Adjusted Body Weight Research Articles

Genetic connection of carotid atherosclerosis with coat color and body weight in an intercross between hyperlipidemic mouse strains.

Atherosclerosis in the carotid artery is a major cause of ischemic stroke and has a strong genetic component. The aim of this study was to identify genetic factors contributing to carotid atherosclerosis. One hundred fifty-four female F2 mice were generated from an intercross between LP/J and BALB/cJ Apoe-null (Apoe-/-) mice and fed 12 wk of Western diet. Atherosclerotic lesions, body weight, and coat color were measured and genotyping was performed using miniMUGA genotyping arrays. A significant quantitative trait locus (QTL) on chromosome (Chr) 7, named Cath20, and five suggestive QTL on Chr 6, 12, 13, 15, and X were identified for carotid lesions. Three significant QTL, Bwfq2, Bw1n, Bwtq6, on Chr 2, 7, and 15 were identified for body weight. Two significant QTL, Chop2 and Albc2, on Chr 4 and 7 were identified for coat color, with Tyr, encoding tyrosinase, being the causal gene of Albc2. Cath20 overlapped with or was close to QTL Bw1n and Albc2 on Chr7. Carotid lesion sizes were significantly correlated with body weight and graded coat color in F2 mice. Cath20 on Chr7 disappeared after adjustment for coat color but remained after adjustment for body weight. Tyr was abundantly expressed in atherosclerotic lesions. These results demonstrate genetic connections of carotid atherosclerosis with body weight and coat color in hyperlipidemic mice and suggest a potential role for Tyr in carotid atherosclerosis.

A Combined Pharmacometrics Analysis of Biomarker Distribution Under Treatment With Standard- or Low-Dose Rivaroxaban in Real-World Chinese Patients With Nonvalvular Atrial Fibrillation

Background: The rivaroxaban dose regimen for patients with nonvalvular atrial fibrillation (NVAF) is complex in Asia. Given the high interindividual variability and the risk of bleeding caused by rivaroxaban in Asians, the influencing factors and the relationship between outlier biomarkers and bleeding events need exploration. Methods: The integrated pharmacokinetics (PK)/pharmacodynamics (PD) models were characterized based on rich PK/PD data from 304 healthy volunteers and sparse PD [anti-factor Xa activity (anti-Xa) and prothrombin (PT)] data from 223 patients with NVAF. The correlations between PD biomarkers and clinically relevant bleedings in 1 year were explored. The final integrated PK/PD model was used to evaluate the influence of dosage and individual covariates on PD parameters. Results: A two-compartment, linear model with sequential zero-order and first-order absorption was adopted. The dose-specific relative bioavailability (F1), diet status, creatinine clearance, and body mass index (BMI) improved the model fit. The apparent systemic clearance was 7.39 L/h, and the central and peripheral volumes were 10.9 and 50.9 L, respectively. The linear direct-effects model with shape factor plus the additive (and/or proportional) error model described the correlation between anti-Xa/PT and plasma concentration. Bodyweight, total cholesterol (TCHO), and diet status were selected as the covariates of the anti-Xa/PT model. Anti-Xa was more sensitive to the increase in rivaroxaban exposure compared with PT. An elevated bleeding tendency was seen with higher peak anti-Xa and PT. For a typical Chinese patient, the peak anti-Xa value (median (5%–95% PI)) of 20 and 15 mg were 309 ng/ml (139–597 ng/ml) and 296 ng/ml (138–604 ng/ml), both median values were within the expected range. For patients with CrCL 30–49 ml/min, the median peak anti-Xa with recommended 10 mg other than 15 mg were within the expected range. Conclusion: Fixed doses of rivaroxaban could be prescribed for patients with NVAF without adjustment for bodyweight, BMI, and TCHO. Randomized studies should be performed to evaluate the efficacy and safety of low-dose rivaroxaban in Chinese patients with NVAF.

Poor performance of predictive equations to estimate resting energy expenditure in patients with Crohn's disease.

Studies exploring the accuracy of equations calculating Resting Energy Expenditure (REE) in patients with Crohn's disease are lacking. The aim of this study was to investigate the accuracy of REE predictive equations against indirect calorimetry in Crohn's disease patients. REE was measured using indirect calorimetry (mREE) after an overnight fasting. Fourteen predictive equations, with and without body composition analysis parameters, were compared with mREE using different body weight approaches. Body composition analysis was performed using dual X-ray absorptiometry. 186 Crohn's disease outpatients (102 males) with mean age 41.3±14.1 years and 37.6% with active disease were evaluated. Mean mREE in the total sample was 1734±443 kcal/day. All equations under-predicted REE and showed moderate correlations with mREE (Pearson's r or Spearman's rho 0.600-0.680 for current weight, all p-values<0.001). Accuracy was low for all equations at the individual level (28-42% and 25-40% for current and adjusted body weight, respectively, 19-33% for equations including body composition parameters). At the group level, accuracy showed wide limits of agreement and proportional biases. Accuracy remained low when sample was studied according to disease activity, sex, body mass index and medication use. All predictive equations underestimated REE and showed low accuracy. Indirect calorimetry remains the best method for estimating REE of patients with Crohn's disease.

Glomerular filtration rate estimation for carboplatin dosing in patients with gynaecological cancers

BackgroundCarboplatin remains integral for treatment of gynaecological malignancies and dosing is based on glomerular filtration rate (GFR). Measurement via radiotracer decay [nuclear medicine GFR (nmGFR)] is ideal. However, this may be unavailable. Therefore GFR is often estimated using formulae that have not been validated in patients with cancer and/or specifically for gynaecological malignancies, leading to debate over optimal estimation. Suboptimal GFR estimation may affect efficacy or toxicity.MethodsWe surveyed several UK National Health Service Trusts to assess carboplatin dosing practise. We then explored single-centre accuracy, bias and precision of various formulae for GFR estimation, relative to nmGFR, before validating our findings in an external cohort.ResultsAcross 18 Trusts, there was considerable heterogeneity in GFR estimation, including the formulae used [Cockcroft–Gault (CG) versus Wright], weight adjustment and area under the curve (AUC; 5 versus 6). We analysed 274 and 192 patients in two centres. Overall, CamGFR v2 (a novel formula for GFR estimation developed at Cambridge University Hospitals NHS Foundation Trust) excelled, showing the highest accuracy and precision. This translated into accuracy of hypothetical carboplatin dosing; nmGFR-derived carboplatin dose fell within 20% of the Cam GFR v2-derived dose in 86.5% and 87% of patients across the cohorts. Among the CG formula and its derivatives, using adjusted body weight in those with body mass index ≥25 kg/m2 [CG-adjusted body weight (CG-AdBW)] was optimal. The Wright and unadjusted CG estimators performed most poorly.ConclusionsWhen compared with nmGFR assessment, accuracy, bias and precision varied widely between GFR estimators, with the newly developed Cam GFR v2 and CG-AdBW performing best. In general, weight (or body surface area)-adjusted formulae excelled, while the unadjusted CG and Wright formulae or the use of AUC6 (versus nmGFR AUC5) produced risk of significant overdose. Thus, individual centres should validate their GFR estimation methods. In the absence of validation, CG-AdBW or CamGFR v2 is likely to perform well while unadjusted CG/Wright formulae or AUC6 dosing should be avoided.

P37 Variable adherence to and effectiveness of a vancomycin continuous infusion protocol within ICUs at a London tertiary-care hospital: a single-centre retrospective service evaluation

BackgroundAppropriate vancomycin dosing and therapeutic monitoring is important to optimize treatment for serious Gram-positive infections. In St George's Hospital ICUs, the treatment protocol is a loading dose (<65 kg, 1000 mg; ≥65 kg, 1500 mg), followed by a continuous infusion based on creatinine clearance (CLCR). Vancomycin serum concentrations are taken daily at 0600 hours (target therapeutic range 20–25 mg/L). Non-therapeutic concentrations may negatively affect clinical outcomes and prolong length of stay.1MethodsElectronic prescribing and medicine administration data (vancomycin dose, dose timings, indication, patient biochemistry and demographics) within a 66-bed ICU service were reviewed retrospectively (July 2020–July 2021). Cockcroft-Gault CLCR was calculated using total body weight (TBW), or adjusted body weight in obese1 patients.Standards(i) Proportion of patients with a therapeutic concentration within two serum samples; and (ii) time taken to achieve therapeutic concentration.ResultsNinety-four percent (51/54) of patients received a correct protocol instructed loading dose, 31% (17/54) received a correct loading and maintenance dose, and 70% (38/54) had a vancomycin serum concentration taken. Forty-one percent (7/17) of correctly protocol dosed and monitored patients were therapeutic at their first day serum concentration, which decreased to 20% (3/15) by their second day serum concentration. Consistently therapeutically dosed patient groups included obese and normal weight patients with CLCR 10–20 mL/min and 21–50 mL/min. Whereas underweight and obese patients with CLCR >50 mL/min and 21–50 mL/min became supratherapeutic by their second day serum concentration. Obese and normal weight patients with CLCR >50 mL/min were consistently subtherapeutic. The mean time taken for non-therapeutic patients who continued treatment (n = 7) to become therapeutic after dose adjustments was 4 days. Patients (n = 17) were 82% male and of a mean age of 62 ± 17 years. Mean TBW was 79 ± 23 kg and mean CLCR 65 ± 48 mL/min. Sepsis was the most common vancomycin indication (65%).ConclusionsMultiple drug recording formats, plus adherence to and dosing of different aspects of the vancomycin protocol, requires review. This is to ensure accurate vancomycin administration documentation and that therapeutic concentrations are achieved more rapidly and consistently, whilst minimizing toxicity. A quality improvement project has been instigated to focus on protocol education, accessibility and improving IT infrastructure. Increased patient volume of distribution and renal function variability within the ICU population adds complexity to vancomycin pharmacokinetics. Research into pharmacokinetic models better representing the local ICU population and AUC24 drug monitoring is being explored based on recent international guidance.1

Mobile Phone Radiation Deflects Brain Energy Homeostasis and Prompts Human Food Ingestion.

Obesity and mobile phone usage have simultaneously spread worldwide. Radio frequency-modulated electromagnetic fields (RF-EMFs) emitted by mobile phones are largely absorbed by the head of the user, influence cerebral glucose metabolism, and modulate neuronal excitability. Body weight adjustment, in turn, is one of the main brain functions as food intake behavior and appetite perception underlie hypothalamic regulation. Against this background, we questioned if mobile phone radiation and food intake may be related. In a single-blind, sham-controlled, randomized crossover comparison, 15 normal-weight young men (23.47 ± 0.68 years) were exposed to 25 min of RF-EMFs emitted by two different mobile phone types vs. sham radiation under fasting conditions. Spontaneous food intake was assessed by an ad libitum standard buffet test and cerebral energy homeostasis was monitored by 31phosphorus-magnetic resonance spectroscopy measurements. Exposure to both mobile phones strikingly increased overall caloric intake by 22–27% compared with the sham condition. Differential analyses of macronutrient ingestion revealed that higher calorie consumption was mainly due to enhanced carbohydrate intake. Measurements of the cerebral energy content, i.e., adenosine triphosphate and phosphocreatine ratios to inorganic phosphate, displayed an increase upon mobile phone radiation. Our results identify RF-EMFs as a potential contributing factor to overeating, which underlies the obesity epidemic. Beyond that, the observed RF-EMFs-induced alterations of the brain energy homeostasis may put our data into a broader context because a balanced brain energy homeostasis is of fundamental importance for all brain functions. Potential disturbances by electromagnetic fields may therefore exert some generalized neurobiological effects, which are not yet foreseeable.

Genetic study of quantitative traits supports the use of Guzerá as dual-purpose cattle

ObjectiveThe aim of this study was to estimate genetic parameters for 305-day cumulative milk yield and components, growth, and reproductive traits in Guzerá cattle.MethodsThe evaluated traits were 305-day first-lactation cumulative yields (kg) of milk (MY305), fat (FY305), protein (PY305), lactose (LY305), and total solids (SY305); age at first calving (AFC) in days; adjusted scrotal perimeter (cm) at the ages of 365 (SP365) and 450 (SP450) days; and adjusted body weight (kg) at the ages of 210 (W210), 365 (W365), and 450 (W450) days. The (co)variance components were estimated using the restricted maximum likelihood method for single-trait, bi-trait and tri-trait analyses. Contemporary groups and additive genetic effects were included in the general mixed model. Maternal genetic and permanent environmental effects were also included for W210.ResultsThe direct heritability estimates ranged from 0.16 (W210) to 0.32 (MY305). The maternal heritability estimate for W210 was 0.03. Genetic correlation estimates among milk production traits and growth traits ranged from 0.92 to 0.99 and from 0.92 to 0.99, respectively. For milk production and growth traits, the genetic correlations ranged from 0.33 to 0.56. The genetic correlations among AFC and all other traits were negative (−0.43 to −0.27). Scrotal perimeter traits and body weights showed genetic correlations ranging from 0.41 to 0.46, and scrotal perimeter and milk production traits showed genetic correlations ranging from 0.11 to 0.30. The phenotypic correlations were similar in direction (same sign) and lower than the corresponding genetic correlations.ConclusionThese results suggest the viability and potential of joint selection for dairy and beef traits in Guzerá cattle, taking into account reproductive traits.

Use of provider education, intra-operative decision support, and an email-feedback system in improving compliance with sugammadex dosage guideline and reducing drug expenditures

Study objectiveDue to excessive sugammadex expenditures at our institution, we designed dosing guidelines that utilize adjusted body weight and informatics-based tools aimed at reducing variability in dosing practices. DesignWe retrospectively reviewed rates of high-dose sugammadex administration in three phases: Pre-intervention - May 2018 to November 2018; First intervention - November 2018 to April 2019; and Second intervention - April 2019 to July 2019. SettingAcademic medical center in the United States - Vanderbilt University Medical Center (VUMC) PatientsN/A InterventionsFirst, anesthesia providers were educated on adjusted body weight-based dosing guidelines. Providers also received intraoperative decision support displaying a patient's actual and adjusted body weight along with rates of high-dose (>200 mg) sugammadex administration for each respective provider. Second, we implemented an email-feedback system to remind providers of the new guidelines. MeasurementsWeekly rate of high-dose sugammadex cases. Main resultsDuring the pre-intervention stage, 1556 (12.3%) cases involved high-dose sugammadex. Comparatively, 550 (4.3%) and 187 (3.1%) high-dose sugammadex cases occurred during the first and second intervention stages, respectively. Segmented regression analysis demonstrated a significant rate change of −3.51% (95% CI: −5.64%, −1.38%) in sugammadex dosing practices after provider education and the implementation of digital improvement initiatives but failed to reveal a significant change after implementation of the email-feedback system. Overall, our interventions were associated with $2563.05 in estimated weekly savings of sugammadex expenditures. ConclusionsProvider education and digital quality improvement was associated with reduced rates of high-dose sugammadex administration, generating cost savings at a large academic medical institution.

Evaluating the Efficacy, Toxicity and Pharmacokinetic Profile of Oral Busulfan in Allogeneic Stem Cell Transplant Patients.

Oral busulfan and intravenous cyclophosphamide (Bu/Cy) are common myeloablative preparations used in allogeneic hematopoietic stem cell transplantation (HSCT). Herein, we investigated the safety of (Bu/Cy) administration during HSCT. Patients administered Bu/Cy for allogeneic HSCT at Royal Perth Hospital and Fiona Stanley Hospital between 2007 and 2017 were reviewed for inclusion in the study. We performed busulfan pharmacokinetic (PK) testing for a subset of patients and allometric scaling modeling to assess the best method of busulfan dosing in patients at extremes of weight. Sixty-nine patients were included in the clinical outcome analysis. The median follow-up period was 32 months (range, 9-114 months). The three-year overall survival rate was 62% (95% confidence interval (CI), 51%-75%), and transplant-related mortality was 4% at 6 months (95% CI, 1-7%), with a low rate of sinusoidal obstruction syndrome of the liver being observed. In addition, relapse was 38% (95% CI, 30%-44%) at 3 years. The PK information of 15 patients receiving busulfan was available after oral dosing. The average per-dose busulfan exposure was 1,350 μmol.min/L (range, 878-1,717 μmol.min/L), and the within target range was 1,000-1,500 μmol.min/L in 73% of patients. Of the size measures investigated, ideal and adjusted body weight (ABW40) provided the best fit. No association was observed between busulfan exposure, toxicity, and relapse. Overall, Bu/Cy administration appeared safe when dosed in relation to weight, showing a low early transplant-related mortality rate following adequate busulfan exposure in majority of the cases. Body size measures, such as ideal body weight or ABW40, are likely more suitable for use during busulfan dosing, particularly at high extremes of the body mass index classification.

Weight-Based Antibiotic Dosing in Osteomyelitis

Source: Kyler KE, Lee BR, Glynn EF, et al. Clinical outcome and antibiotic dosing differences by weight in children with acute osteomyelitis. Hosp Pediatr. 2021;11(10):1112-1120; doi:10.1542/hpeds.2021-005890Investigators from multiple institutions conducted a retrospective study to compare outcomes in children with acute hematogenous osteomyelitis (AHO) who had healthy weights or were overweight or obese and evaluate antibiotic dosing variability by weight category. For the study, they abstracted data from the Cerner Health Facts database, which includes diagnostic and procedure codes, demographic information, inpatient medication orders, length of hospital stay (LOS), and anthropometric measurements on patient encounters from 684 health care facilities in the US. Study participants were children 2–17 years old with a primary diagnosis of AHO (based on ICD-9 and ICD-10 codes), hospitalized between 2010 and 2017. Children were categorized as healthy weight (BMI ≥5th and <85th percentile), overweight (BMI ≥85th and <95th percentile), or obese (≥95th percentile). Primary study outcomes included AHO-related procedures and complications occurring within 6 months of the index hospitalization. Rates of these outcomes were compared for patients in different weight categories using chi-square tests. Secondary outcomes included LOS and AHO antibiotic dose, calculated as the mg/kg/day dose for commonly used drugs. Kruskal-Wallis tests were used to compare LOS and antibiotic dose in children in different weight groups.There were 755 children enrolled. The mean age of study patients was 9.4 years, and 66% were male; 455 (60.3%) were classified as healthy weight, 117 (15.5%) were overweight, and 183 (24.2%) were categorized as obese. A total of 99 (13.1%) patients had an AHO-related procedure. The common procedures in all weight categories were surgical debridement and bone abscess drainage. The rates of procedures were higher in children who were obese or overweight than in healthy weight patients (16.9%, 18.8%, and 10.1%, respectively; P = 0.009). Complications occurred in 273 (36.2%) participants, including pyogenic arthritis in 139 (18.4%), myositis in 78 (10.3%), and sepsis in 43 (5.7%). There was no significant difference in rate of complications among children in different weight categories. LOS varied significantly by weight group (median LOS 4.9 days for healthy weight, 5.8 for overweight, and 5.7 for obese patients; P = 0.03). Among the study patients, 330 (50.3%) received clindamycin, 113 (17.2%) vancomycin, 83 (12.6%) cefazolin, and 26 (3.9%) ceftriaxone. Obese children received significantly lower doses by weight than healthy-weight patients for cefazolin (P <0.05), clindamycin (P <0.05), and ceftriaxone (P ≤0.01). There was no significant difference in dose of vancomycin between those who were obese or healthy weight and no significant difference in dose between those who were overweight vs healthy weight for any antibiotic assessed.The authors conclude that obese and overweight children with AHO had longer LOS and more procedures than healthy-weight patients.Dr Winer has disclosed no financial relationship relevant to this commentary. This commentary does not contain a discussion of an unapproved/investigative use of a commercial product/device.One of the enduring mantras in pediatrics is “children are not just little adults.” Yet, when learning about medication dosing, pediatricians often learn to check whether the weight-based dosing exceeds the typical adult dosing or the maximum listed. Weight-based dosing has its limitations, with increased volume of distribution and differences in clearance rates noted for younger children.1 Further complexity arises with the knowledge that lipophilic medications, including clindamycin, may need to be dosed differently in obese and overweight patients, with some recommending to use ideal or adjusted body weight for hydrophilic medications and total body weight for lipophilic medications.2The investigators of the current study found significant differences in weight-adjusted daily dosing of antibiotics for AHO. As expected, the biggest differences were in the beta-lactams, which are hydrophilic. There was a small but statistically significant decrease in weight-based clindamycin dosing in obese vs normal-weight children. There were no statistically significant weight-based dosing differences in vancomycin, despite it being a hydrophilic antibiotic and having a narrow therapeutic window. This may represent closer drug-level monitoring in obese children.3It is reassuring to see that although overweight and obese children needed more extensive initial surgical treatment and had longer average LOS, there were no differences in the rate of complications among children in the weight categories. Many of the differences seen may be due to differences in obesity-associated biologic factors and not differences in antibiotic prescribing.Differences exist in weight-based antibiotic dosing between normal-weight, overweight, and obese children with AHO. While overweight and obese children have higher rates of surgical intervention and longer LOS, these differences are not associated with increased complication rates. (See AAP Grand Rounds. 2021;46[5]:57.)4The lack of patient-specific data, such as microbiology results and illness severity, raise the possibility that it may be premature to conclude that complication rates and treatment failure do not differ between weight categories in children with AHO.

Improving monitoring of fish health in the oil sands region using regularization techniques and water quality variables

Trout-perch are sampled from the Athabasca River in Alberta, Canada, as a sentinel species for environmental health. The performance of trout-perch populations is known to be influenced by the quality of the water in which they reside. Using climate, environmental, and water quality variables measured in the Athabasca River near trout-perch sampling locations is found to improve model fitting and the predictability of models for the adjusted body weight, adjusted gonad weight, and adjusted liver weight of trout-perch. Given a large number of covariables, three variable selection techniques: stepwise regression, the lasso, and the elastic net (EN) are considered for selecting a subset of relevant variables. The models selected by the lasso and EN are found to outperform the models selected by stepwise regression in general, and little difference is observed between the models selected by the lasso and EN. Uranium, tungsten, tellurium, pH, molybdenum, and antimony are selected for at least one fish response.

Population Pharmacokinetics of Polymyxin B in Obese Patients for Resistant Gram-Negative Infections.

Polymyxin B is an effective but potentially nephrotoxic antibiotic that is commonly used to treat resistant Gram-negative infections. As a weight-based dosing drug, obese patients may be at a high risk of nephrotoxicity. However, the pharmacokinetics and dosing recommendations for this population are currently lacking. This study aimed to describe the polymyxin B population pharmacokinetics and to evaluate pharmacokinetic/pharmacodynamics (PK/PD) target attainment for obese patients. This study included 26 patients (body mass index, BMI >30) who received polymyxin B for ≥3 days. The total body weight (TBW) ranged from 75 to 125 kg, and the BMI ranged from 30.04 to 40.35. A two-compartment model adequately described the data using Phoenix NLME software. Monte Carlo simulation was used to assess polymyxin B exposure and the probability of target attainment (PTA). As a result, body weight had no significant effect on polymyxin B pharmacokinetics. According to model-based simulation, adjusted body weight (ABW)-based regimens had a high probability of achieving optimal exposure with minimal toxicity risk by comparing TBW and ideal body weight (IBW)-based regimens. The fixed dose of 125 mg or 150 mg q12h had a high toxicity risk. PTA results showed that TBW, IBW, and ABW-based regimens had similar PTA values. Therefore, for obese patients, ABW-based regimens but with a daily dose <250 mg have a high likelihood of achieving an AUCss,24h of 50–100 mg h/L and attaining PK/PD targets with the MIC ≤0.5 mg/L.

Evaluating prediction methods for glomerular filtration to optimise drug doses in obese and nonobese patients.

The most suitable method for predicting the glomerular filtration rate (GFR) in obesity is currently debated. Therefore, multiple GFR/creatinine clearance prediction methods were applied to (morbidly) obese and nonobese patients ranging from moderate renal impairment to glomerular hyperfiltration and their predictions were rated based on observed fosfomycin pharmacokinetics, as this model drug is exclusively eliminated via glomerular filtration. The GFR/creatinine clearance predictions via the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI), Modification of Diet in Renal Disease (MDRD; indexed and de-indexed by body surface area) and creatinine clearance via the Cockcroft-Gault formula (CLCRCG ) using different body size descriptors were compared to the fosfomycin clearance (CLFOF ) from 30 surgical patients (body mass index = 20.1-52.0kg m-2 ), receiving 8000 mg as intravenous infusion. The concordance between CLFOF and creatinine clearance predictions was highest for CLCRCG employing either ideal body weight or adjusted body weight (if body mass >1.3ideal body weight; CLCRCG_ABW-Schwartz , concordance-correlation coefficient [95% confidence interval] = 0.474 [0.156; 0.703], CCC) and GFR predictions via the de-indexed MDRD equation (concordance-correlation coefficient = 0.452 [0.137; 0.685]). The proportion of predicted GFR values within ±30% of the observed CLFOF (P30 = 72.3-76.7%) was only marginally lower than the reported P30 in the original CKD-EPI and MDRD publications (P30 = 84.1-90.0%). This analysis represents a successful proof-of-concept for evaluating GFR/creatinine clearance prediction methods: Across all body mass index classes CLCRCG_ABW-Schwartz or the de-indexed MDRD were most suitable for predicting creatinine clearance/GFR also in (morbidly) obese, CKD stage <3B individuals in therapeutic use. Their application is proposed in optimising doses for vital therapies in obese patients requiring monitoring of renal function (e.g. methotrexate dosing).

A Multicenter Retrospective Study of Vancomycin Dosing by Weight Measures in Children.

Vancomycin carries risks of treatment failure and emergent resistance with underexposure and renal toxicity with overexposure. Children with overweight or obesity may have altered pharmacokinetics. We aimed to examine how body weight metrics influence vancomycin serum concentrations and to evaluate alternative dosing strategies. This was a multicenter retrospective cohort study across 3 large, academic hospitals. Patients aged 2 to 18 years old who received ≥3 doses of intravenous vancomycin were included. Weight metrics included total body weight, adjusted body weight, ideal body weight, body surface area, and allometric weight. Outcomes included vancomycin concentration and ratios of area under the curve (AUC) to minimum inhibitory concentration (MIC). Regression analyses were used to examine which body-weight identifier predicted outcomes. Of the 1099 children, 45% were girls, mean age was 9.0 (SD = 5.4) years, 14% had overweight, and 17% had obesity. Seventy-five percent of children had vancomycin concentrations in the subtherapeutic range by trough <10 µg/mL, and 63% had a ratio of AUC to MIC <400 μg-hr/mL. Three percent had a supratherapeutic initial trough >20 µg/mL or ratio of AUC to MIC >600 μg-hr/mL. Serum vancomycin concentrations were higher in children with overweight or obesity compared with children who were at a normal weight or underweight; the mean ratio of AUC to MIC also trended higher in the groups with overweight or obesity. Most children received vancomycin regimens that produced suboptimal trough levels. Children with overweight or obesity experienced higher vancomycin trough levels than children of normal weight despite receiving lower total body weight dosing. Using the ratio of AUC to MIC was a better measure of drug exposure.

Nutritional management and clinical outcome of critically ill patients with COVID-19: A retrospective study in a tertiary hospital

Background & aimsSevere COVID-19 infection is characterized by an inflammatory response and lung injury that can evolve into an acute respiratory distress syndrome that needs support treatment in intensive care unit. Nutritional treatment is an important component of the management of critically ill patients and should be started in the first 48 h of ICU admission to avoid malnutrition. This study describes the characteristics of the patients treated in a tertiary hospital in Madrid during the months of March–May 2020 (first wave), the medical nutrition treatment employed and its influence in the clinical outcome of these patients.MethodsThis is a retrospective study including COVID-19 patients admitted in ICU that needed medical nutrition treatment (MNT). Collected variables included sex, age, BMI, underlying diseases, time from hospitalisation to ICU admission, type of respiratory support (invasive mechanical ventilation (IMV) or high flow nasal cannula (HFNC) or non-invasive ventilation (non-IMV)), caloric and protein requirements (25 kcal/kg adjusted body weight (ABW), 1.3 g/kg ABW/day), MNT type (enteral nutrition (EN), parenteral nutrition (PN), mixed EN + PN), total calories (including propofol) and proteins administered, percentage of caloric and protein goal in ICU day 4th and 7th, metabolic complications, acute kidney failure (AKF), length of stay (LOS) and mortality. Data are expressed as mean ± SD, median (IQR) or frequencies. Statistical analysis was performed with the IBM SPSS Statistics for Windows, Version 25.0. p < 0.05 were considered statistically significant.ResultsA total of 176 patients were included (72.7% male), 60.1 ± 13.5 years, BMI 29.9 ± 5.4 kg/m2. Underlying diseases included 47.4% overweight, 39.8% obesity, 49.1% hypertension, 41.4% dyslipidaemia. 88.6% of patients needed IMV, 89.1% prone position, 2.9% ECMO. Time to ICU admission: 2 (4.75) days. Estimated caloric and protein requirements were 1775 ± 202 kcal and 92.4 ± 10.3 g. Calories and proteins administered at days 4th and 7th were 1425 ± 577 kcal and 66 ± 26 g and 1574 ± 555 and 74 ± 37, respectively. Most of the patients received PN (alone or complementary to EN) to cover nutritional requirements (82.4% at day 4th and 77.9% at day 7th). IVM patients received more calories and proteins during the first week of ICU admission. Complications included 77.8% hyperglycaemia, 13.2% hypoglycaemia, 83.8% hypertriglyceridemia, and 35.1% AKF. ICU LOS was 20.5 (26) days. The mortality rate was 36.4%.ConclusionsIn our series, the majority of patients reached energy and protein requirements in the first week of ICU admission due to the use of PN (total or complementary to EN). Patients with HFNC or non-IMV may be at risk of malnutrition if total or complementary PN to oral diet/ONS/tube feeding is not used to cover nutritional requirements. Therefore, if EN is not possible or insufficient, PN can be safely used in critically ill patients with COVID-19 with a close monitoring of metabolic complications.

P-225: A first-in-human study of FOR46 in patients with triple refractory Multiple Myeloma

<h3>Background</h3> Cluster of differentiation 46 (CD46) is highly expressed in multiple myeloma, especially in patients (pts) with gain of chromosome 1q and in the refractory setting. In vitro studies show upregulation and enhanced cytotoxicity upon treatment with pomalidomide, dexamethasone or lenalidomide. FOR46, an anti-CD46 antibody-drug conjugate with vc-MMAE, recognizes a tumor selective epitope of CD46 and is taken up by malignant cells by macropinocytosis, which is a relatively tumor selective uptake mechanism. <h3>Methods</h3> Pts with MM were enrolled who had progressed on proteasome inhibitors, immunomodulatory drugs and CD38-targeted therapies. An accelerated titration followed by 3+3 dose escalation design was used. FOR46, at protocol specified doses, was infused intravenously over 30-60 minutes on Day 1 of 21-day cycles. Following excess toxicity (neutropenia and fatigue) in a patient (pt) with high body mass index (BMI), dosing was changed from actual weight (AW) to adjusted body weight (ABW). G-CSF secondary prophylaxis was required for pts experiencing grade (gr) ≥ 3 neutropenia during a previous treatment cycle. The initial protocol had 2.4 mg/kg AW as the highest dose. When the MTD was not defined using ABW dosing, escalation was held pending protocol amendment to allow a higher dose and expansion to 10 patients at 2.4 mg/kg ABW began. Safety was evaluated using CTCAE v5.0 and efficacy was evaluated per IMWG criteria. Dexamethasone was only allowed for infusion reaction prophylaxis. CD46 antigen density was determined on patient MM cells via flow cytometry. <h3>Results</h3> Fifteen pts were enrolled at 6 pre-defined dose levels from 0.1 to 2.4 mg/kg with 1 patient each at the 0.1, 0.3 and 0.6 mg/kg dose levels, 3 at 1.2 and 1.8 mg/kg and 6 at 2.4 mg/kg. Median age was 68 (range 33 – 79) with 4 females. Gain 1q was present in 9 pts, absent in 5 pts and unknown in 1. The median number of prior lines of therapy was 6 (range 3-17). The only dose-limiting toxicity (DLT) was gr 4 neutropenia in 1 high BMI patient dosed by AW. This was the only DLT among 6 pts at 2.4 mg/kg dosed by a mix of AW (n=3) and ABW (n=3). One of 3 at 2.4 mg/kg ABW had non-dose limiting gr 4 neutropenia. The most common related adverse event was gr 4 neutropenia in 3 pts (20%). One patient (6.7%) had gr 4 thrombocytopenia and 1 each (6.7%) had gr 3 AST elevation, neutropenia, anemia, nausea, and peripheral neuropathy (PN). Of the 6 response-evaluable pts in the 1.8 and 2.4 mg/kg cohorts, 3 had partial responses (PRs) lasting 21, 30, and 15 weeks, respectively. Of the PRs, 1 pt did not have gain of 1q21. In addition to the fifteen pts in dose escalation cohorts, 10 have been enrolled in an expansion cohort at 2.4 mg/kg by ABW. <h3>Conclusion</h3> FOR46 demonstrates an acceptable toxicity profile using ABW dosing. There is encouraging evidence of efficacy in triple refractory MM. A protocol amendment allowing additional dose escalation to 2.7 mg/kg by ABW has been approved. NCT03650491

A RARE CASE OF RADIATION-PRIMED CRYPTOGENIC ORGANIZING PNEUMONIA

TOPIC: Pulmonary Manifestations of Systemic Disease TYPE: Medical Student/Resident Case Reports INTRODUCTION: Cryptogenic organizing pneumonia (COP) has rarely been associated with radiotherapy for breast cancer since the advent of planned irradiation field therapy. Here we present a case of a woman diagnosed with radiation-primed COP, diagnosed on lung biopsy. CASE PRESENTATION: A 78-year-old female with a medical history of asthma and three year old history of invasive ductal carcinoma of the right breast post lumpectomy, radiotherapy and adjuvant Taxol and Herceptin chemotherapy presented to the hospital with symptoms of progressive dyspnea. CT Chest at the time of admission revealed patchy areas of ground-glass and peripheral nodular consolidation with cavitation superimposed on postradiation fibrosis. She was diagnosed with pneumonia and discharged on a 5 day course of Amoxicillin-Clavulanic Acid.She continued to have persistent dyspnea, dry cough and was retreated with a 7 day course of Levofloxican. She symptoms persisted and a repeat CT Chest performed a month later demonstrated persistent pulmonary opacities concerning for cryptogenic organizing pneumonia and she underwent a CT-guided biopsy. Pathology revealed acute lung injury consistent with organizing pneumonia and cultures were negative for bacteria, fungi or acid-fast bacilli. She was treated with 1 mg/kg of prednisone daily, adjusted body weight, for a total of 3 months and experienced complete resolution of symptoms. DISCUSSION: Radiotherapy is the core treatment of breast cancer with planned field irradiation allows for minimal risk of side effects e.g. pneumonia and fibrosis. Pneumonia typically presents 4 to 12 weeks after radiotherapy; it's characterized by dyspnea, dry cough and alveolar opacities restricted to the treatment port [1]. In rare cases, bilateral lymphocytic alveolitis can develop, in spite of a limited radiation treatment area and it's radiological and histological pattern emulates cryptogenic organizing pneumonia (COP) [2]. Corticosteroid treatment in COP often results in rapid correction of both clinical symptoms and radiological signs; the precise dose and duration of treatment has not yet been defined [1].In our case, the patient presented with the typical signs of pneumonia and failed multiple rounds of treatment with antibiotics. The correct diagnosis was only established months later, after her symptoms persisted and a pathological tissue sample and negative cultures enabled a conclusive diagnosis of radiation-primed COP. Her clinical response to systemic corticosteroid provided further confirmation of her diagnosis. CONCLUSIONS: A high index of suspicion is required in order to diagnose radiation-primed cryptogenic organizing pneumonia. Clinicians must be aware of its chronic and persistent presentation if left untreated, as early diagnosis will prevent significant physical and psychological morbidity. REFERENCE #1: Bradley B, Branley HM, Egan JJ, et al. Interstitial lung disease guideline: the British Thoracic Society in collaboration with the Thoracic Society of Australia and New Zealand and the Irish Thoracic Society [published correction appears in Thorax. 2008 Nov;63(11):1029. multiple author names added]. Thorax. 2008;63 Suppl 5:v1-v58. doi:10.1136/thx.2008.101691 REFERENCE #2: Roberts CM, Foulcher E, Zaunders JJ, Bryant DH, Freund J, Cairns D, Penny R, Morgan GW, Breit SN. Radiation pneumonitis: a possible lymphocyte-mediated hypersensitivity reaction. Ann Intern Med. 1993;118:696–700. DISCLOSURES: No relevant relationships by Suhayb Ranjha, source=Web Response

Evaluation of Thyroid Hormone Replacement Dosing in Morbidly Obese Hypothyroid Patients after Bariatric Surgery-Induced Weight Loss.

The most frequent endocrine disease in obese patients is hypothyroidism. To date, there are no clear data regarding what happens to the dose of levothyroxine (LT4) after bariatric surgery (BS). The objective of the present study was to evaluate thyroid hormone replacement dose in morbidly obese hypothyroid patients after BS-induced weight loss. We explore the best type of measured or estimated body weight for LT4 dosing. We performed an observational study evaluating patients with morbid obesity and hypothyroidism who underwent BS. We included 48 patients (three men). In morbidly obese hypothyroid patients 12 months after BS-induced weight loss, the total LT4 dose or the LT4 dose/kg ideal body weight did not change, while there was a significant increase in LT4 dose/body surface area, LT4 dose/kg weight, LT4 dose/kg adjusted body weight, LT4 dose/kg body fat, and LT4 dose/kg lean body weight. There were no differences in LT4 dose and its variation between sleeve gastrectomy (SG) and Roux-en-Y gastric bypass (RYGB). The present study strongly suggests that LT4 dosing in obese hypothyroid patients can be individually adapted more precisely if it is based on ideal body weight.

Oncologic effects of chemotherapy dose capping in overweight and obese ovarian cancer patients

<h3>Objectives:</h3> Chemotherapy dose capping in overweight and obese advanced ovarian cancer patients remains controversial in regard to its effect on oncologic outcomes and toxicity. <h3>Methods:</h3> Women with stage III or IV ovarian cancer receiving carboplatin and paclitaxel as primary therapy in combination with surgical resection between 1/2007-12/2016 were included in this retrospective study evaluating the interaction between body mass index (BMI) and chemotherapy dose capping on progression free survival (PFS) and toxicity. A calculated carboplatin dose based on the planned AUC and actual body weight (ABW) at the time of the first chemotherapy cycle following debulking surgery was compared to the dose received at this time based on the electronic medical record. A 5% or greater difference in treatment plan dosing received compared to actual weight-based dose was considered clinically significant. <h3>Results:</h3> 263 ovarian cancer patients were included in analysis (233 serous, 7 endometrioid, 14 clear cell, 8 carcinosarcoma, 1 NOS). Median age was 64 years (35-86). 62 (23.6%) received neoadjuvant chemotherapy prior to debulking surgery and 236 (88.2%) of all patients had an optimal cytoreductive surgery of <1cm. Median BMI was 25.1 (range 18.1-54.4). BMI cohorts included BMI <25 (128, 48.7%), BMI 25 to <30 (71, 27%), BMI ≥30. The calculated ABW carboplatin dose was at least 5% more than dose received in 38% of the total population. The rate of underdosing increased as BMI increased (8.6% BMI <25, 63.3% BMI 25 to <30, 68.7% BMI ≥30). There was no difference in PFS detected for patients with BMI <25 compared to BMI 25 or greater (HR 0.92 [CI 0.7-1.2], p=0.576). In patients with BMI of 25 or greater there was a trend toward PFS benefit when actual body weight was used for carboplatin dosing compared to modified adjusted body weight calculation (HR 0.7 [95% CI 0.47-1.04], p=0.078, Figure 1). Importantly, Grade 3 or 4 toxicity of any type did not appear to be increased in patients with BMI ≥25 receiving ABW carboplatin dosing compared to those with BMI ≥25 receiving modified dosing by adjusted body weight (Grade 3–4 toxicity 47.2% IBW dose v 30.4% ABW dose, p=0.068). Grade 3–4 toxicity rate in patient with BMI <25 was 45.3%. <h3>Conclusions:</h3> Carboplatin dose modification using adjusted body weight over a BMI of 25 may have a negative effect on PFS in ovarian cancer patients receiving primary therapy. Toxicity does not appear to be increased in this population when actual body weight is used for carboplatin dosing.

Diagnostic Ability of Methods Depicting Distress of Tumor-Bearing Mice.

Simple SummaryExperiments on animals can provide important information for improving the life expectancy and life quality of patients. At the same time, the welfare of these animals is a growing public concern. Therefore, many laws and international guidelines were established with the goal of minimizing the harm inflicted on these animals. A prerequisite of improving animal welfare is to correctly measure how much distress the experiments cause to these animals. However, it is often unknown as to which methods are appropriate to assess distress. Mice bearing subcutaneous tumors are the most frequently used animal model to study the therapeutic effects of drugs. We evaluated if body weight, faecal corticosterone metabolites concentration, burrowing activity and a distress score were capable of differentiating between mice before cancer cell injection and mice bearing large tumors. We observed that only adjusted body weight change and faecal corticosterone metabolites concentration were capable of measuring distress caused by large subcutaneous tumors. Therefore, these two methods are appropriate to assess the welfare of mice with subcutaneous tumors. This knowledge provides a solid basis to optimize animal welfare in future studies. For example, both methods can define the ideal time point when an experiment should end by finding a good compromise between minimal distress for the animals and maximal knowledge gain for mankind.Subcutaneous tumor models in mice are the most commonly used experimental animal models in cancer research. To improve animal welfare and the quality of scientific studies, the distress of experimental animals needs to be minimized. For this purpose, one must assess the diagnostic ability of readout parameters to evaluate distress. In this study, we evaluated different noninvasive readout parameters such as body weight change, adjusted body weight change, faecal corticosterone metabolites concentration, burrowing activity and a distress score by utilising receiver operating characteristic curves. Eighteen immunocompromised NOD.Cg-Prkdcscid Il2rgtm1Wjl/SzJ mice were used for this study; half were subcutaneously injected with A-375 cells (human malignant melanoma cells) that resulted in large tumors. The remaining mice were inoculated with SCL-2 cells (cutaneous squamous cell carcinoma cells), which resulted in small tumors. The adjusted body weight and faecal corticosterone metabolites concentration had a high diagnostic ability in distinguishing between mice before cancer cell injection and mice bearing large tumors. All other readout parameters had a low diagnostic ability. These results suggest that adjusted body weight and faecal corticosterone metabolites are useful to depict the distress of mice bearing large subcutaneous tumors.