Total Daily Dose Research Articles

Investigation of The Effect of Combined Exercises on Glycemic Control in Individuals with Type 1 Diabetes

The aim of the present study was to investigate the effect of the combined physical exercise protocols on the blood glucose (BG) of children with T1D. The study was conducted over four weeks using self-controlled clinical trials. The first two weeks were control period and the last two weeks were the experimental period. A total of 6 exercise sessions were performed 3 days a week during the experimental period. The exercise program consisted of aerobic, stretching, and resistance exercises. Each exercise session was performed for 40 minutes. A total of 15 children with T1D, whose mean age was 13.3±SD, were included in the study. The blood glucose and insulin dose data of the participants were recorded in both periods through the continuous glucose measurement system and the registry. It was determined that aerobic exercises provided a significant decrease in blood glucose (p < .05). There was no statistically significant difference between the mean BG values in the control (211.7±37.3) and experimental (208.7±40.4) periods (p >0.05). On the other hand, a statistically significant decrease was found in the total daily insulin doses used by participants during the experimental (31.6±20.8 Unit) period (p < 0.001). Physical exercises had an acute positive effect on blood glucose in children with T1D. However, the effect of exercise alone is not sufficient for chronic glycemic control in T1D. For chronic glycemic control, first of all, the injected insulin doses should be carefully regulated according to carbohydrates and exercise.

Assessing Time in Range with Postprandial Glucose-Focused Titration of Ultra Rapid Lispro (URLi) in People with Type1 Diabetes.

To assess time in range (TIR) (70-180mg/dL) with postprandial glucose (PPG)-focused titration of ultra rapid lispro (URLi; Lyumjev®) in combination with insulin degludec in people with type1 diabetes (T1D). This phase2, single-group, open-label, exploratory study was conducted in 31 participants with T1D on multiple daily injection therapy. Participants were treated with insulin degludec and Lispro for an 11-day lead-in and then URLi for a 46-day treatment period consisting of 35-day titration and 11-day endpoint maintenance period. Glucose targets for the titration period were PPG < 140mg/dL or < 20% increase from premeal, fasting glucose 80-110mg/dL, and overnight excursion ± 30mg/dL or less. Participants used the InPen™ bolus calculator and Dexcom G6 continuous glucose monitoring (CGM). Primary endpoint mean TIR (70-180mg/dL) with URLi during the maintenance period was 70.2%. TIR (70-180mg/dL) and times below/above range were not significantly different with URLi (maintenance) versus lispro (lead-in). HbA1c decreased from 7.1% at screening to 6.8% at endpoint (least squares mean [LSM] change from baseline, - 0.36%; P < 0.001). Fructosamine and 1,5-anhydroglucitol improved (P < 0.001). Mean hourly glucose using CGM was reduced from 8:00AM to 4:00PM with URLi. Overall highest PPG excursion across meals was significantly reduced at URLi endpoint compared with lispro lead-in (mean 56.5 vs 72.4mg/dL; P < 0.001). Insulin-to-carbohydrate ratio (U/Xg) was reduced (more insulin given) at breakfast at URLi endpoint vs lead-in (LSM 9.0 vs 9.7g; P = 0.002) and numerically decreased at other meals. Total daily insulin dose (TDD) was higher at URLi endpoint compared with lispro lead-in (mean 50.2 vs 47.0U; P = 0.046) with similar prandial/TDD ratio (mean 52.1% vs 51.2%). There were no severe hypoglycemia events during the study. URLi in a basal-bolus regimen focusing on PPG targets demonstrated improved overall glycemic control and reduced PPG excursions without increased hypoglycemia in participants with T1D. ClinicalTrial.gov, NCT04585776.

47 Clinical Approach to Febrile Urinary Tract Infections in Young Children Presenting to the Paediatric Emergency Department: A Retrospective Study of National Guideline Compliance

Abstract Background Antimicrobial resistance is one of the greatest threats to global health. Antibiotic overuse drives antimicrobial resistance. Suspected urinary tract infection (UTI) is a key area of over-prescribing in many clinical settings but has not been investigated in the paediatric emergency department (ED). Objectives Here, we explore compliance with national UTI management guidelines in a paediatric emergency department setting and characterize patient and provider factors associated with guideline non-compliance. Design/Methods We performed retrospective chart review of patients ages 60 days to 36 months, discharged with a diagnosis of UTI from a single, urban, tertiary care paediatric emergency department (PED) with a diagnosis of UTI. Random visits were chosen using a computer algorithm. Primary outcomes were: 1) proportion of patients receiving guideline-compliant investigation and treatment, and 2) the proportion of children whose antibiotic prescriptions were appropriately adjusted upon return of urine culture and antibiotic susceptibilities (C&amp;S). The guideline was the Canadian Paediatric Society statement on management of UTI, as well as the BC Children’s Hospital institutional UTI management guideline. Descriptive statistics and odds ratios between associations were calculated. Results We reviewed 402 charts. The proportion of infants receiving guideline-compliant testing and treatment was 25.9% (95% CI: 21.8-30.4%). Of those who were prescribed antibiotics, 79.6% (95% CI: 74.7-83.8%) received a first-line recommended agent and 58.9% (95% CI: 53.8-63.8%) received fully compliant therapy with respect to agent, dose, duration, and frequency. 19.4% (15.4-24.2%) of patients who were prescribed empiric cephalexin received an inappropriately high total daily dose. The proportion of patients receiving age-appropriate testing method was 52.2% (95% CI: 47.4-57.1). Febrile children were more likely to receive age-appropriate urine sample collection by catheterized sample (OR: 2.77 95% CI: 1.81-4.25) compared with afebrile children. Ultimately, 50.7% (95% CI: 40.4-49.6%) of patients discharged with a diagnosis of UTI and prescription for antibiotic met diagnostic criteria for UTI based on urinalysis and culture results. Of patients whose C&amp;S mandated a change in therapy, 60.8% (95% CI: 55.8-65.7%) had their agent changed or discontinued. Conclusion Paediatric emergency medicine physicians frequently order inappropriate investigation and empiric treatment of UTI in young children. Discontinuation of empiric antibiotics in culture-negative children may be an impactful stewardship intervention in the PED.

Expected Basal Insulin Requirement during CSII therapy by Age Group, Sex and BMI, based on 25,718 Young People with Type 1 Diabetes in the DPV Registry.

Background Since the introduction of insulin pumps into the therapy of paediatric subjects, different approaches have been taken to find optimal basal rates. Previously, the DPV registry provided circadian basal rate patterns for different age groups. As the number of pump users has increased recently and short-acting insulin analogues are now predominant, we performed a new analysis with a larger data pool. Methods We included all recent basal profiles from T1D patients between 1 and 25 years from the DPV 2021 data pool. We excluded night-time-only pump users, human regular insulin users, and daily basal rates < 0.05 U/kgBW/d and >1.0 U/kgBW/d. Results In the analysis of profiles from 25,718 young persons with T1D, differences in the daily pattern of basal rates were found between age groups. In addition, we saw significant (p<0.001) differences in total daily basal dose between genders in all age groups except adults. In addition, the shape of the expected basal-rate pattern differed by BMI, HbA1c and use of continuous glucose monitoring. Discussion This analysis demonstrates multiple factors influencing basal patterns and insulin requirement, including age group, gender, overweight, HbA1c, bolus frequency and sensor use. As circadian basal rates are still mandatory for initiating insulin pump therapy with or without automation, a multimodal approach is necessary to estimate optimal basal rates.

Impact of a passive clinical decision support tool on potentially inappropriate medications (PIM) use in older adult patients.

Medication related clinical decision support (CDS) interventions may improve patient safety. In older patient populations, there has been effort placed in reducing exposure to potentially inappropriate medications (PIMs). After years of reducing exposure of older adults in our hospitals to PIMs through multi-component interventions, our system chose to expand the scope and attempt a new strategy to lessen alert burden for providers and pharmacists. Based on the American Geriatric Society Beers Criteria and internal data, a passive CDS approach, termed "geriatric context" was established to recommend appropriate medication selection including lower dosage amounts and frequency of administration in older adults. Retrospective descriptive study examining change in a pre and post implementation analysis of medication usage patterns between two 9-month time periods in 2019 and 2021 in patients age ≥65 years across an 8-hospital health system. The primary endpoint is the percentage of each medication intervened with an ordered dose and frequency outside of alignment with recommended context parameters. Secondary endpoints include total daily dose (TDD) and average dose (AD) per patient of the individual PIMs. Exploratory endpoints include frequency of active alerts fired by the CPOE and overridden by providers. A total of 62,738 older adult hospital admissions are included in the overall study period, with 32,969 pre-implementation and 29,769 post-implementation. Haloperidol showed the greatest reduction in inappropriate doses from 41.5% to 21.4% (p < 0.001) of orders, followed by reduction in inappropriate frequencies in orders for diphenhydramine from 57.2% to 39.7% (p < 0.001). Secondary endpoints showed favorable reductions across 11 of the 16 medications in both TDD and AD administered. Exploratory analysis with select medications showed reductions in frequency of alerts fired and overridden. Utilization of a passive CDS positively influences prescribing patterns for older adults and reduces the alert burden to ordering providers.

Rationale and protocol of a double-blind, randomized, placebo-controlled trial to test the efficacy, safety, and tolerability of dimethyl fumarate in Friedreich Ataxia (DMF-FA-201).

Friedreich Ataxia (FRDA) is an autosomal recessive neurodegenerative disorder that causes gait and limb ataxia, dysarthria, and impaired vibratory sense, with cardiomyopathy being the predominant cause of death. There is no approved therapy, which results in the use of symptomatic treatments and the chronic support of physiotherapy. Dimethyl fumarate (DMF) is a fumaric acid ester used for the treatment of psoriasis and Multiple Sclerosis (MS). It induces Nrf2 in vitro and in vivo, and it increases frataxin in FRDA patient lymphoblasts, in mouse models, and in MS treated patients. The aim of our study is to investigate if DMF can increase the expression of the FXN gene and frataxin protein and ameliorate in-vivo detectable measures of mitochondrial dysfunction in FRDA. The study is composed of a screening visit and two sequential 12-week phases: a core phase and an extension phase. During the first phase (core), patients will be randomly assigned to either the DMF or a placebo group in a 1:1 ratio. During the first week, patients will receive a total daily dose of 240 mg of DMF or placebo; from the second week of treatment, the dose will be increased to two 120 mg tablets BID for a total daily dose of 480 mg. During the second phase (extension), all patients will be treated with DMF. EudraCT number 2021-006274-23. The primary endpoint will be a change in FXN gene expression level after 12 weeks of treatment. Secondary endpoints will be frataxin protein level, cardiopulmonary exercise test outputs, echocardiographic measures, Nrf2 pathway and mitochondrial biogenesis gene expression, safety, clinical scales, and quality of life scales. This is the first study aimed at exploring the ability of DMF, an already available treatment for MS and psoriasis, to correct the biological deficits of FRDA and potentially improve mitochondrial respiration in-vivo.

Safety Event Outcomes and Glycemic Control with a Hybrid Closed-Loop System Used by Chinese Adolescents and Adults with Type 1 Diabetes Mellitus.

Background: While evidence supports glycemic control benefits for individuals with type 1 diabetes mellitus (T1DM) using hybrid closed-loop (HCL) systems, HCL automated insulin delivery therapy in China has not been assessed. This study evaluated safety events and effectiveness during HCL system use by Chinese adolescents and adults with T1DM. Methods: Sixty-two participants (n = 12 adolescents with a mean ± standard deviation [SD] of 15.5 ± 1.1 years and n = 50 adults [mean ± SD of 37.6 ± 11.1 years]) with T1DM and baseline A1C of 7.1% ± 1.0% underwent a run-in period (∼2 weeks) using open-loop Manual Mode (sensor-augmented pump) insulin delivery with the MiniMed™ 770G system with the Guardian™ Sensor (3) glucose sensor, followed by a study period (4 weeks) with HCL Auto Mode enabled. Analyses compared continuous glucose monitoring data and insulin delivered during the run-in versus study period (Wilcoxon signed-rank test or t-test). Safety events included rates of severe hypoglycemia and diabetic ketoacidosis (DKA). Results: Compared to baseline run-in, overall Auto Mode use increased time in range (TIR, 70-180 mg/dL) from 75.3% to 80.9% (P < 0.001) and reduced time below range (TBR, <70 mg/dL) from 4.7% to 2.2% (P < 0.001). Subgroup analysis demonstrated that participants (n = 29) with baseline A1C <7.0% had TBR that reduced from 5.6% to 2.0%, while participants (n = 21) with baseline A1C ≥7.5% had time above range (TAR, >180 mg/dL) that reduced from 31.6% to 20.8%. Auto Mode use also increased the percentage achieving combined recommendations for time at sensor glucose ranges (i.e., TIR of >70%, TBR of <4% and TAR of <25%) from 24.2% at baseline to 77.4% at study end. Total daily insulin dose reduced from 42.8 ± 19.8 to 40.7 ± 18.9 U (P = 0.013). There were no severe hypoglycemic, DKA, or serious adverse events. Conclusions: Chinese adolescents and adults, some of whom met target A1C at baseline, safely achieved significantly improved glycemia with 1 month of MiniMed 770G system use when compared to open-loop insulin delivery. ClinicalTrials.gov ID: NCT04663295.

Abstract P192: Provider And Health System Level Variability In Initial Antihypertensive Intensity: A Mixed Modeling Approach In Newly Treated Patients With Hypertension

Background: Initial antiHTN regimen intensity varies across patients, presumably due to factors like age, comorbidities, or baseline BP. However, the extent to which initial regimen intensity is influenced by patient factors, versus provider characteristics or preferences, and health system contexts, is unknown. Methods: We conducted a cross-sectional study of adults with newly-treated HTN in the OneFL+ Consortium with Medicaid or Medicare claims linked to EHR data from their treatment initiation visit. We used linear mixed modeling with prescriber nested within health system as random effects to estimate variability in total therapeutic intensity score (TTIS) – a patient’s total daily dose (TDD) divided by the recommended max TDD for a drug, summed across the initial regimen. We modeled patient- (demographics, BP, BMI, comorbidities) and provider-level (sex, specialty) factors as fixed effects and calculated intraclass correlation coefficients (ICC), to estimate relative variance in TTIS attributable to provider preference (ICC P ) and health system (ICC H ). Results: A total of 3970 patients (mean ± SD age, 59 ± 18.4 y; 58% women; 38% Black) were included. In the full model, 11.4% of the observed TTIS variation was attributed to provider (p&lt;0.0001) and 3.9% to health system context (p=0.17), leaving 84.7% of TTIS variation within patients. The most influential factors in TTIS variation were Black race, male sex, and comorbidity profile (T2DM, CKD) (Table). Conclusion: Provider preference accounted for a significant but modest amount of variation in initial antiHTN regimen intensity. Most of the variance in TTIS was explained by patient factors.

A randomized controlled trial to examine the impact of a multi-strain probiotic on self-reported indicators of depression, anxiety, mood, and associated biomarkers.

To examine the efficacy of supplementing with a multi-strain probiotic (MSP) on changes associated with mood, anxiety, and neurotransmitter levels. In a randomized, double-blind, placebo-controlled fashion, 70 healthy men and women (31.0 ± 9.5 years, 173.0 ± 10.4 cm, 73.9 ± 13.8 kg, 24.6 ± 3.5 kg/m2) supplemented with a single capsule of MSP (a total daily dose of 4 × 109 colony forming units [CFU] comprised of a 1 × 109 CFU dose from each of the following strains: Limosilactobacillus fermentum LF16, Lacticaseibacillus rhamnosus LR06, Lactiplantibacillus plantarum LP01, and Bifidobacterium longum 04, Probiotical S.p.A., Novara, Italy) or a maltodextrin placebo (PLA). After 0, 2, 4, and 6 weeks of supplementation and 3 weeks after ceasing supplementation, study participants completed the Beck Depression Inventory (BDI-II), State-Trait Anxiety Inventory (STAI), and Leiden Index of Depression Sensitivity (LEIDS-R) questionnaires and had plasma concentrations of cortisol, dopamine, serotonin, and C-reactive protein determined. BDI, STAI, and total LEIDS-R scores were reduced from baseline (p < 0.05) with MSP supplementation after 4 and 6 weeks of supplementation and 3 weeks after supplementation while no changes (p > 0.05) were reported in PLA. When compared to PLA, MSP scores for state anxiety, trait anxiety, and LEIDS-R (hopeless, aggression, rumination, and total score) were significantly lower (p < 0.05) after supplementation. Plasma serotonin concentrations in MSP were increased from baseline after 6 weeks of supplementation and 3 weeks after ceasing supplementation. No changes (p > 0.05) in plasma dopamine, C-reactive protein, or cortisol concentrations were observed between groups. MSP supplementation resulted in widespread improvements in several questionnaires evaluating mood, anxiety, and depression in young, healthy men and women. MSP supplementation increased serotonin increased after 6 weeks of MSP supplementation with no change in dopamine, C-reactive protein, or cortisol. https://classic.clinicaltrials.gov/ct2/show/NCT05343533, NCT05343533.

Correlation between Skinfold Thickness and Total Daily Dose of Insulin in Patient with Type 2 Diabetes Mellitus in Dr Soetomo General Hospital

Introduction: Type 2 diabetes mellitus (T2DM) is a non-communicable disease with a high prevalence in Indonesia. T2DM is caused by insulin resistance and relative insulin deficiency. One of the therapy for T2DM is insulin administration which is injected into the subcutaneous tissue. The absorption of insulin in the subcutaneous tissue is influenced by many factors, one of which is the thickness of subcutaneous fat. This study aimed to determine the correlation between the skinfold thickness of T2DM patients with the total daily dose of insulin needed every day. Methods: This was an observational analytic study using a cross-sectional design to analyze the correlation between subcutaneous fat thickness represented by skinfold thickness and the total daily dose of insulin of T2DM patients. Measurement of skinfold thickness was carried out on the triceps using a skinfold caliper. Data on the patient's total daily dose of insulin were obtained from medical records.Results: A total of 53 patients were included in this study. The patient's mean triceps skinfold thickness was 26.29±8.72 mm. The mean total daily dose of insulin was 40.96±18.01 IU. The results of the Spearman Rank correlation test showed a significant correlation between skinfold thickness on the triceps and the patient's total daily dose of insulin (p&lt;0.05). Conclusion: The higher the skinfold thickness, the greater the dose of insulin needed by the patient.

Antibodies to Glutamic Acid Decarboxylase-65 is Associated with Total Daily Dose of Insulin Requirement in Children with Type 1 Diabetes

BACKGROUND: Type 1 diabetes (T1D) mostly occurs due to the destruction of pancreatic beta cells due to autoimmune processes. Diagnosis of T1D can be established by examining the c-peptide levels and the markers of pancreatic autoantibodies, including glutamic acid decarboxylase 65 autoantibodies (GAD-65). However, the association between c-peptide and anti-GAD-65 toward patients’ clinical manifestations needs to be further explored. Hence, the aim of current study was to identify the association of anti-GAD65 with c-peptide and clinical characteristics in children with T1D.METHODS: Case-control study involving 47 T1D children (T1D group) and 41 healthy children (control group) younger than 18 years old was conducted. Secondary data regarding subjects’ demographic characteristics and medical history were collected from subjects, and serum blood was drawn from each subject for the anti-GAD65 and c-peptide measurement. Anti-GAD65 and c-peptide levels were measured using an Enzyme-Linked Immunosorbent Assay (ELISA) methods.RESULTS: Anti-GAD65 antibody was detected in 78.7% T1D group, while only 2.43% were detected in control group subject (p=0.0000). The c-peptide level of T1D group was 0.07±0.19 nmol/L and control group was 1.5±0.77 nmol/L (p=0.0000). The total daily dose of insulin in subjects with positive anti-GAD65 was greater than in the negative anti-GAD65 (p=0.012). The sensitivity and specificity of the anti-GAD65 were 85.4% was 66.7%, respectively.CONCLUSION: The results of this study show that anti-GAD65 was associated with total daily dose of insulin requirement in children with T1D.KEYWORDS: diabetes mellitus, type 1 diabetes, anti-GAD65, c-peptide

Individualized Delivery of Vancomycin by Model-Informed Bayesian Dosing Approach to Maintain an AUC24 Target in Critically Ill Patients

Introduction: Monitoring of AUC24 was updated recommendation in the guideline for the therapeutic drug monitoring (TDM) of vancomycin in Chinese pharmacological society published in 2020. Vancomycin pharmacokinetic profiles are diverse and unique in critically ill patients because of the drastic variability of the patients’ physiological parameters, while the study for population pharmacokinetic (PPK) models in Chinese critically ill patients has been rarely reported. The objectives of this study were to construct a PPK model to describe the pharmacokinetic characteristics of vancomycin in critically ill patients and to individualize vancomycin dosing by model-informed Bayesian estimation for maintenance of AUC24 target at 400–650 mg h/L recommended by the 2020 guideline. Methods: Vancomycin with different dosing was administered intravenously over 1 h for critically ill patients, TDM was started at 48 h or 72 h since initiation of vancomycin therapy for patients. Blood samples were collected from patients for trough concentrations or Cmax. Vancomycin concentrations were determined by high-performance liquid chromatography method with ultraviolet detection. PPK model was performed using the nonlinear mixed-effect model (NONMEM®). Individual PK parameters for critically ill patients treated with vancomycin were estimated using a post hoc empirical Bayesian method based on the final PPK model. AUC24 was calculated as the total daily dose divided by the clearance (L/h). Results: The PPK of vancomycin was determined by a one-compartment model with creatinine clearance as fixed effects. The PK estimates in the final model generally agreed with the median estimates and were contained within the 95% CI generated from the bootstrap results, indicating good precision and stability in the final model. The visual predictive check plots showed the adequate predictive performance of the final PK model and supported a good model fit. The model-informed Bayesian estimation was used to predict the AUC24 of critically ill patient by the acquired TDM results, and the dosing adjustment by maintenance of AUC24 at 400–650 mg h/L had made a great therapeutic effect for the case. Conclusion: This study established a PPK model of vancomycin in Chinese critically ill patients, and individualized dosing of vancomycin by model-informed Bayesian estimation to maintain an AUC24 target at 400–650 mg h/L has been successfully applied in clinic. This result supports the continued use of model-informed Bayesian estimation to vancomycin treatment in critically ill patients.

The effects of large-scale social restriction during the covid-19 pandemic on glycemic control and occurrence of complications in children with type-1 diabetes mellitus

Background The global pandemic of severe acute respiratory syndrome caused by the coronavirus-2 (SARS-CoV-2) infection has resulted in a national large-scale social restriction (LSSR) to limit the spread of the virus.&#x0D; Objective To determine the impacts of LSSR on glycemic controls and the occurrence of complications in type-1 diabetes mellitus (T1DM) children. &#x0D; Methods A retrospective longitudinal study was carried out in Dr. Sardjito Hospital, Yogyakarta. Subjects were 0-18 years old T1DM patients diagnosed before the LSSR with at least six months of disease. Data on demographics, T1DM status, HbA1c level, and complications pre-LSSR, and during LSSR were taken from medical records. Paired T-tests were used to assess the difference in HbA1c level between the two-time points&#x0D; Results: We included information on 21 children based on the inclusion and exclusion criteria. Their median (range) age was 13.9 (1.42-17.3) years, with a median (range) diabetes duration of 2.6 (0.0-10.92) years. Glycemic control improved in 76% of the children. The mean HbA1c before and during LSSR was 10.9 (SD 2.7) and. 9.7 (SD 2.3), respectively; P&lt;0.05. The glycemic control was not associated with sex, age, duration of diabetes, travel time to the clinic, or a total daily insulin dose. There was also no significant difference in the occurrence of complications.&#x0D; Conclusion Despite limitations during LSSR, glycemic control improved in most patients with T1DM. This might be related to improved health awareness during the pandemic, more regular meals, and better parental control.

Age and postoperative opioid use in women undergoing pelvic organ prolapse surgery.

Our objective was to explore the relation between patient age and postoperative opioid use up to 24 hours following pelvic organ prolapse (POP) surgery. We conducted a prospective cohort study following 335 women ranging in age from 26 to 82 years who underwent surgery for multi-compartment POP at a tertiary center in Alberta, Canada. Patient characteristics were measured using baseline questionnaires. Perioperative data were collected from medical chart review during and up to 24 hours following surgery. We used logistic regression to analyze the odds of being opioid-free and linear regression to analyze mean differences in opioid dose, measured as total morphine equivalent daily dose, exploring for a potential non-linear effect of age. Adjusted models controlled for preoperative pain, surgical characteristics and patient health factors. Overall, age was positively associated with greater odds of being opioid-free in the first 24 hours after surgery (adjusted odds ratio per increasing year of age = 1.07, 95% confidence interval [CI] 1.04-1.09, n = 332 women). Among opioid users, age was inversely associated with total opioid dose (adjusted mean difference per increasing year of age = 0.71 mg morphine equivalent daily dose, 95% CI -0.99 to -0.44, n = 204 women). There was no evidence of a non-linear relation between age and postoperative opioid use or dose. In the context of POP surgery, we found that younger women were more likely to use opioids after surgery and to use a higher dose in the first 24 hours when compared with older women. These findings support physicians to consider age when counseling POP patients regarding pain management after surgery, and to direct resources aimed at opioid-free pain control towards younger patients.

IPX203 vs Immediate-Release Carbidopa-Levodopa for the Treatment of Motor Fluctuations in Parkinson Disease

Levodopa has a short half-life and a limited window of opportunity for absorption in the proximal small intestine. IPX203 is an oral, extended-release formulation of carbidopa-levodopa developed to address these limitations. To assess the efficacy and safety of IPX203 vs immediate-release carbidopa-levodopa in patients with Parkinson disease who are experiencing motor fluctuations. RISE-PD was a 20-week, randomized, double-blind, double-dummy, active-controlled, phase 3 clinical trial. The study was conducted between November 6, 2018, and June 15, 2021, at 105 academic and clinical centers in the US and Europe. Patients with Parkinson disease taking a total daily dose of 400 mg or more of levodopa and experiencing an average of 2.5 hours or more daily off-time were included in the study. A total of 770 patients were screened, 140 were excluded (those taking controlled-release carbidopa-levodopa apart from a single daily bedtime dose, Rytary (Amneal Pharmaceuticals), additional carbidopa or benserazide, or catechol O-methyl transferase inhibitors or who had a history of psychosis within the past 10 years), and 630 were enrolled in the trial. Following open-label immediate-release carbidopa-levodopa dose adjustment (3 weeks) and conversion to IPX203 (4 weeks), patients were randomized in a 1:1 ratio to double-blind, double-dummy treatment with immediate-release carbidopa-levodopa or IPX203 for 13 weeks. The primary end point was mean change in daily good on-time (ie, on-time without troublesome dyskinesia) from baseline to the end of the double-blind treatment period. A total of 630 patients (mean [SD] age, 66.5 [8.95] years; 396 [62.9%] men) were enrolled, and 506 patients were randomly assigned to receive IPX203 (n = 256) or immediate-release carbidopa-levodopa (n = 250). The study met its primary end point, demonstrating statistically significant improvement in daily good on-time for IPX203 compared to immediate-release carbidopa-levodopa (least squares mean, 0.53 hours; 95% CI, 0.09-0.97; P = .02), with IPX203 dosed a mean 3 times per day vs 5 times per day for immediate-release carbidopa-levodopa. Good on-time per dose increased by 1.55 hours with IPX203 compared to immediate-release carbidopa-levodopa (95% CI, 1.37-1.73; P < .001). IPX203 was well tolerated. The most common adverse events in the double-blind phase (IPX203 vs immediate-release carbidopa-levodopa) were nausea (4.3% vs 0.8%) and anxiety (2.7% vs 0.0%). In this study, IPX203 provided more hours of good on-time per day than immediate-release carbidopa-levodopa, even as IPX203 was dosed less frequently. ClinicalTrials.gov Identifier: NCT03670953.

Buprenorphine Extended-Release Treatment for Opioid Use Disorder in the Postpartum Period.

Buprenorphine extended-release (XR) is an extended-release monthly injection to treat opioid use disorder (OUD). This retrospective case series includes 15 postpartum patients who were treated with buprenorphine-XR at a single center and reports on their outcomes. The average total daily sublingual buprenorphine dose before initiation of buprenorphine-XR was 16.25 mg (SD±7.76, range 2-32 mg). Overall, 137 total doses of buprenorphine-XR were administered between May 17, 2021, and April 11, 2023. Urine toxicology test results were negative for opioids other than buprenorphine in the majority (80.0%) of patients once appropriate maintenance doses were achieved. Euphoria and intoxication were not reported. A minority of patients (20.0%) discontinued buprenorphine-XR. Although more extensive research is needed before widespread use, buprenorphine-XR may be a favorable treatment for OUD in this high-risk population.

Cumulative health risk in children and adolescents exposed to bis(2-ethylhexyl) phthalate (DEHP)

Bis(2-ethylhexyl) phthalate (DEHP) has been widely concerned owing to its widespread detection and endocrine disrupting effect. Nevertheless, systematic analysis and evaluation of the current status of DEHP contamination are still insufficient for children and adolescents. Dietary exposure and nondietary exposure to DEHP were investigated to estimate the total average daily dose (ADD). The top three contributors were dust exposure, edible oil and vegetable intake. Dietary intake contributed highly (70%) to daily exposure to DEHP. By analyzing the monitoring data on DEHP exposure, the cumulative health risks of DEHP were assessed for different age groups of children and adolescents in East China. The probability distributions of noncarcinogenic and carcinogenic risks were determined by Monte Carlo simulation. The results showed that the risk level reduced with age. The predicted mean noncarcinogenic and carcinogenic risks for all age groups exceeded the acceptable level, indicating that the general population would be at high risk by DEHP overexposure. Schoolchildren at ages 6∼<9 were more susceptible to DEHP exposure, with a 30% possibility of exceeding the safety limit Based on these results, gradual banning and restriction should be carried out to decrease DEHP contamination and potential health risks.

Treatment of high dose of intravenous midazolam abuse: a case report.

This study reports a rare case of high-dose midazolam abuse and Munchausen Syndrome. A 48-year-old female physician was referred by a psychiatrist to the Toxicology Department of Imam Reza Hospital for abstaining from 300 mg/day of parenteral midazolam. She had mimicked the symptoms of Crohn's disease; therefore, she had undergone 15 colonoscopies and 40 times MRI or CT scan, all of which were normal. Six months earlier, she had switched oral methadone to 30 mg/day of intravenous midazolam. She also had several skin lesions on injection sites that she considered pyoderma gangrenosum. When the total daily dose of intravenous midazolam was switched to oral bioequivalence of clonazepam, she could not tolerate withdrawal (Clinical Institute Withdrawal Assessment Scale-Benzodiazepines = 68). Therefore, she received midazolam again as a continuous intravenous infusion. Within 7 days, the whole dose was replaced by the bioequivalence oral dose of clonazepam. She was also treated with carbamazepine and cognitive behavior therapy. Afterward, she was transferred to the psychiatric ward for further psychiatric treatment. Dependency on a high dose of midazolam could be treated by tapering off the long-acting benzodiazepine.

Glucose control during Ramadan in a pediatric cohort with type 1 diabetes on MiniMed standard and advanced hybrid closed‑loop systems: A pilot study

BackgroundHybrid closed-loop (HCL) systems have revolutionized the treatment of diabetes, enabling doctors to cope with challenging conditions that were previously almost impossible to manage or were very risky and difficult. AimsTo assess the efficacy and safety of a hybrid closed-loop (HCL) system during Ramadan fasting in a pediatric cohort with type 1 diabetes (T1D). Research design and methodsGlucose control outcomes in older children and adolescents aged 8–16 years with automated insulin delivery for T1D were analyzed during Ramadan and 1 month before Ramadan. Participants on MiniMed standard HCL (670G) or advanced HCL (780G) systems of Medtronic were categorized as fasting or nonfasting. ResultsThe average age of the 19 participants (8 and 11 were on standard and advanced HCL systems, respectively) was 11.35 ± 2 years. Eleven patients fasted during Ramadan. Pump setup and sensor statistics were the same during Ramadan and the month before; no significant difference was found between the two groups in terms of insulin and glucose control metrics, with practically the same coefficient of variation, time in range (TIR) and time spent in hypoglycemia, maintained within the international recommended targets. Total daily doses were paradoxically higher in patients who fasted during Ramadan (p = 0.01), without repercussions on glucose control metrics. ConclusionsStandard and advanced HCL use during Ramadan were safe and were associated with a maintained optimum TIR (>70 %) and no significant hypoglycemia in adolescents and older children with T1D.

Colchicine efficacy comparison at varying time points in the peri-operative period for coronary artery disease: a systematic review and meta-analysis of randomized controlled trials.

Over the years, it has been found that colchicine offers substantial benefits in secondary prevention in patients with coronary artery disease (CAD). We studied the effects of colchicine timing because there are no guidelines about when to provide it during the perioperative period for patients with CAD. Up to January 1, 2023, seven electronic literature databases were screened (including three English databases and four Chinese databases). Randomized controlled trials included only treatment with colchicine in the perioperative period of CAD. The Cochrane Evaluation Tool was used to judge the risk of bias in research. Statistical analysis was performed by Stata 16.0 software. We evaluated twelve studies that found colchicine to be effective in decreasing the occurrence of major adverse cardiac events (MACEs) (p < 0.00001), but it also raised the rate of adverse events (p = 0.001). Subgroup analysis showed the same benefit in lowering the incidence of MACE with continuous administration of a total daily dose of 0.5 mg postoperatively while minimizing drug-related side effects in the patients (p = 0.03). When it comes to preventing surgical stroke occurrences, postoperative administration is more effective (p = 0.006). While the effect of simultaneous preoperative and postoperative administration was marginally greater than other periods in reducing postoperative hs-CRP levels (p = 0.02). Colchicine, a traditional anti-inflammatory drug, also reduces the risk of MACE by reducing inflammation after PCI. Administration at different periods had no significant effect on decreasing the occurrence of MACE, but when administered postoperatively, we advise continuous administration with a total daily dose of 0.5 mg to obtain the same benefit while minimizing the drug's side effects. Postoperative administration is the better measure to prevent postoperative stroke events. Due to the effective anti-inflammatory effect of colchicine, we recommend its use as early as possible in the perioperative period and its continued use at low doses in the postoperative period. https://www.crd.york.ac.uk/PROSPERO/display_record.php?RecordID=316751, identifier CRD42022316751.