. nov., isolated from pig-production environments.

A Gram-stain-negative, rod-shaped strain isolated from pig-production environments was identified as a new species within the genus Yersinia using multifaceted genomic and biochemical approaches. The genome of this strain was closed using a hybrid assembly approach combining both high accuracy short read sequencing data with long read sequencing technology. Phylogenetic analysis of the 16S rRNA gene showed ~98 % similarity to Yersinia kristensenii and ~98 % similarity to Yersinia enterocolitica. Average nucleotide identity (OrthoANI) values were calculated as 85.79 % to Y. kristensenii ATCC 33638T and 85.73 % to Y. enterocolitica ATCC 9610T thereby providing evidence that this isolate should be considered as a novel species. The type strain is CFS1934T (=NCTC 14222T=LMG 31076T).

CLINICAL PRACTICE GUIDELINES FOR THE PERIOPERATIVE NUTRITION, METABOLIC, AND NONSURGICAL SUPPORT OF PATIENTS UNDERGOING BARIATRIC PROCEDURES - 2019 UPDATE: COSPONSORED BY AMERICAN ASSOCIATION OF CLINICAL ENDOCRINOLOGISTS/AMERICAN COLLEGE OF ENDOCRINOLOGY, THE OBESITY SOCIETY, AMERICAN SOCIETY FOR METABOLIC & BARIATRIC SURGERY, OBESITY MEDICINE ASSOCIATION, AND AMERICAN SOCIETY OF ANESTHESIOLOGISTS - EXECUTIVE SUMMARY.

Objective: The development of these updated clinical practice guidelines (CPGs) was commissioned by the American Association of Clinical Endocrinologists (AACE), The Obesity Society, American Society of Metabolic and Bariatric Surgery, Obesity Medicine Association, and American Society of Anesthesiologists Boards of Directors in adherence with the AACE 2017 protocol for standardized production of CPGs, algorithms, and checklists. Methods: Each recommendation was evaluated and updated based on new evidence from 2013 to the present and subjective factors provided by experts. Results: New or updated topics in this CPG include: contextualization in an adiposity-based chronic disease complications-centric model, nuance-based and algorithm/checklist-assisted clinical decision-making about procedure selection, novel bariatric procedures, enhanced recovery after bariatric surgery protocols, and logistical concerns (including cost factors) in the current health-care arena. There are 85 numbered recommendations that have updated supporting evidence, of which 61 are revised and 12 are new. Noting that there can be multiple recommendation statements within a single numbered recommendation, there are 31 (13%) Grade A, 42 (17%) Grade B, 72 (29%) Grade C, and 101 (41%) Grade D recommendations. There are 858 citations, of which 81 (9.4%) are evidence level (EL) 1 (highest), 562 (65.5%) are EL 2, 72 (8.4%) are EL 3, and 143 (16.7%) are EL 4 (lowest). Conclusion: Bariatric procedures remain a safe and effective intervention for higher-risk patients with obesity. Clinical decision-making should be evidence based within the context of a chronic disease. A team approach to perioperative care is mandatory, with special attention to nutritional and metabolic issues. A1C = hemoglobin A1c; AACE = American Association of Clinical Endocrinologists; ABCD = adiposity-based chronic disease; ACE = American College of Endocrinology; ADA = American Diabetes Association; AHI = Apnea-Hypopnea Index; ASA = American Society of Anesthesiologists; ASMBS = American Society of Metabolic and Bariatric Surgery; BMI = body mass index; BPD = biliopancreatic diversion; BPD/DS = biliopancreatic diversion with duodenal switch; CI = confidence interval; CPAP = continuous positive airway pressure; CPG = clinical practice guideline; CRP = C-reactive protein; CT = computed tomography; CVD = cardiovascular disease; DBCD = dysglycemia-based chronic disease; DS = duodenal switch; DVT = deep venous thrombosis; DXA = dual-energy X-ray absorptiometry; EFA = essential fatty acid; EL = evidence level; EN = enteral nutrition; ERABS = enhanced recovery after bariatric surgery; FDA = U.S. Food and Drug Administration; G4G = Guidelines for Guidelines; GERD = gastroesophageal reflux disease; GI = gastrointestinal; HCP = health-care professional(s); HTN = hypertension; ICU = intensive care unit; IGB = intragastric balloon(s); IV = intravenous; LAGB = laparoscopic adjustable gastric band; LAGBP = laparoscopic adjustable gastric banded plication; LGP = laparoscopic greater curvature (gastric) plication; LRYGB = laparoscopic Roux-en-Y gastric bypass; LSG = laparoscopic sleeve gastrectomy; MetS = metabolic syndrome; NAFLD = nonalcoholic fatty liver disease; NASH = nonalcoholic steatohepatitis; NSAID = nonsteroidal anti-inflammatory drug; OA = osteoarthritis; OAGB = one-anastomosis gastric bypass; OMA = Obesity Medicine Association; OR = odds ratio; ORC = obesity-related complication(s); OSA = obstructive sleep apnea; PE = pulmonary embolism; PN = parenteral nutrition; PRM = pulmonary recruitment maneuver; RCT = randomized controlled trial; RD = registered dietician; RDA = recommended daily allowance; RYGB = Roux-en-Y gastric bypass; SG = sleeve gastrectomy; SIBO = small intestinal bacterial overgrowth; TOS = The Obesity Society; TSH = thyroid-stimulating hormone; T1D = type 1 diabetes; T2D = type 2 diabetes; VTE = venous thromboembolism; WE = Wernicke encephalopathy; WHO = World Health Organization.

THE USE OF VITAMINS AND MINERALS IN SKELETAL HEALTH: AMERICAN ASSOCIATION OF CLINICAL ENDOCRINOLOGISTS AND THE AMERICAN COLLEGE OF ENDOCRINOLOGY POSITION STATEMENT.

ABBREVIATIONS: 25(OH)D = 25-hydroxyvitamin D; BMD = bone mineral density; CV = cardiovascular; GI = gastrointestinal; IOM = Institute of Medicine; PTH = parathyroid hormone; RCT = randomized controlled trial; αTF = α-tocopherol; ucOC = undercarboxylated osteocalcin; VKA = vitamin K antagonist; WHI = Women's Health Initiative.

MtVRN2 is a Polycomb VRN2-like gene which represses the transition to flowering in the model legume Medicago truncatula.

Optimising the timing of flowering contributes to successful sexual reproduction and yield in agricultural plants. FLOWERING LOCUS T (FT) genes, first identified in Arabidopsis thaliana (Arabidopsis), promote flowering universally, but the upstream flowering regulatory pathways can differ markedly among plants. Flowering in the model legume, Medicago truncatula (Medicago) is accelerated by winter cold (vernalisation) followed by long day (LD) photoperiods leading to elevated expression of the floral activator, FT-like gene FTa1. However, Medicago, like some other plants, lacks the activator CONSTANS (CO) and the repressor FLOWERING LOCUS C (FLC) genes which directly regulate FT and are key to LD and vernalisation responses in Arabidopsis. Conversely, Medicago has a VERNALISATION2-LIKE VEFS-box gene (MtVRN2). In Arabidopsis AtVRN2 is a key member of a Polycomb complex involved in stable repression of Arabidopsis FLC after vernalisation. VRN2-like genes have been identified in other eudicot plants, but their function has never been reported. We show that Mtvrn2 mutants bypass the need for vernalisation for early flowering in LD conditions in Medicago. Investigation of the underlying mechanism by transcriptome analysis reveals that Mtvrn2 mutants precociously express FTa1 and other suites of genes including floral homeotic genes. Double-mutant analysis indicates that early flowering is dependent on functional FTa1. The broad significance of our study is that we have demonstrated a function for a VRN2-like VEFS gene beyond the Brassicaceae. In particular, MtVRN2 represses the transition to flowering in Medicago by regulating the onset of expression of the potent floral activator, FTa1.

Predictive modelling of gene expression from transcriptional regulatory elements.

Predictive modelling of gene expression provides a powerful framework for exploring the regulatory logic underpinning transcriptional regulation. Recent studies have demonstrated the utility of such models in identifying dysregulation of gene and miRNA expression associated with abnormal patterns of transcription factor (TF) binding or nucleosomal histone modifications (HMs). Despite the growing popularity of such approaches, a comparative review of the various modelling algorithms and feature extraction methods is lacking. We define and compare three methods of quantifying pairwise gene-TF/HM interactions and discuss their suitability for integrating the heterogeneous chromatin immunoprecipitation (ChIP)-seq binding patterns exhibited by TFs and HMs. We then construct log-linear and ϵ-support vector regression models from various mouse embryonic stem cell (mESC) and human lymphoblastoid (GM12878) data sets, considering both ChIP-seq- and position weight matrix- (PWM)-derived in silico TF-binding. The two algorithms are evaluated both in terms of their modelling prediction accuracy and ability to identify the established regulatory roles of individual TFs and HMs. Our results demonstrate that TF-binding and HMs are highly predictive of gene expression as measured by mRNA transcript abundance, irrespective of algorithm or cell type selection and considering both ChIP-seq and PWM-derived TF-binding. As we encourage other researchers to explore and develop these results, our framework is implemented using open-source software and made available as a preconfigured bootable virtual environment.

Virtual Reference Environments: a simple way to make research reproducible.

'Reproducible research' has received increasing attention over the past few years as bioinformatics and computational biology methodologies become more complex. Although reproducible research is progressing in several valuable ways, we suggest that recent increases in internet bandwidth and disk space, along with the availability of open-source and free-software licences for tools, enable another simple step to make research reproducible. In this article, we urge the creation of minimal virtual reference environments implementing all the tools necessary to reproduce a result, as a standard part of publication. We address potential problems with this approach, and show an example environment from our own work.

ADIPOSITY-BASED CHRONIC DISEASE AS A NEW DIAGNOSTIC TERM: THE AMERICAN ASSOCIATION OF CLINICAL ENDOCRINOLOGISTS AND AMERICAN COLLEGE OF ENDOCRINOLOGY POSITION STATEMENT.

The American Association of Clinical Endocrinologists (AACE) and American College of Endocrinology (ACE) have created a chronic care model, advanced diagnostic framework, clinical practice guidelines, and clinical practice algorithm for the comprehensive management of obesity. This coordinated effort is not solely based on body mass index as in previous models, but emphasizes a complications-centric approach that primarily determines therapeutic decisions and desired outcomes. Adiposity-Based Chronic Disease (ABCD) is a new diagnostic term for obesity that explicitly identifies a chronic disease, alludes to a precise pathophysiologic basis, and avoids the stigmata and confusion related to the differential use and multiple meanings of the term "obesity." Key elements to further the care of patients using this new ABCD term are: (1) positioning lifestyle medicine in the promotion of overall health, not only as the first algorithmic step, but as the central, pervasive action; (2) standardizing protocols that comprehensively and durably address weight loss and management of adiposity-based complications; (3) approaching patient care through contextualization (e.g., primordial prevention to decrease obesogenic environmental risk factors and transculturalization to adapt evidence-based recommendations for different ethnicities, cultures, and socio-economics); and lastly, (4) developing evidence-based strategies for successful implementation, monitoring, and optimization of patient care over time. This AACE/ACE blueprint extends current work and aspires to meaningfully improve both individual and population health by presenting a new ABCD term for medical diagnostic purposes, use in a complications-centric management and staging strategy, and precise reference to the obesity chronic disease state, divested from counterproductive stigmata and ambiguities found in the general public sphere. ABBREVIATIONS: AACE = American Association of Clinical Endocrinologists ABCD = Adiposity-Based Chronic Disease ACE = American College of Endocrinology BMI = body mass index CPG = clinical practice guidelines HCP = health care professionals.

Systems analysis identifies miR-29b regulation of invasiveness in melanoma.

BACKGROUND: In many cancers, microRNAs (miRs) contribute to metastatic progression by modulating phenotypic reprogramming processes such as epithelial-mesenchymal plasticity. This can be driven by miRs targeting multiple mRNA transcripts, inducing regulated changes across large sets of genes. The miR-target databases TargetScan and DIANA-microT predict putative relationships by examining sequence complementarity between miRs and mRNAs. However, it remains a challenge to identify which miR-mRNA interactions are active at endogenous expression levels, and of biological consequence. METHODS: We developed a workflow to integrate TargetScan and DIANA-microT predictions into the analysis of data-driven associations calculated from transcript abundance (RNASeq) data, specifically the mutual information and Pearson's correlation metrics. We use this workflow to identify putative relationships of miR-mediated mRNA repression with strong support from both lines of evidence. Applying this approach systematically to a large, published collection of unique melanoma cell lines - the Ludwig Melbourne melanoma (LM-MEL) cell line panel - we identified putative miR-mRNA interactions that may contribute to invasiveness. This guided the selection of interactions of interest for further in vitro validation studies. RESULTS: Several miR-mRNA regulatory relationships supported by TargetScan and DIANA-microT demonstrated differential activity across cell lines of varying matrigel invasiveness. Strong negative statistical associations for these putative regulatory relationships were consistent with target mRNA inhibition by the miR, and suggest that differential activity of such miR-mRNA relationships contribute to differences in melanoma invasiveness. Many of these relationships were reflected across the skin cutaneous melanoma TCGA dataset, indicating that these observations also show graded activity across clinical samples. Several of these miRs are implicated in cancer progression (miR-211, -340, -125b, -221, and -29b). The specific role for miR-29b-3p in melanoma has not been well studied. We experimentally validated the predicted miR-29b-3p regulation of LAMC1 and PPIC and LASP1, and show that dysregulation of miR-29b-3p or these mRNA targets can influence cellular invasiveness in vitro. CONCLUSIONS: This analytic strategy provides a comprehensive, systems-level approach to identify miR-mRNA regulation in high-throughput cancer data, identifies novel putative interactions with functional phenotypic relevance, and can be used to direct experimental resources for subsequent experimental validation. Computational scripts are available: http://github.com/uomsystemsbiology/LMMEL-miR-miner.

Multidrug-Resistant Escherichia coli in Bovine Animals, Europe.

Of 150 Escherichia coli strains we cultured from specimens taken from cattle in Europe, 3 had elevated MICs against colistin. We assessed all 3 strains for the presence of the plasmid-mediated mcr-1 gene and identified 1 isolate as mcr-1-positive and co-resistant to ß-lactam, florfenicol, and fluoroquinolone antimicrobial compounds.

A novel EGR-1 dependent mechanism for YB-1 modulation of paclitaxel response in a triple negative breast cancer cell line.

Chemotherapy with taxanes such as paclitaxel (PTX) is a key component of triple negative breast cancer (TNBC) treatment. PTX is used in combination with other drugs in both the adjuvant setting and in advanced breast cancer. Because a proportion of patients respond poorly to PTX or relapse after its use, a greater understanding of the mechanisms conferring resistance to PTX is required. One protein shown to be involved in drug resistance is Y-box binding protein 1 (YB-1). High levels of YB-1 have previously been associated with resistance to PTX in TNBCs. In this study, we aimed to determine mechanisms by which YB-1 confers PTX resistance. We generated isogenic TNBC cell lines that differed by YB-1 levels and treated these with PTX. Using microarray analysis, we identified EGR1 as a potential target of YB-1. We found that low EGR1 mRNA levels are associated with poor breast cancer patient prognosis, and that EGR1 and YBX1 mRNA expression was inversely correlated in a TNBC line and in a proportion of TNBC tumours. Reducing the levels of EGR1 caused TNBC cells to become more resistant to PTX. Given that PTX targets cycling cells, we propose a model whereby high YB-1 levels in some TNBC cells can lead to reduced levels of EGR1, which in turn promotes slow cell cycling and resistance to PTX. Therefore YB-1 and EGR1 levels are biologically linked and may provide a biomarker for TNBC response to PTX.

NAIL, a software toolset for inferring, analyzing and visualizing regulatory networks.

UNLABELLED: The wide variety of published approaches for the problem of regulatory network inference makes using multiple inference algorithms complex and time-consuming. Network Analysis and Inference Library (NAIL) is a set of software tools to simplify the range of computational activities involved in regulatory network inference. It uses a modular approach to connect different network inference algorithms to the same visualization and network-based analyses. NAIL is technology-independent and includes an interface layer to allow easy integration of components into other applications. AVAILABILITY AND IMPLEMENTATION: NAIL is implemented in MATLAB, runs on Windows, Linux and OSX, and is available from SourceForge at https://sourceforge.net/projects/nailsystemsbiology/ for all researchers to use. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.

A model system for studying the transcriptomic and physiological changes associated with mammalian host-adaptation by Leptospira interrogans serovar Copenhageni.

Leptospirosis, an emerging zoonotic disease with worldwide distribution, is caused by spirochetes belonging to the genus Leptospira. More than 500,000 cases of severe leptospirosis are reported annually, with >10% of these being fatal. Leptospires can survive for weeks in suitably moist conditions before encountering a new host. Reservoir hosts, typically rodents, exhibit little to no signs of disease but shed large numbers of organisms in their urine. Transmission occurs when mucosal surfaces or abraded skin come into contact with infected urine or urine-contaminated water or soil. In humans, leptospires can cause a variety of clinical manifestations, ranging from asymptomatic or mild fever to severe icteric (Weil's) disease and pulmonary haemorrhage. Currently, little is known about how Leptospira persist within a reservoir host. Prior in vitro studies have suggested that leptospires alter their transcriptomic and proteomic profiles in response to environmental signals encountered during mammalian infection. However, no study has examined gene expression by leptospires within a mammalian host-adapted state. To obtain a more faithful representation of how leptospires respond to host-derived signals, we used RNA-Seq to compare the transcriptome of L. interrogans cultivated within dialysis membrane chambers (DMCs) implanted into the peritoneal cavities of rats with that of organisms grown in vitro. In addition to determining the relative expression levels of "core" housekeeping genes under both growth conditions, we identified 166 genes that are differentially-expressed by L. interrogans in vivo. Our analyses highlight physiological aspects of host adaptation by leptospires relating to heme uptake and utilization. We also identified 11 novel non-coding transcripts that are candidate small regulatory RNAs. The DMC model provides a facile system for studying the transcriptional and antigenic changes associated with mammalian host-adaptation, selection of targets for mutagenesis, and the identification of previously unrecognized virulence determinants.

AMERICAN ASSOCIATION OF CLINICAL ENDOCRINOLOGISTS AND AMERICAN COLLEGE OF ENDOCRINOLOGY COMPREHENSIVE CLINICAL PRACTICE GUIDELINES FOR MEDICAL CARE OF PATIENTS WITH OBESITY.

OBJECTIVE: Development of these guidelines is mandated by the American Association of Clinical Endocrinologists (AACE) Board of Directors and the American College of Endocrinology (ACE) Board of Trustees and adheres to published AACE protocols for the standardized production of clinical practice guidelines (CPGs). METHODS: Recommendations are based on diligent review of clinical evidence with transparent incorporation of subjective factors. RESULTS: There are 9 broad clinical questions with 123 recommendation numbers that include 160 specific statements (85 [53.1%] strong [Grade A]; 48 [30.0%] intermediate [Grade B], and 11 [6.9%] weak [Grade C], with 16 [10.0%] based on expert opinion [Grade D]) that build a comprehensive medical care plan for obesity. There were 133 (83.1%) statements based on strong (best evidence level [BEL] 1 = 79 [49.4%]) or intermediate (BEL 2 = 54 [33.7%]) levels of scientific substantiation. There were 34 (23.6%) evidence-based recommendation grades (Grades A-C = 144) that were adjusted based on subjective factors. Among the 1,790 reference citations used in this CPG, 524 (29.3%) were based on strong (evidence level [EL] 1), 605 (33.8%) were based on intermediate (EL 2), and 308 (17.2%) were based on weak (EL 3) scientific studies, with 353 (19.7%) based on reviews and opinions (EL 4). CONCLUSION: The final recommendations recognize that obesity is a complex, adiposity-based chronic disease, where management targets both weight-related complications and adiposity to improve overall health and quality of life. The detailed evidence-based recommendations allow for nuanced clinical decision-making that addresses real-world medical care of patients with obesity, including screening, diagnosis, evaluation, selection of therapy, treatment goals, and individualization of care. The goal is to facilitate high-quality care of patients with obesity and provide a rational, scientific approach to management that optimizes health outcomes and safety. ABBREVIATIONS: A1C = hemoglobin A1c AACE = American Association of Clinical Endocrinologists ACE = American College of Endocrinology ACSM = American College of Sports Medicine ADA = American Diabetes Association ADAPT = Arthritis, Diet, and Activity Promotion Trial ADHD = attention-deficit hyperactivity disorder AHA = American Heart Association AHEAD = Action for Health in Diabetes AHI = apnea-hypopnea index ALT = alanine aminotransferase AMA = American Medical Association ARB = angiotensin receptor blocker ART = assisted reproductive technology AUC = area under the curve BDI = Beck Depression Inventory BED = binge eating disorder BEL = best evidence level BLOOM = Behavioral Modification and Lorcaserin for Overweight and Obesity Management BLOSSOM = Behavioral Modification and Lorcaserin Second Study for Obesity Management BMI = body mass index BP = blood pressure C-SSRS = Columbia Suicidality Severity Rating Scale CAD = coronary artery disease CARDIA = Coronary Artery Risk Development in Young Adults CBT = cognitive behavioral therapy CCO = Consensus Conference on Obesity CHF = congestive heart failure CHO = carbohydrate CI = confidence interval COR-I = Contrave Obesity Research I CPG = clinical practice guideline CV = cardiovascular CVD = cardiovascular disease DASH = Dietary Approaches to Stop Hypertension DBP = diastolic blood pressure DEXA = dual-energy X-ray absorptiometry DPP = Diabetes Prevention Program DSE = diabetes support and education EL = evidence level ED = erectile dysfunction ER = extended release EWL = excess weight loss FDA = Food and Drug Administration FDG = 18F-fluorodeoxyglucose GABA = gamma-aminobutyric acid GERD = gastroesophageal reflux disease GI = gastrointestinal GLP-1 = glucagon-like peptide 1 HADS = Hospital Anxiety and Depression Scale HDL-c = high-density lipoprotein cholesterol HR = hazard ratio HTN = hypertension HUNT = Nord-Trøndelag Health Study ICSI = intracytoplasmic sperm injection IFG = impaired fasting glucose IGT = impaired glucose tolerance ILI = intensive lifestyle intervention IVF = in vitro fertilization LAGB = laparoscopic adjustable gastric banding LDL-c = low-density lipoprotein cholesterol LES = lower esophageal sphincter LSG = laparoscopic sleeve gastrectomy LV = left ventricle LVH = left ventricular hypertrophy LVBG = laparoscopic vertical banded gastroplasty MACE = major adverse cardiovascular events MAOI = monoamine oxidase inhibitor MI = myocardial infarction MNRCT = meta-analysis of non-randomized prospective or case-controlled trials MRI = magnetic resonance imaging MUFA = monounsaturated fatty acid NAFLD = nonalcoholic fatty liver disease NASH = nonalcoholic steatohepatitis NES = night eating syndrome NHANES = National Health and Nutrition Examination Surveys NHLBI = National Heart, Lung, and Blood Institute NHS = Nurses' Health Study NICE = National Institute for Health and Care Excellence OA = osteoarthritis OGTT = oral glucose tolerance test OR = odds ratio OSA = obstructive sleep apnea PHQ-9 = Patient Health Questionnaire PCOS = polycystic ovary syndrome PCP = primary care physician POMC = pro-opiomelanocortin POWER = Practice-Based Opportunities for Weight Reduction PPI = proton pump inhibitor PRIDE = Program to Reduce Incontinence by Diet and Exercise PSA = prostate specific antigen QOL = quality of life RA = receptor agonist RCT = randomized controlled trial ROC = receiver operator characteristic RR = relative risk RYGB = Roux-en-Y gastric bypass SAD = sagittal abdominal diameter SBP = systolic blood pressure SCOUT = Sibutramine Cardiovascular Outcome Trial SG = sleeve gastrectomy SHBG = sex hormonebinding globulin SIEDY = Structured Interview on Erectile Dysfunction SNRI = serotonin-norepinephrine reuptake inhibitors SOS = Swedish Obese Subjects SS = surveillance study SSRI = selective serotonin reuptake inhibitors STORM = Sibutramine Trial on Obesity Reduction and Maintenance TCA = tricyclic antidepressant TONE = Trial of Nonpharmacologic Intervention in the Elderly TOS = The Obesity Society T2DM = type 2 diabetes mellitus UKPDS = United Kingdom Prospective Diabetes Study U.S = United States VAT = visceral adipose tissue VLDL = very low-density lipoprotein WC = waist circumference WHO = World Health Organization WHR = waist-hip ratio WHtR = waist-to-height ratio WMD = weighted mean difference WOMAC = Western Ontario and McMaster Universities osteoarthritis index XENDOS = XEnical in the Prevention of Diabetes in Obese Subjects.