Leveraging a rationally designed veliparib-based anilide eliciting anti-leukemic effects for the design of pH-responsive polymer nanoformulation.

Careful recruitment of the components of the HDAC inhibitory template culminated in veliparib-based anilide 8 that elicited remarkable cell growth inhibitory effects against HL-60 cell lines mediated via dual modulation of PARP [(IC50 (PARP1) = 0.02 nM) and IC50 (PARP2) = 1 nM)] and HDACs (IC50 value = 0.05, 0.147 and 0.393 µM (HDAC1, 2 and 3). Compound 8 downregulated the expression levels of signatory biomarkers of PARP and HDAC inhibition. Also, compound 8 arrested the cell cycle at the G0/G1 phase and induced autophagy. Polymer nanoformulation (mPEG-PCl copolymeric micelles loaded with compound 8) was prepared by the nanoprecipitation technique. The mPEG-PCL diblock copolymer was prepared by ring-opening polymerization method using stannous octoate as a catalyst. The morphology of the compound 8@mPEG-PCL was examined using TEM and the substance was determined to be monodispersed, spherical in form, and had an average diameter of 138 nm. The polymer nanoformulation manifested pH-sensitive behaviour as a greater release of compound 8 was observed at 6.2 pH as compared to 7.4 pH mimicking physiological settings. The aforementioned findings indicate that the acidic pH of the tumour microenvironment might stimulate the nanomedicine release which in turn can attenuate the off-target effects precedentially claimed to be associated with HDAC inhibitors.

The International Society for Heart and Lung Transplantation (ISHLT): 2024 infection definitions for durable and acute mechanical circulatory support devices.

Infections remain a significant concern in patients receiving mechanical circulatory support (MCS), encompassing both durable and acute devices. This consensus manuscript provides updated definitions for infections associated with durable MCS devices and new definitions for infections in acute MCS, integrating a comprehensive review of existing literature and collaborative discussions among multidisciplinary specialists. By establishing consensus definitions, we seek to enhance clinical care, facilitate consistent reporting in research studies, and ultimately improve outcomes for patients receiving MCS.

Improvements in Psoriasis-Related Work Productivity with Tildrakizumab: Results from a Phase 4 Real-World Study in Patients with Moderate-to-Severe Plaque Psoriasis.

INTRODUCTION: Plaque psoriasis is a chronic condition that may impact patients' work productivity. Tildrakizumab, an interleukin-23 p19 inhibitor, is approved for treatment of moderate-to-severe plaque psoriasis in adults. However, the effect of tildrakizumab treatment on work productivity in patients with psoriasis is not well characterized. METHODS: In this multicenter, open-label, uncontrolled phase 4 study (NCT03718299), patients with moderate-to-severe plaque psoriasis received tildrakizumab 100 mg at week 0, week 4, and every 12 weeks thereafter through week 52. Patients completed the Work Productivity and Activity Impairment Questionnaire: Psoriasis (WPAI:PSO) at baseline and every 12 weeks from week 16 through week 64. The following four domains of the WPAI:PSO were examined: absenteeism (percentage of time missed from work due to psoriasis), presenteeism (percentage reduction of productivity while at work due to psoriasis), total activity impairment (percentage impairment in activities other than work due to psoriasis), and total work productivity impairment (total percentage of work impairment from both absenteeism and presenteeism due to psoriasis). Missing data were not imputed. RESULTS: Of the 55 patients enrolled, 31 patients completed all domains of the WPAI:PSO at week 64. From baseline to week 64, respectively, mean ± standard deviation (SD) scores improved for presenteeism (20.5 ± 21.7 to 2.6 ± 5.8; P < 0.001), total activity impairment (29.5 ± 26.6 to 4.4 ± 9.4; P < 0.001), and total work productivity impairment (20.9 ± 22.2 to 2.6 ± 5.8; P < 0.001). The mean ± SD score for absenteeism decreased from 1.1 ± 5.7 at baseline to 0.0 ± 0.0 at week 64, but this change was not statistically significant. CONCLUSION: Tildrakizumab treatment mitigated work productivity loss due to psoriasis as measured by the presenteeism, total activity impairment, and total work productivity impairment domains of the WPAI:PSO. TRIAL REGISTRATION: ClinicalTrials.gov identifier, NCT03718299.

Hypothermic oxygenated perfusion (HOPE) safely and effectively extends acceptable donor heart preservation times: Results of the Australian and New Zealand trial.

BACKGROUND: Cold static storage preservation of donor hearts for periods longer than 4 hours increases the risk of primary graft dysfunction (PGD). The aim of the study was to determine if hypothermic oxygenated perfusion (HOPE) could safely prolong the preservation time of donor hearts. METHODS: We conducted a nonrandomized, single arm, multicenter investigation of the effect of HOPE using the XVIVO Heart Preservation System on donor hearts with a projected preservation time of 6 to 8 hours on 30-day recipient survival and allograft function post-transplant. Each center completed 1 or 2 short preservation time followed by long preservation time cases. PGD was classified as occurring in the first 24 hours after transplantation or secondary graft dysfunction (SGD) occurring at any time with a clearly defined cause. Trial survival was compared with a comparator group based on data from the International Society of Heart and Lung Transplantation (ISHLT) Registry. RESULTS: We performed heart transplants using 7 short and 29 long preservation time donor hearts placed on the HOPE system. The mean preservation time for the long preservation time cases was 414 minutes, the longest being 8 hours and 47 minutes. There was 100% survival at 30 days. One long preservation time recipient developed PGD, and 1 developed SGD. One short preservation time patient developed SGD. Thirty day survival was superior to the ISHLT comparator group despite substantially longer preservation times in the trial patients. CONCLUSIONS: HOPE provides effective preservation out to preservation times of nearly 9 hours allowing retrieval from remote geographic locations.

Small molecule tractable PARP inhibitors: Scaffold construction approaches, mechanistic insights and structure activity relationship.

Diverse drug design strategies viz. molecular hybridization, substituent installation, scaffold hopping, isosteric replacement, high-throughput screening, induction and separation of chirality, structure modifications of phytoconstituents and use of structural templates have been exhaustively leveraged in the last decade to load the chemical toolbox of PARP inhibitors. Resultantly, numerous promising scaffolds have been pinpointed that in turn have led to the resuscitation of the credence to PARP inhibitors as cancer therapeutics. This review briefly presents the physiological functions of PARPs, the pharmacokinetics, and pharmacodynamics, and the interaction profiles of FDA-approved PARP inhibitors. Comprehensively covered is the section on the drug design strategies employed by drug discovery enthusiasts for furnishing PARP inhibitors. The impact of structural variations in the template of designed scaffolds on enzymatic and cellular activity (structure-activity relationship studies) has been discussed. The insights gained through the biological evaluation such as profiling of physicochemical properties andin vitroADME properties, PK assessments, and high-dose pharmacology are covered.

Effects of bilateral transmucosal sphenopalatine ganglion block on intraoperative anesthetic requirements and recovery profile in children undergoing palatoplasty under general anesthesia.

Background and Aims: Sphenopalatine ganglion block (SPGB) given as injection provides excellent perioperative analgesia during palatoplasty. Our objectives were to assess the effect of transmucosal SPGB on anesthetic requirements, intraoperative hemodynamics, recovery time, and emergence delirium in children undergoing palatoplasty. Material and Methods: This prospective, randomized study was conducted in 30 children with cleft palate undergoing palatoplasty, divided into two equal groups. After induction and intubation, patients in Group B received bilateral SPGB using cotton-tipped applicators soaked in 2% lignocaine, which were passed through both the nares, and the distal tip was positioned just superior to middle turbinate and anterior to pterygopalatine fossa and sphenopalatine ganglion. In Group C, saline-soaked cotton applicators were used. All patients received general anesthesia as per a standardized protocol. Intraoperative heart rate, mean arterial pressure, the requirement of anesthetics, extubation time, and emergence delirium were compared. Results: Compared with Group C, patients in Group B had significantly lower sevoflurane consumption (17.2 ± 2.6 vs. 27.5 ± 5.0mL, P < 0.001) and fentanyl consumption (2.2 ± 0.5 vs. 3.2 ± 0.6 µ/kg, P < 0.001).The extubation time was significantly shorter in Group B (3.9 ± 0.7 vs. 9.5 ± 1.6 minutes, P < 0.001). PAED (Pediatric Anesthesia Emergence Delirium Scale) scores at 5and 10 minutes were significantly higher in Group C (P < 0.001). Intraoperative heart rate was significantly higher in Group C. Group C had significantly higher mean arterial pressure at 15, 60, and 75 minutes. Conclusion: Preoperative, SPGB administered by mucosal application of local anesthetic significantly reduced sevoflurane and fentanyl requirements, with stable hemodynamics, quicker recovery, and less emergence delirium in children undergoing palatoplasty.

Plasma-Enabled Graphene Quantum Dot Hydrogels as Smart Anticancer Drug Nanocarriers.

One of the major challenges on the way to low-cost, simple, and effective cancer treatments is the lack of smart anticancer drug delivery materials with the requisite of site-specific and microenvironment-responsive properties. This work reports the development of plasma-engineered smart drug nanocarriers (SDNCs) containing chitosan and nitrogen-doped graphene quantum dots (NGQDs) for drug delivery in a pH-responsive manner. Through a customized microplasma processing, a highly cross-linked SDNC with only 4.5% of NGQD ratio can exhibit enhanced toughness up to threefold higher than the control chitosan group, avoiding the commonly used high temperatures and toxic chemical cross-linking agents. The SDNCs demonstrate improved loading capability for doxorubicin (DOX) via π-π interactions and stable solid-state photoluminescence to monitor the DOX loading and release through the Förster resonance energy transfer (FRET) mechanism. Moreover, the DOX loaded SDNC exhibits anticancer effects against cancer cells during cytotoxicity tests at minimum concentration. Cellular uptake studies confirm that the DOX loaded SDNC can be successfully internalized into the nucleus after 12 h incubation period. This work provides new insights into the development of smart, environmental-friendly, and biocompatible nanographene hydrogels for the next-generation biomedical applications.

Usefulness of bougie-preloaded proseal laryngeal mask airway versus digital insertion technique in correct placement of the device.

Background and Aims: Digital technique of proseal laryngeal mask airway (PLMA) insertion carries high chance of failed first attempt successful placement. We aimed to compare the number of attempts taken for correct placement of bougie-preloaded PLMA versus traditional digital insertion technique. Ease of insertion, time taken, hemodynamic responses during insertion, and evidence of trauma were also assessed. Material and Methods: This prospective, randomized, open-label study was performed in 60 patients. All patients were administered general anesthesia according to a standardized protocol.After induction of general anesthesia in group P, proseal insertion was performed following the traditional digital technique. In group B, bougie-preloaded PLMA was used. A soft gum elastic bougie was passed through the gastric channel of PLMA, with 15cm protruding distally through the gastric port. Attempts at successful insertion and ease of insertion were noted. Results: Time taken for successful insertion was significantly shorter in group B compared to group P (15.3 ± 4.5 vs. 57 ± 12.02 s, respectively). The first attempt success in group B was 90% versus 60% in group P. The number of moderate to hard insertion was significantly lesser in group B (10 vs. 40, respectively). Blood stain on device was seen in 3.3% in group B compared to 30% in group P. MAP at insertion and at 1, 3, and 5 min was significantly higher in group P. Heart rates were comparable. Conclusion: Bougie-preloaded proseal insertion has significantly higher first attempt insertion success rates and is significantly faster and less traumatic with blunted blood pressure response compared to traditional digital insertion technique.

Accommodation of ring C expanded deoxyvasicinone in the HDAC inhibitory pharmacophore culminates into a tractable anti-lung cancer agent and pH-responsive nanocarrier.

A fragment recruitment process was conducted to pinpoint a suitable fragment for installation in the HDAC inhibitory template to furnish agents endowed with the potential to treat lung cancer. Resultantly, Ring C expanded deoxyvasicinone was selected as an appropriate surface recognition part that was accommodated in the HDAC three-component model. Delightfully, fused quinazolinone 6 demonstrating a magnificent anticancer profile against KRAS and EGFR mutant lung cancer cell lines (IC50 = 0.80-0.96 µM) was identified. Results of the mechanistic studies confirmed that the cell growth inhibitory effects of compound 6 stems for HDAC6 (IC50 = 12.9 nM), HDAC1 (IC50 = 49.9 nM) and HDAC3 inhibition (IC50 = 68.5 nM), respectively. Compound 6 also suppressed the colony formation ability of A549 cells, induced apoptosis, and increased autophagic flux. Key interactions of HDAC inhibitor 6 within the active site of HDAC isoforms were figured out through molecular modeling studies. Furthermore, a pH-responsive nanocarrier (Hyaluronic acid - fused quinazolinone 6 nanoparticles) was designed and assessed using a dialysis bag approach under both normal and acidic circumstances that confirmed the pH-sensitive nature of NPs. Delightfully, the nanoparticles demonstrated selective cell viability reduction potential towards the lung cancer cell lines (A549 lung cancer cell lines) and were found to be largely devoid of cell growth inhibitory effects under normal settings (L929, mouse fibroblast cells).

Chronic hepatitis C: Diagnosis and treatment made easy.

BACKGROUND: Hepatitis C Virus (HCV) is a common cause of chronic liver disease and its ensuing complications. In the last years, there has been a revolution of the treatment for patients with HCV regarding efficacy, simplicity, safety and duration of treatment. The role of the family physician is vital in all steps of care: screening, diagnosis, linkage to treatment, treatment and follow-up. OBJECTIVES: This review aims to summarise the family physician and the important updated recommendations for diagnosis and treatment of patients with chronic HCV. METHODS: The updated recommendations were reviewed and summarised in a short and simple review. RESULTS: Patients with any risk factor for HCV should first be screened for HCV antibodies. In the case of positive antibodies, reflex testing for RNA polymerase chain reaction (PCR) should be done without waiting for genotype. For patients with positive PCR, fibrosis assessment should be conducted using laboratory panels (Fibrosis-4 index (FIB-4) or aspartate aminotransferase to platelet ratio index (APRI)); if advanced fibrosis is suspected, additional non-invasive fibrosis assessment is needed, such as fibrotest or liver elastography. Naïve non-cirrhotic or compensated cirrhosis (Child-Pugh-Score A) could be treated with pangenotypic drugs, Glecaprevir/pibrentasvir (Maviret) for eight weeks, or Sofosbuvir/velpatasvir (Epclusa) for 12 weeks. CONCLUSION: Patients without advanced fibrosis and comorbidities can be treated by the educated family physician. However, patients with comorbidities, cirrhosis or coinfection (HIV, Hepatitis B Virus (HBV)) should be referred to the liver clinic. In case of screening patients with risk factors or likelihood of dormant HCV, health organisations should provide the appropriate resources, logistics, finances and workforce.

Global best practices consensus: Long-term management of patients with hybrid centrifugal flow left ventricular assist device support.

OBJECTIVES: Six months after withdrawal of the HeartWare HVAD System (HVAD; Medtronic) from sale, approximately 4000 patients continue ongoing support with this device. In light of the diminishing experience, this global consensus document summarizes key management recommendations. METHODS: International experts with experience in the management of patients with ongoing HVAD support were invited to summarize key aspects of patient and pump management and highlight differences in the current HeartMate 3 (Abbott Laboratories) ventricular assist device. Clinicians from high-implanting HVAD sites reviewed current literature and reported experience to generate a consensus statement. RESULTS: Specific guidelines to assist in the management of ongoing HVAD patients are developed. Key management protocols and helpful techniques developed from experienced clinicians are combined into a short guideline document. As experience with HeartMate 3 increases, key differences in approach to management are highlighted, where appropriate. CONCLUSIONS: With decreasing worldwide experience in the ongoing management of HVAD-supported patients, this consensus guideline provides a summary of best practice techniques from international centers. Differences in HeartMate 3 management are highlighted.

Highway-rail grade crossings accident prediction using Zero Inflated Negative Binomial and Empirical Bayes method.

INTRODUCTION: Recently the Federal Railroad Administration (FRA) released a new model for accident prediction at railroad grade crossings using a Zero Inflated Negative Binomial (ZINB) model with Empirical Bayes (EB) adjustments for accident history (2). This new model is adopted from the work that was conducted by the authors (3-6). The unique feature of the new FRA model is that it has a single equation for all three warning devices (crossbuck, flashing light, and gates) and uses the same variables regardless of the warning devices at the crossing. Since the New FRA model incorporates the warning device category as one of the variables in its model equation, the predicted accident frequency is higher when a crossing has crossbucks than flashing lights, and higher when it has flashing lights than gates. While this model is significantly better than the old USDOT model (7), its shortcoming is that the single equation does not accurately represent the field condition. METHOD: This paper presents the ZINEBS model (Zero Inflated Negative binomial with Empirical Bayes adjustment System). The ZINEBS model gives three different equations depending on the type of warning device used at the crossings (gates, flashing lights, and crossbucks). The three equations use variables, some of which are common across all warning devices, while other variables are specific to a warning device. The predicted values for the ZINEBS model show a closer agreement with the field data than the new FRA model. This observation was true for all three warning device types analyzed. Practical Applications: Based on the results of this study, the ZINEBS compliments the new FRA model and should be used when the single equation is not adequately representing the role of traffic control device types and relevant variables associated with that device type.

Cardiac Toxicity Associated with Immune Checkpoint Inhibitors: A Systematic Review.

Immune checkpoint inhibitors are immune stimulatory drugs used to treat many types of cancer. These drugs are antibodies against inhibitory proteins, such as CTLA-4 and PD-1/PD-L1, that are expressed on immune cells. When bound, they allow for increased stimulation of T cells to fight tumor cells. However, immune checkpoint inhibitors have several immune-related adverse effects. Many cases have come to light recently of cardiotoxicity as a result of treatment with these drugs. Cardiotoxicity from immune checkpoint inhibitors is unique due to its rarity and high mortality rate. Patients with this toxicity may present with myocarditis, pericarditis, Takotsubo cardiomyopathy, conduction disorders, and others within just a few weeks of starting immune checkpoint inhibitors. We present here a review of the current research on immune checkpoint inhibitors, their associated cardiotoxicities, the timing of presentation of these conditions, lab tests and histology for each condition, and finally the treatment of patients with cardiotoxicity. We observe a positive skew in the onset of presentation, which is significant for the treating physician.

COVID-19 vaccination associated severe immune thrombocytopenia.

BACKGROUND: Coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 has emerged as a deadliest global pandemic after its identification in December 2019 in Wuhan, China resulting in more than three million deaths worldwide. Recently FDA issued emergency authorization for three vaccines for prevention of COVID-19. Here in, we report three cases of severe immune thrombocytopenia (ITP) following COVID-19 vaccination and their clinical course. CASE PRESENTATIONS: Case #1: 53 year old male with past medical history of Crohn's disease was admitted for myalgias and diffuse petechial rash 8 days after receiving second dose of Pfizer-BioNTech COVID-19 vaccine. A complete blood test showed a platelet count of 2 × 109/L. Patient did not have a prior history of thrombocytopenia and other causes of thrombocytopenia were ruled out by history and pertinent lab data. He received two doses of intravenous immunoglobulin and oral dexamethasone for 4 days resulting in normalization of platelet counts. Case #2: 67 year male with past medical history of chronic ITP in remission was admitted for melena 2 days after receiving his first dose of Pfizer-BioNTech COVID-19 vaccine. A complete blood test showed a platelet count of 2 × 109/L. Physical exam showed generalized petechiae. There was no history of recent flares of ITP and patient had normal platelet counts following his splenectomy 4 years ago. He received two doses of IVIG and oral dexamethasone for 4 days with gradual improvement in platelet counts. Case #3: 59 year old female with past medical history of chronic ITP secondary to SLE was admitted for bloody diarrhea 2 days after receiving her first dose of Johnson and Johnson COVID-19 vaccine. Physical exam was unremarkable. A complete blood test showed platelet count of 64 × 109/L which dropped to 27 × 109/L during hospital course. She received oral dexamethasone for 4 days with improvement in platelet counts. CONCLUSION: COVID-19 vaccination induced ITP has been recently acknowledged. However, given very few cases and limited data, currently there are no guidelines for management of ITP caused by COVID-19 vaccine as well as vaccination of people with predisposing conditions.

Isolated Discitis in Melioidosis: An Unknown Presentation and a Microbiological Challenge.

Burkholderia pseudomallei causes Whitmore's disease or melioidosis which is endemic in many South Asian countries including India. This gram-negative bacterium is frequently found in the moist soil and agricultural workers get infected most commonly. Most of the infections are asymptomatic and have a wide spectrum of manifestations as in tuberculosis. Melioidosis of the spine manifests as spondylodiscitis with paravertebral and prevertebral abscess and presentation as discitis alone is not reported. We report the first case of melioidosis causing isolated discitis without any obvious bony involvement. It also highlights the need for preoperative suspicion of these rare manifestations even in seemingly innocuous disc disease presenting as back pain and radiculopathy.

Effect of bilateral infraorbital nerve block on intraoperative anesthetic requirements, hemodynamics, glycemic levels, and extubation in infants undergoing cheiloplasty under general anesthesia.

BACKGROUND: Inappropriate use of intravenous and inhaled anesthetics may be dangerous in infants undergoing facial cleft surgeries. This study primarily aimed to compare the effect of infraorbital nerve block on sevoflurane requirement in infants undergoing cheiloplasty. Intraoperative opioid consumption, hemodynamics, blood glucose levels, extubation time, and delirium were also compared. METHODS: This prospective, randomized, double-blinded study was conducted in 34 infants undergoing cheiloplasty under general anesthesia. After induction, group A received bilateral infraorbital nerve block with 0.5 mL of 0.5% bupivacaine and group B 0.5 mL saline. An increase in heart rate or blood pressure > 20% was managed by increasing sevoflurane by 2-2.5%, followed by fentanyl 0.5 µg/kg bolus. The chi-square test and independent-sample t-test were used where applicable. RESULTS: Demographics, duration of surgery, and intravenous fluids used were comparable between the groups. Compared to group A, patients in group B had significantly higher consumption of fentanyl (14.2 ± 4.4 µg vs. 22.1 ± 6.2 µg) and sevoflurane (14.2 ± 4.8 mL vs. 26.8 ± 15.6 mL). Intraoperative hemodynamic parameters were significantly lower in group A, the number of times increases in hemodynamic parameters occurred, and fentanyl supplemental bolus was required remained significantly lower in group A than in group B. Intraoperative glycemic levels remained higher in group B, and the extubation time was significantly shorter in group A than in group B (4.40 ± 1.60 min vs. 9.2 ± 2.18 min). Group A had a lesser occurrence of postoperative delirium. CONCLUSION: Supplemental infraorbital block in infants undergoing cheiloplasty under general anesthesia resulted in significantly decreased anesthetic requirements and optimal hemodynamic and glycemic levels with faster extubation and lesser delirium.

Extending our understanding of exenatide: a rare case of angio-oedema.

Exenatide is a subcutaneous injectable glucagon-like peptide 1 receptor agonist that has been approved by the Federal Drug Administration for the treatment of type 2 diabetes mellitus. While side effects such as nausea, vomiting and local hypersensitivity reactions are more commonly described, angio-oedema has never been previously reported in the literature. We present the case of a 67-year-old woman who presented to the emergency department with acute-onset tongue swelling, difficulty breathing, dizziness and diffuse itching which began shortly after receiving her first dose of intramuscular extended release (ER) exenatide. This case aims to raise awareness of the potential adverse effect of angio-oedema secondary to exenatide ER and serves as a reminder to clinicians to discuss possible adverse effects of medications and early recognition of symptoms which would prompt further medical attention.