Lack of effectiveness of Bebtelovimab monoclonal antibody among high-risk patients with SARS-Cov-2 Omicron during BA.2, BA.2.12.1 and BA.5 subvariants dominated era.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) Omicron subvariants are expected to be resistant to Bebtelovimab (BEB) monoclonal antibody (MAb) and the real-world experience regarding its effectiveness is scarce. This retrospective cohort study reports a data analysis in Banner Healthcare System (a large not-for-profit organization) between 4/5/2022 and 8/1/2022 and included 19,778 Coronavirus disease-19 (COVID-19) positive (by PCR or direct antigen testing) patients who were selected from Cerner-Electronic Health Record after the exclusions criteria were met. The study index date for cohort was determined as the date of BEB MAb administration or the date of the first positive COVID-19 testing. The cohort consist of COVID-19 infected patients who received BEB MAb (N = 1,091) compared to propensity score (PS) matched control (N = 1,091). The primary composite outcome was the incidence of 30-day all-cause hospitalization and/or mortality. All statistical analyses were conducted on the paired (matched) dataset. For the primary composite outcome, the event counts and percentages were reported. Ninety-five percent Clopper-Pearson confidence intervals for percentages were computed. The study cohorts were 1:1 propensity matched without replacement across 26 covariates using an optimal matching algorithm that minimizes the sum of absolute pairwise distance across the matched sample after fitting and using logistic regression as the distance function. The pairs were matched exactly on patient vaccination status, BMI group, age group and diabetes status. Compared to the PS matched control group (2.6%; 95% confidence interval [CI]: 1.7%, 3.7%), BEB MAb use (2.2%; 95% CI: 1.4%, 3.3%) did not significantly reduce the incidence of the primary outcome (p = 0.67). In the subgroup analysis, we observed similar no-difference trends regarding the primary outcomes for the propensity rematched BEB MAb treated and untreated groups, stratified by patient vaccination status, age (<65 years or ≥65), and immunocompromised status (patients with HIV/AIDS or solid organ transplants or malignancy including lymphoproliferative disorder). The number needed to treat (1/0.026-0.022) with BEB MAb was 250 to avoid one hospitalization and/or death over 30 days. The BEB MAb use lacked efficacy in patients with SARS-CoV-2 Omicron subvariants (mainly BA.2, BA.2.12.1, and BA.5) in the Banner Healthcare System in the Southwestern United States.

Meat production traits of Angora goat 1: fattening, slaughter, and carcass characteristics of intact and castrated kids.

Fattening performance, slaughter, and carcass traits of intact and castrated Angora goat kids slaughtered at different slaughter weights were examined. A total of 96 (48 intact, I-kids, and 48 castrated, C-kids) single Angora kids were fattened, and 48 of them (24 I-kids and 24 C-kids) were slaughtered at slaughter weights (SW) of 20, 25, and 30 kg. Castration negatively affected fattening performance, and the kids showed rising daily weight gain with increasing SW. While dressing percentages were not affected by castration, it caused a tendency for a decrease in offal. However, with the increase in SW, dressing percentages increased, and offal decreased. Castration increased non-carcass fat percentages and back fat depth. The proportions of individual cuts did not generally vary because of castration but changed with SW; foreleg percentages decreased (P < 0.001) while neck percentages increased (P < 0.05). Carcass composition was affected by castration; the percentages of carcass lean (P < 0.001) and bone (P < 0.01) dropped, and total fat (P < 0.001) increased. SW had an impact on carcass composition; the percentages of carcass bone (P < 0.001) declined, and lean (P < 0.001) and total fat (P < 0.001) raised as SW increased. The lean/fat ratio was affected by castration (P < 0.001) and increasing SW (P < 0.05). Castration reduced the lean percentage in all cuts. The leg showed the highest lean percentage, whereas the greatest fat ratio was found in the breast+flank in all SW groups. Consequently, castration of Angora male kids negatively affected fattening performance and altered the carcass composition, while the increase in slaughter weight improved fattening performance and slaughter and carcass characteristics.

Quantitative analyses of CTP-499 and five major metabolites by core-structure analysis.

CTP-499 is a novel oral multi-subtype selective inhibitor of PDEs that is currently in clinical testing, in combination with angiotensin modulators, as a potentially first-in-class treatment for diabetic kidney disease. The compound was discovered and developed by using Concert's proprietary DCE Platform(®) in which deuterium was incorporated at select positions of 1-((S)-5-hydroxyhexyl)-3,7-dimethylxanthine (HDX). CTP-499 metabolizes to five major metabolites: C-21256, D-M2, D-M3, D-M4 and M5, of which all contains deuterium except M5. During in vivo metabolism, however, H/D exchange takes place. As a result, each analyte, except M5, has multiple molecular masses. To accurately quantify the analytes, we developed an LC-MS/MS method focusing on the core structures of the molecules, termed "core-structure analyses". The core-structure analyses method was then validated under GLP guidance in dog, rat and rabbit plasma, with a sample volume of 50 µL. Results demonstrated that this approach accurately quantifies each of the six analytes despite partial exchange of deuterium with hydrogen atoms in the in vivo samples. The validation parameters included accuracy, precision, sensitivity, stability, dilution integrity, hemolysis, matrix effect, selectivity, and recovery. Acceptable intra-run and inter-run assay precision (%CV ≤ 5.5%) and accuracy (90.1-106.7%) were achieved over a linear range of 10-5,000 ng/mL of each analyte. Various stability tests, including bench-top, freeze/thaw, stock solution, and long-term storage, were also performed. All stability results met acceptance criteria. The robustness of the methods was demonstrated by the incurred sample reproducibility (ISR) tests. After validation, the method was successfully used in support of multiple toxicological studies of CTP-499.

Formulation of zolmitriptan sublingual tablets prepared by direct compression with different polymers: in vitro and in vivo evaluation.

First-pass metabolism can be overcome by sublingual drug delivery, and quick drug entry into the systemic circulation can be obtained. In certain diseases such as migraine therapy, taking fast pharmacological response is an important criteria. In this study, zolmitriptan sublingual tablets were prepared by direct compression method using different mucoadhesive polymers such as hydroxypropyl methyl cellulose, chitosan and sodium carboxy methyl cellulose at a concentration range of 0.5-5% to reduce flushing action of saliva and provide enough time for drug to be absorbed. Tablets were evaluated for the physical properties, and optimum formulations were chosen for in vivo studies to carry on sheep model. The tablets disintegrated rapidly, and dissolution tests revealed that zolmitriptan was dissolved from the formulation within the compendial limits. This especially showed us that the concentration range of polymers is in acceptable limit. It was also concluded that microcrystalline cellulose, spray-dried lactose and sodium starch glycolate are the appropriate excipient and formulated in good proportions. In vivo studies indicated that formulation containing 5% chitosan has the maximum C(max) and AUC and minimum t(max) values (p<0.05). As a result, sublingual tablet administration of zolmitriptan formulated with appropriate excipients and especially with chitosan seems promising alternative to traditional routes.

Congenital leptin deficiency and thyroid function.

UNLABELLED: : Thyroid function is closely related to leptin's secretion by the adipose tissue. In states of leptin-deficiency, the circadian rhythm of TSH is altered, leading to central hypothyroidism in animal models. In humans, central hypothyroidism has also been described in rare cases of congenital leptin deficiency. However, the thyroid phenotype in these cases is heterogeneous, with the occurrence of central hypothyroidism in a minority of cases. Here we describe thyroid function in four leptin-deficient humans (2 males aged 5 and 27, and 2 females aged 35 and 40), before and during leptin replacement with recombinant human methionyl leptin (r-metHuLeptin). The child was evaluated for four years, and the adults, for eight years. In addition, the adults were submitted to a brief withdrawal of leptin during six weeks in the sixth year. Our results show that, regardless of leptin replacement, our leptin-deficient patients have normal thyroid function. In spite of having an important role in regulating the hypothalamic-pituitary-thyroidal axis, leptin is not required for normal thyroid function. TRIAL REGISTRATION: ClinicalTrials.gov Identifiers: NCT00659828 and NCT00657605.

Cellular immunity before and after leptin replacement therapy.

BACKGROUND: The few identified leptin-deficient children have immune deficiency. AIMS: To evaluate whether a newly-identified leptin-deficient boy has immune defects; to assess the immune changes during leptin replacement. METHODS: A 5 year-old boy with congenital leptin deficiency was evaluated before, 2 weeks and 6 weeks after the initiation of recombinant methionyl human leptin. Thymic volume was measured by computed tomography. Humoral immunity was assessed by measuring levels of several immunoglobulins. Cellular immunity was evaluated by the analysis of lymphocyte proliferation in response to mitogens. Lymphocyte subsets were quantified by flow cytometry. RESULTS: At baseline, thymic volume was increased. The lymphocyte subsets count and humoral/cellular immunities were normal. After treatment, proliferative response to mitogens increased by 1.5- to 3-fold, and lymphocyte count decreased by 17%. CONCLUSIONS: Immune defects are not an obligatory feature of congenital leptin deficiency. Even in the absence of significant immune defects, leptin replacement therapy enhanced T-cell responsiveness.

Changes in insulin sensitivity during leptin replacement therapy in leptin-deficient patients.

Leptin replacement rescues the phenotype of morbid obesity and hypogonadism in leptin-deficient adults. However, leptin's effects on insulin resistance are not well understood. Our objective was to evaluate the effects of leptin on insulin resistance. Three leptin-deficient adults (male, 32 yr old, BMI 23.5 kg/m(2); female, 42 yr old, BMI 25.1 kg/m(2); female, 46 yr old, BMI 31.7 kg/m(2)) with a missense mutation of the leptin gene were evaluated during treatment with recombinant methionyl human leptin (r-metHuLeptin). Insulin resistance was determined by euglycemic hyperinsulinemic clamps and by oral glucose tolerance tests (OGTTs), whereas patients were on r-metHuLeptin and after treatment was interrupted for 2-4 wk in the 4th, 5th, and 6th years of treatment. At baseline, all patients had normal insulin levels, C-peptide, and homeostatic model assessment of insulin resistance index, except for one female diagnosed with type 2 diabetes. The glucose infusion rate was significantly lower with r-metHuLeptin (12.03 +/- 3.27 vs. 8.16 +/- 2.77 mg.kg(-1).min(-1), P = 0.0016) but did not differ in the 4th, 5th, and 6th years of treatment when all results were analyzed by a mixed model [F(1,4) = 0.57 and P = 0.5951]. The female patient with type 2 diabetes became euglycemic after treatment with r-metHuLeptin and subsequent weight loss. The OGTT suggested that two patients showed decreased insulin resistance while off treatment. During an off-leptin OGTT, one of the patients developed a moderate hypoglycemic reaction attributed to increased posthepatic insulin delivery and sensitivity. We conclude that, in leptin-deficient adults, the interruption of r-metHuLeptin decreases insulin resistance in the context of rapid weight gain. Our results suggest that hyperleptinemia may contribute to mediate the increased insulin resistance of obesity.

Leptin replacement improves cognitive development.

BACKGROUND: Leptin changes brain structure, neuron excitability and synaptic plasticity. It also regulates the development and function of feeding circuits. However, the effects of leptin on neurocognitive development are unknown. OBJECTIVE: To evaluate the effect of leptin on neurocognitive development. METHODOLOGY: A 5-year-old boy with a nonconservative missense leptin gene mutation (Cys-to-Thr in codon 105) was treated with recombinant methionyl human leptin (r-metHuLeptin) at physiologic replacement doses of 0.03 mg/kg/day. Cognitive development was assessed using the Differential Ability Scales (DAS), a measure of general verbal and nonverbal functioning; and selected subtests from the NEPSY, a measure of neuropsychological functioning in children. PRINCIPAL FINDINGS: Prior to treatment, the patient was morbidly obese, hypertensive, dyslipidemic, and hyperinsulinemic. Baseline neurocognitive tests revealed slower than expected rates of development (developmental age lower than chronological age) in a majority of the areas assessed. After two years, substantial increases in the rates of development in most neurocognitive domains were apparent, with some skills at or exceeding expectations based on chronological age. We also observed marked weight loss and resolution of hypertension, dyslipidemia and hyperinsulinemia. CONCLUSIONS: We concluded that replacement with r-metHuLeptin is associated with weight loss and changes in rates of development in many neurocognitive domains, which lends support to the hypothesis that, in addition to its role in metabolism, leptin may have a cognitive enhancing role in the developing central nervous system. TRIAL REGISTRATION: ClinicalTrials.gov NCT00659828.

Classification of EEG recordings by using fast independent component analysis and artificial neural network.

Since there is no definite decisive factor evaluated by the experts, visual analysis of EEG signals in time domain may be inadequate. Routine clinical diagnosis requests to analysis of EEG signals. Therefore, a number of automation and computer techniques have been used for this aim. In this study we aim at designing a MLPNN classifier based on the Fast ICA that accurately identifies whether the associated subject is normal or epileptic. By analyzing a data set consisting of 100 normal and 100 epileptic EEG time series, we have found that the MLPNN classifier based on the Fast ICA achieved and sensitivity rate of 98%, and specificity rate of 90.5%. The results demonstrate that the testing performance of the neural network diagnostic system is found to be satisfactory and we think that this system can be used in clinical studies. Since the time series analysis of EEG signals is unsatisfactory and requires specialist clinicians to evaluate, this application brings objectivity to the evaluation of EEG signals.

Early severe pre-eclamptic findings in a patient with Cushing's syndrome.

Cushing's syndrome occurs rarely in pregnancy because of ovulatory disturbances including anovulation which is caused by hypercortisolism, but it can cause maternal complications such as hypertension, gestational diabetes, spontaneous abortion, premature birth, pre-eclampsia and stillbirth. Herein we present the case of a 22-year-old patient in the 11th week of pregnancy who was admitted to our hospital with Cushing's syndrome complicated by early pre-eclampsia. Severe pre-eclampsia has high maternal and perinatal morbidities, and therefore the possibility of this complication requires that Cushing's syndrome, although rare in pregnancy, be given a high clinical suspicion. Medical therapy and/or surgical therapy should be considered promptly to influence outcome favorably.