Search

Abstract Background Due to the progressive decline in β-cell function, it is often necessary to utilize multiple agents with complementary mechanisms of action to address various facets and achieve glycemic control. Thus, this study aimed to evaluate the efficacy and safety of a fixed-dose combination (FDC) of metformin/sitagliptin/pioglitazone (MSP) therapy vs. metformin/sitagliptin (MS) in type 2 diabetes mellitus (T2DM). Methods In this phase 3, multicenter, double-blind study, patients with T2DM who exhibited inadequate glycemic control with HbA1c of 8.0–11.0% while taking ≥1500 mg/day metformin for at least 6 weeks were randomized to receive either FDC of MSP (1000/100/15 mg) or MS (1000/100 mg) per day for 24 weeks. The primary outcome measure was the change in HbA1c, and secondary outcomes included changes in fasting plasma glucose (FPG), postprandial plasma glucose (PPG), and body weight from baseline to 24 weeks along with safety and tolerability. Results Among the 236 patients randomized, 207 (87.71%) successfully completed the study. All baseline characteristics were comparable between the FDC of MSP and MS groups. There was a subsequent significant reduction of HbA1c in FDC of MSP (− 1.64) vs. MS (− 1.32); between groups was [− 0.32% (95% CI, − 0.59, − 0.05)], P = 0.0208. Similar reductions were found in FPG [− 13.2 mg/dL (95% CI, − 22.86, − 3.71)], P = 0.0068, and PPG [− 20.83 mg/dL (95% CI, − 34.11, − 7.55)], P = 0.0023. There were no significant changes in body weight. A total of 27 adverse effects (AEs) and one severe AE were reported, none of which were related to the study drug. Conclusion The FDC of MSP demonstrated significant efficacy in managing glycemic indices and could serve as a valuable tool for physicians in the management of Indian patients with T2DM. Trial registration Clinical Trials Registry of India, CTRI/2021/10/037461.

Given the current situation of the economy, credit card use has increased significantly. Users can make significant cash payments with these cards without carrying a lot of cash on them. They have simplified the process of conducting cashless transactions and enabled consumers to make payments of any kind with greater ease. While there are many benefits to using this electronic payment method, there are also some risks. In tandem with the expansion of the consumer base. A specific person’s credit card information may be unlawfully acquired and used in fraudulent purchases. To tackle this issue, certain machine learning methods may be applied to gather information. This research offers a comparative analysis of many supervised learning method for identifying real from fake transactions. In this article, we have covered a variety of techniques for spotting credit card fraud.

OBJECTIVE: A cohort of employees with gout were compared to those without to evaluate the differences in prevalence of disorders associated with metabolic syndrome (both those considered underlying and those associated with end-stage morbidity and mortality) as well as the cost of annual medical services (AMS) required for treatment of these conditions. METHODS: Employees with gout were identified by International Classification of Diseases-9 (ICD-9) code during the calendar years of 2001-2004 and compared to propensity-score matched employees without gout using the Human Capital Management Services Research Reference Database. T-tests were then used to compare prevalence and average AMS of comorbid disorders defined from Agency for Healthcare and Research Quality (AHRQ) diagnostic categories. RESULTS: 'Hyperlipidemia', 'essential hypertension', and 'diabetes mellitus without complications' ranked in the top 10 categories of mean number of AMS for employees with gout using AHRQ specific categories; the values were higher than found for those without gout (all p < 0.0001). 'Essential hypertension', 'hyperlipidemia', 'diabetes mellitus without complications', and 'coronary atherosclerosis' showed an approximate 2:1 prevalence ratio for employees with gout over those without (p < or = 0.05). Main study limitations include the small number of subjects with gout, retrospective study design, and possible miscoding and/or non-coding of individuals with the studied disorders. CONCLUSION: These results support the continued need for patients with gout and their clinicians to be aware of the possibility of the increased risk of associated metabolic syndrome and related comorbidities in these individuals, emphasizing the need for prevention when possible and treatment when necessary. [ABSTRACT FROM AUTHOR]

In the present work, characterization of sintering behavior of Tungsten heavy alloy has been done through powder metallurgy route using Spark plasma sintering (SPS). Fine powder of Tungsten (

In SST-1, 42GHz ECRH system has been commissioned to carry out breakdown and heating experiments at 0.75T and 1.5T operating toroidal magnetic fields. The 42GHz ECRH system consists of high power microwave source Gyrotron capable to deliver 500kW microwave power for 500ms duration, approximately 20 meter long transmission line and a mirror based launcher. The ECRH power in fundamental O-mode & second harmonic X-mode is launched from low field side (radial port) of the tokamak. At 0.75T operation, approximately 300 kW ECH power is launched in second harmonic X-mode and successful ECRH assisted breakdown is achieved at low loop_voltage ~ 3V. The ECRH power is launched around 45ms prior to loop voltage. The hydrogen pressure in tokamak is maintained ~ 1×10-5mbar and the pre-ionized density is ~ 4×1012/cc. At 1.5T operating toroidal magnetic field, the ECH power is launched in fundamental O-mode. The ECH power at fundamental harmonic is varied from 100 kW to 250 kW and successful breakdown is achieved in all ECRH shots. In fundamental harmonic there is no delay in breakdown while at second harmonic ~ 40ms delay is observed, which is normal in case of second harmonic ECRH assisted breakdown.

Abstract Background Chronic inflammation may contribute to insulin resistance (IR), metabolic syndrome and atherosclerosis although evidence of causality is lacking in humans. We hypothesized that very low-dose experimental endotoxemia would induce adipose tissue inflammation and systemic IR during a low-grade but asymptomatic inflammatory response and thus provide an experimental model for future tests of pharmacologic and genomic modulation of cardio-metabolic traits in humans. Methods Ten healthy, human volunteers (50% male, 90% Caucasian, mean age 22.7 ± 3.8) were randomized in a double-masked, placebo-controlled, crossover study to separate 36-hour inpatient visits (placebo versus intravenous-LPS 0.6 ng/kg). We measured clinical symptoms via the McGill pain questionnaire and serial vital signs. Plasma and serum were collected for measurement of cytokines, C-reactive protein, insulin and glucose, serial whole blood & subcutaneous adipose tissue mRNA expression were measured by real-time PCR. HOMA-IR, a well-validated measure of IR was calculated to estimate insulin resistance, and frequently sampled intravenous glucose tolerance testing (FSIGTT) was performed to confirm an insulin resistant state. We performed ANOVA and within subject ANOVA to understand the differences in cytokines, adipose tissue inflammation and IR before and after LPS or placebo. Results There was no significant difference between placebo and LPS in clinical responses of symptom scores, body temperature or heart rate. However, low-dose endotoxemia induced a rapid and transient 25-fold induction of plasma TNF-alpha and 100-fold increase in plasma IL-6 (Figure 1B) (p p p = 0.01) increased with MCP-1 (peak 10-fold, F = 5.6, p p p p Conclusions We present a low dose human endotoxemia model of inflammation which induces adipose tissue inflammation and systemic insulin resistance in the absence of overt clinical response. Such a model has the potential for broad and safe application in the study of novel therapeutics and genomic influences in cardio-metabolic disease.

Abstract Background Traditional first line regimens containing a non-nucleoside reverse transcriptase inhibitor or protease inhibitor may not be suitable for a subset of antiretroviral-naïve patients such as those with certain co-morbidities, women of child-bearing potential, and intolerability to components of standard first line therapy. This study was conducted to determine if alternate treatment options may meet the needs of both general and special patient populations. The ACTION study was a randomized, open-label, multicenter, 48-week trial that compared the safety and efficacy of a triple nucleoside regimen versus a protease inhibitor plus a dual nucleoside regimen in HIV-1 treatment-naïve subjects. Results 279 HIV-infected subjects with HIV-1 RNA (VL) >5000 but < 200,000 copies/mL (c/mL) and CD4+ count ≥ 100 cells/mm3 were randomized (1:1) to receive abacavir sulfate/lamivudine/zidovudine (ABC/3TC/ZDV) twice-daily or atazanavir (ATV) once-daily plus lamivudine/zidovudine (3TC/ZDV) twice-daily. Protocol-defined virologic failure was based on multiple failure criteria. Non-inferiority of ABC/3TC/ZDV to ATV+3TC/ZDV was established with 62% vs. 59% of subjects achieving a VL < 50 c/mL at week 48, [ITT(E), M/S = F, 95% CI: -5.9, 10.4]. Similar results were observed in the 230 (82%) subjects with baseline VL Conclusion ABC/3TC/ZDV demonstrated comparable virologic efficacy to ATV+3TC/ZDV in this population over 48 weeks. In those with a baseline VL ≥ 100,000 c/mL, subjects in the ATV+3TC/ZDV showed better virologic efficacy. Both regimens offer benefits in select therapy-naïve subjects. Trial Registration [Clinical Trials Identifier, NCT00082394].

Abstract Background Putatively active drugs are often intraventricularly administered to gain direct access to brain and circumvent the blood-brain barrier. A few studies on the normal central nervous system (CNS) have shown, however, that the distribution of materials after intraventricular injections is much more limited than presumed and their exit from cerebrospinal fluid (CSF) is more rapid than generally believed. In this study, we report the intracranial distribution and the clearance from CSF and adjacent CNS tissue of radiolabeled insulin-like growth factor-1 after injection into one lateral ventricle of the normal rat brain. Methods Under barbiturate anesthesia, 125I-labeled insulin-like growth factor-1 (IGF-1) was injected into one lateral ventricle of normal Sprague-Dawley rats. The subsequent distribution of IGF-1 through the cerebrospinal fluid (CSF) system and into brain, cerebral blood vessels, and systemic blood was measured over time by gamma counting and quantitative autoradiography (QAR). Results Within 5 min of infusion, IGF-1 had spread from the infused lateral ventricle into and through the third and fourth ventricles. At this time, 25% of the infused IGF-1 had disappeared from the CSF-brain-meningeal system; the half time of this loss was 12 min. The plasma concentration of cleared IGF-1 was, however, very low from 2 to 9 min and only began to rise markedly after 20 min. This delay between loss and gain plus the lack of radiotracer in the cortical subarachnoid space suggested that much of the IGF-1 was cleared into blood via the cranial and/or spinal nerve roots and their associated lymphatic systems rather than periventricular tissue and arachnoid villi. Less than 10% of the injected radioactivity remained in the CSF-brain system after 180 min. The CSF and arteries and arterioles within the subarachnoid cisterns were labeled with IGF-1 within 10 min. Between 60 and 180 min, most of the radioactivity within the cranium was retained within and around these blood vessels and by periaqueductal gray matter. Tissue profiles at two sites next to ventricular CSF showed that IGF-1 penetrated less than 1.25 mm into brain tissue and appreciable 125I-activity remained at the tissue-ventricular CSF interface after 180 min. Conclusion Our findings suggest that entry of IGF-1 into normal brain parenchyma after lateral ventricle administration is limited by rapid clearance from CSF and brain and slow movement, apparently by diffusion, into the periventricular tissue. Various growth factors and other neuroactive agents have been reported to be neuroprotective within the injured brain after intraventricular administration. It is postulated that the delivery of such factors to neurons and glia in the injured brain may be facilitated by abnormal CSF flow. These several observations suggest that the flow of CSF and entrained solutes may differ considerably between normal and abnormal brain and even among various neuropathologies.

OBJECTIVE: To determine allopurinol treatment patterns and adherence to published standards of care for patients with gout. PATIENTS AND METHODS: This retrospective claims analysis in a managed care database included patients 18 years or older, with continuous eligibility for 1 year before and after the start date and 2 or more visits during which the gout disease code (274.xx) was assigned or 1 or more pharmacy prescriptions for a gout-specific medication between January 1, 2000, and December 31, 2002 (intake period). Factors associated with compliance with allopurinol therapy were measured based on the medication possession ratio, and adherence to 2 quality-of-care indicators for gout management was assessed using multivariable logistic regression analysis. RESULTS: A total of 64.9% of allopurinol users had a modal daily dose or the most commonly observed daily dose of 300 mg/d, median length of therapy was 3 months, and a high proportion of patients had a medication possession ratio of 10% or less. Suggested quality-of-care Indicators for gout had low performance: 53% of patients with renal impairment received a modal daily dose of 300 mg or greater, and 83% of patients who started taking allopurinol did not have their serum urate levels measured within 180 days. Patients with gout flares were less likely to be compliant with allopurinol (odds ratio, 0.50; 95% confidence interval, 0.40-0.63). Patients with renal impairment at baseline were 3.2 times more likely to undergo serum urate testing than patients without renal impairment (odds ratio, 3.20; 95% confidence Interval, 1.25-8.23). CONCLUSION: There was low compliance with allopurinol therapy for treatment of gout. Patients potentially received suboptimal quality of care as measured by serum urate testing and appropriateness of allopurinol dosing in patients with renal impairment. [ABSTRACT FROM AUTHOR]

Cutaneous Legionella infection is rare and primarily seen in immunosuppressed patients. Herein, we present a case of cutaneous and pulmonary legionellosis presenting with fever and erythematous subcutaneous nodules in a neonate with severe combined immunodeficiency. This case underscores the importance of considering this diagnosis and highlights the use of modern testing modalities to promptly diagnose and treat infections in immunocompromised patients., (© 2024 Wiley Periodicals LLC.)

Abstract: Although the 2022 European LeukemiaNet (ELN) acute myeloid leukemia (AML) risk classification reliably predicts outcomes in younger patients treated with intensive chemotherapy, it is unclear whether it applies to adults ≥60 years treated with lower-intensity treatment (LIT). We aimed to test the prognostic impact of ELN risk in patients with newly diagnosed (ND) AML aged ≥60 years given LIT and to further refine risk stratification for these patients. A total of 595 patients were included: 11% had favorable-, 11% intermediate-, and 78% had adverse-risk AML. ELN risk was prognostic for overall survival (OS) (P < .001) but did not stratify favorable- from intermediate-risk (P = .71). Within adverse-risk AML, the impact of additional molecular abnormalities was further evaluated. Multivariable analysis was performed on a training set (n = 316) and identified IDH2 mutation as an independent favorable prognostic factor, and KRAS, MLL2, and TP53 mutations as unfavorable (P < .05). A "mutation score" was calculated for each combination of these mutations, assigning adverse-risk patients to 2 risk groups: -1 to 0 points ("Beat-AML intermediate") vs 1+ points ("Beat-AML adverse"). In the final refined risk classification, ELN favorable- and intermediate-risk were combined into a newly defined "Beat-AML favorable-risk" group, in addition to mutation scoring within the ELN adverse-risk group. This approach redefines risk for older patients with ND AML and proposes refined Beat-AML risk groups with improved discrimination for OS (2-year OS, 48% vs 33% vs 11%, respectively; P < .001), providing patients and providers additional information for treatment decision-making., (© 2024 by The American Society of Hematology. Licensed under Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0), permitting only noncommercial, nonderivative use with attribution. All other rights reserved.)

Objective: Intracranial complications of pediatric sinusitis are uncommon but are often associated with significant morbidity, especially when appropriate care is delayed. The present study aimed to identify commonalities for the development and progression of these complications in the pediatric population., Data Sources: CENTRAL, CINAHL, Citation searching, ClinicalTrials.gov, Embase, Google Scholar, MEDLINE, PsycINFO, PubMed, Scopus, Web of Science, and World Health Organization., Review Methods: A comprehensive literature search was performed using Preferred Reporting Items for Systematic Reviews and Meta-analyses scoping review guidelines. Studies describing intracranial infections secondary to sinusitis in the pediatric population (age <18 years) were included. Studies in which adult and pediatric data were not separated and studies in which the pediatric cohort was fewer than 10 cases were excluded. Ultimately, 33 studies describing 1149 unique patient cases were included for data collection and analysis., Results: Our analysis revealed intracranial complications were more common in adolescent males. Most children presented with over 1 week of vague symptoms, such as headache and fever. The majority of complications were diagnosed radiographically with computed tomography. Subdural empyema and epidural abscess were the most common intracranial complications reported. On average, patients were admitted for over 2 weeks. Most children were treated with a combination of antibiotics and surgical intervention. Complications were rare, but when present, were often associated with significant morbidity., Conclusion: This scoping review of the available literature has provided insight into commonalities among pediatric patients who develop intracranial complications of sinusitis, providing a foundation for further study to inform medical and surgical decision-making in this population., (© 2024 American Academy of Otolaryngology–Head and Neck Surgery Foundation.)

Background: Andexanet alfa (andexanet) is the only FDA-approved antidote for direct factor Xa (FXa) inhibitors but has been reported to cause resistance to unfractionated heparin (UFH). This has delayed anticoagulation for procedures requiring cardiopulmonary bypass (CPB). The mechanism, andexanet and UFH dose dependence, and thrombotic risk of andexanet-associated heparin resistance are unknown., Methods: The effect of andexanet in vitro was determined using activated clotting times (ACT) and thromboelastography (TEG). Ex vivo CPB circuits were used to determine whether andexanet impaired anticoagulation for extracorporeal circulation. Kinetics of antithrombin (AT) inhibition of FXa and thrombin were measured in the presence of andexanet. Equilibrium modeling and thrombin generation assay (TGA) validation were used to predict the role of andexanet, AT, and UFH concentrations in andexanet-associated heparin resistance., Results: Andexanet prevented UFH-mediated prolongation of ACT and TEG times. At lower concentrations of andexanet, heparin resistance could be overcome with suprapharmacologic doses of UFH, but not at higher andexanet concentrations. Andexanet rendered standard doses of UFH inadequate to prevent circuit thrombosis, and suprapharmacologic UFH doses were only partially able to overcome this. Scanning electron microscopy demonstrated coagulation activation in circuits. Andexanet prevented UFH enhancement of AT-mediated inhibition of FXa and thrombin. Equilibrium modeling and TGA validation demonstrated that andexanet creates a triphasic equilibrium with UFH and AT: initial UFH unresponsiveness, normal UFH responsiveness when andexanet is depleted, and finally AT depletion. Sufficient CPB heparinization can only occur at low therapeutic andexanet doses and normal AT levels. Higher andexanet doses or AT deficiency may require both AT supplementation and very high UFH doses., Conclusions: Andexanet causes heparin resistance due to redistribution of UFH-bound AT. If andexanet cannot be avoided prior to heparinization and direct thrombin inhibitors are undesirable, our in vitro study suggests excess UFH should be considered as a potential strategy prior to AT supplementation., Highlights: Andexanet alfa causes heparin resistance not by depleting antithrombin, but rather by sequestering heparin-bound antithrombin such that it cannot act as an anticoagulant.Heparin responsiveness in the presence of Andexanet alfa is triphasic such that the effect of a dose of heparin can now be predicted in vitro based on the relative concentrations of andexanet, heparin, and antithrombin.The in vitro insights provided by this work provide a rational starting point for further clinical elucidation of the problem and management of andexanet-associated heparin resistance.

Background: Excessive perioperative bleeding is associated with major complications in cardiac surgery, resulting in increased morbidity, mortality, and cost., Methods: An international expert panel was convened to develop consensus statements on the control of bleeding and management of transfusion and to suggest key quality metrics for cardiac surgical bleeding. The panel reviewed relevant literature from the previous 10 years and used a modified RAND Delphi methodology to achieve consensus., Results: The panel developed 30 consensus statements in 8 categories, including prioritizing control of bleeding, prechest closure checklists, and the need for additional quality indicators beyond reexploration rate, such as time to reexploration. Consensus was also reached on the need for a universal definition of excessive bleeding, the use of antifibrinolytics, optimal cessation of antithrombotic agents, and preoperative risk scoring based on patient and procedural factors to identify those at greatest risk of excessive bleeding. Furthermore, an objective bleeding scale is needed based on the volume and rapidity of blood loss accompanied by viscoelastic management algorithms and standardized, patient-centered blood management strategies reflecting an interdisciplinary approach to quality improvement., Conclusions: Prioritizing the timely control and management of bleeding is essential to improving patient outcomes in cardiac surgery. To this end, a cardiac surgical bleeding quality metric that is more comprehensive than reexploration rate alone is needed. Similarly, interdisciplinary quality initiatives that seek to implement enhanced quality indicators will likely lead to improved patient care and outcomes., Competing Interests: Disclosures All authors report that financial support for the consensus project was provided by SABM via a grant received from Baxter. Rawn Salenger reports a relationship with Edwards Lifesciences Corporation that includes: consulting or advisory and speaking and lecture fees; with Terumo Medical Corp that includes: consulting or advisory and speaking and lecture fees; with AtriCure Inc that includes: consulting or advisory and speaking and lecture fees; with La Jolla Pharmaceutical Company that includes: consulting or advisory and speaking and lecture fees; with Encare that includes: consulting or advisory and speaking and lecture fees; and with Zimmer Biomet that includes: consulting or advisory and speaking and lecture fees. Rakesh C. Arora reports a relationship with Edwards Lifesciences Corporation that includes: consulting or advisory; with HLS Therapeutics Inc that includes: consulting or advisory; and with Renibus Therapeutics, Inc that includes: consulting or advisory. Daniel T. Engelman reports a relationship with Edwards Lifesciences Corporation that includes: consulting or advisory; with Renibus Therapeutics, Inc that includes: consulting or advisory; with Alexion that includes: consulting or advisory; with CardioRenal Systems that includes: consulting or advisory; with Genentech that includes: consulting or advisory; with Medela Inc that includes: consulting or advisory; with Arthrex Inc that includes: consulting or advisory; with BioPorto Diagnostics Inc that includes: consulting or advisory; and with AtriCure Inc that includes: consulting or advisory. Caroline Evans reports a relationship with Pharmacosmos UK Ltd that includes: consulting or advisory and speaking and lecture fees; with Pfizer that includes: consulting or advisory and speaking and lecture fees; with Royal College of Anaesthetists Centre for Perioperative Care Guidelines on Anaemia that includes: consulting or advisory; and with British Society of Haematology Guidelines on Preoperative Anaemia that includes: consulting or advisory. Michael C. Grant reports a relationship with ERAS Cardiac Society that includes: board membership. Vicki Morton reports a relationship with ERAS Cardiac Society that includes: board membership; and with Edwards Lifesciences Corporation that includes: speaking and lecture fees. Sherri Ozawa reports a relationship with Accumen Inc that includes: employment; with CSL Vifor that includes: consulting or advisory; with CSL Behring that includes: consulting or advisory; with Werfen that includes: speaking and lecture fees; and with SABM that includes: board membership. Jacob Raphael reports a relationship with Octapharma that includes: consulting or advisory. Linda Shore-Lesserson reports a relationship with CSL Behring that includes: consulting or advisory; and with Vifor Pharma Inc that includes: consulting or advisory. Pierre Tibi reports a relationship with Accumen that includes: consulting or advisory; with HemoSonics LLC that includes: speaking and lecture fees; and with Baxter that includes: speaking and lecture fees. Aryeh Shander reports a relationship with CSL Vifor that includes: consulting or advisory; with Pharmacosmos A/S that includes: consulting or advisory; with Accumen that includes: consulting or advisory; with I-Sep that includes: consulting or advisory; with Grifols Inc that includes: consulting or advisory; with Lindis Corp that includes: consulting or advisory; with Octapharma that includes: consulting or advisory; with Masimo Corporation that includes: consulting or advisory; with HbO(2) Therapeutics LLC that includes: consulting or advisory; a consulting or advisory role was also taken when acting as an expert witness in a class action litigation process. The other authors have no conflicts of interest to disclose., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Abstract: Ivosidenib is a first-in-class mutant isocitrate dehydrogenase 1 (mIDH1) inhibitor with efficacy and tolerability in patients with advanced mIDH1 hematologic malignancies, leading to approval in frontline and relapsed/refractory (R/R) mIDH1 acute myeloid leukemia. We report final data from a phase 1 single-arm substudy of once-daily ivosidenib in patients with R/R mIDH1 myelodysplastic syndrome (MDS) after failure of standard-of-care therapies. Primary objectives were to determine safety, tolerability, and clinical activity. The primary efficacy end point was the complete remission (CR) + partial remission (PR) rate. Nineteen patients were enrolled; 18 were included in the efficacy analysis. Treatment-related adverse events occurred in 8 (42.1%) patients, including a grade 1 QT interval prolongation in 1 (5.3%) patient and grade 2 differentiation syndrome in 2 (10.5%) patients. Rates of CR + PR and objective response (CR + PR + marrow CR) were 38.9% (95% confidence interval [CI], 17.3-64.3) and 83.3% (95% CI, 58.6-96.4), respectively. Kaplan-Meier estimates showed a 68.6% probability of patients in CR achieving a remission duration of ≥5 years, and a median overall survival of 35.7 months. Of note, 71.4% and 75.0% baseline red blood cell (RBC)- and platelet-transfusion-dependent patients, respectively, became transfusion independent (TI; no transfusion for ≥56 days); 81.8% and 100% of baseline RBC and platelet TI patients, respectively, remained TI. One (5.3%) patient proceeded to a hematopoietic stem cell transplant. In conclusion, ivosidenib is clinically active, with durable remissions and a manageable safety profile observed in these patients. This trial was registered at www.ClinicalTrials.gov as #NCT02074839., (© 2024 by The American Society of Hematology. Licensed under Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0), permitting only noncommercial, nonderivative use with attribution. All other rights reserved.)

Objective: The objective is to evaluate and compare the antibacterial efficacy of nitrofurantoin, chitosan, and calcium hydroxide (Ca(OH)2) in combination with propylene glycol (PG) as an intracanal medicament against endodontic pathogens., Materials and Methods: Fifty-two extracted single-rooted maxillary and mandibular anterior teeth and premolars were selected. The root canals were enlarged using Protaper universal rotary files. Clinical isolates of microorganisms collected from retreatment cases were used. Bacterial isolates obtained from infected root canals were introduced into brain-heart infusion (BHI) broth. Incubation of samples for 14 days was carried out to facilitate the development of mature biofilms. Intracanal medicaments were divided into four groups: Group 1 - Nirofurantoin+20% PG, Group 2 - Chitosan+20% PG, Group 3 - Ca(OH)2 + 20% PG, and Group 4 - 20% PG. The prepared root samples were incubated for 7 days. After collecting dentin samples, they were placed in a phosphate-buffered saline solution. Serial dilutions were then performed, and each dilution was plated on BHI agar. The plates were incubated for 24 h at 37°C. The antibacterial efficacy was assessed by calculating the percentage of remaining colony-forming units., Results: Antibacterial efficacy of chitosan paste was significantly higher followed by nitrofurantoin as compared to other groups when used as an intracanal medicament., Conclusions: In the root-canal biofilm model, the combination of chitosan and PG demonstrated a significant reduction in the viability of endodontic pathogens when employed as intracanal medication for 7 days. This suggests its potential as an effective intracanal medicament for endodontic retreatment., Competing Interests: There are no conflicts of interest., (Copyright: © 2024 Journal of Conservative Dentistry and Endodontics.)

Background: Pontocerebellar hypoplasia (PCH) may present with supratentorial phenotypes and is often accompanied by microcephaly. Damaging mutations in the X-linked gene CASK produce self-limiting microcephaly with PCH in females but are often lethal in males. CASK deficiency leads to early degeneration of cerebellar granule cells but its role in other regions of the brain remains uncertain., Method: We generated a conditional Cask knockout mice and deleted Cask ubiquitously after birth at different times. We examined the clinical features in several subjects with damaging mutations clustered in the central part of the CASK protein. We have performed phylogenetic analysis and RT-PCR to assess the splicing pattern within the same protein region and performed in silico structural analysis to examine the effect of splicing on the CASK's structure., Result: We demonstrate that deletion of murine Cask after adulthood does not affect survival but leads to cerebellar degeneration and ataxia over time. Intriguingly, damaging hemizygous CASK mutations in boys who display microcephaly and cerebral dysfunction but without PCH are known. These mutations are present in two vertebrate-specific CASK exons. These exons are subject to alternative splicing both in forebrain and hindbrain. Inclusion of these exons differentially affects the molecular structure and hence possibly the function/s of the CASK C-terminus., Conclusion: Loss of CASK function disproportionately affects the cerebellum. Clinical data, however, suggest that CASK may have additional vertebrate-specific function/s that play a role in the mammalian forebrain. Thus, CASK has an ancient function shared between invertebrates and vertebrates as well as novel vertebrate-specific function/s., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2024. No commercial re-use. See rights and permissions. Published by BMJ.)

Heat stress profoundly affects the reproductive success of buffaloes, which are vital for the dairy industry due to their unique anatomical and physiological characteristics, necessitating careful evaluation under such conditions. Hence, this guided our search for quantifying heat stress' impact on Mehsana buffaloes using the best THI model and evaluating sires' performance. Fertility records (days open converted to daughter pregnancy rate) were collected in the span of over 24 years, w.e.f. 1989 to 2012. Finally, 3070 records of first lactation cows, daughters of 117 sires from DURDA, Gujarat, India, were used in the analysis. Meteorological data were retrieved from IMD, Pune, to understand the relationship between daughter pregnancy rate (DPR) and heat stress indicators. Several heat stress models were compared based on R 2 , adjusted R 2 , AIC, and BIC values, and the impact of heat stress was quantified. The year was classified into different heat stress zones, viz., Non heat stress zone (NHSZ), Heat stress zone (HSZ), and critical heat stress zone (CHSZ), drawing from the findings of DPR and THI. The THI 4th model based on dry and wet bulb temperature was identified as the best-fit model, and DPR significantly changed (P < 0.01) by 1.14% per unit change in THI value based on the month of calving. The average EBVs of the sires for DPR were found to be 20.78% (NHSZ), 38.09% (HSZ), and 39.08% (CHSZ) using BLUP-SM and 20.78% (NHSZ), 37.30% (HSZ), and 38.87% (HSZ) using BLUP-AM. Subsequently, the optimum sire for each of the zones was prioritized. It is noteworthy that bulls that performed better in NHSZ did not perform as well in HSZ and CHSZ, and vice versa. This supports the possibility of evaluating bulls independently in each heat stress zone., Competing Interests: Declaration of competing interest None., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Paediatric Interventional Oncology (IO) lags behind adult IO due to a scarcity of specific outcome data. The suboptimal way to evolve this field is relying heavily on adult experiences. The distinct tumour types prevalent in children, such as extracranial germ cell tumours, sarcomas, and neuroblastoma, differ strongly from those found in adults, presenting a completely different biological behaviour. Compounding this challenge, paediatric interventional radiology often employs adapted or off-label techniques, potentially compromising optimal outcomes. This review outlines the present indications for interventional radiology in paediatric cancer, from biopsy to supportive care, including complication management. It emphasises the role of locoregional approaches, and explores the status of common paediatric oncological diseases, highlighting areas where IO has made progress identifying potential opportunities for future advancements in this evolving field., (© 2024 The Author(s). Journal of Medical Imaging and Radiation Oncology published by John Wiley & Sons Australia, Ltd on behalf of Royal Australian and New Zealand College of Radiologists.)