Insulin sensitivity, disposition index and insulin clearance in cystic fibrosis: a cross-sectional study.

AIMS/HYPOTHESIS: The aim of this study was to investigate insulin secretion, insulin sensitivity, disposition index and insulin clearance by glucose tolerance status in individuals with cystic fibrosis (CF) and exocrine pancreatic insufficiency. METHODS: In a cross-sectional study, we conducted an extended (ten samples) OGTT in individuals with pancreatic-insufficient CF (PI-CF). Participants were divided into normal glucose tolerance (NGT), early glucose intolerance (EGI), impaired glucose tolerance (IGT) and CF-related diabetes (CFRD) groups. We used three different oral minimal models to assess insulin secretion, insulin sensitivity and insulin clearance during the OGTT. We evaluated insulin secretion using total secretion (Φ total), first-phase secretion (Φ dynamic) and second-phase secretion (Φ static) from the model, and we estimated the disposition index by multiplying Φ total and insulin sensitivity. RESULTS: Among 61 participants (NGT 21%, EGI 33%, IGT 16%, CFRD 30%), insulin secretion indices (Φ total, dynamic and static) were significantly lower in the CFRD group compared with the other groups. Insulin sensitivity declined with worsening in glucose tolerance (p value for trend <0.001) and the disposition index declined between NGT and EGI and between IGT and CFRD. Those with CFRD had elevated insulin clearance compared with NGT (p=0.019) and low insulin secretion (Φ total) was also associated with high insulin clearance (p<0.001). CONCLUSIONS/INTERPRETATION: In individuals with PI-CF, disposition index declined with incremental impairment in glucose tolerance due to a reduction in both insulin secretion and insulin sensitivity. Moreover in CF, reduced insulin secretion was associated with higher insulin clearance.

Unlocking potential of oxytocin: improving intracranial lymphatic drainage for Alzheimer's disease treatment.

Background: The impediment to ß-amyloid (Aß) clearance caused by the invalid intracranial lymphatic drainage in Alzheimer's disease is pivotal to its pathogenesis, and finding reliable clinical available solutions to address this challenge remains elusive. Methods: The potential role and underlying mechanisms of intranasal oxytocin administration, an approved clinical intervention, in improving intracranial lymphatic drainage in middle-old-aged APP/PS1 mice were investigated by live mouse imaging, ASL/CEST-MRI scanning, in vivo two-photon imaging, immunofluorescence staining, ELISA, RT-qPCR, Western blotting, RNA-seq analysis, and cognitive behavioral tests. Results: Benefiting from multifaceted modulation of cerebral hemodynamics, aquaporin-4 polarization, meningeal lymphangiogenesis and transcriptional profiles, oxytocin administration normalized the structure and function of both the glymphatic and meningeal lymphatic systems severely impaired in middle-old-aged APP/PS1 mice. Consequently, this intervention facilitated the efficient drainage of Aß from the brain parenchyma to the cerebrospinal fluid and then to the deep cervical lymph nodes for efficient clearance, as well as improvements in cognitive deficits. Conclusion: This work broadens the underlying neuroprotective mechanisms and clinical applications of oxytocin medication, showcasing its promising therapeutic prospects in central nervous system diseases with intracranial lymphatic dysfunction.

A dual target molecular magnetic resonance imaging probe for noninvasive profiling of pathologic alpha-synuclein and microgliosis in a mouse model of Parkinson's disease.

The pathogenesis of Parkinson's disease (PD) is characterized by progressive deposition of alpha-synuclein (α-syn) aggregates in dopaminergic neurons and neuroinflammation. Noninvasive in vivo imaging of α-syn aggregate accumulation and neuroinflammation can elicit the underlying mechanisms involved in disease progression and facilitate the development of effective treatment as well as disease diagnosis and prognosis. Here we present a novel approach to simultaneously profile α-syn aggregation and reactive microgliosis in vivo, by targeting oligomeric α-syn in cerebrospinal fluid with nanoparticle bearing a magnetic resonance imaging (MRI), contrast payload. In this proof-of-concept report we demonstrate, in vitro, that microglia and neuroblastoma cell lines internalize agglomerates formed by cross-linking the nanoparticles with oligomeric α-syn. Delayed in vivo MRI scans following intravenous administration of the nanoparticles in the M83 α-syn transgenic mouse line show statistically significant MR signal enhancement in test mice versus controls. The in vivo data were validated by ex-vivo immunohistochemical analysis which show strong correlation between in vivo MRI signal enhancement, Lewy pathology distribution, and microglia activity in the treated brain tissue. Furthermore, neuronal and microglial cells in brain tissue from treated mice display strong cytosolic signal originating from the nanoparticles, attributed to in vivo cell uptake of nanoparticle/oligomeric α-syn agglomerates.

Lenacapavir Exhibits Atropisomerism - Mechanistic Pharmacokinetics and Disposition Studies of Lenacapavir Reveal Intestinal Excretion as a Major Clearance Pathway.

Lenacapavir (LEN), a long-acting injectable, is the first approved human immunodeficiency virus type 1 capsid inhibitor and one of a few FDA-approved drugs that exhibit atropisomerism. LEN exists as a mixture of two class 2 atropisomers that interconvert at a fast rate (t1/2 <2 hours) with a ratio that is stable over time and unaffected by enzymes or binding to proteins in plasma. LEN exhibits low systemic clearance (CL) in nonclinical species and humans; however, in all species the observed CL was higher than the in vitro predicted CL. The volume of distribution was moderate in nonclinical species and consistent with the tissue distribution observed by whole body autoradiography in rats. LEN does not distribute to brain, consistent with being a P-glycoprotein (P-gp) substrate. Mechanistic drug disposition studies with [14C]LEN in IV-dosed BDC rats and dogs showed a substantial amount of unchanged LEN (31 - 60% of dose) excreted in feces, indicating that intestinal excretion (IE) was a major clearance pathway for LEN in both species. Coadministration of oral elacridar, a P-gp inhibitor, in rats decreased CL and IE of LEN. Renal excretion was <1% of dose in both species. In plasma, almost all radioactivity was unchanged LEN. Low levels of metabolites in excreta included LEN-conjugates with glutathione, pentose, and glucuronic acid, which were consistent with metabolites formed in vitro in Hµrel® hepatocyte co­cultures and those observed in human. Our studies highlight the importance of IE for efflux substrates that are highly metabolically stable compounds with slow elimination rates. Significance Statement LEN is a long-acting injectable that exists as conformationally stable atropisomers. Due to an atropisomeric interconversion rate that significantly exceeds the in vivo elimination rate, the atropisomer ratio of LEN remains constant in circulation. The disposition of LEN highlights that intestinal excretion has a substantial part in the elimination of compounds that are metabolically highly stable and efflux transporter substrates.

Comparison of Relative Activity versus Relative Expression Factors (RAF versus REF) in Predicting Glucuronidation Mediated Drug Clearance Using Recombinant UGTs.

PURPOSE: Predicting the quantitative fraction of glucuronidation (fgluc) by individual UDP-glucuronosyltransferase enzymes (UGTs) is challenging due to the lack of selective inhibitors and inconsistent activity of recombinant UGT systems (rUGTs). Our study compares the relative expression versus activity factors (REF versus RAF) to predict fgluc based on rUGT data to human liver and intestinal microsomes (HLM and HIM). METHODS: REF scalars were derived from a previous in-house proteomics study for eleven UGT enzymes (UGT1A1, UGT1A3, UGT1A4, UGT1A6, UGT1A9, UGT1A10, UGT2B4, UGT2B7, UGT2B10, UGT2B15, and UGT2B17), whereas RAF was calculated by measuring activities in rUGTs to microsomes of selective UGT probe substrates. Protein-normalized activity factor (pnAF) values were generated after correcting activity of individual UGTs to their corresponding protein abundance. The utility of REF and RAF in predicting fgluc was assessed for three UGT substrates-diclofenac, vorinostat, and raltegravir. RESULTS: The REF values ranged from 0.02 to 1.75, RAF based on activity obtained in rUGTs to HLM/HIM were from 0.1 to 274. pnAF values were ~ 5 to 80-fold, except for UGT2B4 and UGT2B15, where pnAF was ~ 180 and > 1000, respectively. The results revealed confounding effect of differential specific activities (per pmol) of rUGTs in fgluc prediction. CONCLUSION: The data suggest that the activity of UGT enzymes was significantly lower when compared to their activity in microsomes at the same absolute protein amount (pmol). Collectively, results of this study demonstrate poor and variable specific activity of different rUGTs (per pmol protein), as determined by pnAF values, which should be considered in fgluc scaling.

More Time Spent with Clear Skin and No Itch with Upadacitinib versus Dupilumab for Atopic Dermatitis.

INTRODUCTION: Atopic dermatitis (AD), with its hallmark symptoms of pruritus and skin lesions, often impairs patients' quality of life. We assessed time spent with clear/almost clear skin and no/minimal itch during upadacitinib treatment versus placebo or dupilumab among patients with moderate-to-severe AD. METHODS: This analysis consisted of a post hoc analysis of Measure Up 1 (NCT03569293), Measure Up 2 (NCT03607422), and Heads Up (NCT03738397). Measure Up 1 and 2 were replicate, randomized, double-blind, placebo-controlled phase 3 studies with patients randomized (1:1:1) to once-daily oral upadacitinib 15 mg, upadacitinib 30 mg, or placebo for 16 weeks. Heads Up was a head-to-head, randomized, double-blind, double-dummy, phase 3b study with patients randomized (1:1) to upadacitinib 30 mg or subcutaneous dupilumab 300 mg for 24 weeks. Skin clearance was assessed with the Eczema Area and Severity Index (EASI) at baseline, weeks 1, 2, and 4, and every 4 weeks thereafter. Itch was assessed using the Worst Pruritus Numerical Rating Scale (WP-NRS) daily over 16 weeks and every 2 weeks thereafter to week 24 in Heads Up. RESULTS: This analysis included 1683 patients in Measure Up 1 and 2 and 673 patients in Heads Up. Through 16 weeks in Measure Up 1 and 2, patients receiving upadacitinib spent 9.8-13.4 times as many days with an EASI 90 response and 7.0-10.3 times as many days with a WP-NRS 0/1 response versus placebo. In Heads Up, patients receiving upadacitinib spent 2.0 and 1.7 times as many days through 16 and 24 weeks, respectively, with an EASI 90 response versus dupilumab. Through 16 and 24 weeks, patients receiving upadacitinib spent 3.0 and 2.6 times as many days, respectively, with a WP-NRS 0/1 response versus dupilumab. CONCLUSIONS: Patients with moderate-to-severe AD spent more time with clear/almost clear skin and no/minimal itch with upadacitinib versus placebo or dupilumab. TRIAL REGISTRATION: ClinicalTrials.gov identifier, Measure Up 1 (NCT03569293), Measure Up 2 (NCT03607422), Heads Up (NCT03738397).

Identifying high-risk undifferentiated emergency department patients with hyperlactatemia: Predictors of 30-day in-hospital mortality.

BACKGROUND: Hyperlactatemia has been recognized as a significant prognostic indicator in critically ill patients. Nonetheless, there remains a gap in understanding the specific risk factors contributing to increased mortality among undifferentiated emergency department (ED) patients presenting with elevated lactate levels. OBJECTIVES: The objective of the study is to investigate potential risk factors for 30-day in-hospital mortality in ED patients with hyperlactatemia. METHODS: All nontraumatic adult presentations to the ED who had a lactate level of ≥2.5 mmol/L were included. Comorbidities, vital signs, lactate levels, lactate clearance, lactate normalization, and final diagnosis were compared with 30-day in-hospital mortality. RESULTS: A 30-day in-hospital mortality rate of 10.4% was observed in 979 patients. The mortality rate was higher in hypotensive patients (odds ratio [OR] 4.973), in nursing home patients (OR 5.689), and bedridden patients (OR 3.879). The area under the curve for the second lactate level (0.804) was higher than the first lactate level (0.691), and lactate clearance (0.747) for in-hospital mortality. A second lactate level >3.15 mmol/l had a sensitivity of 81.3% in predicting in-hospital mortality. The OR for mortality was 6.679 in patients without lactate normalization. A higher mortality rate was observed in patients with acute renal failure (OR 4.305), septic shock (OR 4.110), and acute coronary syndrome (OR 2.303). CONCLUSIONS: A second lactate measurement more accurately predicts in-hospital mortality than lactate clearance and the first lactate level in ED patients. Nursing home patients, bed-ridden patients, hypotensive patients on initial ED presentation, patients without lactate normalization, and patients with a final diagnosis of acute renal failure, septic shock, and acute coronary syndrome had a higher mortality rate.

The Pharmacokinetics, Metabolism, and Clearance Mechanisms of Ritlecitinib, a Janus Kinase 3 and Tyrosine-Protein Kinase Family Inhibitor, in Humans.

Ritlecitinib is an oral once-daily irreversible inhibitor of Janus kinase 3 and tyrosine-protein kinase family being developed for the treatment of moderate-to-severe alopecia areata. This study examined the disposition of ritlecitinib in male participants following oral and intravenous administration using accelerator mass spectroscopy methodology to estimate pharmacokinetic parameters and characterize metabolite profiles. The results indicated ritlecitinib had a systemic clearance of 43.7 L/h, a steady state volume of distribution of 73.8 L, extent of absorption of 89%, time to maximum plasma concentration of ~0.5 hour, and absolute oral bioavailability of 64%. An observed long terminal half-life of total radioactivity was primarily attributed to ritlecitinib binding to plasma albumin. Ritlecitinib was the main circulating drug species in plasma (~30%) with one major pharmacologically inactive cysteine conjugated metabolite (M2) at >10%. Oxidative metabolism (fractional clearance 0.47) and glutathione related conjugation (fractional clearance 0.24) were the primary routes of elimination for ritlecitinib with the greatest disposition of radioactivity shown in the urine (~71%). In vitro phenotyping indicated ritlecitinib cytochrome P450 fraction of metabolism assignments of 0.29 for CYP3A, 0.09 for CYP2C8, 0.07 for CYP1A2, and 0.02 for CYP2C9. In vitro phenotyping in recombinant human glutathione S-transferases indicated ritlecitinib was turned over by a number of cytosolic and microsomal enzyme isoforms. Significance Statement This study provides a detailed understanding of the disposition and metabolism of ritlecitinib, a JAK3 and TEC family kinase inhibitor for alopecia areata, in humans, as well as characterization of clearance pathways and PK of ritlecitinib and its metabolites. As an AMS-based ADME study design, we have expanded on reporting the standard ADME endpoints, providing key pharmacokinetic parameters like clearance, volume of distribution and bioavailability allowing for a more comprehensive understanding of drug disposition.

Plasmodium berghei TatD-like DNase hijacks host innate immunity by inhibiting the TLR9-NF-κB pathway.

Neutrophils and macrophages confine pathogens by entrapping them in extracellular traps (ETs) through activating TLR9 function. However, plasmodial parasites secreted TatD-like DNases (TatD) to counteract ETs-mediated immune clearance. We found that TLR9 mutant mice increased susceptibility to rodent malaria, suggesting TLR9 is a key protein for host defense. We found that the proportion of neutrophils and macrophages in response to plasmodial parasite infection in the TLR9 mutant mice was significantly reduced compared to that of the WT mice. Importantly, PbTatD can directly bind to the surface TLR9 (sTLR9) on macrophages, which blocking the phosphorylation of mitogen-activated protein kinase and nuclear factor-κB, negatively regulated the signaling of ETs formation by both macrophages and neutrophils. Such, P. berghei TatD is a parasite virulence factor that can inhibit the proliferation of macrophages and neutrophils through directly binding to TLR9 receptors on the cell surface, thereby blocking the activation of the downstream MyD88-NF-kB pathways.

Obesity impairs ciliary function and mucociliary clearance in the murine airway epithelium.

Obesity is a risk factor for increased morbidity and mortality in viral respiratory infection. Mucociliary clearance (MCC) in the airway is the primary host defense against viral infections. However, the impact of obesity on MCC is unclear, prompting this study. Using murine tracheal tissue culture and in vitro influenza A virus (IAV) infection models, we analyzed cilia-driven flow and ciliary beat frequency (CBF) in the airway epithelium to evaluate MCC. Short-term IAV infection increased cilia-driven flow and CBF in control mice, but not in high-fat diet-induced obese mice. Basal cilia-driven flow and CBF were also lower in obese mice than in control mice. Mechanistically, the increase of extracellular adenosine triphosphate (ATP) release during IAV infection, which was observed in the control mice, was abolished in the obese mice, although the addition of ATP increased cilia-driven flow and CBF both in control and obese mice to a similar extent. Additionally, RNA sequencing and reverse transcription-polymerase chain reaction revealed the downregulation of several cilia-related genes, including Dnah1, Dnal1, Armc4, and Ttc12 (the dynein-related genes); Ulk4 (the polychaete differentiation gene); Cep164 (the ciliogenesis and intraflagellar transport gene); Rsph4a, Cfap206, and Ppil6 (the radial spoke structure and assembly gene); and Drc3(the nexin-dynein regulatory complex genes) in obese murine tracheal tissues compared to their control levels. In conclusion, our studies demonstrate that obesity attenuates MCC under basal conditions and during IAV infection by downregulating the expression of cilia-related genes and suppressing the release of extracellular ATP, thereby increasing the susceptibility and severity of IAV infection.

Ethical clearance paper as a bottleneck.

The significance of the ethical review process in human-based research undertakings cannot be overemphasized as it is necessary to uphold ethical standards and protect participants. However, the review process per se can act as a bottleneck, potentially hindering research progress and leading to academic dishonesty. The present work explores the benefits and challenges of ethical review, emphasizing issues like intellectual theft, forced authorship, and the stifling of independent researchers. Proposed solutions include leveraging previously approved designs, empowering experienced professors for clearance, establishing panels of researchers, creating voluntary ethical approval offices, utilizing private consultancy offices, and establishing a transnational ethical clearance authority. In conclusion, this work stresses the importance of finding mechanisms to streamline the ethical review process while maintaining ethical standards to foster integrity in research and combat academic dishonesty.

Elevations in plasma glucagon are associated with reduced insulin clearance after ingestion of a mixed-macronutrient meal in people with and without type 2 diabetes.

AIMS/HYPOTHESIS: The temporal suppression of insulin clearance after glucose ingestion is a key determinant of glucose tolerance for people without type 2 diabetes. Whether similar adaptations are observed after the ingestion of a mixed-macronutrient meal is unclear. METHODS: In a secondary analysis of data derived from two randomised, controlled trials, we studied the temporal responses of insulin clearance after the ingestion of a standardised breakfast meal consisting of cereal and milk in lean normoglycaemic individuals (n=12; Lean-NGT), normoglycaemic individuals with central obesity (n=11; Obese-NGT) and in people with type 2 diabetes (n=19). Pre-hepatic insulin secretion rates were determined by the deconvolution of C-peptide, and insulin clearance was calculated using a single-pool model. Insulin sensitivity was measured by an oral minimal model. RESULTS: There were divergent time course changes in insulin clearance between groups. In the Lean-NGT group, there was an immediate post-meal increase in insulin clearance compared with pre-meal values (p<0.05), whereas insulin clearance remained stable at baseline values in Obese-NGT or declined slightly in the type 2 diabetes group (p<0.05). The mean AUC for insulin clearance during the test was ~40% lower in the Obese-NGT (1.3 ± 0.4 l min-1 m-2) and type 2 diabetes (1.4 ± 0.7 l min-1 m-2) groups compared with Lean-NGT (1.9 ± 0.5 l min-1 m-2; p<0.01), with no difference between the Obese-NGT and type 2 diabetes groups. HOMA-IR and glucagon AUC emerged as predictors of insulin clearance AUC, independent of BMI, age or insulin sensitivity (adjusted R2=0.670). Individuals with increased glucagon AUC had a 40% reduction in insulin clearance AUC (~ -0.75 l min-1 m-2; p<0.001). CONCLUSIONS/INTERPRETATION: The ingestion of a mixed-macronutrient meal augments differing temporal profiles in insulin clearance among individuals without type 2 diabetes, which is associated with HOMA-IR and the secretion of glucagon. Further research investigating the role of hepatic glucagon signalling in postprandial insulin kinetics is warranted. TRIAL REGISTRATION: ISRCTN17563146 and ISRCTN95281775.

The epithelial cell types and their multi-phased defenses against fungi and other pathogens.

Mucus and its movements are essential to epithelial tissue immune defenses against pathogens, including fungal pathogens, which can infect respiratory, gastrointestinal or the genito-urinary tracts. Several epithelial cell types contribute to their immune defense. This review focuses on the respiratory tract because of its paramount importance, but the observations will apply to epithelial cell defenses of other mucosal tissue, including the gastrointestinal and genito-urinary tracts. Mucus and its movements can enhance or degrade the immune defenses of the respiratory tract, particularly the lungs. The enhancements include inhaled pathogen entrapments, including fungal pathogens, pollutants and particulates, for their removal. The detriments include smaller lung airway obstructions by mucus, impairing the physical removal of pathogens and impairing vital transfers of oxygen and carbon dioxide between the alveolar circulatory system and the pulmonary air. Inflammation, edema and/or alveolar cellular damage can also reduce vital transfers of oxygen and carbon dioxide between the lung alveolar circulatory system and the pulmonary air. Furthermore, respiratory tract defenses are affected by several fatty acid mediators which activate cellular receptors to manipulate neutrophils, macrophages, dendritic cells, various innate lymphoid cells including the natural killer cells, T cells, γδ T cells, mucosal-associated invariant T cells, NKT cells and mast cells. These mediators include the inflammatory and frequently immunosuppressive prostaglandins and leukotrienes, and the special pro-resolving mediators, which normally resolve inflammation and immunosuppression. The total effects on the various epithelial cell and immune cell types, after exposures to pathogens, pollutants or particulates, will determine respiratory tract health or disease.

Nephrotic Syndrome Without Nephrotic Range Proteinuria.

Nephrotic syndrome in adults is defined as nephrotic-range (≥3.5g/24h) proteinuria with low serum albumin, usually associated with edema, hyperlipidemia, and lipiduria. The 3.5g/24h threshold was selected arbitrarily and might not be reached in certain cases despite severe defects in glomerular permeability. We describe the case of a 57-year-old male who presented with progressively worsening swelling involving his limbs and abdomen. He also reported decreased urine output and fatigue. Physical examination was notable for severe pitting edema over legs, arms, and abdomen, in addition to peri-orbital puffiness. Labs revealed low serum albumin (1.3 g/dL), moderate proteinuria (2.3g/24h), and elevated total cholesterol (334 mg/dL). Renal biopsy showed amyloid light chain (AL) amyloidosis and bone marrow biopsy confirmed the presence of lambda-restricted plasma cells. Computed tomography, ultrasound, elastography, and laboratory findings were congruent with those seen in hepatic amyloidosis. A diagnosis of nephrotic syndrome caused by systemic AL amyloidosis was made despite the absence of nephrotic range proteinuria. The primary abnormality in nephrotic syndrome is increased glomerular permeability, leading to severe proteinuria causing low serum albumin, decreased oncotic pressure, and increased water retention by kidneys due to activation of the epithelial sodium channel (ENaC). The amount of albuminuria is influenced by both the extent of glomerular permeability and the rates of glomerular filtration and albumin synthesis. In cases where albumin synthesis is decreased secondary to concurrent liver disease, as in our case, a steady state of renal protein excretion may be reached at a lower threshold than 3.5g/24h despite severe defects in glomerular permeability.

Serum Lactate Clearance as a Predictive Biomarker for Optimal Graft Perfusion in Living Donor Liver Transplantation.

BACKGROUND: The optimal balance between the graft volume (GV) and portal venous flow (PVF) in living donor liver transplantation (LDLT) is unclear. As lactate is mainly metabolized in the liver, perioperative lactate levels are reportedly a useful biomarker for early graft dysfunction (EGD). The present study analyzed perioperative lactate levels according to the PVF. METHODS: The PVF/GV (mL/min per 100 g GV) of 97 recipients from 1996 to 2022 was retrospectively classified as low (LPVF; PVF/GV ≤ 100, N = 29), moderate (MPVF; PVF/GV 100-250, N = 40), or high (HPVF; PVF/GV > 250, N = 28). Lactate levels were obtained preoperatively (L0), immediately after graft reperfusion (L1), 4 h after reperfusion (L2), and on postoperative day 3 (L3). The lactate clearances were then calculated. RESULTS: The lower the PVF/GV ratio, the younger the age at LDLT and the higher the graft-to-recipient weight ratio. The median L2 and L3 in the HPVF group were significantly higher than those in the other groups (p = 0.019 and p = 0.003, respectively). The median ΔL1 in the HPVF group was lower than that in the LPVF and MPVF groups (0.23 vs. 0.50, p < 0.0001 and 0.23 vs. 0.41, p = 0.011, respectively). ΔL1 was negatively correlated with the PVF/GV. Although no patient had EGD, three patients with HPVF with low ΔL1 developed small-for-size syndrome. CONCLUSIONS: Graft hyperperfusion may delay the recovery of the graft function and result in poor lactate clearance. The combination of the PVF/GV and lactate clearance may be useful as a prognostic marker for optimal graft perfusion in LDLT. LEVEL OF EVIDENCE: IV.

Effects of low-volume court-based sprint interval training on anaerobic capacity and sport-specific performance in competitive tennis players.

Sprint interval training (SIT) is a potent exercise strategy to enhance athletes' anaerobic capacity in a time-efficient manner. This study aimed to investigate the impact of low-volume, court-based SIT on the anaerobic capacity and sport-specific performance in competitive tennis players. Twenty-four competitive collegiate tennis players were randomly assigned to either the SIT group (n = 12; three sessions per week of court-based repeated-sprint training) or the traditional endurance training (ET) group (n = 12; three sessions per week of 45-min continuous treadmill running, n = 12) for a 6-weeks intervention. Baseline and post-intervention assessments included the Wingate Anaerobic Test, elimination rate of blood lactate (BLAer), tennis-specific repeated sprint ability (RSA), and the Yo-Yo Intermittent Recovery Test Level 2 (YoYo-IR2). The results showed that SIT group demonstrated significant improvements in peak and average power during the Wingate test (p = 0.07; p < 0.001), along with a notable increase in YoYo-IR2 performance (7.8% increase, p = 0.04). Significant decreases were observed in both mean (5.1% decrease, p = 0.02) and sum RSA time (5.2% decrease, p = 0.02) in the tennis-specific RSA assessments. Additionally, the SIT group showed significantly higher effective training time and TRIMP in the 90-100% HRmax zone compared to the ET group (p < 0.01). This study underscores the potential benefits of low-volume, court-based SIT in enhancing anaerobic capacity and sport-specific performance in competitive tennis players, in comparison to traditional ET.

Clinical pharmacokinetics of cefpodoxime: a systematic review.

INTRODUCTION: Cefpodoxime, a third-generation cephalosporin, is a broad-spectrum antibiotic widely used to treat acute upper respiratory tract infections (RTI). This systematic review aims to present a comprehensive view of all the available pharmacokinetics (PK) data associated with the pharmacodynamics (PD) parameters of cefpodoxime in humans. AREAS COVERED: The PubMed, Google Scholar, Cochrane Library, and Science Direct, were systematically searched to identify studies on the PK of cefpodoxime. Out of 746 papers, 26 articles meeting the eligibility criteria were included that have reported the PK data. The drug exposure for the patients undergoing hemodialysis was 50% lower than healthy participants. The renal clearance was almost 27% less in pediatric patients than in adults. The plasma concentrations of cefpodoxime exceeded the minimum inhibitory concentration (MIC) for 90% of skin pathogens, including Streptococcus species and Staphylococcus species (i.e.) < 1 µg/mL and 2-4 µg/mL respectively. EXPERT OPINION: The current study includes detailed information on clinical PK of cefpodoxime in healthy, diseased, pediatric populations as well as drug-drug interactions and drug-food interactions. Moreover, this systematic review also explicated PK/PD properties of drug with a specific impact on MIC of drug. The present review will also assist clinicians in the development of PK models for cefpodoxime.

Combined treatment with vitamin C, hydrocortisone and thiamine does not attenuate morbidity and mortality of septic sheep.

BACKGROUND: Sepsis is associated with a highest mortality rate in the ICU. Present study tests the efficacy of combined therapy with vitamin C, hydrocortisone and thiamine (combined therapy) in the ovine model of sepsis induced by Pseudomonas aeruginosa. In this study, sepsis was induced in sheep by instillation of Pseudomonas aeruginosa (1 × 1011 CFU) into the lungs via bronchoscope, under anesthesia. Nine hours after injury, intravenous infusion of vitamin C (0.75 g every 6 h), hydrocortisone (25 mg every 6 h), and thiamine (100 mg every 12 h) or saline was given to the treatment and control groups. Cardiopulmonary variables were recorded. RESULTS: The survival rate was 16.7% in control and 33.3% in treatment groups. In the control group, mean arterial pressure dropped from 93.6 ± 8.6 to 75.5 ± 9.7 mmHg by 9 h, which was not affected by the combined therapy. Pulmonary dysfunction was not attenuated by the combined therapy either. The combined therapy had no effect on increased extravascular lung water content and fluid effusion into thoracic cavity. The bacterial number in the bronchoalveolar lavage fluid was significantly increased in the treatment group than the control group. The blood bacterial number remained comparable between groups. CONCLUSIONS: Combined vitamin C, hydrocortisone, and thiamine did not attenuate severity of ovine sepsis.

Risk management for viral clearance: A case study on adoption of platform validation approach and risk management of process changes.

Viral clearance (VC) studies are routinely required prior to entering clinical trials or for commercial launch of biopharmaceuticals. With increasing prior knowledge and experience, platform validation can be used to eliminate some VC studies and such strategy has been updated into industry guidelines, such as ICH Q5A (R2). In addition, process changes can happen during life-cycle management of a product. In these circumstances, high-risk process parameters need to be identified and corresponding control strategies need to be defined to ensure viral safety of the product. This work describes the design of a science-based risk management tool and how this tool is employed for platform validation and process change scenarios.

Clearance rate of contrast extravasation after endovascular therapy is associated with functional outcome and mediated by cerebral edema.

The brain's function of clearance and transport is closely related to the prognosis of acute ischemic stroke (AIS). In this study, we proposed a novel method, clearance rate of contrast extravasation (CROCE), to measure brain clearance and transport function in AIS patients undergoing endovascular therapy (EVT), and examined its association with cerebral edema and functional outcome. We conducted a pooled analysis of AIS patients of anterior circulation large vessel occlusion who underwent EVT in two academic hospitals. Patients who experienced contrast extravasation but not intracerebral hemorrhage following EVT were included. CROCE was defined as the mass of contrast agent cleared per hour on non-contrast CT (NCCT). Among the 215 patients finally included, we found that high CROCE was significantly associated with 90-day favorable functional outcome, and the association retained after adjustment for potential confounders. Different correlation analysis demonstrated a significant correlation between CROCE, cerebral edema, and functional outcome. Further mediation analysis revealed that cerebral edema mediated the effect of CROCE on functional outcome. These results revealed that CROCE may be a promising indicator of brain clearance function for patients who received EVT and had contrast extravasation.