Deciphering and disrupting PIEZO1-TMEM16F interplay in hereditary xerocytosis.

ABSTRACT: Cell-surface exposure of phosphatidylserine (PS) is essential for phagocytic clearance and blood clotting. Although a calcium-activated phospholipid scramblase (CaPLSase) has long been proposed to mediate PS exposure in red blood cells (RBCs), its identity, activation mechanism, and role in RBC biology and disease remain elusive. Here, we demonstrate that TMEM16F, the long-sought-after RBC CaPLSase, is activated by calcium influx through the mechanosensitive channel PIEZO1 in RBCs. PIEZO1-TMEM16F functional coupling is enhanced in RBCs from individuals with hereditary xerocytosis (HX), an RBC disorder caused by PIEZO1 gain-of-function channelopathy. Enhanced PIEZO1-TMEM16F coupling leads to an increased propensity to expose PS, which may serve as a key risk factor for HX clinical manifestations including anemia, splenomegaly, and postsplenectomy thrombosis. Spider toxin GsMTx-4 and antigout medication benzbromarone inhibit PIEZO1, preventing force-induced echinocytosis, hemolysis, and PS exposure in HX RBCs. Our study thus reveals an activation mechanism of TMEM16F CaPLSase and its pathophysiological function in HX, providing insights into potential treatment.

A Non-Invasive Method for Monitoring Osteogenesis and Osseointegration Using Near-Infrared Fluorescent Imaging: A Model of Maxilla Implantation in Rats.

Currently, computed tomography and conventional X-ray radiography usually generate a micro-artifact around metal implants. This metal artifact frequently causes false positive or negative diagnoses of bone maturation or pathological peri-implantitis around implants. In an attempt to repair the artifacts, a highly specific nanoprobe, an osteogenic biomarker, and nano-Au-Pamidronate were designed to monitor the osteogenesis. In total, 12 Sprague Dawley rats were included in the study and could be chategorized in 3 groups: 4 rats in the X-ray and CT group, 4 rats in the NIRF group, and 4 rats in the sham group. A titanium alloy screw was implanted in the anterior hard palate. The X-ray, CT, and NIRF images were taken 28 days after implantation. The X-ray showed that the tissue surrounded the implant tightly; however, a gap of metal artifacts was noted around the interface between dental implants and palatal bone. Compared to the CT image, a fluorescence image was noted around the implant site in the NIRF group. Furthermore, the histological implant-bone tissue also exhibited a significant NIRF signal. In conclusion, this novel NIRF molecular imaging system precisely identifies the image loss caused by metal artifacts and can be applied to monitoring bone maturation around orthopedic implants. In addition, by observing the new bone formation, a new principle and timetable for an implant osseointegrated with bone can be established and a new type of implant fixture or surface treatment can be evaluated using this system.

Repeatability and reliability of GABA measurements with magnetic resonance spectroscopy in healthy young adults.

PURPOSE: Gamma-aminobutyric acid (GABA) abnormalities have been implicated in a range of neuropsychiatric disorders. Despite substantial interest in probing GABA in vivo, human imaging studies relying on magnetic resonance spectroscopy (MRS) have generally been hindered by technical challenges, including GABA's relatively low concentration and spectral overlap with other metabolites. Although past studies have shown moderate-to-strong test-retest repeatability and reliability of GABA within certain brain regions, many of these studies have been limited by small sample sizes. METHODS: GABA+ (macromolecular-contaminated) test-retest reliability and repeatability were assessed via a Meshcher-Garwood point resolved spectroscopy (MEGA-PRESS) MRS sequence in the rostral anterior cingulate cortex (rACC; n = 21) and dorsolateral prefrontal cortex (dlPFC; n = 20) in healthy young adults. Data were collected on a 3T scanner (Siemens Prisma, Siemens Healthcare, Erlangen, Germany) and GABA+ results were reported in reference to both total creatine (GABA+/tCr) and water (GABA+/water). RESULTS: Results showed strong test-retest repeatability (mean GABA+/tCr coefficient of variation [CV] = 4.6%; mean GABA+/water CV = 4.0%) and reliability (GABA+/tCr intraclass correlation coefficient [ICC] = 0.77; GABA+/water ICC = 0.87) in the dlPFC. The rACC showed acceptable (but comparatively lower) repeatability (mean GABA+/tCr CV = 8.0%; mean GABA+/water CV = 7.5%), yet low-moderate reliability (GABA+/tCr ICC = 0.40; GABA+/water ICC = 0.44). CONCLUSION: The present study found excellent GABA+ MRS repeatability and reliability in the dlPFC. The rACC showed inferior results, possibly because of a combination of shimming impedance and measurement error. These data suggest that MEGA-PRESS can be utilized to reliably distinguish participants based on dlPFC GABA+ levels, whereas the mixed results in the rACC merit further investigation.

Rheumatoid arthritis and risk of spontaneous abortion: a Danish nationwide cohort study.

OBJECTIVES: To investigate the influence of RA or preclinical RA on the risk of spontaneous abortion (SA) while taking age and duration of RA into consideration. METHODS: By linkage of data from Danish national registries, we established a nationwide cohort of pregnancies in Denmark from 1 January 1977 to 31 December 2014. We used multiple logistic regression to estimate; odds ratios (OR) for SA in women with RA or preclinical RA, compared with women without, and OR for SA by maternal age in women with RA or preclinical RA. RESULTS: A total of 2 612 529 pregnancies were included. Women aged <35 years diagnosed with RA <5 years before pregnancy had an increased risk of SA (OR = 1.25 95% CI: 1.07, 1.48), compared with women without RA aged <35. Women at the same age diagnosed with RA ≥5 years before pregnancy had an OR of 1.14 (0.96-1.34), compared with women without. Among women with RA aged ≥35 years and women with preclinical RA at time of pregnancy, no increased risk of SA was found. The risk of SA increased by maternal age in both women with RA, preclinical RA and in women without. CONCLUSION: Among women aged <35 years, the risk of SA was higher in women with RA compared with women without. After the age of 35 years, the risk of SA was no different from that among women without RA, even though the risk of SA increased with increasing age.

Outcomes of nonemergent percutaneous coronary intervention requiring mechanical circulatory support in patients without cardiogenic shock.

BACKGROUND: The utilization of mechanical circulatory support (MCS) for percutaneous coronary intervention (PCI) using percutaneous ventricular assist device (PVAD) or intra-aortic balloon pump (IABP) has been increasing. We sought to evaluate the outcome of coronary intervention using PVAD compared with IABP in noncardiogenic shock and nonacute myocardial infarction patients. METHOD: Using the National Inpatient Sampling (NIS) database from 2005 to 2014, we identified patients who underwent PCI using ICD 9 codes. Patients with cardiogenic shock, acute coronary syndrome, or acute myocardial infarction were excluded. Patient was stratified based on the MCS used, either to PVAD or IABP. Univariate and multivariate logistic regression were performed to study PCI outcome using PVAD compared with IABP. RESULTS: Out of 21,848 patients who underwent PCI requiring MCS, 17,270 (79.0%) patients received IABP and 4,578 (21%) patients received PVAD. PVAD patients were older (69 vs. 67, p < .001), were less likely to be women (23.3% vs. 33.3%, p < .001), and had higher rates of hypertension, diabetes, hyperlipidemia prior PCI, prior coronary artery bypass graft surgery, anemia, chronic lung disease, liver disease, renal failure, and peripheral vascular disease compared with IABP group (p ≤ .007). Using Multivariate logistic regression, PVAD patients had lower in-hospital mortality (6.1% vs. 8.8%, adjusted odds ratio [aOR] 0.62; 95% CI 0.51, 0.77, p < .001), vascular complications (4.3% vs. 7.5%, aOR 0.78; 95% CI 0.62, 0.99, p = .046), cardiac complications (5.6% vs. 14.5%, aOR 0.29; 95% CI 0.24, 0.36, p < .001), and respiratory complications (3.8% vs. 9.8%, aOR 0.37; 95% CI 0.28, 0.48, p < .001) compared with patients who received IABP. CONCLUSION: Despite higher comorbidities, nonemergent PCI procedures using PVAD were associated with lower mortality compared with IABP.

Electronic IR Group Peer Review and Learning Performed during Daily Clinical Rounds.

PURPOSE: To describe the implementation and efficacy of electronic capture of interventional radiology (IR) group peer review performed during morning rounds in an academic institution. MATERIALS AND METHODS: Peer-review submissions 24 months before (July 2012 through June 2014) and 24 months after (July 2014 through June 2016) implementation of an electronic group IR peer review were evaluated. Electronic IR peer review assessed clinical decision-making, patient care, and technique appropriateness by using the following responses: agree, acceptable alternative, or inappropriate. Complications, near-misses, and learning opportunities were also noted, and explanations were provided in the comments. An IR attending physician documented the consensus discussion via an online form or mobile app. RESULTS: After implementation of electronic capture of IR group peer reviews, 9.5% of all IR procedures (773 of 8,152) were reviewed, compared with 0.9% (63 of 7,152) before the implementation (P < .0001). On average, 3.4 ± 0.5 IR attending physicians participated in each review, and 17.3 ± 9.7 IR cases were reviewed per month by each attending physician. Peers fully agreed with the chosen technique in 729 of 773 cases (94.3%) and noted an acceptable alternative technique in 40 of 773 (5.2%). In 4 cases (0.5%), the chosen technique was rated as inappropriate. Peers fully agreed with chosen clinical decision-making and patient care in 765 of 773 cases (99%), with 8 cases (1%) deemed as acceptable alternatives. Learning opportunities were documented in 9.6% of cases (74 of 773). CONCLUSIONS: Electronic IR-specific group peer review captures the clinical decision-making process, patient outcomes, technical appropriateness, and short-term complications and may provide practice-improvement solutions.

A novel missense mutation in NR0B1 causes delayed-onset primary adrenal insufficiency in adults.

A novel missense mutation (c.775T>C; p.ser259Pro) in the NROBI gene cause a late-onset adrenal insufficiency without hypogonadism.

Estimating the Basal metabolic rate from fat free mass in individuals with motor complete spinal cord injury.

STUDY DESIGN: Cross-sectional study. OBJECTIVES: This study aimed to validate the existing basal metabolic rate (BMR) predictive equations that include fat free mass (FFM) as an independent variable and, based on the FFM assessment, to develop a new SCI population-specific equation. SETTING: Outpatient clinic in a general hospital. METHODS: Our study group was formed of 50 individuals with chronic motor complete SCI: 27 patients with tetraplegia and 23 with paraplegia. Both BMR and FFM values were measured by indirect calorimetry (IC) and the whole-body dual energy X-ray absorptiometry, respectively. The BMR values measured by IC were compared with the values estimated from the Cunningham equation. Multiple linear regression analysis was performed to develop a new FFM-based, BMR predictive equation. RESULTS: The mean value of BMR measured by IC was 1274.8 (s.d.=235.2) kcal day-1. The intra-class correlation coefficient (ICC) between values measured by IC and estimated from the Cunningham equation was 0.845 and the limits of agreement ranged from -30.6 to 241.3 kcal. SCI population specific BMR predictive equation was developed; BMR (kcal day-1)=24.5 × FFM (kg)+244.4. The newly developed equation showed ICC of 0.866 with the limits of agreement from -229.0 to 233.1 kcal day-1. CONCLUSIONS: A considerable bias from the BMR values measured by IC was still observed, which warrants clinical consideration when applying FFM-based BMR prediction equations to individuals with SCI.

Severe spasticity in lower extremities is associated with reduced adiposity and lower fasting plasma glucose level in persons with spinal cord injury.

STUDY DESIGN: Cross-sectional study. OBJECTIVES: To investigate the effects of severe lower extremity spasticity on anthropometric dimensions, body composition and metabolic profiles in persons with chronic motor complete spinal cord injury (SCI). SETTING: Outpatient clinic. METHODS: Fifty-five of the 61 participants were divided into two groups (no or mild spasticity group, 28; severe spasticity group, 27) based on the assessment of the extensor muscle spasticity according to the modified Ashworth scale. Anthropometric dimensions (waist circumference (WC), waist-to-height ratio (WtHR)), body composition (fat mass (FM), body fat percentage (BFP), fat-free mass (FFM), fat-free mass percentage (FFMP), bone mineral density (BMD)) and metabolic profiles (leptin, total cholesterol, low-density lipoprotein (LDL), high-density lipoprotein (HDL), triglyceride (TG), fasting plasma glucose (FPG) and glycosylated hemoglobin (HbA1c)) were compared between the two groups with different degree of spasticity. RESULTS: Spasticity of the extensor muscle group negatively correlated with BFP (r=-0.458, P<0.001). Patients with severe spasticity showed a lower WC and WtHR than those in the no or mild spasticity group (P=0.038, P=0.006, respectively). The FM, BFP, leptin and FPG of the severe spasticity group were significantly lower than those of the patients in the no or mild spasticity group (P=0.003, P<0.001, P<0.001 and P=0.037, respectively). However, no differences in BMD, total cholesterol, LDL, HDL, TG and HbA1c were observed between the groups. CONCLUSIONS: The results of this study suggest that severe spasticity in lower extremities is associated with reduced adiposity and lower FPG levels in persons with chronic motor complete SCI.

Temporary work and depressive symptoms in South Korean workers.

BACKGROUND: In many countries, including South Korea, labour market changes have led to an increase in unstable, temporary jobs. There is evidence that workers in such jobs may experience poorer mental health than those in more stable employment. AIMS: To investigate the association between temporary employment and depressive symptoms in South Korean workers. METHODS: We analysed data from the 2010-2014 Korean Welfare Panel Study (KOWEPS). Employment type was categorized into workers paid per day of labour (day labourers), those on short-term contracts (fixed-term workers) and permanent workers. The association between employment type and depressive symptoms, measured using the Center for Epidemiological Studies Depression scale (CES-D 11), was examined using the generalized estimating equation model. RESULTS: A total of 3756 workers aged 20-59 were included in the 2010 baseline population. Day labourers had the highest mean CES-D 11 score, followed by fixed-term workers and permanent workers. With the day labourer group as reference, fixed-term workers (ß: -1.5027, P < 0.001) and permanent workers (ß: -2.1848, P < 0.001) showed statistically significant decreases in depression scores. CONCLUSIONS: Compared with day labourers, fixed-term workers and permanent workers had progressively lower depression scores. The findings of this study suggest that mental health inequalities based on employment type exist in South Korea.

Association of bone mineral density and diabetic retinopathy in diabetic subjects: the 2008-2011 Korea National Health and Nutrition Examination Survey.

UNLABELLED: Because diabetic retinopathy increases fracture risk, we studied the association between bone mineral density (BMD) and diabetic retinopathy in a nationally representative sample. A significant association between the presence of diabetic retinopathy and low BMD was observed. Therefore, diabetic retinopathy might be considered as a marker of low BMD. INTRODUCTION: Several diabetic complications, including nephropathy, retinopathy, and peripheral neuropathy, are associated with a higher fracture risk in diabetic subjects. However, in contrast to diabetic nephropathy and peripheral neuropathy, which are associated with low bone mineral density (BMD), little is known about the association between BMD and diabetic retinopathy. The aim of the present study was to determine whether the prevalence of diabetic retinopathy is associated with BMD. METHODS: This cross-sectional study included a nationally representative sample consisting of 4357 men aged 50 years and older and 4392 postmenopausal women who participated in the Korea National Health and Nutritional Examination Survey (KNHANES) from 2008 to 2011 and underwent BMD measurement by dual-energy X-ray absorptiometry (DXA) and diabetic retinopathy assessments using seven standard gradable photographs. RESULTS: The diabetic women with retinopathy had lower mean BMD at all measured sites than those without retinopathy, although the BMD difference between the two groups was small (3-5 %). In addition, the diabetic women with retinopathy were 2.27 times more likely to have osteoporosis following adjustments for all clinically relevant covariates. However, the prevalence of diabetes mellitus (DM) or diabetic retinopathy was not associated with the prevalence of osteoporosis in men. CONCLUSIONS: This study has shown that the presence of diabetic retinopathy is significantly associated with a reduced BMD and increased prevalence of osteoporosis in diabetic women.

Protein stability changes of the novel p.Arg180Cys mutant A glycosyltransferase resulted in a weak A phenotype.

A novel A subgroup allele (c.538C>T p.Arg180Cys) showing weak A phenotype was found in a 30-year-old Korean woman with ABO discrepancy. Using 3D structural analysis, protein stability prediction and flow cytometric analysis of ABO antigen expression on HeLa cells transfected with plasmids containing the p.Arg180Cys mutant, we found that the Arg180 residue in the loop region of the A glycosyltransferases (GTA) structure plays significant role in stabilizing its closed conformation, which is required for substrate binding and catalysis study.

An effective diagnostic strategy for accurate detection of RhD variants including Asian DEL type in apparently RhD-negative blood donors in Korea.

BACKGROUND AND OBJECTIVES: The purpose of this study was to provide an effective RHD genotyping strategy for the East Asian blood donors. MATERIAL AND METHODS: RhD phenotyping, weak D testing and RhCE phenotyping were performed on 110 samples from members of the RhD-negative club, private organization composed of RhD-negative blood donors, in the GwangJu-Chonnam region of Korea. The RHD promoter, intron 4, and exons 7 and 10 were analysed by real-time PCR. Two nucleotide changes (c.1227 G>A, and c.1222 T>C) in exon 9 were analysed by sequencing. RESULTS: Of 110 RhD-negative club members, 79 (71·8%) showed complete deletion of the RHD gene, 10 (9·1%) showed results consistent with RHD-CE-D hybrid, and 21 (19·1%) showed amplification of RHD promoter, intron 4, and exons 7 and 10. Of the latter group, 16 (14·5%) were in the DEL blood group including c.1227 G>A (N = 14) and c.1222 T>C (N = 2), 2 (1·8%) were weak D, 1(0·9%) was partial D, and 2 (1·8%) were undetermined. The RhD-negative phenotype samples consisted of 58 C-E-c+e+, 19 C-E+c+e+, 3 C-E+c+e-, 21 C+E-c+e-, 6 C+E-c+e+ and 3 C+E-c-e + . Notably, all 58 samples with the C-E-c+e+ phenotype were revealed to have complete deletion of the RHD gene. The C-E-c+e+ phenotype showed 100% positive predictive value for detecting D-negative cases. CONCLUSIONS: RHD genotyping is not required in half of D-negative cases. We suggest here an effective RHD genotyping strategy for accurate detection of RhD variants in apparently RhD-negative blood donors in East Asia.

The complementary nature of peer review and quality assurance data collection.

PURPOSE: To assess the complementary natures of (a) a peer review ( PR peer review )-mandated database for physician review and discrepancy reporting and (b) a voluntary quality assurance ( QA quality assurance ) system for anecdotal reporting. MATERIALS AND METHODS: This study was institutional review board approved and HIPAA compliant; informed consent was waived. Submissions to voluntary QA quality assurance and mandatory PR peer review databases were searched for obstetrics and gynecology-related keywords. Cases were graded independently by two radiologists, with final grades resolved via consensus. Errors were categorized as perceptional, interpretive, communication related, or procedural. Effect of errors was assessed in terms of clinical and radiologic follow-up. RESULTS: There were 185 and 64 cases with issues attributed to 32 and 27 radiologists in QA quality assurance and PR peer review databases, respectively; 23 and nine radiologists, respectively, had cases attributed to only them. Procedure-related entries were submitted almost exclusively through the QA quality assurance database (62 of 64 [97%]). In QA quality assurance and PR peer review databases, respectively, perceptional (47 of 185 [25%] and 27 of 64 [42%]) and interpretative (64 of 185 [34%] and 30 of 64 [47%]) issues constituted most errors. Most entries in both databases (104 of 185 [56%] in QA quality assurance and 49 of 64 [76%] in PR peer review ) were considered minor events: wording in the report, findings already known from patient history or prior imaging or concurrent follow-up imaging, or delay in diagnosing a benign finding. Databases had similar percentages of moderate events (28 of 185 [15%] in QA quality assurance and nine of 64 [14%] in PR peer review ), such as recommending unnecessary follow-up imaging or radiation exposure in pregnancy without knowing the patient was pregnant (nine of 64 [14%] in PR peer review and 28 of 185 [15%] in QA quality assurance ). The PR peer review database had fewer major events (one of 64 [1.6%]) than the QA quality assurance database (32 of 185 [17%]). CONCLUSION: The two quality improvement systems are complementary, with the QA quality assurance database yielding less frequent but more clinically important errors, while the PR peer review database serves to establish benchmarks for error rate in radiologists' performance.

Identification of a novel HLA-C*03 variant allele, C*03:280 by sequence-based typing.

The new allele, HLA-C*03:280 differs from C*03:04:01 by one nucleotide substitution at codon 35 (CGG→CAG).

Clinical characteristics of Raoultella ornithinolytica bacteremia.

PURPOSE: Raoultella ornithinolytica is not well known as a clinical pathogen. We performed a retrospective review of R. ornithinolytica bacteremia to investigate its clinical features, antimicrobial susceptibility, and overall patient outcomes. METHODS: R. ornithinolytica bacteremia cases were collected from an electronic database of all cases of bacteremia over a 10-year period. Medical records were retrospectively reviewed. Demographic data, clinical information, the presence of underlying comorbidities, the results of antimicrobial susceptibility testing, and the antimicrobial regimen administered were investigated. RESULTS: R. ornithinolytica was isolated from blood culture specimens in 16 cases. The majority of these patients had an underlying malignant condition of advanced stage (15 patients, 94 %). Seven of these patients had a solid tumor with lesions or metastases that extended to the bile duct or biliary tract. Neutropenic fever following hematologic stem cell transplantation was found in three cases. No resistance to piperacillin/tazobactam or imipenem was found. Four cases showed resistance to cefoxitin, while one of these cases showed resistance to multiple cephalosporins. In overall outcomes, seven patients (44 %) did not recover from the infection and subsequently expired. CONCLUSIONS: R. ornithinolytica bacteremia occurs mainly in patients with underlying malignancies. The overall outcome was not favorable, despite favorable antimicrobial susceptibility test results. The findings of this study contradict those of other studies that demonstrated that infection from Raoultella species have good prognoses.

Thiazolidinediones and associated risk of bladder cancer: a systematic review and meta-analysis.

AIMS: To determine whether thiazolidinedione use is associated with a risk of bladder cancer. METHODS: We searched MEDLINE and EMBASE in June 2012 (with PubMed update to July 2013) and conducted meta-analysis on the overall risks of bladder cancer with pioglitazone or rosiglitazone and the risk with different categories of cumulative dose or duration of drug use. RESULTS: We screened 230 citations and included 18 studies, comprising five randomized controlled trials (RCTs) and 13 observational studies. Meta-analysis showed a significantly higher overall risk of bladder cancer with pioglitazone in RCTs [7878 participants; odds ratio (OR) 2.51, 95% confidence interval (CI) 1.09-5.80] and observational studies (>2.6 million patients; OR for 'ever' users vs. non-users 1.21, 95% CI 1.09-1.35). Subgroup analysis of observational studies by cumulative dose showed the risk of bladder cancer to be greatest with >28.0 g of pioglitazone (OR 1.64, 95% CI 1.28-2.12). A significantly increased risk was found with both 12-24 months (OR 1.41, 95% CI 1.16-1.71) and >24 months (OR 1.51, 95% CI 1.26-1.81) cumulative durations of pioglitazone exposure. No significant risk was seen with rosiglitazone in RCTs (OR 0.84, 95% CI 0.35-2.04) or 'ever' users vs. non-users in observational studies (OR 1.03, 95% CI 0.94-1.12); the evidence for any relationship between bladder cancer risk and rosiglitazone cumulative duration is limited and inconsistent. Direct comparison of pioglitazone to rosiglitazone 'ever' users yielded an OR of 1.25 (95% CI 0.91-1.72). CONCLUSIONS: A modest but clinically significant increase in the risk of bladder cancer with pioglitazone was found, which appears to be related to cumulative dose and duration of exposure. We recommend that prescribers limit pioglitazone use to shorter durations.

Low virulence? Clinical characteristics of Raoultella planticola bacteremia.

PURPOSE: Numerous case reports regarding Raoultella planticola infection have accumulated in the literature; however, its significance as a clinical pathogen remains unknown. We performed a retrospective review of R. planticola bacteremia to characterize its clinical features, antimicrobial susceptibility, and patient outcome. METHODS: Raoultella planticola bacteremia cases were culled from an electronic database of all bacteremia cases occurring over a 4-year-period. Medical records were retrospectively reviewed and demographic data, clinical findings, presence of underlying disease, results of antimicrobial susceptibility testing, and the antibiotic regimens administered during the treatment were evaluated. RESULTS: Raoultella planticola was isolated from blood culture specimens in 20 cases. The majority of these patients had underlying malignant conditions (17 patients, 85%). The most prevalent causes of malignancy were adenocarcinoma involving the gallbladder or bile duct (7 patients) and hematologic malignancies (6 patients). No cases with resistance to carbapenem or third generation cephalosporins were found. All 14 patients with R. planticola as the sole microbial isolate recovered with the use of empirical antibiotics. Of the six patients with polymicrobial infection, three did not recover and subsequently expired. CONCLUSIONS: Raoultella planticola bacteremia seemed to occur mainly in immunocompromised patients, and was also frequently found in patients with lesions involving the gallbladder or bile duct. The overall outcome was favorable when R. planticola was treated with administration of empirical antibiotics. Mixed outcomes were found when blood cultures yielded multiple species of microbes.

Niclosamide potentiates TMEM16A and induces vasoconstriction.

The TMEM16A calcium-activated chloride channel is a promising therapeutic target for various diseases. Niclosamide, an anthelmintic medication, has been considered a TMEM16A inhibitor for treating asthma and chronic obstructive pulmonary disease (COPD) but was recently found to possess broad-spectrum off-target effects. Here, we show that, under physiological Ca2+ (200-500 nM) and voltages, niclosamide acutely potentiates TMEM16A. Our computational and functional characterizations pinpoint a putative niclosamide binding site on the extracellular side of TMEM16A. Mutations in this site attenuate the potentiation. Moreover, niclosamide potentiates endogenous TMEM16A in vascular smooth muscle cells, triggers intracellular calcium increase, and constricts the murine mesenteric artery. Our findings advise caution when considering clinical applications of niclosamide as a TMEM16A inhibitor. The identification of the putative niclosamide binding site provides insights into the mechanism of TMEM16A pharmacological modulation and provides insights into developing specific TMEM16A modulators to treat human diseases.

Evaluating the American Heart Association/American College of Cardiology Guideline-Recommended and Contemporary Pretest Probability Models in a Mixed Asian Cohort: The Contribution of Coronary Artery Calcium.

BACKGROUND: Most pretest probability (PTP) tools for obstructive coronary artery disease (CAD) were Western -developed. The most appropriate PTP models and the contribution of coronary artery calcium score (CACS) in Asian populations remain unknown. In a mixed Asian cohort, we compare 5 PTP models: local assessment of the heart (LAH), CAD Consortium (CAD2), risk factor-weighted clinical likelihood, the American Heart Association/American College of Cardiology and the European Society of Cardiology PTP and 3 extended versions of these models that incorporated CACS: LAH(CACS), CAD2(CACS), and the CACS-clinical likelihood. METHODS AND RESULTS: The study cohort included 771 patients referred for stable chest pain. Obstructive CAD prevalence was 27.5%. Calibration, area under the receiver-operating characteristic curves (AUC) and net reclassification index were evaluated. LAH clinical had the best calibration (χ2 5.8; P=0.12). For CACS models, LAH(CACS) showed least deviation between observed and expected cases (χ2 37.5; P<0.001). There was no difference in AUCs between the LAH clinical (AUC, 0.73 [95% CI, 0.69-0.77]), CAD2 clinical (AUC, 0.72 [95% CI, 0.68-0.76]), risk factor-weighted clinical likelihood (AUC, 0.73 [95% CI: 0.69-0.76) and European Society of Cardiology PTP (AUC, 0.71 [95% CI, 0.67-0.75]). CACS improved discrimination and reclassification of the LAH(CACS) (AUC, 0.88; net reclassification index, 0.46), CAD2(CACS) (AUC, 0.87; net reclassification index, 0.29) and CACS-CL (AUC, 0.87; net reclassification index, 0.25). CONCLUSIONS: In a mixed Asian cohort, Asian-derived LAH models had similar discriminatory performance but better calibration and risk categorization for clinically relevant PTP cutoffs. Incorporating CACS improved discrimination and reclassification. These results support the use of population-matched, CACS-inclusive PTP tools for the prediction of obstructive CAD.