Predictors of Loss to Follow Up and Mortality Among Children ?12 Years Receiving Anti Retroviral Therapy During the First Year at a Referral Hospital in Bali

Background and purpose: Many HIV-infected children in Bali have started antiretroviral therapy (ART), but loss to follow up (LTFU) is a continuing concern, and the issue of childhood adherence is more complex compared to adults.Methods: This was a retrospective study among cohort of 138 HIV+ children on ART in Sanglah General Hospital, Denpasar, Bali from January 2010 to December 2015. Kaplan-Meier analysis was used to describe incidence and median time to LTFU/mortality and Cox Proportional Hazard Model was used to identify predictors. Variables which were analysed were socio-demographic characteristics, birth history, care giver and clinical condition of the children.Results: Mean age when starting ARV therapy was 3.21 years. About 25% experienced LTFU/death by 9.1 month resulting in an incidence rate of 3.28 per 100 child month. The higher the WHO stage, the higher the risk for LTFU/mortality along with low body weight (AHR=0.90; 95%CI: 0.82-0.99).Conclusion: Clinical characteristics were found as predictors for LTFU/mortality among children on ART

Real-world use of ticagrelor versus clopidogrel in percutaneous coronary intervention-treated ST-elevation myocardial infarction patients: A single-center registry study

Objectives: The primary aim was to investigate the efficacy and safety of dual antiplatelet therapy (DAPT) using ticagrelor (T-DAPT) versus clopidogrel (C-DAPT) in a real-world ST-elevation myocardial infarction (STEMI) population. Methods: We retrospectively analyzed 655 consecutive patients having primary percutaneous coronary intervention (PCI) for STEMI at Liverpool Hospital, Sydney, Australia (from January 2013 to April 2016). Medical and procedural therapies were at clinician discretion. Patient data were retrieved from hospital records and primary clinicians. Results: T-DAPT (65%) was used more frequently, and in patients with lower mean CRUSADE (Can Rapid Risk Stratification of Unstable Angina Patients Suppress Adverse Outcomes with Early Implementation of the American College of Cardiology/American Heart Association Guidelines) score, than C-DAPT (24.6 vs. 32.2; p < 0.0001, respectively). All-cause mortality was 9.0% at 2.7 years follow-up, with fewer deaths for T-DAPT (4.5% vs. 17.2%; p < 0.0001). T-DAPT incurred less BARC (Bleeding Academic Research Consortium) 3–5 major bleeding (5.0% vs. 12.4%; p < 0.0001). Multivariate regression showed that C-DAPT, GRACE (Global Registry of Acute Cardiac Events) score, and renal insufficiency were independently associated with mortality. Intra-aortic balloon pump (IABP) and GRACE score independently predicted BARC 3–5 bleeding. Early DAPT discontinuation (1.7%) and ticagrelor intolerance (7.6%) was rare. Switching DAPT regimen was infrequent (21.7%) and mostly attributed to clinician preference (73.2%). Independent determinants of C-DAPT selection were older age, diabetes, prior PCI, IABP, and higher CRUSADE score. Conclusion: Ticagrelor was preferred in low bleeding risk patients, which may have contributed to less BARC 3–5 bleeding and lower mortality for T-DAPT. Thus, bleeding mitigation is a clinical priority when selecting DAPT for PCI-treated STEMI patients. Continuation of initial DAPT regimen was typical, but early switching from clopidogrel to ticagrelor shows willingness to optimize DAPT. Patients with very low CRUSADE scores (<21.5) may be appropriate for switching to a potent P2Y12 inhibitor

Patient-reported outcome instruments used in immune-checkpoint inhibitor clinical trials in oncology: a systematic review.

Immune-checkpoint inhibitors (ICI) have shown significant benefits for overall survival across various cancer types. Patient-reported outcomes (PROs) are assessed in clinical trials as a measure of efficacy. However, it remains unclear to what extent current PRO instruments capture symptoms specific to ICI toxicities. We conducted a systematic review to identify the use and content validity of PRO instruments in ICI clinical trials in oncology. Literature was retrieved from PubMed, Embase, PsycINFO, Medline and CINAHL databases. Articles presenting ICI clinical trials' PRO results, clinical trial study protocols, and conference abstracts stating the use of PRO measures were assessed. We evaluated the validity of identified instruments by comparing their symptom-related content with the adverse events reported in each ICI clinical trial. From database inception until January 2020, we identified 191 ICI clinical trials stating the use of PRO measures of which 26 published PRO results. The cancer-specific EORTC QLQ-C30 and the generic EQ-5D questionnaires were the most widely used instruments, often in combination with disease-specific PROs. Instruments used to report PRO symptom-related toxicities covered 45% of the most frequently reported AEs, whereas 23% of AEs were partially covered and 29% were not covered at all. Of non-covered AEs, 59% referred to the dermatologic system. Partially covered AEs related to endocrine and specific types of pain. Despite the high frequency of symptom-related toxicities related to ICI, these events are only partially covered (or not addressed) by current PRO instruments, even when combined. Further research is needed to develop new strategies to tailor PRO instruments to specific ICI toxicities

Incidence and predictors of left ventricular thrombus formation following acute ST-segment elevation myocardial infarction: A serial cardiac MRI study

Aims: Left ventricular (LV) thrombus is a complication of acute ST-segment elevation myocardial infarction (STEMI). We determined the incidence and predictors of LV thrombus formation using serial cardiac magnetic resonance (CMR) and two-dimensional echocardiography studies. Methods and results: Two hundred and ten patients underwent CMR (median 4 days [IQR 3-7]) and transthoracic echocardiography (median 4 days [IQR 3-7]) early after STEMI presentation with serial follow-up CMR (median 55 days [IQR 46-64]) and echocardiography studies (median 54 days [IQR 45-64]) performed subsequently. The incidence of LV thrombus was 12.3% (26/210) by CMR and 6.2% (13/210) by two-dimensional echocardiography. Echocardiography had 50% sensitivity and 100% specificity for LV thrombus detection compared to CMR. LV thrombus was found in 23.6% of patients with anterior STEMI (22/93). Ischaemic stroke occurred in 1.4% of patients (3/210). Patients with LV thrombus had lower baseline LV ejection fraction (LVEF) (34.9% vs 47.4%, p < 0.001). Microvascular obstruction was more common in patients with LV thrombus (77% vs 39%, p < 0.001). Patients with LV thrombus had increased LV dimensions with larger LV end-diastolic (19 ml [IQR 9-44] vs 6 ml [IQR -4-18], p < 0.001) and end-systolic volumes (10 ml [IQR 0–22] vs -4 ml [IQR -12-4], p < 0.001). Conclusion: CMR increases the detection of LV thrombi which standard echocardiography may underestimate. Serial studies post-STEMI may improve detection of LV thrombus, which is more prevalent in patients with anterior infarction, moderate LV dysfunction and adverse LV remodelling. This subgroup of patients may represent a high-risk group for targeted serial screening with CMR

Sex Differences in Outcome and Prescribing Practice in ST-elevation MI Patients with Multivessel Disease and Incomplete Revascularisation

Objective: To investigate the extent to which multivessel disease, incomplete revascularisation and prescribing differences contribute to sex-based outcome disparities in patients with ST-elevation MI (STEMI) and establish whether differences in cardiac death and MI (CDMI) rates persist at long-term follow-up. Methods and results: This observational study evaluates sex-based outcome differences (median follow-up 3.6 years; IQR [2.4–5.4]) in a consecutive cohort of patients (n=2,083) presenting with STEMI undergoing percutaneous coronary intervention). Of the studied patients 20.3% (423/2,083) were women and 38.3% (810/2,083) had multivessel disease (MVD). Incomplete revascularisation was common. The median residual SYNTAX score (rSS) was 5.0 (IQR [0–9]) in women and 5.0 (IQR [1–11]) in men (p=0.369), and in patients with MVD it was 9 (IQR [6–17]) in women and 10 (IQR [6–15]) in men (p=0.838). The primary endpoint CDMI occurred in 20.3% of women (86/423) and in 13.2% of men (219/1,660) (p=0.028). Differences persisted following multivariable risk adjustment: female sex was independently associated with CDMI (aHR 1.33; IQR [1.02–1.74]). Women with MVD had CDMI more often than all other groups (p8. Observed differences in P2Y12 prescribing practices may contribute to poor outcomes for women with MVD and incomplete revascularisation

Exploring the theme: Synthesis and biological properties of tridentate cyclometalated gold(III) complexes

A family of cyclometalated Au(III) complexes featuring a tridentate C^N^C scaffold has been synthesized and characterized. Microwave assisted synthesis of the ligands has also been exploited and optimized. The biological properties of the thus formed compounds have been studied in cancer cells and demonstrate generally moderate antiproliferative effects. Initial mechanistic insights have also been gained on the gold complex [Au(C^N^C)(GluS)] (3), and support the idea that the thioredoxin system may be a target for this family of compounds together with other relevant intracellular thiol-containing molecules

Utility of prehospital electrocardiogram interpretation in ST-segment elevation myocardial infarction utilizing computer interpretation and transmission for interventional cardiologist consultation

Objectives: We examined the appropriateness of prehospital cardiac catheter laboratory activation (CCL-A) in ST-segment elevation myocardial infarction (STEMI) utilizing the University of Glasgow algorithm (UGA) and remote interventional cardiologist consultation. Background: The incremental benefit of prehospital electrocardiogram (PH-ECG) transmission on the diagnostic accuracy and appropriateness of CCL-A has been examined in a small number of studies with conflicting results. Methods: We identified consecutive PH-ECG transmissions between June 2, 2010 and October 6, 2016. Blinded adjudication of ECGs, appropriateness of CCL-A, and index diagnoses were performed using the fourth universal definition of MI. The primary outcome was the appropriate CCL-A rate. Secondary outcomes included rates of false-positive CCL-A, inappropriate CCL-A, and inappropriate CCL nonactivation. Results: Among 1088 PH-ECG transmissions, there were 565 (52%) CCL-As and 523 (48%) CCL nonactivations. The appropriate CCL-A rate was 97% (550 of 565 CCL-As), of which 4.9% (n = 27) were false-positive. The inappropriate CCL-A rate was 2.7% (15 of 565 CCL-As) and the inappropriate CCL nonactivation rate was 3.6% (19 of 523 CCL nonactivations). Reasons for appropriate CCL nonactivation (n = 504) included nondiagnostic ST-segment elevation (n = 128, 25%), bundle branch block (n = 132, 26%), repolarization abnormality (n = 61, 12%), artefact (n = 72, 14%), no ischemic symptoms (n = 32, 6.3%), severe comorbidities (n = 26, 5.2%), transient ST-segment elevation (n = 20, 4.0%), and others. Conclusions: PH-ECG interpretation utilizing UGA with interventional cardiologist consultation accurately identified STEMI with low rates of inappropriate and false-positive CCL-As, whereas using UGA alone would have almost doubled CCL-As. The benefits of cardiologist consultation were identifying “masquerading” STEMI and avoiding unnecessary CCL-As

Late Outcomes of Patients With Prehospital ST-Segment Elevation and Appropriate Cardiac Catheterization Laboratory Nonactivation

BACKGROUND: Patients with suspected ST-segment–elevation myocardial infarction (STEMI) and cardiac catheterization laboratory nonactivation (CCL-NA) or cancellation have reportedly similar crude and higher adjusted risks of death compared with those with CCL activation, though reasons for these poor outcomes are not clear. We determined late clinical outcomes among patients with prehospital ECG STEMI criteria who had CCL-NA compared with those who had CCL activation. METHODS AND RESULTS: We identified consecutive prehospital ECG transmissions between June 2, 2010 to October 6, 2016. Diagnoses according to the Fourth Universal Definition of myocardial infarction (MI), particularly rates of myocardial injury, were adjudicated. The primary outcome was all-cause death. Secondary outcomes included cardiovascular death/MI/stroke and noncardiovascular death. To explore competing risks, cause-specific hazard ratios (HRs) were obtained. Among 1033 included ECG transmissions, there were 569 (55%) CCL activations and 464 (45%) CCL-NAs (1.8% were inappropriate CCL-NAs). In the CCL activation group, adjudicated index diagnoses included MI (n=534, 94%, of which 99.6% were STEMI and 0.4% non-STEMI), acute myocardial injury (n=15, 2.6%), and chronic myocardial injury (n=6, 1.1%). In the CCL-NA group, diagnoses included MI (n=173, 37%, of which 61% were non-STEMI and 39% STEMI), chronic myocardial injury (n=107, 23%), and acute myocardial injury (n=47, 10%). At 2 years, the risk of all-cause death was higher in patients who had CCL-NA compared with CCL activation (23% versus 7.9%, adjusted risk ratio, 1.58, 95% CI, 1.24–2.00), primarily because of an excess in noncardiovascular deaths (adjusted HR, 3.56, 95% CI, 2.07–6.13). There was no significant difference in the adjusted risk for cardiovascular death/MI/stroke between the 2 groups (HR, 1.23, 95% CI, 0.87–1.73). CONCLUSIONS: CCL-NA was not primarily attributable to missed STEMI, but attributable to “masquerading” with high rates of non-STEMI and myocardial injury. These patients had worse late outcomes than patients who had CCL activation, mainly because of higher rates of noncardiovascular deaths

Alterations of immune response of non-small lung cancer with azacytidine

Innovative therapies are needed for advanced Non-Small Cell Lung Cancer (NSCLC). We have undertaken a genomics based, hypothesis driving, approach to query an emerging potential that epigenetic therapy may sensitize to immune checkpoint therapy targeting PD-L1/PD-1 interaction. NSCLC cell lines were treated with the DNA hypomethylating agent azacytidine (AZA - Vidaza) and genes and pathways altered were mapped by genome-wide expression and DNA methylation analyses. AZA-induced pathways were analyzed in The Cancer Genome Atlas (TCGA) project by mapping the derived gene signatures in hundreds of lung adeno (LUAD) and squamous cell carcinoma (LUSC) samples. AZA up-regulates genes and pathways related to both innate and adaptive immunity and genes related to immune evasion in a several NSCLC lines. DNA hypermethylation and low expression of IRF7, an interferon transcription factor, tracks with this signature particularly in LUSC. In concert with these events, AZA up-regulates PD-L1 transcripts and protein, a key ligand-mediator of immune tolerance. Analysis of TCGA samples demonstrates that a significant proportion of primary NSCLC have low expression of AZA-induced immune genes, including PD-L1. We hypothesize that epigenetic therapy combined with blockade of immune checkpoints - in particular the PD-1/PD-L1 pathway - may augment response of NSCLC by shifting the balance between immune activation and immune inhibition, particularly in a subset of NSCLC with low expression of these pathways. Our studies define a biomarker strategy for response in a recently initiated trial to examine the potential of epigenetic therapy to sensitize patients with NSCLC to PD-1 immune checkpoint blockade

Biological Parts for Kluyveromyces marxianus Synthetic Biology

Kluyveromyces marxianus is a non-conventional yeast whose physiology and metabolism lends itself to diverse biotechnological applications. While the wild-type yeast is already in use for producing fragrances and fermented products, the lack of standardised tools for its genetic and metabolic engineering prevent it from being used as a next-generation cell factory for bio-based chemicals. In this paper, we bring together and characterise a set of native K. marxianus parts for the expression of multiple genes for metabolic engineering and synthetic biology. All parts are cloned and stored according to the MoClo/Yeast Tool Kit standard for quick sharing and rapid construction. Using available genomic and transcriptomic data, we have selected promoters and terminators to fine-tune constitutive and inducible gene expression. The collection includes a number of known centromeres and autonomously replication sequences (ARS). We also provide a number of chromosomal integration sites selected for efficiency or visible phenotypes for rapid screening. Finally, we provide a single-plasmid CRISPR/Cas9 platform for genome engineering and facilitated gene targeting, and rationally create auxotrophic strains to expand the common range of selection markers available to K. marxianus. The curated and characterised tools we have provided in this kit will serve as a base to efficiently build next-generation cell factories from this alternative yeast. Plasmids containing all parts are available at Addgene for public distribution