Noni (Morinda citrifolia) leaf extract incorporated methylcellulose active films: A sustainable strategy for browning inhibition in apple slice packaging.

Methylcellulose, a prominent polysaccharide prevalent in the food sector, was considered to fabricate the active films with glutaraldehyde as a crosslinker and Noni (Morinda citrifolia) Leaf Extract (NLE) as an active agent. FTIR analysis confirms the intermolecular -OH bonding, and SEM micrograms demonstrate methylcellulose active films' homogeneous, dense morphologic appearance. Due to the crosslinking effect of glutaraldehyde and noni leaf extract, tensile strength (41.83 ±â€¯0.134 MPa) and crystallinity (62.91 %) of methylcellulose films were improved. Methylcellulose active films suppress water and moisture uptake at various relative humidities. The inhibition capability against foodborne pathogens and the excellent antioxidant activity [DPPH (93.191 ±â€¯1.384 %) and ABTS (90.523 ±â€¯1.412 %)] of NLE incorporation suggested that food packed in methylcellulose active films were effective against pathogenic and oxidative attacks. During preservation, to ensure the apple slices' nutritional values, they are covered with physiochemically enhanced methylcellulose active films for up to 120 h. The minimum reduction in vitamin C, reducing sugar content, percentage weight loss, pH, and total phenolic content of apple slices preserved in MGN active films at room temperature suggests it is an affordable and efficient replacement to traditional single-use plastic packaging in the cut fruit industry.

Rv2231c, a unique histidinol phosphate aminotransferase from Mycobacterium tuberculosis, supports virulence by inhibiting host-directed defense.

Nitrogen metabolism of M. tuberculosis is critical for its survival in infected host cells. M. tuberculosis has evolved sophisticated strategies to switch between de novo synthesis and uptake of various amino acids from host cells for metabolic demands. Pyridoxal phosphate-dependent histidinol phosphate aminotransferase-HspAT enzyme is critically required for histidine biosynthesis. HspAT is involved in metabolic synthesis of histidine, phenylalanine, tyrosine, tryptophan, and novobiocin. We showed that M. tuberculosis Rv2231c is a conserved enzyme with HspAT activity. Rv2231c is a monomeric globular protein that contains α-helices and ß-sheets. It is a secretory and cell wall-localized protein that regulates critical pathogenic attributes. Rv2231c enhances the survival and virulence of recombinant M. smegmatis in infected RAW264.7 macrophage cells. Rv2231c is recognized by the TLR4 innate immune receptor and modulates the host immune response by suppressing the secretion of the antibacterial pro-inflammatory cytokines TNF, IL-12, and IL-6. It also inhibits the expression of co-stimulatory molecules CD80 and CD86 along with antigen presenting molecule MHC-I on macrophage and suppresses reactive nitrogen species formation, thereby promoting M2 macrophage polarization. Recombinant M. smegmatis expressing Rv2231c inhibited apoptosis in macrophages, promoting efficient bacterial survival and proliferation, thereby increasing virulence. Our results indicate that Rv2231c is a moonlighting protein that regulates multiple functions of M. tuberculosis pathophysiology to increase its virulence. These mechanistic insights can be used to better understand the pathogenesis of M. tuberculosis and to design strategies for tuberculosis mitigation.

Population pharmacokinetic/pharmacodynamic target attainment analysis of IV fosfomycin for the treatment of MDR Gram-negative bacterial infections.

BACKGROUND: IV fosfomycin is used against MDR Gram-negative bacilli (GNB) but has dose-limiting side effects, especially in patients with impaired kidney function. OBJECTIVES: To determine the optimal dosage of IV fosfomycin for patients with varying degrees of kidney function. METHODS: Adult patients receiving IV fosfomycin for treatment of GNB were eligible. Five serial blood samples were collected after at least three doses of fosfomycin; plasma was assayed by LC-MS/MS and modelled by population pharmacokinetic analysis. The PTA for AUC24/MIC of 98.9 for Escherichia coli and Klebsiella pneumoniae, and 40.8 for Pseudomonas aeruginosa were computed by Monte Carlo simulations. Cumulative fractions of response (CFR) were analysed for each pathogen using EUCAST MIC distributions. RESULTS: A total of 24 patients were included. Creatinine clearance (CLCR) and gender significantly influenced fosfomycin clearance. The kidney function-adjusted dosing regimens are proposed by using the lowest dose that can achieve ≥90% PTA for AUC24/MIC of 98.9 at an MIC of ≤32 mg/L (EUCAST v.13 susceptibility breakpoint for Enterobacterales). For patients with normal kidney function (CLCR 91-120 mL/min), a dosage of 15 g/day is suggested. This regimen achieved 97.1% CFR against E. coli, whereas CFR was 72.9% for K. pneumoniae and 76.7% for P. aeruginosa. CONCLUSIONS: A fosfomycin dosage of 15 g/day with adjustment according to kidney function provided high PTA and CFR when treating E. coli. This dosage is lower than that used in current practice and may improve tolerability. Higher dosages may be needed for P. aeruginosa; however, safety data are limited.

Revolutionizing Daptomycin Dosing: A Single 7-11 Hour Sample for Pragmatic Application.

Precision daptomycin dosing faces clinical implementation barriers despite known exposure-safety concerns with the use of twice the regulatory-approved doses. We propose achieving a single 7-11 hour post-dose plasma target concentration of 30 mg/L to 43 mg/L to be a practical starting point to facilitate precision daptomycin dosing.

Balancing the scales: achieving the optimal beta-lactam to beta-lactamase inhibitor ratio with continuous infusion piperacillin/tazobactam against extended spectrum beta-lactamase producing Enterobacterales.

Piperacillin/tazobactam (TZP) is administered intravenously in a fixed ratio (8:1) with the potential for inadequate tazobactam exposure to ensure piperacillin activity against Enterobacterales. Adult patients receiving continuous infusion (CI) of TZP and therapeutic drug monitoring (TDM) of both agents were evaluated. Demographic variables and other pertinent laboratory data were collected retrospectively. A population pharmacokinetic approach was used to select the best kidney function model predictive of TZP clearance (CL). The probability of target attainment (PTA), cumulative fraction of response (CFR) and the ratio between piperacillin and tazobactam were computed to identify optimal dosage regimens by continuous infusion across kidney function. This study included 257 critically ill patients (79.3% male) with intra-abdominal, bloodstream, and hospital-acquired pneumonia infections in 89.5% as the primary indication. The median (min-max range) age, body weight, and estimated glomerular filtration rate (eGFR) were 66 (23-93) years, 75 (39-310) kg, and 79.2 (6.4-234) mL/min, respectively. Doses of up to 22.5 g/day were used to optimize TZP based on TDM. The 2021 chronic kidney disease epidemiology equation in mL/min best modeled TZP CL. The ratio of piperacillin:tazobactam increased from 6:1 to 10:1 between an eGFR of <20 mL/min and >120 mL/min. At conventional doses, the PTA is below 90% when eGFR is ≥100 mL/min. Daily doses of 18 g/day and 22.5 g/day by CI are expected to achieve a >80% CFR when eGFR is 100-120 mL/min and >120-160 mL/min, respectively. Inadequate piperacillin and tazobactam exposure is likely in patients with eGFR ≥ 100 mL/min. Dose regimen adjustments informed by TDM should be evaluated in this specific population.

Autonomy and factors affecting dental health care seeking behaviour in women: An application of theory of planned behaviour.

Background: Understanding oral health care seeking behaviour and it's determinants is essential in improving oral health. The health care utilization in women was found to be influenced by their autonomy. A socio-cognitive model that can explain variance in dental attendance behaviour in women including autonomy has yet to be validated. The Theory of Planned Behaviour (TPB), which takes into account women's autonomy, attitude, subjective norms, and perceived behavioural control, is empirically tested in this study with regard to self-reported dental visiting intentions and dental health seeking behaviour. Method: Cross sectional study using self-administered questionnaires was conducted to assess socio-demographic factors, autonomy, dental visiting behaviors as well as constructs of TPB model in 400 women aged 18 years or older in Bangalore city selected via stratified cluster sampling method. Two-stage structural equation modelling (SEM) was used to test the hypothesized TPB model. Results: The proposed correlated 5-factor measurement model was confirmed through confirmatory factor analysis (CFA). In SEM subjective norm (ß = 0.17), perceived behavioural control (ß = -0.27) and autonomy (ß = 0.49) significantly predicted dental visiting intentions in women. Intention (ß = 0.56) and autonomy (ß = 0.25) explained dental visiting behaviour. It also revealed indirect effect of autonomy and perceived behaviour control on dental visiting behaviour through intentions. The hypothesized model predicted 27.6 % and 23.8% of the variance in intention and dental visiting behaviour respectively. Conclusion: The hypothesized model was successful in predicting intention and dental visiting behaviour in women. This could explain the multidimensional nature of dental care utilization in women which in turn might be helpful in improving access to dental care among them in future.

Evaluation of association between time in range, a continuous glucose monitoring metric, and cardiac autonomic neuropathy in type 2 diabetes patients.

Introduction: Time in range (TIR), a metric of continuous glucose monitoring (CGM) provides better information regarding the individual's glycemic variability than a static measure like glycated hemoglobin (HbA1c). TIR is emerging as an independent risk factor for diabetic complications, both microvascular and macrovascular complications independent of HbA1c. Hence, this study evaluates the association between TIR and cardiac autonomic neuropathy (CAN) in type 2 diabetic patients. Materials and Methods: A total of 42 patients with type 2 diabetes mellitus were enrolled in this study and underwent a 3-day CGM using the "FreeStyle Libre Pro Flash Glucose Monitoring System Sensor" along with tests for CAN within the 3 days of attaching the CGM. Results: Out of 42 patients, 36 patients (85.7%) were diagnosed with CAN (early CAN 57.1% and definite CAN 28.6%) and the mean TIR was 64.4% ±23.5%. Out of those with TIR <70%, 42.9% were affected with definite CAN compared to only 14.3% among those with TIR >70%. Patients with more severe CAN were found to have a lower TIR (P = 0.115). Conclusion: The study found a high prevalence of cardiac autonomic neuropathy (CAN) of around 85.7% in type 2 diabetes patients. Lower TIR values were associated with a higher incidence of definite CAN (42.9% vs. 14.3% in TIR <70% vs. >70% groups). The findings suggest TIR is inversely associated with the presence and severity of cardiac autonomic neuropathy in type 2 diabetic patients and also a potential link between TIR and CAN severity.

Résumé Introduction: Le temps dans l'intervalle (TIR), une mesure de la surveillance continue du glucose (SGC), fournit de meilleures informations sur l'état de santé de l'individu. variabilité glycémique qu'une mesure statique comme l'hémoglobine glyquée (HbA1c). Le TIR est en train de devenir un facteur de risque indépendant pour les diabétiques complications microvasculaires et macrovasculaires indépendantes de l'HbA1c. Par conséquent, cette étude évalue l'association entre le TIR et la neuropathie autonome cardiaque (CAN) chez les patients diabétiques de type 2. Matériel et méthodes: Un total de 42 patients atteints de diabète sucré de type 2 ont été inclus dans cette étude et ont subi une SGC de 3 jours à l'aide du " FreeStyle Libre Pro Flash Glucose Monitoring System Sensor " ainsi que des tests de CAN dans les 3 jours suivant la fixation de la CGM. Résultats: Sur 42 patients, 36 patients (85,7 %) ont reçu un diagnostic de CAN (CAN précoce 57.1 % et CAN définitif 28.6 %) et le TIR moyen était de 64.4 % ±23.5 %). Parmi ceux qui ont un TIR, 70 %. Les patients atteints d'une CAN plus sévère présentaient un TIR plus faible (p = 0,115).Conclusion: L'étude a révélé une prévalence élevée de neuropathie autonome cardiaque (CAN) d'environ 85.7 % dans le diabète de type 2 patient. Des valeurs de TIR plus faibles étaient associées à une incidence plus élevée de CAN défini (42.9 % contre 14.3 % dans les groupes TIR <70 % contre >70 %). Le Les résultats suggèrent que le TIR est inversement associé à la présence et à la gravité de la neuropathie autonome cardiaque chez les patients diabétiques de type 2 et Il existe également un lien potentiel entre la gravité du TIR et celle du CAN. Mots-clés: Neuropathie autonome cardiaque, surveillance continue de la glycémie, temps au-dessus de la plage, temps en dessous de la plage, temps dans la plage, type 2 diabète sucré.

Bone Mineral Density and Bone Turnover Marker in a Subclinical Thyrotoxic State in Young Premenopausal Women.

BACKGROUND: Subclinical thyrotoxicosis (SCH) is characterized by normal serum thyroid hormone levels and low thyrotropin levels. The impact of this condition on the skeletal system may vary depending on its cause, yet the relationship is not fully comprehended in premenopausal women. Studies are scarce about its effects on bone health in our population. OBJECTIVES: This study aims to evaluate the bone mineral density (BMD) and bone turnover markers in premenopausal women with SCH and determine if any differences exist based on the condition's etiology. METHODS: A cross-sectional study was conducted at Ramaiah Medical College involving 36 participants for one year and six months after approval from the Ethics Committee. The carboxy-terminal telopeptide of type I collagen in blood and BMD were measured at the lumbar vertebrae (L1-L4) and femoral neck by dual-energy x-ray absorptiometry (Hologic v 2.0, Hologic, Massachusetts, U.S.). Statistical analysis was done using IBM SPSS Statistics for Windows, Version 20 (Released 2011; IBM Corp., Armonk, New York, United States).  Results: The mean age of the study population was 35.2 ± 7.2 years. The etiology was Graves' disease [n=11 (33.3%)], iatrogenic [n=14(38.8%)], toxic adenoma [n=6 (15.1%)], and multi-nodular goiter [n=5 (15.1%)]. The mean BMI was 23.5 ± 3.8 kg/m2, and the mean levels of corrected calcium, phosphorus, and 25 hydroxy-vitamin D were 9.12 ± 0.25 mg/dl, 2.95 ± 0.34 mg/dl, and 29.4 ± 6.4 ng/ml, respectively. The mean BMD at hip and spine was 0.81 ±0.16 g/cm2 and 0.92±0.08 g/cm2 respectively. The mean Z-score was (-0.02 ± 0.8) and (-0.92± 0.08) at the hip and spine. No significant difference was observed in the BMD at the hip (p = 0.14) or spine (p = 0.44) between the endogenous and exogenous subclinical thyrotoxic subgroups. At the same time, the carboxy-terminal telopeptide of type I collagen was significantly different between the two groups (p<0.05). CONCLUSION: In our cross-sectional study of premenopausal women with SCH, BMD at the hip or spine as measured by dual-energy X-ray absorptiometry did not reveal any significant reduction. The subclinical thyrotoxic state may not have an adverse effect on bone health in premenopausal females with sufficient levels of serum 25-hydroxy-vitamin D in the short term.

A Comprehensive Mixed-Method Approach to Characterize the Source of Diurnal Tacrolimus Exposure Variability in Children: Systematic Review, Meta-analysis, and Application to an Existing Data Set.

Tacrolimus is widely reported to display diurnal variation in pharmacokinetic parameters with twice-daily dosing. However, the contribution of chronopharmacokinetics versus food intake is unclear, with even less evidence in the pediatric population. The objectives of this study were to summarize the existing literature by meta-analysis and evaluate the impact of food composition on 24-hour pharmacokinetics in pediatric kidney transplant recipients. For the meta-analysis, 10 studies involving 253 individuals were included. The pooled effect sizes demonstrated significant differences in area under the concentration-time curve from time 0 to 12 hours (standardized mean difference [SMD], 0.27; 95% confidence interval [CI], 0.03-0.52) and maximum concentration (SMD, 0.75; 95% CI, 0.35-1.15) between morning and evening dose administration. However, there was significant between-study heterogeneity that was explained by food exposure. The effect size for minimum concentration was not significantly different overall (SMD, -0.09; 95% CI, -0.27 to 0.09) or across the food exposure subgroups. A 2-compartment model with a lag time, linear clearance, and first-order absorption best characterized the tacrolimus pharmacokinetics in pediatric participants. As expected, adding the time of administration and food composition covariates reduced the unexplained within-subject variability for the first-order absorption rate constant, but only caloric composition significantly reduced variability for lag time. The available data suggest food intake is the major driver of diurnal variation in tacrolimus exposure, but the associated changes are not reflected by trough concentrations alone.

Morphomics-informed population pharmacokinetic and physiologically-based pharmacokinetic modeling to optimize cefazolin surgical prophylaxis.

INTRODUCTION: Cefazolin is the leading antibiotic used to prevent surgical site infections worldwide. Consensus guidelines recommend adjustment of the cefazolin dose above and below 120 kg without regard to body composition. Algorithms exist to repurpose radiologic data into body composition (morphomics) and inform dosing decisions in obesity. OBJECTIVES: To compare the current standard of body weight to morphomic measurements as covariates of cefazolin pharmacokinetics and aid dose stratification of cefazolin in patients with obesity undergoing colorectal surgery. METHODS: This prospective study measured cefazolin plasma, fat, and colon tissue concentrations in colorectal surgery patients in order to develop a morphomics-informed population pharmacokinetic (PopPK) model to guide dose adjustments. A physiologically-based pharmacokinetic (PBPK) model was also constructed to inform tissue partitioning in morbidly obese patients (n = 21, body mass index ≥35 kg/m2 with one or more co-morbid conditions). RESULTS: Morphomics and pharmacokinetic data were available in 58 patients with a median [min, max] weight and age of 95.9 [68.5, 148.8] kg and 55 [25, 79] years, respectively. The plasma-to-subcutaneous fat partition coefficient was predicted to be 0.072 and 0.060 by the PopPK and PBPK models, respectively. The estimated creatinine clearance (eCLcr ) and body depth at the third lumbar vertebra (body depth_L3) were identified as covariates of cefazolin exposure. The probability of maintaining subcutaneous fat concentrations above 2 µg/mL for 100% of a 4-h surgical period was below 90% when eCLcr ≥105 mL/min and body depth_L3 ≥ 300 mm and less sensitive to the rate of infusion between 5 and 60 min. CONCLUSIONS: Kidney function and morphomics were more informative than body weight as covariates of cefazolin target site exposure. Data from more diverse populations, consensus on target cefazolin exposure, and comparative studies are needed before a change in practice can be implemented.

Bioanalysis of six antibiotics from volumetric microsamples: a new tool for precision dosing in critically ill children.

Background: Volumetric absorptive microsamples (VAMS) can support pharmacokinetic / pharmacodynamic studies. We present the bioanalytical method development for the simultaneous quantification of ampicillin, cefepime, ceftriaxone, meropenem, piperacillin, tazobactam, and vancomycin from VAMS. Methods & results: Optimal extraction, chromatographic, and mass spectrometry conditions were identified. Maximum extraction recoveries included 100 µl of water for rehydration and methanol for protein precipitation. Chromatographic separation used Phenomenex Kinetex™ Polar C18 column with a mobile phase comprising water/acetonitrile with formic acid and was fully validated. Hematocrit effects were only observed for vancomycin. Samples were stable for 90 days at -80°C except for meropenem, which was stable for 60 days. Conclusion: Multiple antibiotics can be assayed from a single VAMS sample to facilitate pharmacokinetic/pharmacodynamic studies.

Prevalence of cardiac autonomic neuropathy in patients with type 2 diabetes mellitus.

Introduction: Cardiac autonomic neuropathy (CAN) is one of the microvascular complications of diabetes mellitus, which is due to the involvement of autonomic nerve fibers innervating the heart and blood vessels. CAN was found to have a greater degree of morbidity and mortality than their non-CAN counterparts as it is underdiagnosed. Hence, this study aims to determine the prevalence and severity of CAN in type 2 diabetics in the South Indian setting. Materials and Methods: Forty-two patients with type 2 diabetes mellitus were enrolled in the study. Patients underwent tests for CAN, with the severity of CAN estimated as a CAN score, which was the sum of the scores of the four cardiovascular autonomic function tests. Results: Out of the 42 patients, a total of 36 patients (85.7%) were diagnosed with CAN. Among those with CAN, 24 patients had early CAN (57.1%), and 12 were diagnosed with definite CAN (28.6%). Patients with any form of CAN (early and definite CAN) had higher HbA1c and mean glucose values than those without CAN. CAN was also found to be more severe among older patients with diabetes. Conclusion: In the present study, we found that more than 50% of the study population had early CAN and around 28.6% patients had definite CAN indicating higher prevalence of CAN in our population. Also, there was a positive correlation between the severity of CAN and the age of the patients. This study highlights the importance of understanding the importance of screening the diabetic patients for CAN to prevent adverse cardiovascular events.

Optimizing anidulafungin exposure across a wide adult body size range.

Echinocandins like anidulafungin are first-line therapies for candidemia and invasive candidiasis, but their dosing may be suboptimal in obese patients. Our objective was to quantify anidulafungin exposure in a cohort of adults across a wide body size range to test if body size affects anidulafungin pharmacokinetics (PK). We enrolled 20 adults between the ages of 18 and 80 years, with an equal distribution of patients above and below a body mass index of 30 kg/m2. A single 100-mg dose of anidulafungin was administered, followed by intensive sampling over 72 h. Population PK analysis was used to identify and compare covariates of anidulafungin PK parameters. Monte Carlo simulations were performed to compute the probability of target attainment (PTA) based on alternative dosing regimens. Participants (45% males) had a median (range) age of 45 (21-78) years and a median (range) weight of 82.7 (42.4-208.3) kg. The observed median (range) of AUC0-∞ was 106.4 (51.9, 138.4) mg∙h/L. Lean body weight (LBW) and adjusted body weight (AdjBW) were more influential than weight as covariates of anidulafungin PK parameters. The conventional 100 mg daily maintenance is predicted to have a PTA below 90% in adults with an LBW > 55 kg or an AdjBW > 75 kg. A daily maintenance dose of 150-200 mg is predicted in these heavier adults. Anidulafungin AUC0-∞ declines with increasing body size. A higher maintenance dose will increase the PTA compared to the current approach in obese patients.

Physicochemical and antioxidant properties of tannic acid crosslinked cationic starch/chitosan based active films for ladyfinger packaging application.

In the present study, cationic starch (CS)/chitosan (CH) incorporated with tannic acid (TA)(CSCT) eco-friendly films were prepared by employing an inexpensive solvent casting technique. Influence of TA on the physicochemical and antimicrobial properties of CS/CH polymer matrix were studied. The FTIR findings and homogeneous, dense SEM micrographs confirms the effective interaction of TA with CS/CH polymer matrix. CSCT-3 active film displayed tensile strength of 26.99±1.91 MPa, which is more substantial than commercially available polyethylene (PE) (12-16 MPa) films. The active films exhibited excellent barrier properties against moisture and water, supported by increased water contact angle values (86.97±0.29°). Overall migration rate of active films was found to be below the permitted limit of 10mg/dm2. The active films showed around 56% of degradation in soil within 15 days. Besides, the active films showed concurring impact against food borne pathogens like E. coli, S. aureus and C. albicans. The CSCT-3 active film presented 90.83% of antioxidant capacity, demonstrating the effective prevention of food oxidation related deterioration. Ladyfinger packaging was inspected to examine the ability of active films as packaging material resulted in effectively resisting deterioration and extending shelf life in comparison with traditional PE packaging.

Kidney function as a key driver of the pharmacokinetic response to high-dose L-carnitine in septic shock.

STUDY OBJECTIVE: Levocarnitine (L-carnitine) has shown promise as a metabolic-therapeutic for septic shock, where mortality approaches 40%. However, high-dose (≥ 6 grams) intravenous supplementation results in a broad range of serum concentrations. We sought to describe the population pharmacokinetics (PK) of high-dose L-carnitine, test various estimates of kidney function, and assess the correlation of PK parameters with pre-treatment metabolites in describing drug response for patients with septic shock. DESIGN: Population PK analysis was done with baseline normalized concentrations using nonlinear mixed effect models in the modeling platform Monolix. Various estimates of kidney function, patient demographics, dose received, and organ dysfunction were tested as population covariates. DATA SOURCE: We leveraged serum samples and metabolomics data from a phase II trial of L-carnitine in vasopressor-dependent septic shock. Serum was collected at baseline (T0); end-of-infusion (T12); and 24, 48, and 72 h after treatment initiation. PATIENTS AND INTERVENTION: Patients were adaptively randomized to receive intravenous L-carnitine (6 grams, 12 grams, or 18 grams) or placebo. MEASUREMENTS AND MAIN RESULTS: The final dataset included 542 serum samples from 130 patients randomized to L-carnitine. A two-compartment model with linear elimination and a fixed volume of distribution (17.1 liters) best described the data and served as a base structural model. Kidney function estimates as a covariate on the elimination rate constant (k) reliably improved model fit. Estimated glomerular filtration rate (eGFR), based on the 2021 Chronic Kidney Disease Epidemiology collaboration (CKD-EPI) equation with creatinine and cystatin C, outperformed creatinine clearance (Cockcroft-Gault) and older CKD-EPI equations that use an adjustment for self-identified race. CONCLUSIONS: High-dose L-carnitine supplementation is well-described by a two-compartment population PK model in patients with septic shock. Kidney function estimates that leverage cystatin C provided superior model fit. Future investigations into high-dose L-carnitine supplementation should consider baseline metabolic status and dose adjustments based on renal function over a fixed or weight-based dosing paradigm.

Reconsideration of the current models of estimated kidney function-based drug dose adjustment in older adults: The role of biological age.

Human lifespan has increased from a median of 46.5 years in 1950 to 71.7 years in 2022. As people age, one of the inevitable consequences is a decline in kidney function and glomerular filtration rate (GFR) which can have direct or indirect effects on the pharmacokinetic and pharmacodynamic profiles of many drugs. Numerous equations have been developed to generate estimated GFR (eGFR) using the two principal biomarkers: serum creatinine and serum cystatin C. However, the trajectory of changes with aging is dissimilar in these equations. In addition, there is recognition that chronological age (lifespan) often does not reflect biological age (healthspan) as an essential parameter in kidney function equations. In the past decade, there has been an increasing interest in quantifying biological age and new commercially available assays have entered the marketplace. In this narrative review, we illustrate how dominant equations of eGFR model the fractional change in this parameter very differently across chronological age. In addition, we review various biological age indicators (aging clocks) and challenges to their application in clinical practice. Importantly, by comparing vancomycin's mean clearance as a drug with limited metabolism and unchanged elimination between two age milestones in some recent population pharmacokinetic models, we show how efforts to quantify kidney function in older adults optimally remain under-explored, particularly those at the upper end of their lifespan. We also propose considering new models that integrate biological age as a new pathway to improve precision drug dosing in older adults.

Pheochromocytoma: Clinical Experience From a Single Tertiary Care Center in India.

INTRODUCTION: Pheochromocytoma is a catecholamine-secreting tumor arising from adrenomedullary chromaffin cells that has a varied clinical presentation. Identification of this tumor, which has episodic symptoms, is a diagnostic challenge for clinicians. Diagnosis at an appropriate time is important because it is associated with significant morbidity and mortality. This study aims to mitigate the limited availability of data in our geographical area. AIMS AND OBJECTIVES: To assess the clinical, biochemical, and radiological features and outcomes of patients diagnosed with pheochromocytoma at our center. MATERIALS AND METHODS: This is a retrospective study. Patients diagnosed with pheochromocytoma during 2015-2023 were included in the study. Clinical, biochemical, and radiological data were collected at presentation, post-surgery, discharge, and until the last follow-up; data were retrieved from hospital records. Statistical analysis was done using IBM Corp. Released 2011. IBM SPSS Statistics for Windows, Version 20.0. Armonk, NY: IBM Corp. RESULTS: This study included 19 patients, of whom 10 (52.6%) were female. The most common clinical presentation was a hypertensive crisis in patients with pre-existing hypertension (63.1%), followed by headache (47.3%). The classical triad of headache, palpitation, and sweating was seen in only three patients (15.7%). The mean tumor size was 5.01±2.06 cm, with a range of 2.5 to 12 cm. All patients underwent adrenalectomy; six patients (31.5%) had perioperative complications, with post-operative hypotension being the most common at 21% (n = 4), followed by an acute coronary event during alpha blockade in one patient (0.05%) and an intra-operative hypertensive crisis in one patient (5%). A biochemical remission rate post-surgery was achieved in 17 (89.47%) patients. CONCLUSIONS: Hypertensive crisis in patients with pre-existing hypertension was the predominant presenting feature in most of our patients. Female predominance was noted (52.3%) compared to males. Perioperative complications were observed in 31.5% of patients, with post-operative hypotension being the most common complication.

Structural and Biophysical properties of therapeutically important proteins Rv1509 and Rv2231A of Mycobacterium tuberculosis.

Through comparative analyses using BLASTp and BLASTn of the 25 target sequences, our research identified two unique post-transcriptional modifiers, Rv1509 and Rv2231A, which serve as distinctive and characteristic proteins of M.tb - the Signature Proteins. Here, we have characterized these two signature proteins associated with pathophysiology of M.tb which may prove to be therapeutically important targets. Dynamic Light Scattering and Analytical Gel Filtration Chromatography exhibited that Rv1509 exists as a monomer while Rv2231A as a dimer in solution. Secondary structures were determined using Circular Dichroism and further validated through Fourier Transform Infrared spectroscopy. Both the proteins are capable of withstanding a wide range of temperature and pH variations. Fluorescence spectroscopy based binding affinity experiments showed that Rv1509 binds to iron and may promote organism growth by chelating iron. In the case of Rv2231A, a high affinity for its substrate RNA was observed, which is facilitated in presence of Mg2+ suggesting it might have RNAse activity, supporting the prediction through in-silico studies. This is the first study on biophysical characterization of these two therapeutically important proteins, Rv1509 and Rv2231A, providing important insights into their structure -function correlations which are crucial for development of new drugs/ early diagnostics tools targeting these proteins.

Prolonging the therapeutic window for valproic acid treatment in a swine model of traumatic brain injury and hemorrhagic shock.

BACKGROUND: It has previously been shown that administration of valproic acid (VPA) can improve outcomes if given within an hour following traumatic brain injury (TBI). This short therapeutic window (TW) limits its use in real-life situations. Based upon its pharmacokinetic data, we hypothesized that TW can be extended to 3 hours if a second dose of VPA is given 8 hours after the initial dose. METHOD: Yorkshire swine (40-45 kg; n = 10) were subjected to TBI (controlled cortical impact) and 40% blood volume hemorrhage. After 2 hours of shock, they were randomized to either (1) normal saline resuscitation (control) or (2) normal saline-VPA (150 mg/kg × two doses). First dose of VPA was started 3 hours after the TBI, with a second dose 8 hours after the first dose. Neurologic severity scores (range, 0-36) were assessed daily for 14 days, and brain lesion size was measured via magnetic resonance imaging on postinjury day 3. RESULTS: Hemodynamic and laboratory parameters of shock were similar in both groups. Valproic acid-treated animals had significantly less neurologic impairment on days 2 (16.3 ± 2.0 vs. 7.3 ± 2.8) and 3 (10.9 ± 3.6 vs. 2.8 ± 1.1) postinjury and returned to baseline levels 54% faster. Magnetic resonance imaging showed no differences in brain lesion size on day 3. Pharmacokinetic data confirmed neuroprotective levels of VPA in the circulation. CONCLUSION: This is the first study to demonstrate that VPA can be neuroprotective even when given 3 hours after TBI. This expanded TW has significant implications for the design of the clinical trial.

Experimental investigation of the structural features of polycarbonate (PC) filled with bismuth nitrate pentahydrate (BNP) composite films in terms of free volume defects probed by positron annihilation lifetime spectroscopy.

The effect of bismuth nitrate pentahydrate (BNP) on the properties and microstructural features of polycarbonate (PC) has been investigated using PALT, XRD, SEM, EDX, TG, ATR-FTIR and tensile mechanical measurements. Positron Annihilation Lifetime Spectroscopy reveals that the ortho-positronium lifetime and its corresponding intensity significantly decrease as the filler level of BNP in PC (in the composite) increases from 0.3 wt% up to 5.0 wt%. This is due to the increasing fraction of positrons that annihilate with the filler particles and also in the interfacial layers of the filler and the host polymer. Fourier Transform Infrared spectra show that there is no significant shift in the IR bands of the composite when compared to those of pure PC, and so there is little molecular level interaction between PC and BNP. The micrographs of SEM revealed a random distribution of filler particles in the composite, and there is the formation of agglomerates of BNP at higher filler levels. There is an increase in the degree of crystallinity of the composite films due to the addition of the crystalline filler, which was confirmed by XRD analysis. Tensile mechanical tests confirmed the improved tensile strength of prepared composites at lower and moderate filler levels, from 0.0 wt % up to 2.5 wt%. The free volume properties of the composite films are correlated with its tensile mechanical properties.