Daily Dose Research Articles

Interventions to reduce opioid use for patients with chronic non-cancer pain in primary care settings: A systematic review and meta-analysis.

This systematic review and meta-analysis aimed to assess interventions to reduce opioid use for patients with chronic non-cancer pain (CNCP) versus usual care or active controls in primary care settings. In this registered study (PROSPERO: CRD42022338458), we searched MEDLINE, Embase PsycInfo, CINAHL, and Cochrane Library from inception to December 28th 2021, and updated on Dec 14th 2023 for randomized controlled trials (RCTs) and cohort studies with no restrictions. Methodological quality was assessed using the Cochrane Risk of Bias tool for RCTs and Newcastle Ottawa Scale for cohort studies. Primary outcomes included mean reduction in morphine equivalent daily dose (reported as mean differences [MDs] mg/day; 95% confidence intervals [95%CIs]) and/or opioid cessation proportion. Secondary outcomes were mean changes in pain severity (reported as standardized mean difference [SMDs]; 95%CIs) and (serious) adverse events. Meta-analyses were performed using random-effects models. We identified 3,826 records, of which five RCTs (953 participants) and five cohort studies (901 participants) were included. Overall, opioid dosage was significantly reduced in intervention groups compared to controls (MD: -28.63 mg/day, 95%CI: -39.77 to -17.49; I2 = 31.25%; eight studies). Subgroup analyses revealed significant opioid dose reductions with mindfulness (MD: -29.36 mg/day 95%CI: -40.55 to -18.17; I2 = 0.00%; two trials) and CBT-based multimodalities (MD: -41.68 mg/day; 95%CI: -58.47 to -24.89; I2 = 0.00%; two cohort studies), respectively, compared to usual care. No significant differences were observed in opioid cessation (Odds ratio: 1.10, 95%CI: -0.48 to 2.67, I2 = 58.59%; two trials) or pain severity (SMD: -0.13, 95%CI: -0.37 to 0.11; I2 = 33.51%; three trials). Adverse events were infrequently examined, with withdrawal symptoms commonly reported. The studied interventions were effective in reducing opioid dosage for people with CNCP in primary care. They highlighted the importance of multidisciplinary collaboration. Large-scale RCTs measuring the long-term effects and cost of these interventions are needed before their implementation.

One-Year Effect of Elexacaftor/Tezacaftor/Ivacaftor Therapy on HbA1c Levels and Insulin Requirement in Patients with Insulin-Dependent Cystic Fibrosis-Related Diabetes: A Retrospective Observational Study.

The impact of ETI therapy on pulmonary function and nutritional status has been widely studied; the literature on the possible outcomes on glycemic control and insulin requirement in patients affected by CFRD is controversial. The main objective of our study was to evaluate HbA1c levels in patients with cystic fibrosis-related diabetes (CFRD) after one year of therapy with elexacaftor/tezacaftor/ivacaftor (ETI). The secondary objective was to study the changes in the total daily insulin dose (TDD), pulmonary function and metabolism in this population. A retrospective single-center observational study was conducted at the Regional Cystic Fibrosis Centre and Diabetology Centre of IRCCS Istituto Giannina Gaslini. The observation period was divided into four different time points: initiation (T0), 3 months (T3mo), 6 months (T6mo) and 12 months (T12mo) of ETI therapy. Demographic and clinical data were collected. The results were then stratified by genotype (homozygous or heterozygous F508del). Twenty-eight patients with CFRD undergoing insulin therapy were included. TDD (IU) significantly decreased at T3mo and T6mo, but not at T12mo, whereas HbA1c decreased significantly at all three times. The number of hospitalizations and pulmonary exacerbations decreased significantly. We demonstrated both improvement in glycemic control (by means of HbA1c) and insulin requirement in insulin-dependent CFRD patients after one year of ETI treatment.

Progression of cyclosporine A-blood levels in experimental cats receiving a high-dose treatment protocol.

Cyclosporine A (CsA) is used as a steroid-sparing or alternative immunosuppressing agent in cats with various immune-mediated diseases such as immune-mediated hemolytic anemia. Daily treatment dosages of 5-20 mg/kg have been described. Interindividual variations in CsA blood levels are known to occur. To determine when steady-state conditions are reached and thus the earliest advisable time for monitoring CsA blood levels during the course of treatment, a prospective experimental study was conducted in six healthy adult Domestic Shorthair cats. Cats were treated with an oral dosage of 7 mg/kg CsA q 12 h for 10 days. On days 1, 2, 3, 5, 7, and 10 after the start of CsA administration (i.e., after 1, 3, 5, 9, 13, and 19 CsA administrations), EDTA blood was collected to measure the CsA level 12 h after the CsA administration (trough values) using high-performance liquid chromatography coupled to mass spectrometry (HPLC-MS/MS). Statistical analysis revealed a significant increase in mean CsA blood levels up to day 5 (2,050 ± 964.2 ng/mL [mean ± SD], 832-3,203 ng/mL [minimum-maximum]; repeated-measures ANOVA: p = 0.0021), while values on days 5 and 7 did not differ significantly from CsA concentrations on day 10. CsA concentrations showed markedly interindividual variability. Cyclosporine A blood levels reached a steady state on day 5 of high dosages of CsA q 12 h (i.e., after nine CsA administrations), indicating that this time point is suitable for monitoring blood levels in clinical patients. Results confirmed the well-known remarkable interindividual variability of CsA, indicating the need for treatment monitoring. The assessed treatment regime resulted in significantly higher mean CsA trough levels than the target range for immunosuppressive therapy (200-600 ng/mL).

In Vivo Effects of a GHR Synthesis Inhibitor during Prolonged Treatment in Dogs

Background: The activation of the growth hormone receptor (GHR) is a major determinant of body growth. Defective GHR signaling, as seen in human Laron dwarfism, resulted in low plasma IGF-1 concentrations and limited growth, but also marked absence in the development of breast cancer and type 2 diabetes. In vitro, we identified a small molecule (C#1) that inhibits the translation of GHR mRNA to receptor protein. Methods: Before its application in humans as a potential anticancer drug, C#1 was tested in animals to evaluate whether it could be administered to achieve a plasma concentration in vivo that inhibits cell proliferation in vitro without causing unwanted toxicity. To evaluate the efficacy and toxicity of C#1, a group of six intact female Beagle dogs was treated daily each morning for 90 days with an oral solution of C#1 in Soiae oleum emulgatum at a dose of 0.1 mg/kg body weight. During treatment, dogs were closely monitored clinically, and blood samples were taken to measure plasma C#1 concentrations, complete blood counts (CBC), clinical chemistry, and endocrinology. At the end of the treatment, dogs were euthanized for gross and histopathological analysis. An additional group of six female Beagle dogs was included for statistical reasons and only evaluated for efficacy during treatment for 30 days. Results: Daily administration of C#1 resulted in a constant mean plasma concentration of approximately 50 nmol/L. In both groups, two out of six dogs developed decreased appetite and food refusal after 4–5 weeks, and occasionally diarrhea. No significant effects in CBC or routine clinical chemistry were seen. Plasma IGF-1 concentrations, used as biomarkers for defective GHR signaling, significantly decreased by 31% over time. As plasma growth hormone (GH) concentrations decreased by 51% as well, no proof of GHR dysfunction could be established. The measured 43% decrease in plasma acylated/non-acylated ghrelin ratios will also lower plasma GH concentrations by reducing activation of the GH secretagogue receptor (GHSR). C#1 did not directly inhibit the GHSR in vivo, as shown in vitro. There were no significant effects on glucose, lipid, or folate/homocysteine metabolism. Conclusions: It is concluded that with daily dosing of 0.1 mg C#1/kg body weight, the induction of toxic effects prevented further increases in dosage. Due to the concomitant decrease in both IGF-1 and GH, in vivo inhibition of GHR could not be confirmed. Since the concept of specific inhibition of GHR synthesis by small molecules remains a promising strategy, searching for compounds similar to C#1 with lower toxicity should be worthwhile.

Efficacy and safety of 10mg versus 30mg of oral prednisolone for acute CPP crystal arthritis: findings of a randomized controlled trial.

The optimal prednisolone dose for managing acute calcium pyrophosphate (CPP) crystal arthritis remains unclear. We compared the efficacy and safety of 10- and 30-mg daily doses of prednisolone for acute CPP crystal arthritis. This randomized, controlled, open-label trial included patients with acute CPP crystal arthritis and symptoms that had begun less than 72h earlier. Patients without CPP crystals, those with septic arthritis, and those with uncontrolled infections were excluded. Participants received either 10 or 30mg of prednisolone daily for 7days. The primary outcome was time until complete resolution of symptoms; secondary outcomes included time until clinical resolution, recurrence rates, laboratory profiles, and adverse events, adjusted for confounders. Seventy-nine patients participated. Baseline characteristics were comparable, except that the 30-mg recipients had more initial inpatient visits (p = 0.03). The median time until complete resolution was 7days in both groups (p = 0.73). The 30-mg recipients exhibited faster clinical resolution (1 vs. 3days; p = 0.03), but adjusted analyses revealed no significant differences in time until complete resolution (6.2 vs. 6.5days; p = 0.68) or clinical resolution (2.4 vs. 2days; p = 0.27). The overall recurrence rate was 14.3%; the 30-mg recipients experienced slightly more recurrences (p = 0.08). The other secondary outcomes did not differ significantly. The 10- and 30-mg daily doses of prednisolone were equally effective in treating acute symptoms of CPP crystal arthritis, with no significant differences in resolution time, recurrence rates, or safety outcomes.

Toxicological characterization of the insecticide metofluthrin and assessment of the carcinogenic risk to human health due to its chronic inhalation effect

The aim of the investigation is the toxicological characterization and analysis of the danger criteria of the insecticide metofluthrin with an assessment of the carcinogenic risk to health caused by chronic inhalation exposure to the substance at the level of the maximum possible concentrations in the air environment of human life. The analysis of scientific reports of the US Environmental Protection Agency (US EPA) and the European Chemicals Agency (ECHA) on the toxicological properties of metofluthrin was carried out. The assessment of the risk of the development of carcinogenic effects due to chronic inhalation exposure to metofluthrin was carried out taking into account the average daily dose of the substance that can enter the human body during the natural life span (LADD) and the carcinogenic potential factor (SF) in accordance with domestic guidelines. Classification of levels of carcinogenic risk was carried out using domestic and international approaches. It was established that the limiting criteria for the danger of metofluthrin are the average lethal concentration in air (LC50 =1080 mg/m³) and the size of the zone of chronic action (Zch=7.46), which characterizes the danger of occurrence of chronic intoxication due to long-term inhalation exposure. According to these indicators, metofluthrin is classified as a dangerous substance (hazard class 2). The key effects of the toxic action of metofluthrin are determined – neurotoxicity, hepatotoxicity and nephrotoxicity. The threshold non-genotoxic oncogenic potential of metofluthrin according to the phenobarbital type was established. Individual carcinogenic risk under different scenarios of chronic inhalation exposure to metofluthrin was calculated. The substance concentration of 3.54 mg/m³ leads to a high level of risk (1.5×10-3), which is considered unacceptable for production conditions and the population. At concentrations of 0.28 mg/m³ and 1.0 mg/m³, the risk is estimated as average and acceptable for production conditions (1.1-4.1×10-4). The risk of exposure to a concentration of 0.14 mg/m³ is classified as low and acceptable for the population (5.7×10-5). Thus, the results obtained in the study indicate that such concentrations of metofluthrin in the air as 0.14 – 0.28 – 1.0 mg/m³ are safe for human health, subject to compliance with medical and sanitary regulations at the stage of production and application of insecticides based on metofluthrin as prescribed.

Exploring the Impact of Developmental Clearance Saturation on Propylene Glycol Exposure in Adults and Term Neonates Using Physiologically Based Pharmacokinetic Modeling.

Propylene glycol (PG) is a pharmaceutical excipient which is generally regarded as safe (GRAS), though clinical toxicity has been reported. PG toxicity has been attributed to accumulation due to saturation of the alcohol dehydrogenase (ADH)-mediated clearance pathway. This study aims to explore the impact of the saturation of ADH-mediated PG metabolism on its developmental clearance in adults and neonates and assess the impact of a range of doses on PG clearance saturation and toxicity. Physiologically based pharmacokinetic (PBPK) models for PG in adults and term neonates were developed using maximum velocity (Vmax) and Michaelis-Menten's constant (Km) of ADH-mediated metabolism determined in vitro in human liver cytosol, published physicochemical, drug-related and ADH ontogeny parameters. The models were validated and used to determine the impact of dosing regimen on PG clearance saturation and toxicity in adults and neonates. The Vmax and Km of PG in human liver cytosol were 1.57 nmol/min/mg protein and 25.1 mM, respectively. The PG PBPK model adequately described PG PK profiles in adults and neonates. The PG dosing regimens associated with saturation and toxicity were dependent on both dose amount and cumulative in standard dosing frequencies. Doses resulting in saturation were higher than those associated with clinically observed toxicity. In individuals without impaired clearance or when PG exposure is through formulations that contain excipients with possible interaction with PG, a total daily dose of 100-200 mg/kg/day in adults and 25-50 mg/kg/day in neonates is unlikely to result in toxic PG levels or PG clearance saturation.

Potentiometric analysis of fluoride in commonly consumed beverages: Method development, evaluation, and risk assessment

In this research paper, a potentiometric analytical method for the determination of Fluoride was developed and applied to analyse the most commonly consumed beverages. Considering all the beverages studied, the fluoride levels ranged from the detection limit (0.02 mg L−1) to 3.5 mg L−1, measured in tea samples obtained from an automatic dispenser. In conclusion, the investigated beverages do not pose a problem for humans if they are consumed in moderation. For coffees, barley-based drinks, infusions, chamomiles, herbal teas and teas, which are commonly prepared with tap or bottled water, the fluoride content of the water should also be added to the results obtained to assess the real contribution. The only drink potentially causing a risk, especially for children, could be tea prepared by infusing the leaves contained in paper filters because it contributes significantly to the daily dose of fluoride. This dose would increase if the fluoride contribution from water were taken into account.

Chronic oral toxicity protocol for adult solitary bees (Osmia bicornis L.): Reduced survival under long-term exposure to a “bee-safe” insecticide

Pollinators are essential for crop productivity. Yet, in agricultural areas, they may be threatened by pesticide exposure. Current pesticide risk assessments predominantly focus on honey bees, with a lack of standardized protocols for solitary bees. This study addresses this gap by developing a long-term oral exposure protocol tailored for O. bicornis. We conducted initial trials to determine optimal container sizes and feeding methods, ensuring high survival rates and accurate syrup consumption measurements. A validation test involving five laboratories was then conducted with the insecticide Flupyradifurone (FPF). Control mortality thresholds were set at ≤ 15% at 10 days. Three laboratories achieved ≤10%, demonstrating the protocol's effectiveness in maintaining healthy test populations. The seasonal timing of experiments influenced control mortality, underscoring the importance of aligning tests with the natural flight period of the population used. Our findings revealed dose-dependent effects of FPF on syrup consumption, showing stimulatory effects at lower concentrations and inhibitory effects at higher ones. The 10-day median lethal daily dose (LDD50) of FPF for O. bicornis (531.92 ng/bee/day) was 3.4-fold lower than that reported for Apis mellifera (1830 ng/bee/day), indicating Osmia's higher susceptibility. Unlike other insecticides, FPF did not exhibit time-reinforced toxicity. This study introduces a robust protocol for chronic pesticide exposure in solitary bees, addressing a critical gap in current risk assessment. Based on its low risk to honey bees and bumblebees, FPF is approved for application during flowering. However, our results suggest that it may threaten Osmia populations under realistic field conditions. Our findings underscore the need for comparative toxicity studies to ensure comprehensive protection of all pollinators and the importance of accounting for long term exposure scenarios in risk assessment. By enhancing our understanding of chronic pesticide effects in solitary bees, our study should contribute to the development of more effective conservation strategies and sustainable agricultural practices.

Cinnamon potential in alleviating early postmenopause symptoms: a randomized clinical trial

Abstract Objective Menopause is a substantial physical, mental, and emotional transition in a woman's life. Most women suffer symptoms during menopause, impacting their quality of life for a decade or more. This study aimed to determine the effect of cinnamon on the severity of postmenopause symptoms. Methods A randomized, triple-blind, parallel clinical trial was conducted on 60 postmenopausal women in the health centers of Hamadan, Iran. The study included women aged 45 to 60 years who were 1 to 3 years after their last menstrual period. The participants were assigned to two groups using a permuted block randomization method. The intervention group received a daily dose of one cinnamon capsule (1 g) for 2 months, whereas the control group received a placebo. The participants, researchers, and statistical analysts were all blinded. The study measured the severity of menopause symptoms using the Menopause Rating Scale before and 2 months later. Data were analyzed using Stata-13 software. Results Data from 59 individuals were analyzed. The analyses were adjusted for baseline Menopause Rating Scale scores. After the intervention, the severity of menopause symptoms was lower in the intervention group (13.95 ± 4.16) compared to the control group (16.64 ± 4.16) (P = 0.01), with an effect size of 0.65 (95% CI, 0.12-1.17). Additionally, the intervention group had lower scores for psychological symptoms compared to the control group (P = 0.006), with an effect size of 0.74 (95% CI, 0.21-1.27). Conclusions The consumption of cinnamon in postmenopausal women has been found to improve the severity of menopause symptoms, with a particular emphasis on the psychological domain.

Effects of licorice root (Glycyrrhiza glabra) extract on the livers of obese rats.

We have investigated anti-obesity effects of the extract of licorice (Glycyrrhiza glabra) root in rats with diet-induced obesity and hyperlipidemia by using histopathological and biochemical methods. Thirty-two Wistar albino rats were divided to four groups of eight: normal control (C), high fat diet (HFD), high fat Diet + Glycyrrhiza glabra (HFD+M), and normal diet with Glycyrrhiza glabra (M). The high fat diet contained 300 g/kg fat (4000 kcal/kg); the daily dosage of Glycyrrhiza glabra extract was 1g/kg body weight by orogastric gavage. Supplementation of Glycyrrhiza glabra extract dramatically reduced increases in body weight caused by the induction of obesity. A hepatoprotective effect of Glycyrrhiza glabra extract was supported by the almost normal histology in the livers of the HFD+M rats, in contrast to the degenerative changes in the HFD rats, which included macrovesicular and microvesicular fat deposits, hydropic degeneration, dilatation of sinusoids and coagulation necrosis of some hepatocytes. Serum levels of alanine transaminase (ALT), aspartic transaminase (AST), alkaline phosphatase (ALP), lactate dehydrogenase (LDH), cholesterol (HDL and LDL) and triglycerides, were ameliorated by Glycyrrhiza glabra extract treatment. We conclude that Glycyrrhiza glabra extract given together with HFD could prevent obesity and reduce liver damage in rats.

A 7-Year Retrospective Review of Flexor Sheath Infections.

Background: Flexor sheath infections require prompt diagnosis, and management with intravenous antibiotics and/or surgical washout followed by hand therapy. Complication rates as high as 38% have been reported. Our unit takes a relatively conservative approach to the management of flexor sheath infections and select patients are managed non-surgically via our outpatient antibiotic service where they are clinically reviewed and receive a once daily dose of intravenous antibiotics. The aim of this study is to determine if outpatient management of flexor sheath infections was associated with an increased risk of complications compared to those admitted as an inpatient. Methods: A retrospective review was carried out with all patients clinically diagnosed with flexor sheath infection who were seen at our unit between January 2014 and December 2020. Age, gender, co-morbidities, cause of infection, management and subsequent complications were recorded. Results: A total of 128 patients with flexor sheath infections were treated. And 68% were male. Mean age was 50.4 years. A trend towards fewer presentations each year with animal bites, foreign bodies and penetrating trauma as the main cause of infection was noted. And 89% (n = 114) required admission with the other 11% (n = 14) treated as an outpatient. And 77% (n = 98) underwent surgical washout. And 6% (n = 8) suffered a complication. Conclusions: While flexor sheath washout continues to be standard practice, 23% of patients were safely managed with intravenous antibiotics and 11% purely via an outpatient service. Level of Evidence: Level IV (Therapeutic).

A test method for assessing chronic oral toxicity of a pesticide to solitary nesting orchard bees, Osmia spp. (Hymenoptera: Megachilidae).

Orchard bees of the genus Osmia Panzerare important pollinators of fruit trees in various regions of the world, with some species commercially available in the United States and Europe. In addition to their pollination services, Osmia lignaria, Osmia cornifrons, Osmia bicornis, and Osmia cornuta have been identified as potential model species for solitary bees in pesticide risk assessment and have been used for the development of new methods to test acute lethal effects via contact and oral routes of exposure. Our goal was to expand the available methodology to characterize the toxicity of pesticides for these solitary bees through a chronic oral test for adult bees. Chronic oral toxicity of pesticides to orchard bees has been reported, but methods differ among research groups. In our study, O. lignaria, O. cornifrons, O. bicornis, and O. cornuta female bees had access to sucrose solution ad libitum in separate, species-specific 10-day tests. Mean body mass, mean daily consumption, and survival differed among the studied bee species. The dose-response test design was validated with dimethoate, a reference toxic compound, and chronic toxicity endpoints were estimated for the 4 Osmia species. The median lethal daily doses normalized by weight for O. lignaria, O. bicornis, O. cornuta, and O. cornifrons were within the same order of magnitude at 0.23, 0.26, 0.49, and 0.61 µg dimethoate/g bee/day, respectively. The methodology described here was aligned as much as possible with the available honey bee and bumble bee standard methods to facilitate the comparison of chronic toxicity profiles among bee species.

Evaluation of the Efficacy of Methylene Blue Administration in SARS-CoV-2-Affected Patients: A Proof-of-Concept Phase 2, Randomized, Placebo-Controlled, Single-Blind Clinical Trial

The SARS-CoV-2 pandemic has revolutionized the scientific and medical world in recent years. Methylene blue (MB) is a well-known molecule. The aim of our study was to assess the efficacy of MB against early-phase SARS-CoV-2 infections. All patients with a positive swab for SARS-CoV-2 were eligible for the trial. The intervention was a starting dose of 200 mg MB or placebo in the morning and 100 mg in the evening on the first day and afterwards the standard daily dose of 200 mg. Patients were followed up for safety and efficacy until day 84. We analyzed 21 patients for the safety profile and 19 for the efficacy objective: of these, there were 11 in the MB group and 8 in the placebo one. In both groups, patients had undetectable RNA from day 3 and 10 out of 11 subjects in the MB group were virus free by day 12 vs. 6 out of 8 in the placebo one. None of the patients experienced serious adverse events. MB has proved to be a safe and well-tolerated drug. We did not find superiority of efficacy or viral clearance of MB compared to the placebo. Given the good in vitro efficacy, larger studies are needed to assess MB efficacy against COVID-19 in vivo.

Arsenic content in tissues, Fungus combs, Herbs, Termite mounds and Soils of termites of the genus Macrotermes and assessment of the health risk associated with their food use in the industrial zone of the Societe Nouvelle Des phosphates du Togo (SNPT)

Arsenic is present in different environmental matrices of the phosphate mining and processing area of the Société Nouvelle des Phosphates du Togo; including termite tissues, termite waste, termite mounds, termite Fungus combs, soils and nearby herbs. Arsenic levels vary across matrices, with termite waste having the highest concentration (approximately 27.01 mg/kg) compared to the outside herbs, which have the lowest. Phosphate mining sites, including Hahotoé-Kpogamé and Akoumapé, have higher levels of As contamination in soils and termite tissues compared to the phosphate processing site. A positive correlation is observed between As levels in termite tissues and termite waste; suggesting an ability of termites to eliminate arsenic via their waste. Regarding health risks, the hazard quotient (HQ) for arsenic in termites exceeds 1, and for non-threshold effects, the excess individual risk (EIR) assessment gives EIR > 10-4 in both adults and children; which would mean that termite consumption poses a significant health risk, including cancer risks for human populations, particularly children. However, it should be noted that the estimation in this study includes total As (organic and inorganic). Since the toxicological reference values were calculated on the basis of inorganic arsenic, which presents more hazard and whose fraction represents 10% of total As, the daily exposure dose values for adults and children represent 1.40.10-4 mg/kg/d and 1.02.10-4 mg/kg/d of inorganic arsenic, respectively. These doses will then become lower than the toxicological reference value (TRV) with the consequence of hazard quotient (HQ) lower than 1 and resulting in low risks of carcinogenic effects. It is therefore necessary to specifically determine the inorganic fraction to refine the risk assessment and to extend this study to other trace elements in the prospected area.

Eosinophilic dermatosis of haematologic malignancy treated with ibrutinib: A case report

AbstractEosinophilic dermatosis of haematologic malignancy is an infrequent skin disorder characterised by severe pruritus and skin lesions resembling arthropod bites. It primarily affects individuals with underlying haematological conditions, most commonly chronic lymphocytic leukaemia (CLL). While it does not correlate with a worse prognosis for the haematological disease itself, it significantly impacts patients' quality of life due to the distressing pruritus and recurring nature. Clinical presentation typically shows erythematous papules resembling arthropod bites, with less frequent occurrences of urticarial plaques or bullous lesions. Histologically, an intense and polymorphous inflammatory infiltrate is found both in the superficial and deep dermis, marked by an abundance of eosinophils and the absence of atypical cells. Treatment of this disease remains uncertain, with corticosteroids often being the only effective therapy. Here, we present the case of an 80‐year‐old patient with a history of CLL, who experienced a widespread, itchy eruption of papules and plaques over 2 months. Despite various therapeutic attempts, the lesions only responded to high‐dose corticosteroids. Following the initiation of ibrutinib at a daily dose of 420 mg, both the skin lesions and pruritus resolved within 3 months. Ibrutinib, a tyrosine kinase inhibitor, is approved as a first‐line treatment for CLL. However, its potential as a remedy for refractory eosinophilic dermatosis has not been reported thus far.

Glyphosate impairs both structure and function of GABAergic synapses in hippocampal neurons

Glyphosate (Gly) is a broad-spectrum herbicide responsible for the inhibition of the enzyme 5-enolpyruvylshikimate-3-phosphate synthase known to be expressed exclusively in plants and not in animals. For decades Gly has been thought to be ineffective in mammals, including humans, until it was demonstrated that rodents treated with the Gly-based herbicide Roundup showed reduced content of neurotransmitters (e.g., serotonin, dopamine, norepinephrine, and acetylcholine), increased oxidative stress in the brain associated with anxiety and depression-like behaviors and learning and memory deficits. Despite compelling evidence pointing to a neurotoxic effect of Gly, an in-depth functional description of its effects on synaptic transmission is still lacking. To investigate the synaptic alterations dependent on Gly administration we performed whole-cell patch-clamp recordings and immunocytochemistry on mouse primary cultured hippocampal neurons. Our findings reveal that 30 min incubation of Gly at the acceptable daily intake dose severely impaired inhibitory GABAergic synapses. Further analysis pointed out that Gly decreased the number of postsynaptic GABAA receptors and reduced the amplitude of evoked inhibitory postsynaptic currents, the readily releasable pool size available for synchronous release and the quantal size. Finally, a decreased number of release sites has been observed. Consistently, morphological analyses showed that the density of both pre- and post-synaptic inhibitory compartments decorating pyramidal cell dendrites was reduced by Gly. In conclusion, our experiments define for the first time the effects induced by Gly on GABAergic synapses, and reveal that Gly significantly impairs both pre- and postsynaptic mechanisms.

A complex ePrescribing antimicrobial stewardship-based (ePAMS+) intervention for hospitals: mixed-methods feasibility trial results

BackgroundAntibiotic resistant infections cause over 700,000 deaths worldwide annually. As antimicrobial stewardship (AMS) helps minimise the emergence of antibiotic resistance resulting from inappropriate use of antibiotics in healthcare, we developed ePAMS+ (ePrescribing-based Anti-Microbial Stewardship), an ePrescribing and Medicines Administration (EPMA) system decision-support tool complemented by educational, behavioural and organisational elements.MethodsWe conducted a non-randomised before-and-after feasibility trial, implementing ePAMS+ in two English hospitals using the Cerner Millennium EPMA system. Wards of several specialties were included. Patient participants were blinded to whether ePAMS+ was in use; prescribers were not. A mixed-methods evaluation aimed to establish: acceptability and usability of ePAMS+ and trial processes; feasibility of ePAMS+ implementation and quantitative outcome recording; and a Fidelity Index measuring the extent to which ePAMS+ was delivered as intended. Longitudinal semi-structured interviews of doctors, nurses and pharmacists, alongside non-participant observations, gathered qualitative data; we extracted quantitative prescribing data from the EPMA system. Normal linear modelling of the defined daily dose (DDD) of antibiotic per admission quantified its variability, to inform sample size calculations for a future trial of ePAMS+ effectiveness.ResultsThe research took place during the SARS-CoV-2 pandemic, from April 2021 to November 2022. 60 qualitative interviews were conducted (33 before ePAMS+ implementation, 27 after). 1,958 admissions (1,358 before ePAMS+ implementation; 600 after) included 24,884 antibiotic orders.Qualitative interviews confirmed that some aspects of ePAMS+ , its implementation and training were acceptable, while other features (e.g. enabling combinations of antibiotics to be prescribed) required further development. ePAMS+ uptake was low (28 antibiotic review records from 600 admissions; 0.047 records per admission), preventing full development of a Fidelity Index. Normal linear modelling of antibiotic DDD per admission showed a residual variance of 1.086 (log-transformed scale). Unavailability of indication data prevented measurement of some outcomes (e.g. number of antibiotic courses per indication).ConclusionsThis feasibility trial encountered unforeseen circumstances due to contextual factors and a global pandemic, highlighting the need for careful adaptation of complex intervention implementations to the local setting. We identified key refinements to ePAMS+ to support its wider adoption in clinical practice, requiring further piloting before a confirmatory effectiveness trial.Trial registrationISRCTN Registry ISRCTN13429325, 24 March 2022.

Linezolid Pharmacokinetics in Critically Ill Patients: Continuous Versus Intermittent Infusion.

Linezolid has been found to have considerable interindividual variability, especially in critically ill patients, which can lead to suboptimal plasma concentration. To overcome this shortcoming, several solutions have been proposed. These include using loading dose, higher maintenance doses, and dose stratification according to the patient's particularities, therapeutic drug monitoring, and drug administration via continuous infusion (CI) instead of intermittent infusion (II). In the present study, we aim to compare the pharmacokinetic (PK) parameters of linezolid after administration as II versus CI to critically ill patients. In a prospective study conducted in an intensive care unit, we compared the same two daily doses of linezolid administered via II versus CI. The serum concentration was measured, and pharmacokinetic parameters were calculated. The pharmacokinetic/pharmacodynamic (PK/PD) indices for efficacy chosen were area under the concentration-time curve at steady state divided by the minimum inhibitory concentration over 80 (AUC24-48/MIC > 80). Greater serum concentration variability was observed in the II group than in the CI group. The %T > MIC > 80% was achieved for MICs of 1 and 2 µg/mL 100% of the time, whereas for the II group, this was 93% and 73%, respectively. AUC24-48/MIC > 80 was reached in 100% of cases in the CI group compared with 87% in the II group for a MIC of 1 µg/mL. The two infusion methods may be used comparably, but utilizing CI as an alternative to II may have potential benefits, including avoiding periods of suboptimal concentrations, which may enhance safety profiles and clinical outcomes. Considering the relatively few studies performed on linezolid to date, which are increasing in number, the results of the present study may be of interest.

COMPARATIVE EFFICACY OF METHYLPREDNISOLONE AND TOCILIZUMAB IN PATIENTS WITH A SEVERE FORM OF COVID-19

Background. Recently, we have again noted an increase in the incidence of COVID-19. The treatment of patients with severe coronavirus infection poses a significant medical challenge. Objectives. The purpose of this research was to compare the efficacy of standard therapy and pulses of methylprednisolone in combination with or without tocilizumab in patients with a severe form of COVID-19. Patients and methods. In a retrospective study, the medical charts of 220 patients with a severe course of COVID-19 were reviewed. Patients were divided into four groups: those on daily methylprednisolone at a dose of 32 mg enterally; patients who received methylprednisolone pulses (500 mg daily intravenously for three consecutive days, with a subsequent change to the 32 mg of methylprednisolone daily); patients who received a single dose of 400 mg tocilizumab in combination with a 32 mg of methylprednisolone daily; patients who received a single dose of 400 mg tocilizumab in combination with methyl­prednisolone pulse therapy. At the end of therapy, 28-day mortality and the number of intubations in each group one week after the end of therapy were analyzed. Results. Patients treated with a combination of tocilizumab and pulse methylprednisolone therapy had the lowest risk of death (p<0.001), OR=0.03 (95 % CI 0.01-0.16), compared to patients treated only with 32 mg of methylprednisolone. Conclusions. Methylprednisolone pulses therapy is more effective than therapy with methylprednisolone at a daily dose of 32 mg. The combination of methylprednisolone and tocilizumab is more effective than the isolated administration of methylprednisolone. The combination of tocilizumab with methylprednisolone pulse therapy had the highest therapeutic effect.