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.

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.

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.

A Validated Model for Sudden Cardiac Death Risk Prediction in Pediatric Hypertrophic Cardiomyopathy.

BACKGROUND: Hypertrophic cardiomyopathy is the leading cause of sudden cardiac death (SCD) in children and young adults. Our objective was to develop and validate a SCD risk prediction model in pediatric hypertrophic cardiomyopathy to guide SCD prevention strategies. METHODS: In an international multicenter observational cohort study, phenotype-positive patients with isolated hypertrophic cardiomyopathy <18 years of age at diagnosis were eligible. The primary outcome variable was the time from diagnosis to a composite of SCD events at 5-year follow-up: SCD, resuscitated sudden cardiac arrest, and aborted SCD, that is, appropriate shock following primary prevention implantable cardioverter defibrillators. Competing risk models with cause-specific hazard regression were used to identify and quantify clinical and genetic factors associated with SCD. The cause-specific regression model was implemented using boosting, and tuned with 10 repeated 4-fold cross-validations. The final model was fitted using all data with the tuned hyperparameter value that maximizes the c-statistic, and its performance was characterized by using the c-statistic for competing risk models. The final model was validated in an independent external cohort (SHaRe [Sarcomeric Human Cardiomyopathy Registry], n=285). RESULTS: Overall, 572 patients met eligibility criteria with 2855 patient-years of follow-up. The 5-year cumulative proportion of SCD events was 9.1% (14 SCD, 25 resuscitated sudden cardiac arrests, and 14 aborted SCD). Risk predictors included age at diagnosis, documented nonsustained ventricular tachycardia, unexplained syncope, septal diameter z-score, left ventricular posterior wall diameter z score, left atrial diameter z score, peak left ventricular outflow tract gradient, and presence of a pathogenic variant. Unlike in adults, left ventricular outflow tract gradient had an inverse association, and family history of SCD had no association with SCD. Clinical and clinical/genetic models were developed to predict 5-year freedom from SCD. Both models adequately discriminated between patients with and without SCD events with a c-statistic of 0.75 and 0.76, respectively, and demonstrated good agreement between predicted and observed events in the primary and validation cohorts (validation c-statistic 0.71 and 0.72, respectively). CONCLUSION: Our study provides a validated SCD risk prediction model with >70% prediction accuracy and incorporates risk factors that are unique to pediatric hypertrophic cardiomyopathy. An individualized risk prediction model has the potential to improve the application of clinical practice guidelines and shared decision making for implantable cardioverter defibrillator insertion. Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT0403679.

Berlin Heart EXCOR Support in the First Year of Life: A Single Centre Experience.

BACKGROUND: Berlin Heart EXCOR Pediatric Ventricular Assist Device (BHE) (Berlin Heart AG, Berlin, Germany, BHE) is used worldwide for mechanical circulatory support as a bridge to transplantation or recovery for children with end-stage heart failure. The study aim was to evaluate morbidity and mortality of children less than one year old supported with BHE to identify predictors of adverse outcomes. METHODS: Data of all children aged less than one year supported with BHE between 2005 and 2018 at the Royal Children's Hospital, Melbourne were reviewed. Adverse events were defined using PediMACS criteria. RESULTS: Fourteen (14) children under 1 year of age were implanted with BHE at a median age and weight of 0.37 years (IQR 0.09-0.7) and 5.7 kg (IQR 3.5-7.95) respectively. Four (4) patients were neonates, and 10 were older infants. Twelve (12) patients had cardiomyopathy and two, myocarditis. Preoperative extracorporeal membrane oxygenation (ECMO) support was required in six patients for a mean of 9 days (IQR 6-13). Sepsis occurred in five patients (36%) and thromboembolic stroke in two patients (14%). Survival to bridge to transplantation (11) and recovery (1) was achieved in 12 patients (86%). Mortality was 14%. The median duration of BHE support was 110 days (IQR 40-161). Both patients who died were neonates with myocarditis and required surgical re-intervention during BHE support. CONCLUSIONS: BHE provides excellent support as a bridge to transplantation or recovery in infants, with a low incidence of neurological dysfunction. Neonates with myocarditis may be at greater risk for death after BHE implantation.

Family screening for hypertrophic cardiomyopathy: Is it time to change practice guidelines?

AIMS: Current guidelines recommend initiating family screening for hypertrophic cardiomyopathy (HCM) after age 10 or 12 years unless early screening criteria are met. The aim was to evaluate if current screening guidelines miss early onset disease. METHODS AND RESULTS: Children who underwent family screening for HCM before age 18 years were analysed. Major cardiac events (MaCEs) were defined as death, sudden cardiac death (SCD), or need for major cardiac interventions (myectomy, implantable cardioverter-defibrillator insertion, transplantation). Of 524 children screened, 331 were under 10 years of age, 9.9% had echocardiographic evidence of HCM, and 1.1% were symptomatic at first screening. The median (interquartile range) age at HCM onset was 8.9 (4.7-13.4) years, and at MaCE was 10.9 (8.5-14.3) years with a median time to MaCE from HCM onset of 1.5 (0.5-4.1) years. About 52.5% phenotype-positive children and 41% with MaCEs were <10 years old. Only 69% children with early HCM met early screening criteria. Cox regression identified male gender, family history of SCD, and pathogenic variants in MYH7/MYBPC3 as a predictor of early onset HCM and MaCEs. CONCLUSION: A third of children not eligible for early screening by current guidelines had phenotype-positive HCM. MYH7 and MYBC3 mutation-positive patients were at highest risk for developing early HCM and experiencing an event or requiring a major intervention. Our findings suggest that younger family members should be considered for early clinical and genetic screening to identify the subset in need of closer monitoring and interventions.

Management of People With a Fontan Circulation: a Cardiac Society of Australia and New Zealand Position statement.

The Fontan circulation describes the circulatory state resulting from an operation in congenital heart disease where systemic venous return is directed to the lungs without an intervening active pumping chamber. As survival increases, so too does recognition of the potential health challenges. This document aims to allow clinicians, people with a Fontan circulation, and their families to benefit from consensus agreement about management of the person with a Fontan circulation. The document was crafted with input from a multidisciplinary group of health care providers as well as individuals with a Fontan circulation and families. It is hoped that the shared common vision of long-term wellbeing will continue to drive improvements in care and quality of life in this patient population and eventually translate into improved survival. KEYPOINTS.

Is a difficult gallbladder worth removing in its entirety? - Outcomes of subtotal cholecystectomy.

BACKGROUND: Laparoscopic Cholecystectomy one of the commonest procedures performed worldwide isn't spared from the risks of disastrous iatrogenic complications. In patients with obscured anatomy, the idea of performing a safe total cholecystectomy can be hindered with a high risk of biliovascular injuries. In such a situation STC (subtotal cholecystectomy) comes to the rescue, where the diseased organ can be tackled fairly, without any further damage. AIMS AND OBJECTIVES: The primary aim was to look at the immediate and long-term outcomes of subtotal cholecystectomy. Subgroup analysis was done based on demographics, indications and surgical approach. MATERIALS AND METHODS: We reviewed our prospectively maintained computerized operation database over nine years. STC was defined as leaving behind any portion of gallbladder other than the cystic duct. They were subclassified as per the description given by Palanivelu. Patients were evaluated with laboratory and radiological assessment. RESULTS: A total of 70 out of 602 patients (11.6%) underwent STC. Dense adhesion at the calot's was the most important reason for STC. Subtype B was the most common. Nine patients (12.85%) had a bile leak in the postoperative period. There were no biliary/vascular injuries and 30-day mortality was zero. 22.8% developed SSI (surgical site infection). Over a median follow up of 38 months (range 5-98), clinical examination, LFT and USG revealed no abnormality in any of the patients. CONCLUSION: Subtotal cholecystectomy is a useful alternative during difficult gallbladder surgery. It should be considered early into the procedure preferably prior to conversion to an open procedure. Biliovascular injuries can be avoided and the Immediate and long-term outcomes are acceptable.

Quality of life in adult survivors after paediatric heart transplantation in Australia.

BACKGROUND: Paediatric heart transplantation in Australia is centralised at The Royal Children's Hospital, Melbourne. Survival to adulthood is improving but the ongoing need for complex medical therapy, surveillance, and potential for late complications continues to impact on quality of life. Quality of life in adults who underwent heart transplantation in childhood in Australia has not been assessed. METHODS: Cross-sectional quality of life data were collected from paediatric heart transplant survivors >18 years of age using Rand 36-Item Health Survey. Self-reported raw scores were transformed to a 0-100 scale with higher scores indicating better quality of life. Mean scores were compared to National Health Survey Short Form-36 Population Norms data using the independent sample t-test. RESULTS: A total of 64 patients (64/151) who underwent transplantation at The Royal Children's Hospital between 1988 and 2016 survived to adulthood. In total 51 patients (51/64, 80%) were alive at the time of the study and 27 (53%) responded with a mean age of 25 ± 6 years, being a median of 11 years (interquartile range 7-19) post-transplantation. Most self-reported quality of life subscale scores were not significantly different from the Australian normative population data. However, self-reported 'General Health' was significantly worse than normative data (p = 0.02). Overall, 93% (25/27) reported their general health as being the same or better compared to 1-year ago. CONCLUSION: Adult survivors after paediatric heart transplantation in Australia report good quality of life in multiple domains and demonstrate independence in activities of daily living and employment. However, lifelong medical treatment may affect perceptions of general health.

Elements of a successful hospital-based deceased donation programme in India: Zero to eighty-five in two years.

Background: Legislation has made organ donation after brain death (DBD) possible in India since 1994. However, no organs are donated in most parts of the country; the national organ donation rate is estimated at between 0.08 and 0.34 donors per million population-one of the lowest in the world. Methods: A 350-bedded private hospital in Kochi started its DBD programme in September 2013 with a structured approach based on counselling of family members of critically ill individuals. A counsellor trained to diagnose family dynamics, and recognize different stages of the grieving process, chose the right time, and the correct family member to whom the donation request could be made. Regular debriefing sessions of the core team consisting of a transplant surgeon, a transplant coordinator, an ICU counsellor and a unit administrator resulted in setting up systems that supported families of patients with catastrophic brain injury, and created an environment conducive to obtaining consent. Results: A total of 85 organ donations took place in the first 24 months (September 2013 to September 2015) of instituting the programme. Conclusion: It is possible with hospital-based teamwork and a structured approach to consistently elicit organ donation.

Percutaneous management of patients with acute coronary syndromes from unprotected left main disease: A comprehensive review and presentation of a treatment algorithm.

The patient with acute coronary syndrome, particularly with myocardial infarction, from an unprotected left main coronary stenosis represents one of the highest risk subgroups with mortality exceeding 25-50%. Once a patient develops cardiogenic shock, the risk of death during index hospitalization is exceedingly high. Percutaneous coronary intervention may improve short- and long-term outcome, particularly if performed prior to shock development. Should the patient survive index hospitalization, survival tends to be rather good. This review summarizes current knowledge and proposes a clinical algorithm for evaluation and treatment. © 2015 Wiley Periodicals, Inc.

Relationship of Right Ventricular Size and Function with Respiratory Status in Duchenne Muscular Dystrophy.

The relationship between pulmonary function and right ventricle (RV) in Duchenne muscular dystrophy (DMD) has not been evaluated. Using cardiac magnetic resonance (CMR), we describe the relationship of RV size and function with spirometry in a DMD cohort. Fifty-seven boys undergoing CMR and pulmonary function testing within 1 month at a single center (2013-2015) were enrolled. Comparisons of RV ejection fraction (RVEF) and end-diastolic volume index (RVEDVI) were made across categories of percent forced vital capacity (FVC%), and relationships were assessed. Mean age was 15.5 ± 3.5 years. Spirometry and CMR were performed within 3.9 ± 4.1 days. Median FVC% was 92.0 % (67.5-116.5 %). Twenty-three (40 %) patients had abnormal FVC% (<80 %) of which 13 (57 %) had mild (FVC% 60-79 %), 6 (26 %) had moderate (FVC% 40-59 %), and 4 (17 %) had severe (FVC <40 %) reductions. Mean RVEF was 58.3 ± 3.7 %. Patients with abnormal FVC% were older and had lower RVEF and RVEDVI. Both RVEF and RVEDVI were significantly associated with FVC% (r = 0.31, p = 0.02 and r = 0.39, p = 0.003, respectively). In a large DMD cohort, RVEF and RVEDVI were related to FVC%. Worsening respiratory status may guide monitoring of cardiac function in these patients.

Do they hear what we speak? Assessing the effectiveness of communication to families of critically ill neurosurgical patients.

BACKGROUND AND AIMS: Clinician-family communication must be effective for medical decision making in any Intensive Care Unit (ICU) setting. We performed a prospective study to assess the effectiveness of communication to families of critically ill neurosurgical patients based on the two criteria of comprehension and satisfaction. MATERIALS AND METHODS: The study was conducted on 75 patients in a 15 bedded neurosurgical ICU. An independent investigator assessed the comprehension and satisfaction of families between the 3(rd) and the 5(th) day of admission in ICU. Comprehension was tested using three components, that is, comprehension of diagnosis, prognosis and treatment. The satisfaction was measured using a modified version of the Critical Care Family Needs Inventory (CCFNI) (score of 56-extreme dissatisfaction and 14-extreme satisfaction). RESULTS: Poor comprehension was noted in 52 representatives (71.2%). The mean satisfaction score as measured by the CCFNI score was 28. Factors associated with poor comprehension included increasing age of patient representative (P = 0.024), higher simplified acute physiology score (P = 0.26), nonoperated patients (P = 0.0087) and clinician estimation of poor prognosis (P = 0.01). Operated patients had significantly better satisfaction score (P = 0.04). CONCLUSION: Families of patients were reasonably satisfied, but had poor comprehension levels of the patient's illness. The severity of the patient's illness, poor prognosis as estimated by the physician and nonoperated patients were independent predictors of poor comprehension. Extra effort to communicate with patient representatives at risk of poor comprehension and provision of a family information leaflet could possibly remedy this situation.

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.

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.

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.

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.