The quest for optimal ketamine dosing formula in treatment-resistant major depressive disorder.

BACKGROUND: Emerging evidence indicates that intravenous ketamine is effective in managing treatment-resistant unipolar and bipolar depression. Clinical studies highlight its favorable efficacy, safety, and tolerability profile within a dosage range of 0.5-1.0 mg/kg based on actual body weight. However, data on alternative dosage calculation methods, particularly in relation to body mass index (BMI) and therapeutic outcomes, remain limited. METHODS: This retrospective analysis of an open-label study aims to evaluate dose calculation strategies and their impact on treatment response among inpatients with treatment-resistant major depressive disorder (MDD) (n = 28). The study employed the Boer and Devine formulas to determine lean body mass (LBM) and ideal body weight (IBW), and the Mosteller formula to estimate body surface area (BSA). The calculated doses were then compared with the actual doses administered or converted to a dosage per square meter for both responders and non-responders. RESULTS: Regardless of treatment response, defined as a reduction of 50% in the Montgomery-Åsberg Depression Rating Scale, the use of alternative ketamine dosing formulas resulted in underdosing compared to the standardized dose of 0.5 mg/kg. Only two participants received higher doses (102.7% and 113.0%) when the Devine formula was applied. CONCLUSIONS: This study suggests that ketamine dosing formulas, alternative to the standardized 0.5 mg/kg based on body weight, may lead to underdosing and potentially impact outcome interpretation. To enhance dosing accuracy, future studies should consider incorporating body impedance analysis and waist-to-hip ratio measurements, as this study did not account for body composition.

Comparison of Quantile Regression and Gaussian (Z-scores) Percentiles to BSA in Growth Charts With a Pakistani Population.

Introduction: In the current study, we construct growth charts of body surface area (BSA) for adults using the quantile regression (QR) approach and growth charts of different Gaussian Percentiles (Z-scores) against age. Methods: A cross-sectional data consisting of 3,473 individuals aged 5 or more, both males and females were taken from Multan city. Quantile regression (QR) was used to construct BSA growth charts. Growth charts for different Z-scores were also constructed. Results: For our data set, the mean BSA is 0.48750. The BSA percentiles show a trending higher after the age of 5 until the age of 22, then decrease between age 22 and 35, and then finally increase after age 35. The Z-score curve increases slightly after age 5 and then proceeds higher until age 22. After age 22 and before 35 it plateaus and then increases slightly after age 35. Conclusion: Since the use of empirical BSA percentiles and Z-scores with grouped age provides a discrete approximation for the population percentiles and Z-scores, it is more accurate to use continuous BSA percentile and Z-score, curves against given ages while using quantile regression and Z-score approach. Furthermore, this approach can also be adopted to construct many other growth charts for physiological and medical sciences.

Impact of body surface area on efficacy and safety in patients with EGFR-mutant non-small cell lung cancer treated with osimertinib as a first-line treatment.

BACKGROUND: The most recommended treatment for stage IV EGFR-positive lung cancer is osimertinib monotherapy. The dosage of osimertinib is fixed at 80 mg/day regardless of body surface area (BSA), however some patients withdraw or reduce the dosage due to adverse events (AEs). METHODS: We performed a retrospective cohort study of 98 patients with EGFR mutation-positive non-small cell lung cancer (NSCLC), who received 80 mg osimertinib as the initial treatment. We investigated the impact of BSA on efficacy and safety of osimertinib. RESULTS: The cut-off value of BSA was estimated using the receiver operating characteristics curve, and was determined to be 1.5 m2. There were 44 patients in the BSA < 1.5 group and 54 patients in the BSA ≥ 1.5 group. There was no significant difference in the incidence of AEs (hematologic toxicity of ≥grade 3 or higher, and non-hematologic toxicity of ≥grade 3) between the two groups. However, the incidence of dose reduction due to AEs was significantly higher in the BSA < 1.5 group compared with the BSA ≥ 1.5 group (16 patients vs 5 patients, p = 0.003). The main reasons were fatigue, anorexia, diarrhea, and liver disfunction. Median progression-free survival (PFS) was not significantly different (16.9 months in the BSA < 1.5 group vs 18.1 months in the BSA ≥ 1.5 group, p = 0.869). CONCLUSION: Differences in BSA affected the optimal dose of osimertinib. However, the PFS with osimertinib treatment was not affected by BSA. Therefore, when using osimertinib as an initial treatment for patients with EGFR-mutant NSCLC, dose reduction to control AEs should be considered, especially in the BSA<1.5 group.

Body Surface Area-Based Dosing of Infliximab is Superior to Standard Weight-Based Dosing in Children With Very Early Onset Inflammatory Bowel Disease.

Background and Aims: Children with very early onset inflammatory bowel disease (VEO-IBD) are uniquely at risk of inadequate infliximab (IFX) exposure. We studied the association between standard body weight (BW)-based and body surface area (BSA)-based dosing strategies and outcomes. Methods: We identified VEO-IBD patients treated with IFX before 9 years at a single center. Patients were separated into those that received a BSA-based dose (200 mg/m2) and standard BW dosing (5 mg/kg). IFX drug levels, dose intensification, time on steroids, and long-term outcomes were compared. Receiver operator characteristic curves determined the optimal BW- and BSA-based dose to achieve a trough ≥10 µg/ml at dose 4 (IFX#4). Results: Forty-three children with VEO-IBD were identified. Receiver operator characteristic curves demonstrated optimal BW- and BSA-based doses to achieve IFX trough ≥10 µg/ml at IFX#4 were 7.5 mg/kg and 180mg/m2. Children were classified to standard BW dosing (22/43) and BSA dosing (10/43). IFX#4 trough was significantly higher in those who received BSA dosing (BSA 18.6 µg/ml [interquartile range 10.8-28.1] vs BW 5.1 µg/ml [interquartile range 2.6-10.7], P = .04). BSA dosing was more likely to achieve a target drug level >10 µg/ml at IFX#4 (BSA 70% vs BW 18%, P = .02). BW dosing was associated with a greater likelihood of dose escalation (BW 82% vs BSA 30%, P < .01) and a shorter time to first escalation. BSA dosing was associated with shorter time spent on steroids (P = .02). Conclusion: Young children require higher IFX dosing to achieve adequate drug exposure. Our data support the use of a BSA-based dose of 200 mg/m2 or, if a BW-based approach is used, 7.5 mg/kg. BSA dosing allows the use of a consistent dose over the age and weight spectrum.

Population Pharmacokinetics of Loxoprofen and its alcoholic metabolites in healthy Korean men.

BACKGROUND: Loxoprofen has been actively used clinically to relieve musculoskeletal pain and inflammatory symptoms. However, there are few reports on quantitative pharmacokinetic (PK) prediction tools and diversity analyzes for loxoprofen within populations. OBJECTIVES: The aim of this study was to identify effective covariates associated with explaining inter-individual PK variability through a population pharmacokinetic (Pop-PK) modeling approach for loxoprofen, and to provide a starting point for establishing scientific dosing regimens. METHOD: The bioequivalence PK results of loxoprofen performed on 52 healthy Korean men and the physiological and biochemical parameters derived from each individual were used as base data for the development of a Pop-PK model of loxoprofen. In order to simultaneously predict the PKs of the active form according to loxoprofen exposure, previously reported PK results of trans-alcohol loxoprofen, an active metabolite of loxoprofen, were used to expand the model. RESULTS: The Pop-PK profiles of loxoprofen were described in terms of the basic structure of a non-sequential two absorption with 2-disposition compartment, and for inter-individual PK variations, peripheral compartment volume of distribution could be correlated with body surface area (BSA), and central compartment clearance with creatinine clearance (CrCL) and albumin levels. As a result of the model simulation, the concentrations of loxoprofen and its alcoholic metabolites in plasma significantly decreased as CrCL and albumin levels increased and decreased, respectively. On the other hand, it was confirmed that the higher the BSA, the greater the distribution of loxoprofen to the periphery, and the minimum concentrations of loxoprofen and alcoholic metabolites in plasma in steady-state increased by approximately 1.78-2 times, while the fluctuation between maximum and minimum concentrations decreased. The results suggest that patients with large BSA, impaired renal function, and high serum albumin levels may have significantly higher plasma exposure to loxoprofen and trans-alcohol loxoprofen. It was also suggested that the potential side effects in the gastrointestinal system and various tissues and the level of exposure in plasma due to long-term application of loxoprofen in this patient group could be causally explained. CONCLUSION: This study provides a very useful starting point for a scientific precision medicine approach to loxoprofen by discovering effective covariates and establishing a quantitative model that can explain the diversity of loxoprofen PKs within the population. CLINICAL TRIAL REGISTRATION: The clinical study protocol used in this study was thoroughly reviewed and approved by the Institutional Review Board of the Institute of Bioequivalence and Bridging Study, Chonnam National University, Gwangju, Republic of Korea. The bioequivalence study permit numbers are as follows: 041113; 10.15.2004.

Predictor of left main coronary artery size: an intravascular ultrasound study in Southeast Asia population.

Left main (LM) percutaneous coronary intervention (PCI) has expanded rapidly in the past decade, with up to fourfold increase annually. Recent trials found that intravascular imaging (IVI)-guided LM PCI resulted in lower risks of cardiac death and stent failure due to suboptimal PCI compared to angiography-guided PCI. IVI usage has increased in recent years; however, its utilization remains variable across regions and is still incredibly low in developing countries. Furthermore, to date, there is no data about LM size in the Southeast Asian population. This study aims to determine the mean external elastic membrane (EEM) diameter, cross-sectional area (CSA) of LM, and its predictor. This is a cross-sectional observational study on 100 patients with coronary artery disease (CAD) who underwent IVUS-guided PCI with a pullback to LM in Dr. Hasan Sadikin General Hospital Bandung, Indonesia, from January 2020 until December 2022. Linear regression was used to determine the predictors of LM size. There were 100 segments of LM. LM's mean EEM diameter and CSA were 5.02 ± 0.43 mm and 19.93 ± 3.48 mm2. Body surface area (BSA) is an independent predictor of EEM diameter and CSA with a positive linear relationship (p 0.001 and p 0.0001). Hypertension is an independent predictor of EEM diameter with a positive linear relationship (p 0.034). The linear equation to predict EEM diameter and CSA were (2.741 + 1.272BSA(m2) + 0.165 hypertension (yes)) and (2.745 + 9.601BSA(m2)), respectively. The LM coronary artery size of the Southeast Asian population was comparable with the previous studies. BSA and hypertension are independent predictors of EEM diameter, with BSA being stronger than hypertension. Neither sex nor other cardiovascular risk factors affect the LM size. The knowledge of coronary artery size will help the clinician have a reference for intervention, especially when no intravascular imaging is available.

A convenient calf proportion index calculator for survival prediction in overweight and obese patients with cancer.

OBJECTIVE: This study aimed to define the calf proportion index (CPI) and investigate its association with malnutrition and survival in overweight and obese patients with cancer. METHODS: This multicenter observational cohort study included 3499 patients diagnosed with cancer, including 3145 overweight and 354 obese individuals. The CPI was defined as the ratio of the cross-sectional area of the calf circumference (CC) to the body surface area (BSA). A CPI calculator that automatically calculated the CPI and survival probability based on the patient's sex, height, weight, and CC was developed. RESULTS: During a median follow-up of 44.1 months, 935 deaths were recorded. Receiver operating characteristic curves revealed that the CPI was better than CC and BSA as a predictor of survival, with AUCs for the 3-year mortality rate were 0.574, 0.553 and 0.529, respectively. In overweight and obese patients with cancer, the optimal CPI cut-off value was 0.65 % for men and 0.57 % for women. The Kaplan-Meier curve revealed that patients with a low CPI had lower survival. After adjusting confounding factors, a low CPI was an independent risk factor for overweight (hazard ratio [HR]: 1.29, 95 % confidence interval [CI]: 1.11-1.51, P < 0.001) and obesity (HR: 1.92, 95 % CI: 1.20-3.09, P = 0.007) in patients with cancer. The CPI exhibited significant prognostic value in patients with lung and digestive system cancers. The risk of malnutrition was significantly higher in patients with a low CPI (HR: 1.25, 95 % CI: 1.04-1.50, P = 0.019). CONCLUSIONS: The CPI is a useful prognostic indicator in overweight and obese patients with cancer, especially in obese patients.

Fluorine-18 FDG PET/CT and New NIMS Grading System for Chemotherapy Response in Breast Cancer.

Background: Positron emission tomography with computed tomography (PET-CT) using fluorine 18-fluorodeoxyglucose (F-18 FDG) is increasingly used to stage patients with locally advanced breast cancer and for assessing treatment response after neoadjuvant chemotherapy (NACT). Aims and Objectives: The aim of the study was to assess the correlation between PET-CT parameters and pathologic response of breast primary after NACT in breast cancer patients and to devise a grading system called NIMS grading system for response assessment using PET quantitative parameters. Materials and Methods: 55 patients who underwent F-18 FDG PET-CT before starting the therapy and again after completion of therapy were identified and included in the study. The clinical data and the histopathologic findings were recorded. All the patients received chemotherapy followed by surgery with axillary lymph node dissection. The PET-CT results were interpreted both qualitatively by visual analysis and quantitatively by estimating maximum Standardized uptake values(SUVmax) and other parameters - SUVmean, SUL, SUVBSA, Metabolic tumor volume (MTV) and Total lesion glycolysis (TLG). Results: The sensitivity and specificity of F-18 FDG PET-CT to detect the residual disease after neoadjuvant chemotherapy was 75.6% & 92.8% respectively. Differences between complete response and residual disease were significant for ΔSUVmax(p=0.005), ΔSUVmean(p=0.006), ΔSUL (0.005) and ΔSUVBSA(0.004), while ΔMTV and ΔTLG were not significantly different between the two groups. The new NIMS grading system included scoring of ΔSUVmax, ΔSUVBSA, ΔTLG and ΔMTV on scale of 1 to 4 and correlated well with PERCIST criteria. Conclusion: F-18 FDG PET-CT had a good accuracy in the detection of residual disease after completion of NACT. Pre chemotherapy PET-CT is not adequate to predict the response of primary tumour to chemotherapy. However, changes in the values of various PET-CT parameters are a sensitive tool to assess the response to chemotherapy. The new grading system is easy to use and showed good correlation to PERCIST.

Cardiac output in patients with small annuli undergoing transcatheter aortic valve implantation with self-expanding versus balloon expandable valve (COPS-TAVI).

BACKGROUND: There is limited data on cardiac output in patients with small aortic annuli undergoing trans-catheter aortic valve implantation (TAVI) according to the implanted platform of balloon-expandable (BEV) compared to self-expanding valves (SEV). METHODS: This is a retrospective analysis of consecutive patients with severe aortic stenosis and small annuli who underwent successful TAVI. Cardiac output was measured using echocardiography within 4 weeks following TAVI. Data were recorded and analysed by an experienced operator who was not aware of the type of the implanted valve. RESULTS: 138 patients were included in the analysis, of whom 57 % underwent TAVI with BEV. Clinical and echocardiographic characteristics were comparable between the two platforms, except for more frequent previous cardiac surgery and smaller indexed aortic valve in the BEV group. There was no relationship between computed tomography-derived aortic annulus area and cardiac output post TAVI. When compared to patients who underwent TAVI with BEV, those with SEV had larger cardiac output [mean difference - 0.50 l/min, 95 % CI (-0.99, -0.01)] and cardiac index [mean difference - 0.20 l/min/m2, 95 % CI (-0.47, 0.07)], although the latter did not reach statistical significance. Unlike patients with small body surface area, in those with large body surface area both cardiac output and cardiac index were statistically larger in patients who underwent SEV compared to BEV. CONCLUSION: Cardiac output, as measured by echocardiography, was larger in patients with small annuli who underwent TAVI procedure with SEV compared to BEV. Such difference was more evident in patients with large body surface area.

The impact of obesity on body surface area adjusted estimated glomerular filtration rate in patients with chronic kidney disease.

BACKGROUND: Assessment of kidney function is necessary for prescribing renally excreted drugs. The estimated glomerular filtration rate (eGFR) routinely reported by laboratories is indexed to a body surface area (BSA) of 1.73 m2. In obese patients, the indexed eGFR may underestimate directly measured GFR. AIMS: To determine the prevalence of obesity in patients with chronic kidney disease (CKD) and examine the effect of adjusting the indexed eGFR for patient BSA (deindexing) across CKD Stages 2-5. METHODS: We conducted a cross-sectional study of 575 adults with stable CKD from two general nephrology clinics over 6 months. Dialysis and kidney transplant patients were excluded. We used four equations (Mosteller, Dubois, Haycock and Schlich) to determine BSA based on actual body weight and applied Bland-Altman plots and piecewise linear regression to examine the relationship between deindexed and indexed eGFR. RESULTS: The median age was 68 years (58% male). The prevalence of overweight and obesity was 31% and 47% respectively. Mean body mass index was 29.7 kg/m2. The Schlich equation for BSA produced the smallest adjustment in eGFR, while the Haycock equation produced the largest adjustment. Males experienced the largest change in eGFR from deindexing because of larger BSAs. Although bias became increasingly positive with higher eGFR, the linear regression stratified by CKD stage indicated that deindexing had little impact with eGFR <45 mL/min/1.73 m2. CONCLUSIONS: In CKD, deindexing the Chronic Kidney Disease Epidemiology Collaboration eGFR may not be necessary when the eGFR is <45 mL/min/1.73 m2, particularly if the patient is female.

Validation of IGA*BSA in Assessing Disease Severity and Response in Patients with Atopic Dermatitis: A Retrospective Cohort Study in China.

Background: Accurate evaluation of atopic dermatitis (AD) severity is crucial to determine and adjust treatment options. Previous studies have found the product of Investigator's Global Assessment (IGA) and affected body surface area (BSA) to be a simple tool, which requires further verification. Objective: To determine the validity of IGA*BSA in assessing the severity of AD across all age, sex, BMI and disease severity groups. Method: We performed a retrospective study of AD using data from a national cohort (China Type II Inflammatory Skin Disease Clinical Research and Standardized Diagnosis and Treatment Project). Results: Overall, 3051 participants were included in the final analysis. IGA*BSA correlated better with objective measures than with subjective measures. IGA*BSA significantly correlated with Eczema Area and Severity Index (EASI) (r = 0.81), which was stronger than either IGA or BSA alone with EASI, regardless of age, sex, Body Mass Index (BMI), and disease severity groups. Besides, IGA*BSA mild, moderate, and severe groups were associated with significantly higher scores of other assessments and had moderate to fair concordance with other assessments severity strata. At follow-up, the concordance of improvement between IGA*BSA 50/75/90 and EASI 50/75/90 was observed (ĸ = 0.65, 0.62, 0.58, respectively). Conclusion: IGA*BSA appears to be a valid objective assessment of AD severity and improvement over time across all age, sex, BMI, and disease severity subgroups in the clinical practice.

Prediction of the 10-year incidence of type 2 diabetes mellitus based on advanced anthropometric indices using machine learning methods in the Iranian population.

BACKGROUND: Type 2 diabetes mellitus (T2DM) is a growing chronic disease that can lead to disability and early death. This study aimed to establish a predictive model for the 10-year incidence of T2DM based on novel anthropometric indices. METHODS: This was a prospective cohort study comparing people with (n = 1256) and without (n = 5193) diabetes mellitus in phase II of the Mashhad Stroke and Heart Atherosclerotic Disorder (MASHAD) study. The association of several anthropometric indices in phase I, including Body Mass Index (BMI), Body Adiposity Index (BAI), Abdominal Volume Index (AVI), Visceral Adiposity Index (VAI), Weight-Adjusted-Waist Index (WWI), Body Roundness Index (BRI), Body Surface Area (BSA), Conicity Index (C-Index) and Lipid Accumulation Product (LAP) with T2DM incidence (in phase II) were examined; using Logistic Regression (LR) and Decision Tree (DT) analysis. RESULTS: BMI followed by VAI and LAP were the best predictors of T2DM incidence. Participants with BMI < 21.25 kg/m2 and VAI ≤ 5.9 had a lower chance of diabetes than those with higher BMI and VAI levels (0.033 vs. 0.967 incident rate). For BMI > 25 kg/m2, the chance of diabetes rapidly increased (OR = 2.27). CONCLUSIONS: BMI, VAI, and LAP were the best predictors of T2DM incidence.

Association between overweight and obesity with coronary artery bypass graft failure: an individual patient data analysis of clinical trials.

OBJECTIVES: The association between obesity and graft failure after coronary artery bypass grafting has not been previously investigated. METHODS: We pooled individual patient data from randomized clinical trials with systematic postoperative coronary imaging to evaluate the association between obesity and graft failure at the individual graft and patient levels. Penalized cubic regression splines and mixed-effects multivariable logistic regression models were performed. RESULTS: Six trials comprising 3928 patients and 12 048 grafts were included. The median time to imaging was 1.03 (interquartile range 1.00-1.09) years. By body mass index (BMI) category, 800 (20.4%) patients were normal weight (BMI 18.5-24.9), 1668 (42.5%) were overweight (BMI 25-29.9), 983 (25.0%) were obesity class 1 (BMI 30-34.9), 344 (8.8%) were obesity class 2 (BMI 35-39.9) and 116 (2.9%) were obesity class 3 (BMI 40+). As a continuous variable, BMI was associated with reduced graft failure [adjusted odds ratio (aOR) 0.98 (95% confidence interval (CI) 0.97-0.99)] at the individual graft level. Compared to normal weight patients, graft failure at the individual graft level was reduced in overweight [aOR 0.79 (95% CI 0.64-0.96)], obesity class 1 [aOR 0.81 (95% CI 0.64-1.01)] and obesity class 2 [aOR 0.61 (95% CI 0.45-0.83)] patients, but not different compared to obesity class 3 [aOR 0.94 (95% CI 0.62-1.42)] patients. Findings were similar, but did not reach significance, at the patient level. CONCLUSIONS: In a pooled individual patient data analysis of randomized clinical trials, BMI and obesity appear to be associated with reduced graft failure at 1 year after coronary artery bypass grafting.

Ixekizumab Demonstrates Rapid and Consistent Efficacy for Patients with Psoriatic Arthritis, Regardless of Psoriasis Severity.

INTRODUCTION: Skin involvement in patients with psoriatic arthritis (PsA) worsens the severity and burden of disease. Ixekizumab (IXE), a selective interleukin (IL)-17A antagonist, was compared to placebo (PBO) in the SPIRIT-P1 (NCT01695239) and SPIRIT-P2 (NCT02349295) studies in patients with PsA and evidence of plaque psoriasis. This post hoc analysis reports musculoskeletal, skin, and nail outcomes through week 24 in patients from SPIRIT-P1 and SPIRIT-P2, stratified by mild, moderate, or psoriasis at baseline. METHODS: This post hoc analysis pooled patients from SPIRIT-P1 and SPIRIT-P2 who were randomly assigned to PBO or IXE 80 mg every 4 weeks (Q4W) or every 2 weeks (Q2W). Efficacy outcomes were analyzed through week 24 by baseline psoriasis severity, defined by percent body surface area (BSA) affected; mild = BSA < 3%, moderate = 3% ≤ BSA ≤ 10%, severe = BSA > 10%. The primary outcomes assessed were the proportion of patients achieving American College of Rheumatology (ACR)20, ACR50, and ACR70 responses. Secondary outcomes included musculoskeletal, disease activity, skin and nail, and health-related quality-of-life measures. RESULTS: Similar proportions of patients achieved ACR20/ACR50/ACR70 over time across all severity subgroups and treatment arms. More than one-third of IXE-treated patients achieved ACR20 at week 4, or ACR50 at week 24, with no significant differences according to psoriasis severity at baseline. Disease activity outcomes were similar through week 24 with both IXEQ4W and IXEQ2W, regardless of psoriasis severity at baseline. There were no significant differences over 24 weeks in the proportions of IXE-treated patients with mild, moderate, or severe baseline psoriasis who achieved Minimal Disease Activity (MDA). Across all severity subgroups, IXE demonstrated Psoriasis Area Severity Index 100 response as early as week 4, and approximately one-third of IXE-treated patients achieved total skin clearance at week 24. CONCLUSION: IXE demonstrated rapid and consistent efficacy in joint, skin, and nail for patients with PsA, regardless of baseline psoriasis severity. TRIAL REGISTRATION: SPIRIT-P1 (NCT01695239), SPIRIT-P2 (NCT02349295).

Baricitinib Improvement Across Regions in Atopic Dermatitis Patients with Baseline Body Surface Area up to 40% and Severe Itch.

INTRODUCTION: Patients with moderate-to-severe atopic dermatitis (AD) who are most likely to respond to the Janus kinase (JAK) 1/2 inhibitor baricitinib (BARI) are known to have an impacted body surface area (BSA) ≤ 40% and severe itch (numerical rating scale [NRS] ≥ 7], collectively termed 'BARI itch-dominant' patients. Our objective is to build on our previous work by providing a body region-specific, clinical characterization of the BARI itch-dominant patient at baseline and their response to BARI 4 mg. METHODS: BREEZE-AD7 was a phase 3 trial in adults with moderate-to-severe AD receiving placebo or 2 mg or 4 mg BARI in combination with topical corticosteroids. Assessing only data from BARI itch-dominant patients, we summarized the baseline characteristics and conducted body region-specific analyses on Eczema Area and Severity Index (EASI) data in order to report the response to placebo versus BARI 4 mg within this patient subtype. RESULTS: BARI 4 mg was highly effective across all body regions; at week 16, 75% improvement was seen in EASI scores (EASI75), and response rates with BARI 4 mg (head/neck, 58.3%; trunk, 69.2%; upper extremities, 61.5%; lower extremities, 87.5%) all exceeded those with placebo (head/neck: 37.5%; trunk, 40.6%; upper extremities, 18.8%; lower extremities, 40.6%) as well as the overall EASI75 rates of the intent-to-treat (ITT) population (BARI, 48.0%; placebo, 23.0%). At baseline, most BARI itch-dominant patients presented with involvement of all regions (mean regional BSA 22.7%-40.3%), highest in the head and neck, mean EASI region scores of 15.7-24.0, and considerably severe sign ratings (mean EASI sub-scores: 1.4-2.3, out of 3), especially for erythema. CONCLUSION: BARI itch-dominant patients exhibit AD involvement across all body regions and considerable sign severity, especially erythema. In response to BARI 4 mg, EASI quickly improved across regions, substantially more so in this subtype than in the ITT population.

Sex bias in prediction and diagnosis of cardiac surgery associated acute kidney injury.

BACKGROUND: Female sex has been recognized as a risk factor for cardiac surgery associated acute kidney injury (CS-AKI). The current study sought to evaluate whether female sex is a risk factor for CS-AKI, or modifies the association of peri-operative change in serum creatinine with CS-AKI. METHODS: Observational study of adult patients undergoing cardiac surgery between 2000 and 2019 in a single U.S. center. The main variable of interest was registered patient sex, identified from electronic medical records. The main outcome was CS-AKI within 2 weeks of surgery. RESULTS: Of 58526 patients, 19353 (33%) were female; 12934 (22%) incurred AKI based on ≥ 0.3 mg/dL or ≥ 50% rise in serum creatinine (any AKI), 3320 (5.7%) had moderate to severe AKI, and 1018 (1.7%) required dialysis within 2 weeks of surgery. Female sex was associated with higher risk for AKI in models that were based on preoperative serum creatinine (OR, 1.35; 95% CI, 1.29-1.42), and lower risk with the use of estimated glomerular filtration, (OR, 0.90; 95% CI, 0.86-0.95). The risk for moderate to severe CS-AKI for a given immediate peri-operative change in serum creatinine was higher in female compared to male patients (p < .0001 and p < .0001 for non-linearity), and the association was modified by pre-operative kidney function (p < .0001 for interaction). CONCLUSIONS: The association of patient sex with CS-AKI and its direction was dependent on the operational definition of pre-operative kidney function, and differential outcome misclassification due to AKI defined by absolute change in serum creatinine.

Body surface area is positively associated with ankle-brachial index.

BACKGROUND: Ankle-brachial index (ABI) measurement is a widely used diagnostic test for lower extremity artery disease. Previously, a larger body surface area (BSA) has been associated with lower blood pressure and lower 2-h post-load glucose concentrations in the oral glucose tolerance test. Our aim was to evaluate whether BSA has an impact on ABI and the prevalence of lower ABI values. METHODS: ABI measurements were performed on 972 subjects aged 45 to 70 years at high cardiovascular disease (CVD) risk. Subjects with previously diagnosed kidney disease, CVD, and diabetes were excluded. Their BSA was calculated by the Mosteller formula. Study subjects were divided into five BSA levels corresponding to 12.5th, 25th, 25th, 25th, and 12.5th percentiles of the total distribution. Effect modification by BSA in ABI between sexes was derived from a four-knot restricted cubic splines regression model. RESULTS: After adjustments for age, sex, pulse pressure, glucose regulation, waist circumference, alcohol intake, smoking status, leisure-time physical activity and medication, BSA level had a positive linear relationship with ABI (p for linearity <0.001). When BSA was less than 2.0 m2, there was no difference between the sexes, but when BSA was higher than 2.0 m2, men had higher ABI. CONCLUSION: BSA shows a positive linear relationship with ABI in CVD risk subjects without manifested CVD. The difference in ABI between men and women is modified by BSA and is appreciable when BSA is larger than 2.0 m2.

New limits proposed for the management of non-mutagenic impurities.

Multiple international guidelines exist that describe both quality and safety considerations for the control of the broad spectrum of impurities inherent to drug substance and product manufacturing processes. However, regarding non-mutagenic impurities (NMI) the most relevant ICH Q3A/B guidelines are not applicable during early phases of drug development leading to confusion about acceptable limits at this stage. Thus, there is need for more flexible approaches that ensure that patient safety remains paramount, while taking into consideration the limited duration of exposure. An EFPIA survey, which collected quantitative data from different types of studies applied to qualify impurities in accordance with ICH Q3A, shows that no toxicities could be attributed to any of the 467 impurities at any tested level in vivo. This data combined with earlier published toxicological datasets encompassing drug substances and intermediates, food related substances and chemicals provide convincing evidence that for NMIs, the application of a generic 5 mg/day limit for an exposure duration <6 months, and a 1 mg/day generic limit for life-long exposure, provides sufficient margins to ensure patient safety. Hence, application of these absolute limits to trigger qualification studies (instead of the relative limits described in Q3A/B), is considered warranted. This approach will prevent conduct of unnecessary dedicated impurity qualification studies and the resulting use of animals.

Body surface area is a predictor of 90-day all-cause mortality in critically ill patients with acute kidney injury.

OBJECTIVE: To clarify the prognosis effect between body surface area (BSA) and patients with acute kidney injury (AKI), we attempted to analyze the association between BSA and 90-day all-cause mortality in critically ill patients with AKI. METHODS: Clinical data of 9195 critically ill patients with AKI were retrieved from the Medical Information Mart for Intensive Care III database were then retrospectively analyzed. BSA were calculated using the Mosteller formula. We analyzed the correlation between BSA and 90-day all-cause mortality in critically ill patients with AKI based on Kaplan-Meier curve analysis and adjusted Cox regression model. RESULTS: Of the 9195 critically ill patients with AKI, there were 3778 (41.1%) female patients and 2001 90-day all-cause deaths (female: 22.2%, male: 21.5%). Kaplan-Meier curve analysis revealed that a lower body surface area indicated a higher 90-day all-cause mortality in both male and female patients with AKI (log-rank P < 0.001). Cox regression model showed that a higher BSA was independently correlated with a lower 90-day all-cause mortality (female: hazard ratio=0.657, 95% confidence interval: 0.550-0.784, P < 0.001; male: hazard ratio=0.655, 95% confidence interval: 0.565-0.760, P < 0.001). CONCLUSIONS: BSA was negatively correlated with 90-day all-cause mortality in critically ill patients with AKI. BSA can therefore be used as a prognostic indicator for poor outcomes in critically ill patients with AKI.