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In this paper, we develop a least-squares support vector machine (LS-SVM) for solving a nonlinear fractional-order Volterra’s population model in a closed system. The fractional rational Legendre functions with an orthogonal property on a semi-infinite domain have been used as the kernel of LS-SVM. Learning the solution is done by solving a non-linear constrained optimization problem. To accelerate the learning process, we propose two different approaches based on the orthogonality of kernels and a shared-memory task parallelization scheme for multi-core systems. By carrying out several experiments, it is seen that the proposed approaches provide accurate solutions for fractional-order Volterra’s population model.

Summary: Background: Insulin resistance (IR) is an important risk factor for multiple chronic diseases, increasing mortality and reducing life expectancy. The associations between emerging surrogates for IR, triglyceride-glucose index (TyG) and TyG-related indicators, with all-cause mortality and life expectancy in middle-aged and older patients in primary care are unclear. Methods: This study originated from the Polish primary care cohort LIPIDOGRAM2015, including patients aged ≥45 years. Baseline fasting triglycerides and fasting glucose were used to derive TyG. Other TyG-related indicators included TyG-adjusted body mass index (TyG-BMI), TyG-adjusted waist circumference (TyG-WC), TyG-adjusted waist-to-hip, and TyG-adjusted waist-to-height. In this longitudinal analysis, we assessed associations between TyG-related indicators with total all-cause mortality, premature (age at death ≤75 years) all-cause mortality and years of life lost (YLL). Findings: We included 10,688 patients (mean age 61.8 ± 9.3 years; 63.5% female). Cumulative total and premature all-cause mortality were 7.2% and 4.6%, respectively, during 5.7 years (IQR 5.6–5.7) of follow-up. Lowest (Q1) and highest quartile (Q4) of TyG-BMI and TyG-WC were associated with total all-cause mortality (second quartile [Q2]: reference; TyG-BMI: Q1: aHR 1.33, 95% CI 1.07–1.65, Q4: aHR 1.28, 95% CI 1.03–1.58; TyG-WC: Q1: aHR 1.44, 95% CI 1.14–1.82, Q4: aHR 1.29, 95% CI 1.04–1.59), similar results for premature all-cause mortality. Within age 45–80 years, compared with Q2 and third quartile, YLL were 4.49 and 5.46 years for TyG-BMI Q1 and Q4, respectively, 3.24 and 5.31 years for TyG-WC Q1 and Q4, respectively. Interpretation: TyG-BMI and TyG-WC demonstrated a U-shaped association with total and premature all-cause mortality. Low and high levels of TyG-BMI and TyG-WC were associated with reduced life expectancy. Despite the relatively short follow-up period, significant associations were still observed, but longer follow-up studies are required to further explore these relationships. Funding: Polish Lipid Association, College of Family Physician in Poland, Valeant in Poland.

Recent fMRI resting-state findings show aberrant functional connectivity within somatomotor network (SMN) in schizophrenia. Moreover, functional connectivity aberrations of the motor system are often reported to be related to the severity of psychotic symptoms. Thus, it is important to validate those findings and confirm their relationship with psychopathology. Therefore, we decided to take an entirely data-driven approach in our fMRI resting-state study of 30 chronic schizophrenia outpatients and 30 matched control subjects. We used independent component analysis (ICA), dual regression, and seed-based connectivity analysis. We found reduced functional connectivity within SMN in schizophrenia patients compared to controls and SMN hypoconnectivity with the cerebellum in schizophrenia patients. The latter was strongly correlated with the severity of alogia, one of the main psychotic symptoms, i.e. poverty of speech and reduction in spontaneous speech,. Our results are consistent with the recent knowledge about the role of the cerebellum in cognitive functioning and its abnormalities in psychiatric disorders, e.g. schizophrenia. In conclusion, the presented results, for the first time clearly showed the involvement of the cerebellum hypoconnectivity with SMN in the persistence and severity of alogia symptoms in schizophrenia., Competing Interests: Declaration of competing interest All authors declare no conflicts of interest., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

Background: The study objective was to assess disparities in outcomes in the waitlist and post-heart transplantation (HT) according to socioeconomic status (SES) in the old and new U.S. HT allocation systems., Methods: Adult HT candidates in the United Network for Organ Sharing database from 2014 through 2021 were included. Old or new system classification was according to listing before or after October 18, 2018. SES was stratified by patient ZIP code and median household income via U.S. Census Bureau and classified into terciles. Competing waitlist outcomes and post-transplantation survival were compared between systems., Results: In total, 26,450 patients were included. Waitlisted candidates with low SES were more frequently younger, female, African American, and with higher body mass index. Reduced cumulative incidence (CI) of HT in the old system occurred in low SES (53.5%) compared to middle (55.7%, p = 0.046), and high (57.9%, p < 0.001). In the new system, the CI of HT was 65.3% in the low SES vs middle (67.6%, p = 0.002) and high (70.2%, p < 0.001), and SES remained significant in the adjusted analysis. In the old system, CI of death/delisting was similar across SES. In the new system, low SES had increased CI of death/delisting (7.4%) vs middle (6%, p = 0.012) and high (5.4%, p = 0.002). The old system showed similar 1-year survival across SES. In the new system, recipients with low SES had decreased 1-year survival (p = 0.041)., Conclusions: SES affects waitlist and post-transplant outcomes. In the new system, all SES had increased access to HT; however, low SES had increased death/delisting due to worsening clinical status and decreased post-transplant survival., (Copyright © 2023 International Society for the Heart and Lung Transplantation. Published by Elsevier Inc. All rights reserved.)

Historically, patients with restrictive (RCM) and hypertrophic cardiomyopathy (HCM) experienced longer wait-times for heart transplant (HT) and increased waitlist mortality. Recently, a new HT allocation system was implemented in the United States. We sought to determine the impact of the new HT system on RCM/HCM patients. Adult patients with RCM/HCM listed for HT between November 2015 and September 2019 were identified from the UNOS database. Patients were stratified into two groups: old system and new system. We identified 872 patients who met inclusion criteria. Of these, 608 and 264 were classified in the old and new system groups, respectively. The time in the waitlist was shorter (25 vs. 54 days, P < .001), with an increased frequency of HT in the new system (74% vs. 68%, P = .024). Patients who were transplanted in the new system had a longer ischemic time, increased use of temporary mechanical circulatory support and mechanical ventilation. There was no difference in posttransplant survival at 9 months (91.1% vs. 88.9%) (p = .4). We conclude that patients with RCM/HCM have benefited from the new HT allocation system, with increased access to HT without affecting short-term posttransplant survival., (© 2020 The American Society of Transplantation and the American Society of Transplant Surgeons.)

Breast cancer resistance protein (BCRP) is a point of interest in drug-drug interaction safety testing. Therefore, a consensus probe that can be applied as victim in multiple experimental settings is of great benefit. Identification of candidates has been driven by the amount and quality of available clinical data, and as a result, drugs such as sulfasalazine and rosuvastatin have been suggested. In this article, the in vitro performance of 5 possible alternatives was evaluated: atorvastatin, chlorothiazide, dantrolene, topotecan, and teriflunomide, and benchmarked against sulfasalazine and rosuvastatin in reference in vitro assays for BCRP drug-drug interaction testing. Based on the results, teriflunomide is proposed as an alternate in vitro BCRP probe., (Copyright © 2018 American Pharmacists Association®. Published by Elsevier Inc. All rights reserved.)

We present a case of a 57-year-old woman with a past medical history of end-stage renal disease and a recent history of electrical defibrillation who arrived for her annual mammogram with no breast-related complaints. The mammogram showed interval development of unusual clusters of heterogeneous calcifications. The patient underwent stereotactic core-needle biopsy for definitive diagnosis. The pathologic evaluation revealed fibrosis, abnormal adipocytes, and calcifications with no evidence of malignancy. The constellation of findings was consistent with fat necrosis and fibrosis related to tissue damage sustained during the recent defibrillation.

Background: Up to 40% of patients with rheumatoid arthritis treated with anti-tumour necrosis factor (TNF) drugs do not respond because of primary inefficacy or loss of response. Although one explanation is that immunogenicity leads to the development of anti-drug antibodies and low drug concentrations, the clinical usefulness of pharmacological monitoring is debated. Our aim was to assess whether the presence of anti-drug antibodies and non-trough drug concentrations could predict treatment response in patients with rheumatoid arthritis treated with anti-TNF drugs., Methods: 331 patients were selected from a multicentre prospective cohort (160 treated with adalimumab, 171 etanercept). Serum samples were collected at 3, 6, and 12 months after treatment initiation. Anti-drug antibodies were measured with RIA, drug concentrations with ELISAs, and Disease Activity Score in 28 joints (DAS28) at each timepoint. Linear and logistic regression, generalised estimating equation (GEE), and receiver operating characteristic curves were used to test the association and predictive value of anti-drug antibodies and non-trough drug concentrations on treatment response (ΔDAS28)., Findings: 835 serial samples were tested (414 adalimumab, 421 etanercept). Anti-adalimumab antibodies were detected in 31 (24·8%) of 125 patients who had completed 12 month follow-up and none of the etanercept patients. The presence of anti-drug antibodies was associated with lower adalimumab concentrations (Spearman r=-0·66, p=0·0041). At 3 months, anti-drug antibody formation and low adalimumab concentrations were significant predictors of poor treatment response at 12 months (area under curve [AUC] 0·68, 95% CI 0·54-0·81, and 0·66, 0·55-0·77, respectively; and both combined 0·71, 0·57-0·85). Adalimumab concentration was the most significant independent predictor of ΔDAS28 after adjustment for confounders (regression coefficient 0·12, 95% CI 0·06-0·18; p=0·003). High etanercept concentrations were associated with better treatment response (p=0·01), but low concentrations at 3 months were not a significant predictor of poor treatment response at 12 months (AUC 0·58, 95% CI 0·46-0·70). In the combined GEE model including adalimumab and etanercept, a body-mass index of 30 kg/m(2) or more was associated with low drug concentrations (regression coefficient 0·78, 95% CI 0·37-1·18; p<0·0001)., Interpretation: Pharmacological testing in anti-TNF initiated patients is clinically useful even in the absence of trough levels. At 3 months, presence of anti-drug antibodies and low adalimumab concentrations are a significant predictor for poor treatment response at 12 months. Strengths of this study include a large, prospective cohort and use of RIA to measure antibodies (less prone to drug interference). Although non-trough concentrations might have underestimated the frequency of antibodies, their presence still predicted response., Funding: MJ is a MRC Clinical Training Fellow supported by the North West England Medical Research Council Fellowship Scheme in Clinical Pharmacology and Therapeutics, which is funded by the UK Medical Research Council (grant number G1000417/94909), ICON, GlaxoSmithKline, AstraZeneca, and the Medical Evaluation Unit. Arthritis Research UK (grant ref 20385)., (Copyright © 2015 Elsevier Ltd. All rights reserved.)

Drug transporter proteins recruit to pharmacological barrier tissues and profoundly affect the ADME properties of a large number of drugs. In vitro assays optimized for drug transporters have grown into routine tools in the determination of molecular level interactions as well as prediction of barrier penetration and system level pharmacokinetics. Regulatory position mandates increasing interest in the application of these assays during drug development.

The thiazide diuretic chlorothiazide is poorly metabolized, and is predominantly excreted via the kidneys. We have previously shown that chlorothiazide is transported by ATP-binding cassette transporter G2, suggesting a potential role for this transporter in apical efflux of chlorothiazide in the kidney. However, because of the poor passive permeability of the drug, it is likely that uptake transporters on the basolateral membrane are also involved to facilitate vectorial transport in the renal proximal tubule. Two suggested candidate transporters for this role are the human organic anion transporters, OAT1 and OAT3. By using mammalian cells stably expressing these transporters, we have demonstrated OAT1- and OAT3-dependent uptake of chlorothiazide with Michaelis constant values of 14.5 and 37.6 µM, respectively. Furthermore, we have found that probenecid, furosemide, and diclofenac inhibit chlorothiazide transport by OAT1 and OAT3, of which the probenecide-mediated inhibition may be of clinical importance. © 2013 Wiley Periodicals, Inc. and the American Pharmacists Association J Pharm Sci 102:1683-1687, 2013., (Copyright © 2013 Wiley Periodicals, Inc.)

We are showing that chlorothiazide, a diuretic, is an ABCG2 substrate. It is a Biopharmaceutics Classification System/Biopharmaceutics Drug Distribution and Classification System (BCS/BDDCS) Class IV drug with low bioavailability. Therefore, we tested if chlorothiazide interacts with major apically located intestinal efflux transporters. Our data show that chlorothiazide is transported by ABCG2 with a Km value of 334.6 µM and does not interact with ABCB1 or ABCC2. The chlorothiazide-ABCG2 interaction results in a vectorial transport in MDCKII-BCRP and Caco-2 cells with efflux ratios of 36 and 8.1 respectively. Inhibition of ABCG2 in Caco-2 cells reduced the efflux ratio to 1.4, suggesting that ABCG2 plays a role in limiting chlorothiazide bioavailability in humans.

Aim: To evaluate the performance of an automated BACTEC MGIT 960, a non-radioactive, non-invasive liquid culture system for cultivation of M. tuberculosis complex in terms of recovery rate and time., Materials and Methods: From March 2005 to December 2007, 14,597 specimens were processed using the MGIT 960 system and the results were compared with conventional L.J medium. We standardised r-nitro benzoic acid (PNBA) assay on MGIT 960 TB system for identification of M. tuberculosis complex and evaluated its usefulness by comparing the results with an in-house molecular assay and sequencing., Results and Discussion: Of the total 6143 (42%) isolates positive for M. tuberculosis complex, 6015 (41%) were positive by MGIT 960 TB system. In contrast, 3526 (24%) M. tuberculosis complex isolates grew on the conventional L.J medium. The mean turn around time for mycobacterial growth in smear-positive specimens was nine days for MGIT 960, and 38 days for L.J. medium whereas in smear negative specimens it was 16 days by MGIT vs. 48 days by L.J., Conclusion: MGIT 960 system with PNBA assay for identification of M. tuberculosis complex is a rapid and useful method in laboratories processing a large number of specimens.

La0.7Sr0.3MnO3 nanoparticles doped with cerium (La0.7-xCe(x)Sr0.3MnO3 where 0 < or = x < or = 0.7) as well as the La(1-y)Sr(y)MnO3 nanoparticles with different values of y (La/Sr ratio) are evaluated for cytotoxicity and heating application. Considering hyperthermia as one of the possible application domains of such materials, the cytotoxicity studies were done on human skin carcinoma and human fibrosarcoma cell lines. All the samples showed the desired heating effect when subjected to high-frequency exposure at 2.45 GHz. Cytotoxicity studies revealed extremely low cytotoxicity in Ce-doped samples as well as in samples with a reduced La/Sr ratio. A maximum percentage cell viability on exposure to these nanoparticles was 95% and 85% for the two groups of samples, respectively, with a dose of 20 microg/mL for the x = 0.4 sample. The issues of dopant solubility and nonstoichiometry are discussed.