Nipsnap1-A regulatory factor required for long-term maintenance of non-shivering thermogenesis.

OBJECTIVE: The activation of non-shivering thermogenesis (NST) has strong potential to combat obesity and metabolic disease. The activation of NST however is extremely temporal and the mechanisms surrounding how the benefits of NST are sustained once fully activated, remain unexplored. The objective of this study is to investigate the role of 4-Nitrophenylphosphatase Domain and Non-Neuronal SNAP25-Like 1 (Nipsnap1) in NST maintenance, which is a critical regulator identified in this study. METHODS: The expression of Nipsnap1 was profiled by immunoblotting and RT-qPCR. We generated Nipsnap1 knockout mice (N1-KO) and investigated the function of Nipsnap1 in NST maintenance and whole-body metabolism using whole body respirometry analyses. We evaluate the metabolic regulatory role of Nipsnap1 using cellular and mitochondrial respiration assay. RESULTS: Here, we show Nipsnap1 as a critical regulator of long-term thermogenic maintenance in brown adipose tissue (BAT). Nipsnap1 localizes to the mitochondrial matrix and increases its transcript and protein levels in response to both chronic cold and ß3 adrenergic signaling. We demonstrated that these mice are unable to sustain activated energy expenditure and have significantly lower body temperature in the face of an extended cold challenge. Furthermore, when mice are exposed to the pharmacological ß3 agonist CL 316, 243, the N1-KO mice exhibit significant hyperphagia and altered energy balance. Mechanistically, we demonstrate that Nipsnap1 integrates with lipid metabolism and BAT-specific ablation of Nipsnap1 leads to severe defects in beta-oxidation capacity when exposed to a cold environmental challenge. CONCLUSION: Our findings identify Nipsnap1 as a potent regulator of long-term NST maintenance in BAT.

Analysis of Worsening Heart Failure Events in an Integrated Health Care System.

BACKGROUND: There is growing interest to disentangle worsening heart failure (WHF) from location of care and move away from hospitalization as a surrogate for acuity. OBJECTIVES: The purpose of this study was to describe the incidence of WHF events across the care continuum from ambulatory encounters to hospitalizations. METHODS: We studied calendar year cohorts of adults with diagnosed heart failure (HF) from 2010-2019 within a large, integrated health care delivery system. Electronic health record (EHR) data were accessed for outpatient encounters, emergency department (ED) visits/observation stays, and hospitalizations. WHF was defined as ≥1 symptom, ≥2 objective findings including ≥1 sign, and ≥1 change in HF-related therapy. Symptoms and signs were ascertained using natural language processing. RESULTS: We identified 103,138 eligible individuals with mean age 73.6 ± 13.7 years, 47.5% women, and mean left ventricular ejection fraction of 51.4% ± 13.7%. There were 1,136,750 unique encounters including 743,039 (65.4%) outpatient encounters, 224,670 (19.8%) ED visits/observation stays, and 169,041 (14.9%) hospitalizations. A total of 126,008 WHF episodes were identified, including 34,758 (27.6%) outpatient encounters, 28,301 (22.5%) ED visits/observation stays, and 62,949 (50.0%) hospitalizations. The annual incidence (events per 100 person-years) of WHF increased from 25 to 33 during the study period primarily caused by outpatient encounters (7 to 10) and ED visits/observation stays (4 to 7). The 30-day rate of hospitalizations for WHF ranged from 8.2% for outpatient encounters to 12.4% for hospitalizations. CONCLUSIONS: ED visits/observation stays and outpatient encounters account for approximately one-half of WHF events, are driving the underlying growth in HF morbidity, and portend a poor short-term prognosis.

Reasons for Initiating Canakinumab among Patients with Systemic Juvenile Idiopathic Arthritis and Adult-Onset Still's Disease in the U.S. Real-World Settings.

INTRODUCTION: The aim of this study was to understand the reasons for canakinumab initiation among patients with Still's disease, including systemic juvenile idiopathic arthritis (SJIA) and adult-onset Still's disease (AOSD), in US clinical practice. METHODS: Physicians retrospectively reviewed the medical charts of patients with Still's disease (regardless of age at symptom onset) who were prescribed canakinumab from 2016 to 2018. Patients aged < 16 years at symptom onset were classified as having SJIA and those aged ≥ 16 years at symptom onset (calculated from case-record forms) were classified as having AOSD. Patient treatment history and physician reasons for canakinumab initiation were analyzed. Overall results were presented as SJIA/AOSD. Sensitivity analyses were performed for the robustness of the results. RESULTS: Forty-three physicians in the USA (rheumatologists/dermatologists/immunologists/allergists: 51.2/27.9/11.6/9.3%; subspecialty in adults/pediatrics: 67.4/32.6%) abstracted information for 72 patients with SJIA/AOSD (SJIA/AOSD/age unknown at symptom onset: 75.0/18.1/6.9%; mean age 19.4 years; children 61.1%; females 56.9%). Most patients (90.3%) received treatment directly preceding canakinumab initiation (etanercept 27.7%; anakinra 18.5%; adalimumab 16.9%); the respective treatment was discontinued due to lack of efficacy/effectiveness (43.1%) and availability of a new treatment (27.8%). Most common reasons for canakinumab initiation were physician perceived/experienced efficacy/effectiveness of canakinumab (77.8%; children/adults: 81.8/71.4%), lack-of-response to previous treatment (45.8%; children/adults: 36.4/60.7%), convenient administration/dosing (26.4%; children/adults: 29.5/21.4%) and ability to discontinue/spare steroids (25.0%; children/adults: 20.5/32.1%). The sensitivity analysis provided similar results. CONCLUSIONS: In US clinical practice, physician perceived/experienced efficacy/effectiveness of canakinumab and lack-of-response to previous treatment were the primary reasons for canakinumab initiation among patients with SJIA/AOSD. Physician perceived/experienced efficacy/effectiveness and convenient administration/dosing of canakinumab were the most common reasons for canakinumab initiation among children, whereas lack-of-response to previous treatment and ability to discontinue/spare steroids being the most frequent reasons among adults.

A Natural Language Processing-Based Approach for Identifying Hospitalizations for Worsening Heart Failure Within an Integrated Health Care Delivery System.

Importance: The current understanding of epidemiological mechanisms and temporal trends in hospitalizations for worsening heart failure (WHF) is based on claims and national reporting databases. However, these data sources are inherently limited by the accuracy and completeness of diagnostic coding and/or voluntary reporting. Objective: To assess the overall burden of and temporal trends in the rate of hospitalizations for WHF. Design, Setting, and Participants: This cohort study, performed from January 1, 2010, to December 31, 2019, used electronic health record (EHR) data from a large integrated health care delivery system. Exposures: Calendar year trends. Main Outcomes and Measures: Hospitalizations for WHF (ie, excluding observation stays) were defined as 1 symptom or more, 2 objective findings or more including 1 sign or more, and 2 doses or more of intravenous loop diuretics and/or new hemodialysis or continuous kidney replacement therapy. Symptoms and signs were identified using natural language processing (NLP) algorithms applied to EHR data. Results: The study population was composed of 118 002 eligible patients experiencing 287 992 unique hospitalizations (mean [SD] age, 75.6 [13.1] years; 147 203 [51.1%] male; 1655 [0.6%] American Indian or Alaska Native, 28 451 [9.9%] Asian or Pacific Islander, 34 903 [12.1%] Black, 23 452 [8.1%] multiracial, 175 840 [61.1%] White, and 23 691 [8.2%] unknown), including 65 357 with a principal discharge diagnosis and 222 635 with a secondary discharge diagnosis of HF. The study population included 59 868 patients (20.8%) with HF with a reduced ejection fraction (HFrEF) (<40%), 33 361 (11.6%) with HF with a midrange EF (HFmrEF) (40%-49%), 142 347 (49.4%) with HF with a preserved EF (HFpEF) (≥50%), and 52 416 (18.2%) with unknown EF. A total of 58 042 admissions (88.8%) with a primary discharge diagnosis of HF and 62 764 admissions (28.2%) with a secondary discharge diagnosis of HF met the prespecified diagnostic criteria for WHF. Overall, hospitalizations for WHF identified on NLP-based algorithms increased from 5.2 to 7.6 per 100 hospitalizations per year during the study period. Subgroup analyses found an increase in hospitalizations for WHF based on NLP from 1.5 to 1.9 per 100 hospitalizations for HFrEF, from 0.6 to 1.0 per 100 hospitalizations for HFmrEF, and from 2.6 to 3.9 per 100 hospitalizations for HFpEF. Conclusions and Relevance: The findings of this cohort study suggest that the burden of hospitalizations for WHF may be more than double that previously estimated using only principal discharge diagnosis. There has been a gradual increase in the rate of hospitalizations for WHF with a more noticeable increase observed for HFpEF.

Reasons for canakinumab initiation among patients with periodic fever syndromes: a retrospective medical chart review from the United States.

BACKGROUND: Although canakinumab has demonstrated efficacy in multiple trials in patients with periodic fever syndromes (PFS), the evidence on initiation of canakinumab among PFS patients in real world setting is not well understood. We aimed to characterize the reasons for canakinumab initiation among patients with PFS, specifically, cryopyrin-associated periodic syndrome (CAPS), hyperimmunoglobulin D syndrome/mevalonate kinase deficiency (HIDS/MKD), TNF receptor-associated periodic syndrome (TRAPS) and familial Mediterranean fever (FMF). METHODS: Physicians retrospectively reviewed the medical charts of PFS patients prescribed canakinumab between 2016 and 2018. Information collected included patient clinical characteristics, reasons for previous treatment discontinuation and canakinumab initiation. The results were summarized for overall patients, and by children (< 18 years) and adults and by subtype of PFS. RESULTS: Fifty-eight physicians in the US (rheumatologists, 44.8 %; allergists/immunologists, 29.3 %; dermatologists, 25.9 %) abstracted information for 147 patients (children, 46.3 %; males, 57.1 %; CAPS, 36.7 %; TRAPS, 26.5 %; FMF, 26.5 %; HIDS/MKD, 6.8 %; Mixed, 3.4 %). Overall, most patients (90.5 %) received treatment directly preceding canakinumab (NSAIDs, 27.8 % [40.0 % in HIDS/MKD]; anakinra, 24.1 % [32.7 % in CAPS]; colchicine, 21.8 % [35.9 % in FMF]), which were discontinued due to lack of efficacy/effectiveness (39.5 %) and availability of a new treatment (36.1 %). The common reasons for canakinumab initiation were physician perceived efficacy/effectiveness (81.0 %; children, 75.0 %; adults, 86.1 %), lack of response to previous treatment (40.8 %; children, 38.2 %; adults, 43.0 %) and favorable safety profile/tolerability (40.1 %; children, 42.6 %; adults, 38.0 %). Within subtypes, efficacy/effectiveness was the most stated reason for canakinumab initiation in HIDS/MKD (90.9 %), lack of response to previous treatment in FMF (52.4 %) and convenience of administration/dosing in CAPS (27.1 %). CONCLUSIONS: This study provided insights into how canakinumab is initiated in US clinical practice among PFS patients, with physician perceived efficacy/effectiveness of canakinumab, lack of response to previous treatment and favorable safety profile/tolerability of canakinumab being the dominant reasons for canakinumab initiation in all patients and in children and adults and PFS subtypes. Notably, the favorable safety profile/tolerability of canakinumab was more often the reason for initiation among children versus adults.

Developmental ethanol exposure causes central nervous system dysfunction and may slow the aging process in a Drosophila model of fetal alcohol spectrum disorder.

Alcohol is a known teratogen, and developmental exposure to ethanol results in fetal alcohol spectrum disorder (FASD). Children born with FASD can exhibit a range of symptoms including low birth weight, microcephaly, and neurobehavioral problems. Treatment of patients with FASD is estimated to cost 4 billion dollars per year in the United States alone, and 2 million dollars per affected individual's lifetime. We have established Drosophila melanogaster as a model organism for the study of FASD. Here we report that mutations in Dementin (Dmtn), the Drosophila ortholog of the Alzheimer's disease-associated protein TMCC2, convey sensitivity to developmental ethanol exposure, and provide evidence that Dmtn expression is disrupted by ethanol. In addition, we find that flies reared on ethanol exhibit mild climbing defects suggestive of neurodegeneration. Surprisingly, our data also suggest that flies reared on ethanol age more slowly than control animals, and we find that a number of slow-aging mutants are sensitive to developmental ethanol exposure. Finally, we find that flies reared on ethanol showed a persistent upregulation of genes encoding antioxidant enzymes, which may contribute to a reduced rate of central nervous system aging. Thus, in addition to the well-documented negative effects of developmental alcohol exposure on the nervous system, there may be a previously unsuspected neuroprotective effect in adult animals.

Interventions of hospital pharmacists in improving drug therapy in children: a systematic literature review.

Medicines' management or pharmaceutical care in paediatric patients is particularly demanding, mainly because the majority of available drugs have been developed for use in adults. As a result, in children, drugs are often unlicensed or used off-label, suitable formulations or appropriate strengths are lacking, and drugs have to be extemporaneously prepared, liquids and injections diluted, and tablets split. These factors increase the likelihood of medication errors and may lead to a reduction in drug effect. Age-specific changes in pharmacokinetics and pharmacodynamics further complicate drug therapy in children. All these challenges provide unique opportunities for pharmacists to improve the quality of care for paediatric patients. We conducted a systematic literature review examining whether the interventions of hospital pharmacists improve drug therapy in children. Several medical and pharmaceutical databases were searched systematically to identify articles investigating hospital pharmacists' interventions that were intended to improve drug therapy in children. Inclusion criteria were English language, primary research papers and studies in which clinical pharmacists contributed directly to patient care. Exclusion criteria were reviews, editorials, questionnaire studies, modelling studies, letters and studies only available in abstract form. This systematic search identified 18 articles documenting the role of a clinical hospital pharmacist in paediatric care. These articles were divided into the following groups based on study type: (i) studies documenting interventions made by pharmacists and their role in inpatients; (ii) articles presenting the outcomes of a satellite pharmacy; and (iii) articles examining pharmacist involvement in paediatric outpatient clinics. No randomised study comparing pharmacist interventions with standard care was found. In conclusion, although it was difficult to compare the various studies identified because of the different settings, design, duration, size, methodology and definition, all these studies highlighted the importance of hospital pharmacists to medicines' management in paediatric patients. On the basis of this review, we can conclude that pharmacist reviewing of medication charts is very important in identifying medication errors; hence, it is likely to be the most effective method of improving drug therapy in children.