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OBJECTIVES: Ceftazidime/avibactam is a key antibiotic for carbapenemase-producing Enterobacterales (CPE) Gram-negative infections, but current dosing may be suboptimal to grant activity. This study explores the population pharmacokinetics/pharmacodynamics (PK/PD) of continuous infusion (CI) ceftazidime/avibactam for maximizing treatment efficacy in critically ill patients. METHODS: A retrospective analysis of adult patients receiving CI ceftazidime/avibactam and therapeutic drug monitoring (TDM) of both compounds was performed. Population PK/PD modelling identified the most accurate method for estimating ceftazidime/avibactam clearance based on kidney function and Monte Carlo simulations investigated the relationship between various CI dosing regimens and aggressive joint PK/PD target attainment of ceftazidime/avibactam. RESULTS: The European Kidney Function Consortium (EKFC) equation best described kidney function for ceftazidime/avibactam clearance. The findings challenge the current approach of only reducing the ceftazidime/avibactam dose based on kidney function by identifying dose adjustments in patients with augmented kidney function. Our CI ceftazidime/avibactam dosing strategies, adjusted by TDM, showed promise for achieving optimal aggressive joint PK/PD targets and potentially improving clinical/microbiological outcomes against KPC- and OXA-48-producing Enterobacterales. The risk of neurotoxicity associated with these strategies appears acceptable. CONCLUSIONS: This study suggests that adjusting ceftazidime/avibactam dosing regimen based solely on eCLcr might be suboptimal for critically ill patients. Higher daily doses delivered by CI and adjusted based on TDM have the potential to improve aggressive joint PK/PD target attainment and potentially clinical/microbiological outcomes. Further investigations are warranted to confirm these findings and establish optimal TDM-guided dosing strategies for ceftazidime/avibactam in clinical practice.
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CONTEXT: Adrenal incidentalomas (AIs) are relatively uncommon neoplasms in 2% of apparently healthy individuals requiring evaluation for functionality and malignancy. AIM: We aimed to study the clinical, biochemical, and radiological profiles of patients presenting with AI and histopathological outcomes of those undergoing adrenalectomy. Materials and Methods: This retrospective study enrolled 62 AI patients attending a tertiary care center in South India between January 2016 and October 2023. Demographic details, radiological features, functionality, and histopathological data were analyzed. RESULTS: Out of 62 patients, total masses evaluated were 65 indicating bilaterality in 3 patients. The female: male ratio was 1.69, with a median age of 55 years (interquartile range: 44-64 years). 45.1% of individuals were >60 years. The most common indication for imaging was pain abdomen in 43 (69.4%). The median size was 3.2 cm. Fifty-five (88.7%) were assessed for functionality and 27 (49.1%) were functional. Among the 62 individuals, 14 (20.2%) had hypercortisolism, 11 (15.9%) had pheochromocytoma, 5 (7.24%) had primary hyperaldosteronism (PA), and 4 (5.7%) had hyperandrogenism including plurihormonal in 7. A mass size of 3.2 cm was of great value in distinguishing functional tumors with a sensitivity of 72% and specificity of 66% with an area under the curve of 0.682. A total of 34 (54.8%) patients underwent adrenalectomy. On histopathological examination, Adenoma (44.1%) was the most common followed pheochromocytoma (26.5%), adrenal cysts (8.8%), and Myelolipoma (5.9%). Two (5.9%) incidentalomas were adrenocortical carcinoma (ACC). Eight (53.3%) adenomas were functional with 6 having hypercortisolism (including 1 with hyperandrogenism) and 2 with PA. CONCLUSION: In our experience, the incidence of pheochromocytoma was second most common after adenoma. Since most functional tumors (60%) and all ACCs were ≥4 cm, a thorough biochemical evaluation for hormonal excess and evaluation for malignancy followed by surgery should be considered for lesions, especially ≥4 cm. Thus, we report the baseline demographic and clinical characteristics of patients with AI from a single center in South India.
Résumé Contexte:Les incidents surrénaliens (AIS) sont des néoplasmes relativement rares chez 2% des individus apparemment en bonne santé nécessitant une évaluation de la fonctionnalité et de la malignité. Objectif: Nous visions à étudier les profils cliniques, biochimiques et radiologiques des patients présentant IA et résultats histopathologiques de ceux qui subissent une surrénalectomie.Matériaux et méthodes:Cette étude rétrospective a inscrit 62 patients AI fréquentant un centre de soins tertiaires dans le sud de l'Inde entre janvier 2016 et octobre 2023. Les détails démographiques, les caractéristiques radiologiques, les fonctionnalités et les données histopathologiques ont été analysés.Résultats:Sur 62 patients, les masses totales évaluées étaient 65 indiquant la bilatéralité chez 3 patients. Le ratio féminin: mâle était de 1,69, avec un âge médian de 55 ans (intervalle interquartile: 4464 ans). 45,1% des individus étaient> 60 ans. L'indication la plus courante pour l'imagerie était l'abdomen de la douleur dans 43 (69,4%). La taille médiane était de 3,2 cm. Cinquante-cinq (88,7%) ont été évaluées pour les fonctionnalités et 27 (49,1%) étaient fonctionnelles. Parmi les 62 individus, 14 (20,2%) avaient un hypercortisolisme, 11 (15,9%) Le phéochromocytome, 5 (7,24%) avait une hyperaldostéronisme primaire (PA), et 4 (5,7%) avaient l'hyperandrogénisme, y compris le plurihormonal dans 7. Une taille de masse de 3,2 cm était d'une grande valeur dans la distinction des tumeurs fonctionnelles avec une sensibilité de 72% et une spécificité distinctive de 66% avec une zone sous la courbe de 0,682. Au total, 34 (54,8%) patients ont subi une surrénalectomie. À l'examen histopathologique, l'adénome (44,1%) était le phéochromocytome suivi le plus courant (26,5%), les kystes surrénaliens (8,8%) et le myélolipome (5,9%). Deux incidentsalomes (5,9%) étaient un carcinome surrénocortical (ACC). Huit (53,3%) adénomes étaient fonctionnels avec 6 souffrant d'hypercortisolisme (dont 1 avec l'hyperandrogénisme) et 2 avec PA.Conclusion:D'après notre expérience, l'incidence du phéochromocytome était la deuxième plus courante après l'adénome. Étant donné que la plupart des tumeurs fonctionnelles (60%) et tous les ACC étaient ≥ 4 cm, une évaluation biochimique approfondie pour l'excès hormonal et l'évaluation de la malignité suivie d'une chirurgie doivent être envisagées pour les lésions, en particulier ≥4 cm. Ainsi, nous rapportons les caractéristiques démographiques et cliniques de base des patients atteints d'IA d'un seul centre du sud de l'Inde.
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AIMS: Dried blood volumetric absorptive microsamples (VAMS) may facilitate home-based sampling to enhance therapeutic drug monitoring after transplantation. This study aimed to clinically validate a liquid chromatography-tandem mass spectrometry assay using 2 VAMS devices with different sampling locations (Tasso-M20 for the upper arm and Mitra for the finger). Patient preferences were also evaluated. METHODS: Clinical validation was performed for tacrolimus and mycophenolic acid by comparison of paired VAMS and venipuncture samples using Passing-Bablok regression and Bland-Altman analysis. Conversion of mycophenolic acid VAMS to serum concentrations was evaluated using haematocrit-dependent formulas and fixed correction factors defined a priori. Patients' perspectives, including useability, acceptability and feasibility, were also investigated using established questionnaires. RESULTS: Paired samples (n = 50) were collected from 25 kidney transplant recipients. Differences for tacrolimus whole-blood concentration were within ±20% for 86 and 88% of samples from the upper arm and fingerstick, respectively. Using correction factors of 1.3 for the upper-arm and 1.47 for finger-prick samples, 84 and 76% of the paired samples, respectively, were within ±20% for mycophenolic acid serum concentration. Patient experience surveys demonstrated limited pain and acceptable useability of the upper-arm device. CONCLUSIONS: Tacrolimus and mycophenolic acid can be measured using 2 common VAMS devices with similar analytical performance. Patients are supportive of home-based monitoring with a preference for the Tasso-M20 device.
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BACKGROUND: Daptomycin is a high-use intravenous antimicrobial agent affording the convenience of once-daily dosing. Prior studies suggest an opportunity to use a more operationally convenient fixed rather than weight-based dosing but this approach has not been studied prospectively. METHODS: This study quantified the probability of toxicity and efficacy end points by prospectively testing a fixed dose regimen of daptomycin (750 mg) in obese and non-obese adults. At least, three daptomycin concentrations were measured at steady-state for each patient. A population pharmacokinetic model was constructed to evaluate concentration-time profiles and investigate covariates of daptomycin clearance. Simulations were performed to evaluate the probability of achieving efficacy (24-h area under the curve (AUC0-24) ≥ 666 mgâh/L) and toxicity (minimum concentration (C min) ≥24.3 mg/L) targets for fixed (500-1000 mg) and weight-based (6-12 mg/kg) daptomycin doses. RESULTS: Thirty-one patients (16 females, 15 males) with median (interquartile range (IQR)) age of 50 (30, 62) years and weight of 74 (54, 156) kg were included in the final analysis. Fixed dose daptomycin (750 mg) resulted in similar exposure across weights with a median (IQR) AUC0-24 of 819 (499, 1501) mgâh/L and 749 (606, 1265) mgâh/L in patients weighing ≤74 kg and >74 kg, respectively. Overall, male sex and increased kidney function necessitate higher fixed and weight-based doses to achieve efficacy. Creatine phosphokinase elevation was observed in two patients (6.5%) and predicted to be lower with fixed versus weight-based regimens. CONCLUSIONS: Fixed daptomycin dosing adjusted for sex and kidney function is expected to improve the efficacy-to-toxicity ratio, transitions of care, and costs compared to weight-based doses. However, no empiric dosing approach is predicted to achieve ≥90% efficacy while minimizing the risk of toxicity, so therapeutic drug monitoring should be considered on a patient-specific basis.
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Antibacterianos , Daptomicina , Infecções Estafilocócicas , Daptomicina/farmacocinética , Daptomicina/administração & dosagem , Daptomicina/farmacologia , Humanos , Masculino , Feminino , Antibacterianos/farmacocinética , Antibacterianos/administração & dosagem , Antibacterianos/farmacologia , Pessoa de Meia-Idade , Adulto , Infecções Estafilocócicas/tratamento farmacológico , Estudos Prospectivos , Área Sob a Curva , Relação Dose-Resposta a Droga , Modelos Biológicos , Obesidade/tratamento farmacológico , Staphylococcus aureus/efeitos dos fármacos , Peso Corporal , Testes de Sensibilidade MicrobianaRESUMO
Biodegradable and sustainable food preservation materials have gained immense global importance to mitigate plastic pollution and environmental impact. Biopolymers like cellulose offer significant advantages for food preservation, including biodegradability and the ability to extend shelf life. Therefore, the present study aims to prepare gallic acid (GA) and zinc oxide nanoparticles (ZnO NPs) incorporated methylcellulose (MC) composite films by employing a solvent casting technique. The homogeneous SEM micrographs and FTIR spectra evidenced high compatibility among MC and GA/ZnO NPs. The UV barrier capacity, mechanical properties and surface hydrophobicity are remarkably enhanced by GA/ZnO NPs. However, the water vapour permeability and oxygen permeability of MGZ films were reduced by 49.19 % and 57.75 % respectively. Moreover, the MGZ films demonstrated exceptional antioxidant efficacy (â¼94.48 %) and inhibition against food-borne pathogens such as B. subtilis, S. aureus (Gram-positive), E. coli, P. aeruginosa (Gram-negative), and C. albicans fungi. Furthermore, the GA/ZnO NPs extended the shelf life of MGZ coated tomato samples up to 27 days and exhibited controlled microbial growth after the preservation study. These results support the application of MGZ films as suitable and effective coating materials for food packaging applications.
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Antioxidantes , Conservação de Alimentos , Ácido Gálico , Metilcelulose , Solanum lycopersicum , Óxido de Zinco , Ácido Gálico/química , Óxido de Zinco/química , Metilcelulose/química , Conservação de Alimentos/métodos , Antioxidantes/química , Antioxidantes/farmacologia , Embalagem de Alimentos/métodos , Permeabilidade , Nanopartículas/química , Interações Hidrofóbicas e HidrofílicasRESUMO
OBJECTIVES: With the menopausal transition, there is a decline in estrogen concentration with potential health consequences affecting the quality of life. The loss of muscle mass, strength, and function, known as sarcopenia is common in postmenopausal women. The primary objective of this study is to assess the quality of life in postmenopausal women and its association with sarcopenia. METHODS: This was a cross-sectional study conducted in 106 postmenopausal women. Menopausal symptoms and risk of sarcopenia were assessed with Menopause Rating Scale (MRS) and Strength Assistance walking Rising from a chair Climbing stairs and Falls (SARC-F) questionnaires, respectively. Sarcopenia was defined and assessed according to the Asian Working Group for Sarcopenia guidelines 2019. RESULTS: The mean age was 59.34 ± 7.21 years and the mean age at menopause was 49.50 ± 2.67 years. The majority (80.2%) of the women had high MRS scores (≥9). The majority had mild somatic, moderate psychologic, and severe urogenital symptoms. SARC-F score was low in 85.8% of women. Most of the women (45.3%) had sarcopenia. Somatic symptoms were significant in women with sarcopenia. Urogenital symptoms were significant with greater menopausal duration. Appendicular skeletal muscle mass index was significantly less with greater menopausal duration. MRS score positively correlated with both SARC-F score and sarcopenia. Sarcopenia was significantly associated with greater menopausal duration. CONCLUSIONS: Most of the women had moderate to severe MRS scores suggestive of a poor quality of life. The majority of the women had sarcopenia. Most of the women felt they were strong (according to SARC-F score) despite sarcopenia. Although quality of life did not differ significantly with the duration of menopause, urogenital symptoms were significantly severe with greater menopausal duration. Despite no significant association between quality of life and sarcopenia in postmenopausal women, somatic symptoms were significant in women with sarcopenia. The greater menopausal duration was associated significantly with sarcopenia.
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Pós-Menopausa , Qualidade de Vida , Sarcopenia , Humanos , Feminino , Pós-Menopausa/fisiologia , Pós-Menopausa/psicologia , Estudos Transversais , Pessoa de Meia-Idade , Inquéritos e Questionários , IdosoRESUMO
Mycobacterium tuberculosis (M. tb) genome encompasses 4,173 genes, about a quarter of which remain uncharacterized and hypothetical. Considering the current limitations associated with the diagnosis and treatment of tuberculosis, it is imperative to comprehend the pathomechanism of the disease and host-pathogen interactions to identify new drug targets for intervention strategies. Using in-silico comparative genome analysis, we identified one of the M. tb genes, Rv1509, as a signature protein exclusively present in M. tb. To explore the role of Rv1509, a likely methyl transferase, we constructed a knock-in Mycobacterium smegmatis (M. smegmatis) constitutively expressing Rv1509 (Ms_Rv1509). The Ms_Rv1509 led to differential expression of many transcriptional regulator genes as assessed by RNA-seq analysis. Further, in-vitro and in-vivo studies demonstrated an enhanced survival of Ms_Rv1509 inside the host macrophages. Ms_Rv1509 also promoted phagolysosomal escape inside macrophages to boost bacterial replication and dissemination. In-vivo infection studies revealed that Ms_Rv1509 survives better than BCG and causes pathological manifestations in the pancreas after intraperitoneal infection. Long-time survival of Ms_Rv1509 resulted in lymphocyte migration, increased T regulatory cells, giant cell formation, and likely granuloma formation in the pancreas, pointing toward the role of Rv1509 in M. tb pathogenesis.
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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 ± 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 ± 1.384 %) and ABTS (90.523 ± 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.
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Antioxidantes , Embalagem de Alimentos , Malus , Metilcelulose , Morinda , Extratos Vegetais , Folhas de Planta , Morinda/química , Extratos Vegetais/química , Extratos Vegetais/farmacologia , Folhas de Planta/química , Embalagem de Alimentos/métodos , Antioxidantes/farmacologia , Antioxidantes/química , Metilcelulose/química , Malus/químicaRESUMO
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.
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Macrófagos , Mycobacterium tuberculosis , Transaminases , Camundongos , Mycobacterium tuberculosis/patogenicidade , Mycobacterium tuberculosis/imunologia , Mycobacterium tuberculosis/enzimologia , Mycobacterium tuberculosis/metabolismo , Animais , Células RAW 264.7 , Virulência , Macrófagos/microbiologia , Macrófagos/imunologia , Macrófagos/metabolismo , Transaminases/metabolismo , Transaminases/genética , Proteínas de Bactérias/metabolismo , Proteínas de Bactérias/genética , Mycobacterium smegmatis/patogenicidade , Mycobacterium smegmatis/metabolismo , Mycobacterium smegmatis/genética , Mycobacterium smegmatis/enzimologia , Citocinas/metabolismo , Receptor 4 Toll-Like/metabolismo , Humanos , Imunidade Inata , Interações Hospedeiro-Patógeno/imunologia , Tuberculose/imunologia , Tuberculose/microbiologiaRESUMO
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.
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Antibacterianos , Farmacorresistência Bacteriana Múltipla , Fosfomicina , Infecções por Bactérias Gram-Negativas , Klebsiella pneumoniae , Testes de Sensibilidade Microbiana , Pseudomonas aeruginosa , Humanos , Fosfomicina/farmacocinética , Fosfomicina/administração & dosagem , Fosfomicina/farmacologia , Fosfomicina/efeitos adversos , Feminino , Masculino , Antibacterianos/farmacocinética , Antibacterianos/administração & dosagem , Antibacterianos/farmacologia , Pessoa de Meia-Idade , Idoso , Infecções por Bactérias Gram-Negativas/tratamento farmacológico , Infecções por Bactérias Gram-Negativas/microbiologia , Adulto , Klebsiella pneumoniae/efeitos dos fármacos , Pseudomonas aeruginosa/efeitos dos fármacos , Escherichia coli/efeitos dos fármacos , Idoso de 80 Anos ou mais , Administração Intravenosa , Método de Monte Carlo , Espectrometria de Massas em Tandem , Bactérias Gram-Negativas/efeitos dos fármacosRESUMO
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 7-11â hour post-dose plasma target concentration of 30â mg/L to 43â mg/L to be a practical starting point to facilitate precision daptomycin dosing.
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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.
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Gammaproteobacteria , Inibidores de beta-Lactamases , Adulto , Humanos , Masculino , Idoso , Idoso de 80 Anos ou mais , Feminino , Inibidores de beta-Lactamases/farmacocinética , Antibacterianos/farmacocinética , beta-Lactamas , Estudos Retrospectivos , Ácido Penicilânico/uso terapêutico , Ácido Penicilânico/farmacocinética , Combinação Piperacilina e Tazobactam/farmacocinética , Piperacilina/farmacocinética , Tazobactam , beta-Lactamases , Testes de Sensibilidade MicrobianaRESUMO
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.
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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.
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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.
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Diabetes Mellitus Tipo 2 , Doenças do Sistema Nervoso , Humanos , Diabetes Mellitus Tipo 2/complicações , Diabetes Mellitus Tipo 2/diagnóstico , Hemoglobinas Glicadas , Glicemia , Automonitorização da Glicemia , Monitoramento Contínuo da GlicoseRESUMO
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.
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Transplante de Rim , Tacrolimo , Humanos , Criança , Imunossupressores/farmacocinética , Taxa de Depuração Metabólica , Área Sob a CurvaRESUMO
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.
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Cefazolina , Obesidade Mórbida , Humanos , Cefazolina/farmacocinética , Obesidade Mórbida/cirurgia , Estudos Prospectivos , Antibioticoprofilaxia , Antibacterianos , Infecção da Ferida Cirúrgica/prevenção & controleRESUMO
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.
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Antibacterianos , Vancomicina , Criança , Humanos , Antibacterianos/farmacologia , Meropeném , Estado Terminal , Espectrometria de Massas em Tandem/métodos , Água , Coleta de Amostras Sanguíneas/métodosRESUMO
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.
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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) mgâh/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.