Median Daily Dose Research Articles

New insights from a Malaysian real-world deep brain stimulation cohort

Background The availability of deep brain stimulation (DBS), a highly efficacious treatment for several movement disorders, remains low in developing countries, with scarce data available on utilization and outcomes. Objective We characterized the DBS cohort and outcomes at a Malaysian quaternary medical center. Methods A retrospective chart review was done on DBS-related surgery at the University of Malaya, including clinico-demographic, genetics, and outcomes data focusing on post-operative medication reduction and complications. Results 149 Parkinson's disease (PD) patients underwent DBS targeting the subthalamic nucleus. Six had globus pallidus internus DBS (primarily for dystonia). Only 16.1% of patients were government-funded. Of the 133 PD patients operated in the past decade (2013–2022), 25 (18.8%) had disease duration <5 years. At 6–12 months post-DBS, median levodopa-equivalent daily dose (LEDD) reduction was 440.5 [418.9] mg/day, corresponding to a reduction of ≥50% and ≥30% in 42.2% and 69.8% of patients, respectively. LEDD reductions were larger in the early-onset and short-duration subgroups. Three patients (1.9% of 155) had symptomatic intracranial hemorrhage, resulting in stroke in two. Pathogenic monogenic or GBA1 variants were detected in 12/76 (16%) of patients tested, mostly comprising the “severe” GBA1 variant p.L483P (12%). Conclusions This is the largest report on DBS from Southeast Asia. The procedures were effective, and complication rates on par with international norms. Our study found a high frequency of GBA1-PD; and included a substantial number of patients with short-duration PD, who had good outcomes. It also highlights regional inequities in access to device-aided therapy.

Impact of metabolic and bariatric surgery on weight loss and insulin requirements in type 1 and insulin-treated type 2 diabetes.

Metabolic and Bariatric Surgery (MBS) is effective in improving metabolic outcomes and reducing weight in patients with obesity and diabetes, with less explored benefits in type 1 diabetes (T1D). This study aimed to evaluate the impact of MBS on weight loss and insulin requirements in T1D patients compared to insulin-treated type 2 diabetes (T2D) patients over a 5-year period. This retrospective analysis included patients who underwent primary sleeve gastrectomy (SG) or Roux-en-Y gastric bypass (RYGB) with a confirmed preoperative diagnosis of either T1D or insulin-treated T2D. Primary endpoints focusing on weight loss and secondary outcomes assessing changes in insulin dosage and glycemic control. After 5 years, weight loss was similar across groups, with total weight loss at 14.2% for T1D and 17.6% for insulin-treated T2D in SG, and 22.6% for T1D vs. 26.8% for insulin-treated T2D in RYGB. Additionally, there was a significant reduction in median daily insulin doses from 140.5 units at baseline to 77.5 units at 1 year postoperatively, sustained at 90 units at 5 years. The differential impact of MBS procedure was also highlighted, where RYGB patients showed a more pronounced and enduring decrease in insulin requirements compared to SG.

Automated insulin delivery systems in elderly patients with brittle type 2 diabetes

PurposeGeriatric diabetes is complicated by the frailty of this population, and hypoglycemia with insulin is not uncommon in these patients. Automated Insulin Delivery (AID) systems may provide better glycemic control in elderly patients with brittle type 2 diabetes. MethodsThirty-four patients (≥ 60 years) including cancer patients with brittle diabetes were switched to an AID system from multiple-dose insulin (MDI) treatment. HbA1c level, weight, total daily insulin requirement, and C-peptide, creatinine, and lipids were followed for at least six months. ResultsThere were 34 patients (14 male, 41.2 %) with a median age of 67 (IQR 63.0–75.5). Six patients (17.6 %) were on chemotherapy and/or steroids (Ch/S). The patients’ initial median HbA1c % was 9.3 (IQR 7.6–11.0), c-peptide level was 0.9 (IQR 0.5–2.2) ng/mL, and median total daily insulin dose was 41 IU (IQR 32–53).Six months after the patients were switched to an AID system their HbA1c % decreased to 7.1 (IQR 6.5–8.1), p < 0.001 and c-peptide increased to 1.21 (IQR 0.2–1.7) ng/mL, p = 0.878. Total insulin dose decreased with AID systems [32 IU (IQR 23.9–37.8)), p < 0.001].There was a decrease in median HbA1c % in patients on Ch/S [8.7 (IQR 7.0–11.5) to 6.9 (IQR 6.3–9.2)] however it didn’t reach statistical significance p = 0.225. Total insulin dose also decreased without statistical significance [33 IU (IQR 41–28) to 28 (IQR 23–35), p = 0.173].The mean time in range (TIR) percent of the patients with AID systems were as follows; <54 mg/dL was 0.5 %, 56–70 mg/dL was 1.3 %, 70–180 mg/dL was 64.8 %, >180 mg/dL was 26.7 % and > 250 mg/dL was 6.7 %. ConclusionAlthough AID systems are tested mostly in young type 1 patients our results show that elderly patients with brittle type 2 diabetes also benefit from an AID system. Even in very frail patients such as cancer patients, improvement can be seen.

Real-life use of temocillin in the treatment of bone and joint infections due to extended spectrum β-lactamase-producing Enterobacterales.

The aim of this study is to describe the real-life use of temocillin in bone and joint infections (BJI). We performed a monocentric retrospective study, including all patients treated by temocillin for a BJI due to extended spectrum β-lactamase-producing Enterobacterales (ESBL-E) between 1 January 2015 and 31 December 2022. Outcomes were evaluated at least 3 months after the end of antimicrobial treatment. Clinical cure was defined as the absence of recurrence of BJI during follow-up among patients who completed at least 7 days of temocillin. If the patient discontinued temocillin due to ineffectiveness, the outcome was considered to be unfavourable. Seventeen patients were treated with temocillin for ESBL-E associated BJI during the study period. Infections included osteomyelitis of the foot (7/17; 41.2%), femoral osteomyelitis (4/17; 23.5%), disco-vertebral infections (2/17; 11.8%), total knee prosthesis infections (2/17; 11.8%) and total hip prosthesis infections (2/17; 11.8%). All patients except one (n = 16) had surgical management of the infection. The main bacteria identified were the Enterobacter cloacae complex (n = 9) and Klebsiella pneumoniae (n = 5). The median daily dose was 6 g for a median duration of 42 days (IQR 14-42 days). The median duration of follow-up was 12 months (IQR 5.25-14.5). Overall, 12 patients completed at least 3 months of follow-up, and clinical cure was observed in eight of them (8/12; 66.7%). So far, this is the first report of BJI successfully treated with temocillin. This suggests that temocillin may be an alternative to treat BJI involving difficult-to-treat Enterobacterales when oral therapy is not available.

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.

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.

Opioid tapering and discontinuation for head and neck cancer (HNC) survivors.

366 Background: Older HNC survivors often experience post-treatment pain, and they fill opioid prescriptions more often than similar cancer-free adults for the first 5 years after HNC diagnosis. To better understand whether ongoing opioid use is likely explained by continued opioid prescribing from the time of cancer treatment, we aimed to quantify the extent to which opioids prescribed near the end of treatment are reduced in dose (tapered) and discontinued after treatment completion. Methods: Using linked Surveillance, Epidemiology, and End Results (SEER) registry and Medicare claims data, we identified adults age &gt;65 diagnosed 2014-2017 with stage I-III HNC with ≥6 months treatment-free follow-up prior to censoring at further treatment, new cancer, hospice, 3 months prior to death, or end 2019. We evaluated the presence of a new or ongoing opioid prescription 2 weeks following treatment completion (baseline) and calculated daily baseline dose in morphine milligram equivalents (MME). Among those with an opioid prescription (“on opioids”) at baseline, we described cross-sectional metrics of opioid receipt and dose every 30 days: proportion of survivors on opioids (who were also on opioids the prior month), initial and current dose of opioids for those currently on opioids, and proportion of survivors on opioids whose dose declined ≥50% from baseline. Results: Among 5135 HNC survivors, 894 were on opioids at baseline (average daily dose 44 MME). By 1 month, 29% of survivors on opioids at baseline (N=260) had a current opioid fill, and 7% had an opioid dose &lt;50% of the baseline dose. Discontinuation of opioids increased each month; median daily dose each month ranged from 44 MME at 30 days to 60 MME at 180 days. Those who remained on opioids over 6 months had the highest opioid dose than those who discontinued earlier (median 45 MME at 90 days; Table). Conclusions: About 1 in 6 HNC survivors had an opioid prescription filled at the end of cancer treatment, and opioids were generally discontinued within a few months. Given the low median dose at baseline, the limited evidence of tapering likely results from low initial opioid doses rather than a failure to taper from long-term or high-dose use. Opioid use among older treatment-free HNC survivors that is apparent years after treatment completion is unlikely to result from inadequate tapering. Instead, it may be due to new or worsening cancer-related pain, as well as to non-cancer pain. Dose reduction and discontinuation (N=894). Days after baseline Off opioids On opioids Starting dose in MME among those on opioids Current dose in MME among those on opioids Tapered to &lt;50% starting dose N (%) N (%) Median (IQR) Median (IQR) N (%) 30 634 (71) 260 (29) 53 (30, 80) 44 (29, 60) 61 (7) 60 772 (86) 122 (14) 45 (30, 67.5) 44 (29, 60) 15 (2) 90 820 (92) 74 (8) 58 (30, 90) 45 (29, 60) 7 (1) 120 838 (94) 56 (6) 60 (30, 90) 45 (25, 60) 7 (1) 150 849 (95) 45 (5) 56 (30, 65) 48 (29, 60) 2 (&lt;1) 180 856 (96) 38 (4) 51 (30, 65) 60 (30, 90) 1 (&lt;1)

Effect of nut consumption on blood lipids: An updated systematic review and meta-analysis of randomized controlled trials

AimsNuts are nutrient-dense foods touted for their health-promoting effects, especially regarding cardiovascular health, yet inconsistencies in the literature remain in relation to their effect on blood lipids. Hence, a systematic review and meta-analysis of randomized controlled trials (RCTs) was conducted to determine the effect of nut intake on blood lipids. Data synthesisMEDLINE-PubMed and Cochrane databases were searched. 113 unique trials met eligibility criteria (n = 8060 adults with various health status) assessing the effect of a median daily dose of 45.5 g/d of nuts compared to a non-nut control on blood lipid outcomes met inclusion criteria. Overall, nut consumption resulted in moderate reductions in total cholesterol (mean difference, −0.14 mmol/L [95 % confidence interval, −0.18 to −0.10 mmol/L]) and LDL-C (−0.12 mmol/L [-0.14 to −0.09 mmol/L]), with small reductions in triglycerides (−0.05 mmol/L [-0.07 to −0.03 mmol/L]), TC:HDL-C (−0.11 [-0.16 to −0.06]), LDL-C:HDL-C (−0.19 [-0.24 to −0.12]), and apolipoprotein B (−0.04 g/L [-0.06 to −0.02 g/L]). There was no significant impact on HDL-cholesterol or other assessed measures. Certainty of evidence was high for apolipoprotein A, and generally moderate/low for all other outcomes. Sensitivity analysis did not change the evidence on the main outcomes. Significant effect modifications in subgroup analysis were shown for most of the lipid parameters assessed. None of these subgroup effects altered the evidence of heterogeneity for any primary outcome. ConclusionsCurrent evidence provides a good indication that consuming nuts may advantageously affect blood lipids in adults with a mix of health status. Prospero registrationPROSPERO identifier, CRD42022358688.

Target Attainment and Population Pharmacokinetics of Cefazolin in Patients with Invasive Staphylococcus aureus Infections: A Prospective Cohort Study.

This study aimed to determine cefazolin target attainment in patients with invasive Staphylococcus aureus (S. aureus) infections and to develop a population pharmacokinetic (PK) model. Adult patients with invasive S. aureus infections treated with cefazolin bolus infusions were included. Unbound and total trough and mid-dose cefazolin concentrations were measured, and strain-specific MICs were determined. The primary outcome was the proportion of patients attaining 100% fT>MIC at all time points evaluated. A population PK model was developed, using non-linear mixed-effects modelling. Overall, 51 patients were included, with a total of 226 unbound and total cefazolin concentrations measured (mean: 4.4 per patient). The median daily dosage in patients with an estimated glomerular filtration rate of >60 mL/min/m2 was 8 g. The median age was 74 years (interquartile range (IQR) 57-82) and 26% were female. A history of chronic kidney disease and acute kidney injury were present in 10/51 (19.6%) and 6/51 (11.7%), respectively. Achievement of 100% fT>MIC occurred in 86% of the patients and decreased to 45% when a target of 100% fT>4xMIC was evaluated. The mean unbound cefazolin fraction was 27.0% (standard deviation (SD) 13.4). Measured and estimated mean cefazolin trough concentrations differed significantly [13.1 mg/L (SD 23.5) vs. 7.4 mg/L (SD 7.9), p < 0.001]. In the population PK model, elevated estimated creatinine clearance and bolus instead of continuous application were covariates for target non-attainment. In conclusion, cefazolin target achievement was high, and the measurement of the unbound cefazolin concentration may be favored. The Monte Carlo simulations indicated that target attainment was significantly improved with continuous infusion.

Comparison of High-Dose versus Low-Dose Trimethoprim-Sulfamethoxazole for Treating Pneumocystis jirovecii Pneumonia among Hemodialysis Patients: A Nationwide Database Study in Japan.

Background: Hemodialysis patients are at high risk for developing Pneumocystis jirovecii pneumonia (PJP), and trimethoprim-sulfamethoxazole (TMP-SMX) is the first-line agent for treating this disease. However, there is a lack of consensus on the required dosage of TMP-SMX for hemodialysis patients. Methods: This study used the nationwide Japanese Diagnosis Procedure Combination database to review hemodialysis patients hospitalized for PJP from April 2014 to March 2022. Eligible patients were divided into high-dose and low-dose groups based on the median daily dose per body weight of TMP. The 90-day mortality and adverse events after propensity score matching were compared between the groups. Results: A total of 126 hemodialysis patients with PJP were included, and the median daily dose per body weight of TMP was 5.74 mg/kg/day (interquartile range: 4.33-8.18 mg/kg/day). Thirty-two pairs were analyzed after the propensity score matching. No significant differences in the 90-day mortality and proportion of adverse events were observed between the high-dose and low-dose groups. Conclusions: A high dose of TMP-SMX is unlikely to decrease the in-hospital mortality and adverse events among hemodialysis patients with PJP. However, the results should be interpreted with caution, given the lack of power and lack of long-term follow-up. Additional prospective interventional studies are required to validate these results.

A systematic review and meta-analysis of randomized trials of substituting soymilk for cow’s milk and intermediate cardiometabolic outcomes: understanding the impact of dairy alternatives in the transition to plant-based diets on cardiometabolic health

BackgroundDietary guidelines recommend a shift to plant-based diets. Fortified soymilk, a prototypical plant protein food used in the transition to plant-based diets, usually contains added sugars to match the sweetness of cow’s milk and is classified as an ultra-processed food. Whether soymilk can replace minimally processed cow’s milk without the adverse cardiometabolic effects attributed to added sugars and ultra-processed foods remains unclear. We conducted a systematic review and meta-analysis of randomized controlled trials, to assess the effect of substituting soymilk for cow’s milk and its modification by added sugars (sweetened versus unsweetened) on intermediate cardiometabolic outcomes.MethodsMEDLINE, Embase, and the Cochrane Central Register of Controlled Trials were searched (through June 2024) for randomized controlled trials of ≥ 3 weeks in adults. Outcomes included established markers of blood lipids, glycemic control, blood pressure, inflammation, adiposity, renal disease, uric acid, and non-alcoholic fatty liver disease. Two independent reviewers extracted data and assessed risk of bias. The certainty of evidence was assessed using GRADE (Grading of Recommendations, Assessment, Development, and Evaluation). A sub-study of lactose versus sucrose outside of a dairy-like matrix was conducted to explore the role of sweetened soymilk which followed the same methodology.ResultsEligibility criteria were met by 17 trials (n = 504 adults with a range of health statuses), assessing the effect of a median daily dose of 500 mL of soymilk (22 g soy protein and 17.2 g or 6.9 g/250 mL added sugars) in substitution for 500 mL of cow’s milk (24 g milk protein and 24 g or 12 g/250 mL total sugars as lactose) on 19 intermediate outcomes. The substitution of soymilk for cow’s milk resulted in moderate reductions in non-HDL-C (mean difference, − 0.26 mmol/L [95% confidence interval, − 0.43 to − 0.10]), systolic blood pressure (− 8.00 mmHg [− 14.89 to − 1.11]), and diastolic blood pressure (− 4.74 mmHg [− 9.17 to − 0.31]); small important reductions in LDL-C (− 0.19 mmol/L [− 0.29 to − 0.09]) and c-reactive protein (CRP) (− 0.82 mg/L [− 1.26 to − 0.37]); and trivial increases in HDL-C (0.05 mmol/L [0.00 to 0.09]). No other outcomes showed differences. There was no meaningful effect modification by added sugars across outcomes. The certainty of evidence was high for LDL-C and non-HDL-C; moderate for systolic blood pressure, diastolic blood pressure, CRP, and HDL-C; and generally moderate-to-low for all other outcomes. We could not conduct the sub-study of the effect of lactose versus added sugars, as no eligible trials could be identified.ConclusionsCurrent evidence provides a good indication that replacing cow’s milk with soymilk (including sweetened soymilk) does not adversely affect established cardiometabolic risk factors and may result in advantages for blood lipids, blood pressure, and inflammation in adults with a mix of health statuses. The classification of plant-based dairy alternatives such as soymilk as ultra-processed may be misleading as it relates to their cardiometabolic effects and may need to be reconsidered in the transition to plant-based diets.Trial registrationClinicalTrials.gov identifier, NCT05637866.

Increased risk of adverse drug reactions by higher linezolid dose per weight in multidrug-resistant tuberculosis

ObjectivesLinezolid treatment has a high risk of toxicity and adverse drug reactions (ADR) are frequent. Few studies have investigated risk factors of major ADRs separately, therefore, we aimed to evaluate major ADRs including peripheral neuropathy in relation to risk factors and drug concentration levels of linezolid in a high-resource setting for multidrug-resistant tuberculosis (MDR-TB). MethodsWe conducted a retrospective cohort study including participants treated with a linezolid-containing MDR-TB regimen in Sweden 1992–2018. Data was collected from medical records. ADRs were classified according to Common Terminology Criteria for Adverse Events (version 5.0). ResultsOf all participants (n = 132), 43.2% were female and the median age 28 y. The median linezolid treatment was 6.5 months (IQR 3.0–12.7) with a median daily dose of 9.6 mg/kg/d. Any ADR was seen in 58.3% (n = 77) of participants, with 35.6% having peripheral neuropathy (n = 47), 27.3% anaemia (n = 36), 22.0% leukopenia (n = 36) while 6.1% (n = 8) had optic neuritis. The median time for peripheral neuropathy was 3.6 months (IQR 2.1–5.9) and 8.3 months (6.2–10.7) for optic neuritis. A >2.0 mg/L trough concentration (n = 40) was associated with anaemia (P = 0.0038) and thrombocytopenia (P = 0.009) but not with peripheral neuropathy. In multivariable analysis, a dose ≥12 mg/kg/d was associated with time to peripheral neuropathy (HR 2.89, 95% CI 1.08–7.74, P = 0.035), anaemia (HR 6.62, 95% CI 2.22–19.8, P = 0.001) and leukopenia (HR 5.23, 95% CI 1.48–18.5, P = 0.010). ConclusionsLinezolid ADRs were frequent in a high-resource setting. Structured, regular follow-up for ADRs and adjusting dosing according to body weight followed-up by monitoring of drug concentrations early may reduce toxicity.

Understanding pregabalin misuse and dependence: Insights from a North Indian addiction treatment center

Background: Pregabalin, approved for various medical conditions, has shown increasing misuse potential globally. However, limited research exists on pregabalin dependence in India. This study aimed to investigate the prevalence and characteristics of pregabalin dependence among individuals seeking substance use disorder (SUD) treatment in North India. Methods: A cross-sectional, analytical study was conducted on patients enrolled between August 2022 and July 2023 at an academic institution-based addiction treatment center. Case records of patients with pregabalin dependence were retrieved and compared with controls with opioid dependence but no history of pregabalin use. Results: Among 3766 registered patients, 135 had pregabalin dependence (prevalence: 3.58 per 100 registered patients). Pregabalin-dependent patients were male, with a median usage duration of eight months and a median daily dose of 1200 mg. Most had concurrent opioid dependence, primarily heroin, used via the injection route. The odds of pregabalin dependence among those with opioid dependence were significantly higher than those with other substance dependence (OR 1.44, 95% CI 1.13–1.85). Reasons for pregabalin use included opioid craving reduction, sedation, and euphoria. Patients with pregabalin dependence were more likely to have lower socioeconomic status (P &lt; 0.0001) and urban residence (P = 0.032), an earlier age of substance use initiation (P = 0.02) and treatment seeking (P &lt; 0.0001), and a higher co-occurrence of psychiatric disorders (P = 0.007) and less occurrence of alcohol dependence (P = 0.03). Conclusion: Findings underscore the need for heightened awareness, screening, and intervention efforts targeting pregabalin misuse within SUD treatment. Further research should focus on longitudinal studies to elucidate pregabalin dependence’s trajectory.

Impact of hydroxyurea on follicle density in patients with sickle cell disease

AbstractThe impact of hydroxyurea (HU) on the ovarian reserve of female patients with sickle cell disease (SCD) remains poorly elucidated. Only direct histological analysis of ovarian follicle density can effectively evaluate HU’s effect on ovarian reserve. By analyzing digitized slides of ovarian tissue from girls and young women with SCD who underwent ovarian tissue cryopreservation (OTC) before hematological stem cell transplantation, we meticulously counted follicles and categorized them based on their growth stage. We then calculated the densities of different follicle types and assessed their correlation with patient characteristics, clinical manifestations, and treatments extracted from medical records. Seventy-six patients with SCD participated in the study, with a median age at OTC of 10.2 years (interquartile range [IQR], 7.5-14.6), and 50 (65.8%) were prepubertal. Of these, 35 patients (46.1%) had received HU, with a median daily dosage of 23.0 mg/kg (IQR, 20.0-25.0) and median exposure time of 44 months (IQR, 24.0-54.0). Primordial follicle density was comparable between the HU and non-HU groups (5.8 follicles per mm2 [IQR, 1.0-13.3] vs 4.2 follicles per mm2 [IQR, 1.1-14.4], respectively; P = .95). However, in the HU group, after adjusting for age, the density of growing follicles was marginally lower than that in the non-HU group (P = .09). Notably, other parameters such as vaso-occlusive crisis did not affect follicular density. In conclusion, exposure to HU did not demonstrate a reduction in ovarian reserve in girls or women with SCD. Therefore, fertility preservation measures before initiating HU treatment do not seem necessary.

A population pharmacokinetic model for sertraline in women during the perinatal period-A contribution from the ConcePTION project.

Sertraline is frequently prescribed for mental health conditions in both pregnant and breastfeeding women. According to the limited available data, only small amounts of sertraline are transferred into human milk, yet with a large amount of unexplained interindividual variability. This study aimed to develop a population pharmacokinetic (popPK) model to describe the pharmacokinetics of sertraline during the perinatal period and explain interindividual variability. Pregnant women treated with sertraline were enrolled in the multicenter prospective cohort SSRI-Breast Milk study. A popPK model for sertraline maternal plasma and breast milk concentrations was developed and allowed estimating the milk-to-plasma ratio (MPR). An additional fetal compartment allowed cord blood concentrations to be described. Several covariates were tested for significance. Ultimately, model-based simulations allowed infant drug exposure through placenta and breast milk under various conditions to be predicted. Thirty-eight women treated with sertraline were included in the study and provided 89 maternal plasma, 29 cord blood and 107 breast milk samples. Sertraline clearance was reduced by 42% in CYP2C19 poor metabolizers compared to other phenotypes. Doubling milk fat content increased the MPR by 95%. Simulations suggested a median daily infant dosage of 6.9μg kg-1 after a 50 mg maternal daily dose, representing 0.95% of the weight-adjusted maternal dose. Median cord blood concentrations could range from 3.29 to 33.23 ng mL-1 after maternal daily doses between 25 and 150 mg. Infant exposure to sertraline, influenced by CYP2C19 phenotype and breast milk fat content, remains low, providing reassurance regarding the use of sertraline during pregnancy and breastfeeding.

Opioid Administration Practice Patterns in Patients With Acute Respiratory Failure Who Undergo Invasive Mechanical Ventilation.

The opioid crisis is impacting people across the country and deserves attention to be able to curb the rise in opioid-related deaths. To evaluate practice patterns in opioid infusion administration and dosing for patients with acute respiratory failure receiving invasive mechanical ventilation. Retrospective cohort study. Patients from 21 hospitals in Kaiser Permanente Northern California and 96 hospitals in Philips electronic ICU Research Institute. We assessed whether patients received opioid infusion and the dose of said opioid infusion. We identified patients with a diagnosis of acute respiratory failure who were initiated on invasive mechanical ventilation. From each patient, we determined if opioid infusions were administered and, among those who received an opioid infusion, the median daily dose of fentanyl infusion. We used hierarchical regression models to quantify variation in opioid infusion use and the median daily dose of fentanyl equivalents across hospitals. We included 13,140 patients in the KPNC cohort and 52,033 patients in the eRI cohort. A total of 7,023 (53.4%) and 16,311 (31.1%) patients received an opioid infusion in the first 21 days of mechanical ventilation in the KPNC and eRI cohorts, respectively. After accounting for patient- and hospital-level fixed effects, the hospital that a patient was admitted to explained 7% (95% CI, 3-11%) and 39% (95% CI, 28-49%) of the variation in opioid infusion use in the KPNC and eRI cohorts, respectively. Among patients who received an opioid infusion, the median daily fentanyl equivalent dose was 692 µg (interquartile range [IQR], 129-1341 µg) in the KPNC cohort and 200 µg (IQR, 0-1050 µg) in the eRI cohort. Hospital explained 4% (95% CI, 1-7%) and 20% (95% CI, 15-26%) of the variation in median daily fentanyl equivalent dose in the KPNC and eRI cohorts, respectively. In the context of efforts to limit healthcare-associated opioid exposure, our findings highlight the considerable opioid exposure that accompanies mechanical ventilation and suggest potential under and over-treatment with analgesia. Our results facilitate benchmarking of hospitals' analgesia practices against risk-adjusted averages and can be used to inform usual care control arms of analgesia and sedation clinical trials.

Khảo sát tình hình điều trị thuốc cho người bệnh parkinson tại Bệnh viện Đại học Y dược TP. Hồ Chí Minh

Background: Parkinson's disease is one of the most common progressive neurodegenerative disorders. There's currently no cure for Parkinson's disease. Current therapies only help patients relieve the symptoms and improve their quality of life. Objectives: To determine the rate of drugs prescribed to treat Parkinson's disease motor symptoms, the rate of the types of drug combinations, and the frequency of drug-induced motor complications in Parkinson's disease patients. Methods: This cross-sectional study was conducted at the University Medical Center HCMC, Ho Chi Minh City. The patient was diagnosed with Parkinson's disease based on the criteria of the International Parkinson's Disease and Movement Disorder Society (IPMDS). Patients' demographic data, information about Parkinson's disease, and medications used to treat Parkinson's disease were collected. Rating scales include MDS-UPRRS (Movement Disorder Society-Unified Parkinson's Disease Rating Scale), and Hoehn &amp; Yahr. Results: Among 218 Parkinson's patients, 33 (15.1%) patients received levodopa monotherapy, 126 (57.8%) patients received combination therapy of levodopa and dopamine agonists, 07 (3.2%) ) patients received combination therapy of levodopa and trihexyphenidyl, 1 (0.5%) patient received combination therapy of dopamine agonist and trihexyphenidyl, and 51 (23.4%) patients received combination therapy of both levodopa, dopamine agonist and trihexyphenidyl. A total of 217 patients were prescribed levodopa at a median dose of 375 mg. The median daily levodopa equivalent dose was 500 mg. A total of 177 patients (81.2%) used the dopamine agonist (pramipexole) with a median dose of 0.75 mg. 27.9 % of patients used an anticholinergic drug (trihexyphenidyl) with a median dose of 2 mg. The proportion of Parkinson's disease patients with motor complications was 32.6%. Conclusion: Levodopa was the medication most commonly prescribed to treat motor symptoms in patients with Parkinson's disease. The combination of levodopa and dopamine agonist was most popularly used. Drug-induced motor complications were common in Parkinson’s disease.

Induction cyclophosphamide with maintenance immunosuppression in high-risk myasthenia gravis: long-term follow-up and safety profile

BackgroundPatients with refractory or high-risk myasthenia gravis (MG) respond poorly to conventional immunosuppressive therapy, requiring rescue therapies and often experiencing treatment toxicity. Rescue and injectable therapies do not induce remission...

Prophylactic Effect of Clarithromycin on Radiation Pneumonitis in IMRT for Lung Cancer.

To evaluate the association between prophylactic administration of clarithromycin (CAM) and the development of radiation pneumonitis (RP) in patients treated with intensity modulated radiation therapy (IMRT) for lung cancer. A total of 89 patients who underwent definitive or salvage IMRT for lung cancer were retrospectively evaluated. The median total and daily doses were 60 Gy and 2 Gy, respectively. A total of 39 patients (44%) received CAM for a median of three months after the start of IMRT. The relationship between the development of RP and certain clinical factors was analyzed. RP of Grade ≥2 was recognized in 10 (11%) patients; Grade 2 in six patients and Grade 3 in four patients. The incidence of Grade ≥2 RP was 3% (1/39) in patients treated with CAM, which was significantly lower than that of 18% (9/50) in patients without CAM. The median lung V20 and V5 in the 10 patients with RP Grade ≥2 were 24% and 46%, respectively, compared with 18% and 37% in the 79 patients with RP Grade 0-1, and the differences were significant. Durvalumab administration after IMRT was also a significant factor for RP Grade ≥2. Prophylactic administration of CAM may reduce Grade ≥2 RP in patients treated with IMRT for lung cancer. Therefore, further clinical trials are warranted.

Evaluation of Empiric Voriconazole Dosing and Therapeutic Drug Monitoring in Hospitalized Pediatric Patients.

Invasive fungal infections are a significant cause of morbidity and mortality in children with immunodeficiencies. Current dosing recommendations for voriconazole often result in subtherapeutic exposure in pediatric patients. In this single-center retrospective study, we reviewed hospitalized pediatric patients receiving voriconazole with at least one inpatient serum trough concentration measured. Patient characteristics and voriconazole dosing courses with associated trough concentrations were summarized for all patients as well as grouped by age (0 to 1 y, 2 to 11 y, and 12 to 18 y). Of 106 included patients, the median age was 9 years (range, 29 d to 18 y). Five hundred ninety courses of voriconazole were administered with 365 associated troughs. Most troughs were subtherapeutic (49%) and 30% of patients never attained a therapeutic trough. The median oral daily dose associated with a therapeutic trough was higher in younger age groups: 21.6 mg/kg 0 to 1 year, 17.9 mg/kg 2 to 11, and 9.5 mg/kg 12 to 18 years ( P <0.001). Patients younger than 2 years had the largest proportion of subtherapeutic troughs and variability in dosing. Attainment of therapeutic voriconazole concentrations was challenging across all pediatric age groups. Higher starting doses for patients younger than 2 years are likely needed.