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Aims: To investigate levels of vitamin D and parathyroid hormone (PTH) in a population of heart failure (HF) patients, and to evaluate whether vitamin D and PTH are related to prognosis.Methods and Results: This was a prospective study of 148 HF outpatients (mean age 68 years, 102 men) with follow-up for mortality after 3½ years. Levels of N-terminal pro-brain natriuretic peptide (NT-proBNP), PTH, 25-hydroxyvitamin D (25-OHD), and several other biomarkers were examined. Mortality and cardiovascular mortality were analysed in multivariable regression analyses adjusting for other independent prognostic variables. Vitamin D deficiency (≤50 nmol/L) was prevalent in 43% of the population; 26% had elevated PTH levels; none had primary hyperparathyroidism. We found a strong and independent significant association of both PTH and vitamin D to mortality, which was independent of other clinically important parameters [NT-proBNP, estimated glomerular filtration rate (eGFR), age, and left ventricular ejection fraction (LVEF)]. Both PTH and vitamin D were also significantly associated with all cause mortality. In an adjusted model, we found a hazard ratio of 1.9 (confidence interval 1.1-3.4) for vitamin D deficiency and 2.0 (1.0-3.8) for the upper median of PTH, respectively.Conclusion: In this relatively small prospective study, PTH and vitamin D were independently associated with all cause and cardiovascular mortality in patients with HF. This was independent of other known risk factors such as eGFR, LVEF, NT-proBNP, and age. [ABSTRACT FROM AUTHOR]

Two SARS-CoV-2 XBB sub-variants, FL.1 and GE.1, have been increasing in prevalence worldwide, but limited information is available about their ability to evade the immune system. FL.1 and GE.1 are emerging Omicron XBB variants possessing additional mutations in the spike RBD raising concerns of increased neutralization escape. In this study, we assessed the neutralizing ability of eleven FDA-approved monoclonal antibody combinations against different Omicron variants, including BA.2.75, BA.2.76, BA.4/5, XBB.1.5, and CH.1.1. Among the eleven antibodies, Sotrovimab was the only antibody to show broad neutralization ability against XBB.1.5. However, Sotrovimab showed attenuated neutralization efficiency against recently emerging XBB sub-lineages EG.5, FL.1, and GE.1 compared to XBB.1.5. Additionally, XBB.1.5 seropositive convalescent sera displayed lower neutralization activity against EG.5, FL.1, and GE.1. Overall, our findings present enhanced immune evasion capacity of emerging XBB variants and emphasize the importance of continued monitoring of novel variants., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

To restore dystrophin protein in various mutation patterns of Duchenne muscular dystrophy (DMD), the multi-exon skipping (MES) approach has been investigated. However, only limited techniques are available to induce a large deletion to cover the target exons spread over several hundred kilobases. Here, we utilized the CRISPR-Cas3 system for MES induction and showed that dual crRNAs could induce a large deletion at the dystrophin exon 45-55 region (∼340 kb), which can be applied to various types of DMD patients. We developed a two-color SSA-based reporter system for Cas3 to enrich the genome-edited cell population and demonstrated that MES induction restored dystrophin protein in DMD-iPSCs with three distinct mutations. Whole-genome sequencing and distance analysis detected no significant off-target deletion near the putative crRNA binding sites. Altogether, dual CRISPR-Cas3 is a promising tool to induce a gigantic genomic deletion and restore dystrophin protein via MES induction., Competing Interests: Conflict of interests A.H. is a scientific adviser of C4U. Y.Kita, Y.Kojima, and A.H. have submitted a patent regarding this study., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

Selection-free, scarless genome editing in human pluripotent stem cells (PSCs) by utilizing ribonucleoprotein (RNP) of CRISPR-Cas9 is a useful tool for a variety of applications. However, the process can be hampered by time-consuming subcloning steps and inefficient delivery of the RNP complex and ssDNA template. Here, we describe the optimized protocol to introduce a single nucleotide change or a loxP site insertion in feeder-free, xeno-free iPSCs by utilizing MaxCyte and 4D-Nucleofector electroporators. For complete details on the use and execution of this protocol, please refer to Kagita et al. (2021) and Xu et al. (2019)., Competing Interests: P.G. is an employee of MaxCyte Inc. The other authors declare no competing interests., (© 2021 The Author(s).)

Delivery and labour pain is normally the most painful event in a woman's lifetime. Physical and psychological factors may influence the severity of labour pain, and labour pain relief is an important issue for the obstetric anaesthetist. We describe the current most effective pharmacological techniques used for labour analgesia: systemically with remifentanil and regionally with epidural analgesia.

This is an update on the treatment of anaphylactic shock in pregnant women. Most guidelines recommend adrenaline as first-line treatment in all patients, but in pregnant patients some recommend ephedrine due to a potential risk of utero-placental hypoperfusion with adrenaline. However, ephedrine is a less potent vasopressor than adrenaline and does not possess the same anti-inflammatory or broncho-dilating effects. As immediate and correct treatment is essential for both the maternal and the fetal outcome, adrenaline should be first-line treatment also in pregnant women.

Background: In HIV-1-infected individuals, levels of CD4+ T lymphocytes are depleted and regulatory T-lymphocytes (Tregs) are elevated. In vitro studies have demonstrated effects of vitamin D on the growth and differentiation of these cells. We speculated whether supplementation with vitamin D could have an effect on CD4+ T lymphocytes or Tregs in HIV-1-infected males., Methods: We conducted a placebo-controlled randomized study that ran for 16 weeks and included 61 HIV-1-infected males, of whom 51 completed the protocol. The participants were randomized to 1 of 3 daily treatments: (1) 0.5-1.0 µg calcitriol and 1200 IU (30 µg) cholecalciferol, (2) 1200 IU cholecalciferol, (3) placebo. Percentages of the following T-lymphocyte subsets were determined: naïve CD4+ and CD8+ cells, activated CD4+ and CD8+ cells, and CD3+CD4+CD25+CD127low Tregs. Furthermore 1,25-dihydroxyvitamin D, 25-hydroxyvitamin D, and parathyroid hormone were measured., Results: No significant changes of the studied T-lymphocyte subsets occurred in the treatment groups compared to the placebo group. Increases in 1,25-dihydroxyvitamin D were associated with increases in activated CD4+ T lymphocytes (P = .001) and Tregs (P = .01) in adjusted models. Changes in parathyroid hormone correlated inversely with Tregs (P = .02). Smokers had higher levels of naïve CD4+ T lymphocytes (37% vs 25%;P = .01), naïve CD8+ T lymphocytes (28% vs 19%; P = .03), and Tregs (9% vs 7%; P = .03)., Conclusion: Cholecalciferol and calcitriol administered during 16 weeks did not change the levels of T-lymphocyte fractions compared to placebo. However, increases in 1,25-dihydroxyvitamin D were associated with an expansion of activated CD4+ cells and Tregs.

Aims: It has been assumed that both plasma cholinesterase (EC 3.1.1.8) and oxidative enzymes are needed for optimum formation of the bronchodilator terbutaline from its biscarbamate prodrug bambuterol. The present study aimed at investigating the fate of bambuterol in subjects with deficient plasma cholinesterase but with normal oxidative (CYP2D6) capability., Methods: The pharmacokinetics of bambuterol and terbutaline were studied in four healthy subjects (two men and two women) being homozygous for the atypical gene for plasma cholinesterase. Their oxidative metabolism was apparently good as they were all rapid metabolizers of debrisoquine. Bambuterol hydrochloride 20 mg was given orally once daily for 10 days, and plasma and urine samples were taken for 1.5 days (plasma) and 4.5 days (urine) after administration of the last dose., Results: The pharmacokinetic parameters in the present study were grossly similar to those found in a study of bambuterol in subjects with normal plasma cholinesterase activity (N). However, subjects with atypical cholinesterase had a shorter terminal half-life of bambuterol (a measure of uptake rate), 4.8-12.6 h vs 8.3-22.3 h in N, and slightly higher plasma concentrations of bambuterol (average concentrations 1.9-3.7 nmol l(-1) vs 1.5-3.1 nmol l(-1) in N). Peak/trough terbutaline plasma concentrations ratios (2.1-3.2) were somewhat increased, but average plasma concentrations (8.3-14.5 nmol l(-1)) and terminal half-life (16.5-21.8 h) of terbutaline did not differ., Conclusions: In Caucasian populations, one subject out of 2500 is homozygous for the atypical gene for plasma cholinesterase. The atypical enzyme has a much lower affinity for bambuterol than the normal enzyme. Nevertheless, the subjects with atypical cholinesterase were able to produce terbutaline as efficiently as normal subjects. This might be explained by an altered uptake and metabolism in the absence of plasma cholinesterase, or the importance of this enzyme for the formation of terbutaline from bambuterol in vivo may have been overestimated.

Train-of-four (TOF) monitoring of neuromuscular block at submaximal current stimulation has been recommended because it is less painful than monitoring at supramaximal stimulation. The measurement error, however, when using submaximal stimulation has not as yet been fully elucidated. The authors therefore quantified the measurement error of TOF monitoring at low currents near the initial threshold for stimulation (ITS) by assessing precision (the difference between duplicated TOF ratios measured at the same current) and accuracy (the difference between TOF ratios at lesser currents and the TOF ratio at 58 mA, which served as the reference standard method). A stable neuromuscular block at a TOF ratio of 0.40 and subsequently 0.70 was established in 20 patients using a continuous infusion of atracurium. The ulnar nerve was stimulated at the wrist using TOF stimulation, and the evoked twitch response of the adductor pollicis muscle was measured with a force-displacement transducer. The stimulating current was varied in 5-mA steps between ITS and 55 mA. Whereas there were no statistical significant differences between the mean TOF ratios at the different currents, the standard deviation increased with decreasing currents (P less than 0.01 at currents less than 40 mA). The precision was acceptable except at ITS, where the limits of precision (mean intracurrent difference in TOF ratio +/- two standard deviations) exceeded 0.05, which was the chosen acceptable difference. The standard deviation of the accuracy was significantly increased at currents less than or equal to ITS + 25 mA (P less than 0.01).(ABSTRACT TRUNCATED AT 250 WORDS)

Twelve patients undergoing elective cholecystectomy received as analgesic medication a single dose of methylprednisolone (30 mg/kg) preoperatively and thoracic epidural analgesia with plain bupivacaine for 48 hours + epidural morphine 4 mg and systemic indomethacin 100 mg, both every 8 hours for 96 hours. Assessments of pain, various parameters of response to injury, peak flow and subjective fatigue were made preoperatively, before and 3 and 6 hours after skin incision and 1, 2, 4 and 8 days postoperatively. These patients were matched with 24 from a previous study who were treated with either intermittent nicomorphine and acetaminophen or with epidural analgesia + systemic indomethacin as analgesic medication. Preoperative methylprednisolone resulted in improved pain relief, with concomitantly reduced need for epidural bupivacaine, prevention of hyperthermic response, improved postoperative pulmonary function and lessened fatigue, while the leucocytic and acute phase responses were unmodified. There were no side effects. These results may be explained by inhibition of various trauma-induced inflammatory mediators.

Pathogenetical factors possibly responsible for recurrence of nontoxic goitre in a nonendemic area are evaluated. A group of 22 female patients admitted for surgical treatment of recurrent nontoxic goitre was compared with a control group of 86 female nontoxic goitrous patients not operated upon before. Preoperative serum baseline thyrotrophin levels in the recurrent goitre group were low normal and did not differ significantly from those in the control group. Circulating thyroid microsomal autoantibodies, thyroglobulin antibody titers, and the densities of lymphocytic aggregation in goitrous tissue did not differ significantly in the two groups. Thus, none of the parameters studied were likely explanations of regrowth of goitre.

Flunitrazepam (Rohypnol) 2.0 mg was given as a single dose by the oral or sublingual route to ten volunteers using a cross-over design. Plasma concentrations of the drug were measured by gas-liquid chromatography for up to 6 hours after administration. The highest mean concentration occurred 45 min after administration irrespective of route. No significant differences were found between the two treatments at any time. Since the sublingual route compares favorably with other routes of administration, these findings suggest that sublingual flunitrazepam is valuable for premedication.