Crystal structure and mechanistic studies of the PPM1D serine/threonine phosphatase catalytic domain.

Protein phosphatase 1D (PPM1D, Wip1) is induced by the tumor suppressor p53 during DNA damage response signaling and acts as an oncoprotein in several human cancers. Although PPM1D is a potential therapeutic target, insights into its atomic structure were challenging due to flexible regions unique to this family member. Here, we report the first crystal structure of the PPM1D catalytic domain to 1.8 Å resolution. The structure reveals the active site with two Mg2+ ions bound, similar to other structures. The flap subdomain and B-loop, which are crucial for substrate recognition and catalysis, were also resolved, with the flap forming two short helices and three short ß-strands that are followed by an irregular loop. Unexpectedly, a nitrogen-oxygen-sulfur bridge was identified in the catalytic domain. Molecular dynamics simulations and kinetic studies provided further mechanistic insights into the regulation of PPM1D catalytic activity. In particular, the kinetic experiments demonstrated a magnesium concentration-dependent lag in PPM1D attaining steady-state velocity, a feature of hysteretic enzymes that show slow transitions compared with catalytic turnover. All combined, these results advance the understanding of PPM1D function and will support the development of PPM1D-targeted therapeutics.

Systematic Review and Meta-analysis of the Impact of Surgeon-Physician Co-management Models on Short Term Outcomes for Vascular Surgery Inpatients.

OBJECTIVE: As the population ages, vascular surgeons are treating progressively older, multimorbid patients at risk of peri-operative complications. An embedded physician has been shown to improve outcomes in general and orthopaedic surgery. This systematic review and meta-analysis aimed to investigate the impact of surgeon-physician co-management models on morbidity and mortality rates in vascular inpatients. DATA SOURCES: PubMed, Scopus, Embase, conference abstract listings, and clinical trial registries. REVIEW METHODS: Studies comparing adult vascular surgery inpatients under co-management with standard of care were eligible. The relative risks (RRs) of death, medical complications, and 30 day re-admission between co-management and standard care were calculated. The effect of co-management on the mean length of stay was calculated using weighted means. Risk of bias was assessed using the Methodological Index for Non-Randomised Studies, and certainty assessment with the GRADE analysis tools. RESULTS: No randomised controlled trials were identified. Eight single institution studies between 2011 and 2020 with 7 410 patients were included. All studies were observational using before-after methodology. Studies were of high to moderate risk of bias, and outcomes were of very low GRADE certainty of evidence. Co-management was associated with a statistically significant lower relative risk of death (RR 0.64, 95% confidence interval [CI] 0.44 - 0.92; p = .02), cardiac complications (RR 0.47, 95% CI 0.25 - 0.87; p = .02), and infective complications (RR 0.49, 95% CI 0.35 - 0.67; p < .001) in vascular inpatients. No statistically significant differences in length of stay (standard mean difference -0.6 days, 95% CI -1.44 - 0.24 days; p = .16) and 30 day re-admission (RR 0.96, 95% CI 0.84 - 1.08; p = .49) were noted. CONCLUSION: Early results of physician and surgeon co-management for vascular surgery inpatients showed promising results from very low certainty data. Further well designed, prospective studies are needed to determine how to maximise the impact of physicians within a vascular service to improve patient outcomes while using hospital resources effectively.

Second-site suppressor mutations reveal connection between the drug-binding pocket and nucleotide-binding domain 1 of human P-glycoprotein (ABCB1).

Human P-glycoprotein (P-gp) or ABCB1 is overexpressed in many cancers and has been implicated in altering the bioavailability of chemotherapeutic drugs due to their efflux, resulting in the development of chemoresistance. To elucidate the mechanistic aspects and structure-function relationships of P-gp, we previously utilized a tyrosine (Y)-enriched P-gp mutant (15Y) and demonstrated that at least 15 conserved residues in the drug-binding pocket of P-gp are responsible for optimal substrate interaction and transport. To further understand the role of these 15 residues, two new mutants were generated, namely 6Y with the substitution of six residues (F72, F303, I306, F314, F336 and L339) with Y in transmembrane domain (TMD) 1 and 9Y with nine substitutions (F732, F759, F770, F938, F942, M949, L975, F983 and F994) in TMD2. Although both the mutants were expressed at normal levels at the cell surface, the 6Y mutant failed to transport all the tested substrates except Bodipy-verapamil, whereas the 9Y mutant effluxed all tested substrates in a manner very similar to that of the wild-type protein. Further mutational analysis revealed that two second-site mutations, one in intracellular helix (ICH) 4 (F916Y) and one in the Q loop of nucleotide-binding domain (NBD) 1 (F480Y) restored the transport function of 6Y. Additional biochemical data and comparative molecular dynamics simulations of the 6Y and 6Y+F916Y mutant indicate that the Q-loop of NBD1 of P-gp communicates with the substrate-binding sites in the transmembrane region through ICH4. This is the first evidence for the existence of second-site suppressors in human P-gp that allow recovery of the loss of transport function caused by primary mutations. Further study of such mutations could facilitate mapping of the communication pathway between the substrate-binding pocket and the NBDs of P-gp and possibly other ABC drug transporters.

Editor's Choice - Systematic Review and Meta-Analysis of Lower Extremity Vascular Complications after Arterial Access for Resuscitative Endovascular Balloon Occlusion of the Aorta (REBOA): An Inevitable Concern?

OBJECTIVE: Resuscitative endovascular balloon occlusion of the aorta (REBOA) is used to temporise non-compressible torso haemorrhage. Recent data have suggested that vascular access complications secondary to REBOA placement are higher than initially anticipated. This updated systematic review and meta-analysis aimed to determine the pooled incidence rate of lower extremity arterial complications after REBOA. DATA SOURCES: PubMed, Scopus, Embase, conference abstract listings, and clinical trial registries. REVIEW METHODS: Studies including more than five adults undergoing emergency REBOA for exsanguinating haemorrhage that reported access site complications were eligible for inclusion. A pooled meta-analysis of vascular complications was performed using the DerSimonian-Laird weights for the random effects model, presented as a Forest plot. Further meta-analyses compared the relative risk of access complications between different sheath sizes, percutaneous access techniques, and indications for REBOA. Risk of bias was assessed using the Methodological Index for Non-Randomised Studies (MINORS) tool. RESULTS: No randomised controlled trials were identified, and the overall study quality was poor. Twenty-eight studies including 887 adults were identified. REBOA was performed for trauma in 713 cases. The pooled proportion rate of vascular access complications was 8.6% (95% confidence interval 4.97 - 12.97), with substantial heterogeneity (I2 = 67.6%). There was no significant difference in the relative risk of access complications between 7 and > 10 F sheaths (p = .54), or between ultrasound guided and landmark guided access (p = .081). However, traumatic haemorrhage was associated with a significantly higher risk of complications compared with non-traumatic haemorrhage (p = .034). CONCLUSION: This updated meta-analysis aimed to be as comprehensive as possible considering the poor quality of source data and high risk of bias. It suggested that lower extremity vascular complications were higher than originally suspected after REBOA. While the technical aspects did not appear to impact the safety profile, a cautious association could be drawn between REBOA use for traumatic haemorrhage and a higher risk of arterial complications.

Optimal Management of Asymptomatic Carotid Artery Stenosis: A Systematic Review and Network Meta-Analysis.

OBJECTIVE: Management of asymptomatic carotid artery stenosis (ACAS), including carotid endarterectomy (CEA), carotid artery stenting (CAS), and best medical treatment (BMT), remains inconsistent in current practice. Early studies reported a benefit of CEA vs. BMT; however, the current risk-benefit profile of invasive therapy lacks consensus. By evaluating the effects of modern BMT vs. invasive intervention on patient outcomes, this study aimed to influence the future management of ACAS. METHODS: A systematic review and series of network meta-analyses were performed assessing peri-operative (within 30 days) and long term (30 days - 5 years) stroke and mortality risk between ACAS interventions. Total stroke, major, minor, ipsilateral, and contralateral stroke subtypes were assessed independently. Traditional (pre-2000) and modern (post-2000) BMT were compared to assess clinical improvements in medical therapy over the previous two decades. Risks of myocardial infarction (MI) and cranial nerve injury (CNI) were also assessed. RESULTS: Seventeen reports of 14 310 patients with > 50% ACAS were included. CEA reduced the odds of a peri-operative stroke event occurring vs. CAS (odds ratio [OR] 1.6, 95% confidence interval [CI] 1.1 - 2.2 [0 - 20 fewer/1 000]). CEA and CAS reduced the long term odds of minor strokes (OR 0.35, 95% CI 0.21 - 0.59 [20 fewer/1 000]) and ipsilateral strokes (OR 0.27, 95% CI 0.19 - 0.39 [30 fewer/1 000]) vs. all BMT. CEA reduced the odds of major strokes and combined stroke and mortality vs. traditional BMT; however, no difference was found between CEA and modern BMT. CAS reduced the odds of peri-operative MI (OR 0.49, 95% CI 0. 26 - 0.91) and CNI (OR 0.07, 95% CI 0.01 - 0.42) vs. CEA. CONCLUSION: Modern BMT demonstrates similar reductions in major stroke, combined stroke, and mortality to CEA. The overall risk reductions are low and data were unavailable to assess subgroups which may benefit from intervention. However, BMT carries the potential to reduce the requirement for surgical intervention in patients with ACAS.

Reversing the direction of drug transport mediated by the human multidrug transporter P-glycoprotein.

P-glycoprotein (P-gp), also known as ABCB1, is a cell membrane transporter that mediates the efflux of chemically dissimilar amphipathic drugs and confers resistance to chemotherapy in most cancers. Homologous transmembrane helices (TMHs) 6 and 12 of human P-gp connect the transmembrane domains with its nucleotide-binding domains, and several residues in these TMHs contribute to the drug-binding pocket. To investigate the role of these helices in the transport function of P-gp, we substituted a group of 14 conserved residues (seven in both TMHs 6 and 12) with alanine and generated a mutant termed 14A. Although the 14A mutant lost the ability to pump most of the substrates tested out of cancer cells, surprisingly, it acquired a new function. It was able to import four substrates, including rhodamine 123 (Rh123) and the taxol derivative flutax-1. Similar to the efflux function of wild-type P-gp, we found that uptake by the 14A mutant is ATP hydrolysis-, substrate concentration-, and time-dependent. Consistent with the uptake function, the mutant P-gp also hypersensitizes HeLa cells to Rh123 by 2- to 2.5-fold. Further mutagenesis identified residues from both TMHs 6 and 12 that synergistically form a switch in the central region of the two helices that governs whether a given substrate is pumped out of or into the cell. Transforming P-gp or an ABC drug exporter from an efflux transporter into a drug uptake pump would constitute a paradigm shift in efforts to overcome cancer drug resistance.

Adipose-derived stem cells in patients with venous ulcers: Systematic review.

OBJECTIVES: Few studies have reported on the safety and durability of adipose-derived stem cells (ADSCs) to support healing in patients with venous leg ulcers (VLU). To establish if there is any evidence to support ADSC use in VLU patients, a systematic review was conducted. METHODS: A systematic review was conducted following the PRISMA guidelines. PubMed and Embase databases were searched for relevant papers. References from retrieved papers were reviewed to identify any extra eligible studies. RESULTS: After duplicate removal, 950 papers were screened for eligibility of which 932 were excluded based on title and abstract. Four papers were included in the final analysis (one randomised study and three non-randomised studies). 66 patients in total received ADSCs for VLU treatment. The only randomised paper reported 6-month healing rates of 75% with ADSCs compared to 50% in controls. 100% healing was achieved in one study. The remaining 2 studies reported 25% and 58% healing; however, they included patients with relatively large VLUs. Pain scores decreased after ADSCs application where reported. No serious procedure related complications were reported. CONCLUSION: ADSCs may enhance ulcer healing in patients with chronic VLU and appears safe based on initial reports. Large, randomised trials are needed to definitively establish the technique's role in VLU patients.

Systematic review of the relationship between Hollenhorst plaques and cerebrovascular events.

BACKGROUND: Few studies have evaluated the association between asymptomatic cholesterol emboli on fundoscopy (known as Hollenhorst plaque) and the subsequent risk of stroke or death.1. AIM: To evaluate the association between the presence of asymptomatic cholesterol retinal emboli and the risk of cerebrovascular events, with assessment of the need for carotid intervention. METHODS: PubMed, Embase, and Cochrane Library databases were searched using appropriate terms. The systematic review was conducted according to PRISMA guidelines. RESULTS: Initial search revealed 43 in Medline and 46 in Embase databases. Twenty-four potentially eligible studies were included after duplicate and non-related studies were excluded based on title and abstract. Three more studies were identified from reference lists. Seventeen studies were included in the final analysis. Asymptomatic cholesterol emboli were present in 1343 patients. Approximately 17.8% (n = 181) had history of either cerebro-vascular Accident (CVA) or transient ischaemic attacks (TIAs) at presentation (more than 6 months). Nine studies mentioned the incidence of cerebrovascular events during follow-up. Of 780 patients, 93 evolved to stroke, TIAs, or death from a major carotid event during the follow-up period (6-86 m), an incidence of about 12%. Death due to stroke was documented in 3 studies (n = 12). CONCLUSION: The presence of asymptomatic retinal emboli indicates a risk of a cerebrovascular event when compared to patients with no plaques seen on fundoscopy. The evidence suggests that these patients warrant referral for medical optimization of cardiovascular risk factors. Currently, there is no recommendation to support carotid endarterectomy in patients with Hollenhorst plaques, or retinal emboli, and further studies are needed to assess this.

Reintervention and mortality risk after total anomalous pulmonary venous connection repair.

BACKGROUND: Management of total anomalous pulmonary venous connections has been extensively studied to further improve outcomes. Our institution previously reported factors associated with mortality, recurrent obstruction, and reintervention. The study purpose was to revisit the cohort of patients and evaluate factors associated with reintervention, and mortality in early and late follow-up. METHODS: A retrospective review at our institution identified 81 patients undergoing total anomalous pulmonary venous connection repair from January 2002 to January 2018. Demographic and operative variables were evaluated. Anastomotic reintervention (interventional or surgical) and/or mortality were primary endpoints. RESULTS: Eighty-one patients met the study criteria. Follow-up ranged from 0 to 6,291 days (17.2 years), a mean of 1263 days (3.5 years). Surgical mortality was 16.1% and reintervention rates were 19.8%. In re-interventions performed, 80% occurred within 1.2 years, while 94% of mortalities were within 4.1 months. Increasing cardiopulmonary bypass times (p = 0.0001) and the presence of obstruction at the time of surgery (p = 0.025) were predictors of mortality, while intracardiac total anomalous pulmonary venous connection type (p = 0.033) was protective. Risk of reintervention was higher with increasing cardiopulmonary bypass times (p = 0.015), single ventricle anatomy (p = 0.02), and a post-repair gradient >2 mmHg on transesophageal echocardiogram (p = 0.009). CONCLUSIONS: Evaluation of a larger cohort with longer follow-up demonstrated the relationship of anatomic complexity and symptoms at presentation to increased mortality risk after total anomalous pulmonary venous connection repair. The presence of a single ventricle or a post-operative confluence gradient >2 mmHg were risk factors for reintervention. These findings support those found in our initial study.

The role of tranexamic acid in reducing post-operative bleeding and seroma formation in breast surgery: A meta-analysis.

INTRODUCTION: Tranexamic acid (TXA) reduces blood loss and blood transfusion requirements in surgery. Seroma and haematoma formation occur as complications of breast surgery. We aimed to perform a meta-analysis evaluating TXA in reducing post-operative haematoma and seroma formation for breast surgery. METHODS: A systematic review was performed in accordance with PRISMA guidelines. Results were expressed as dichotomous variables pooled as odds ratios (OR) with corresponding 95% confidence intervals (CIs) using the Mantel-Haenszel method. RESULTS: Seven studies including 1446 patients were included. There were 1830 breast surgery procedures performed with TXA administered in 797 cases (43.6%). There was a significant reduction in haematoma rates in the TXA group (TXA: 3.184% (22/691) vs Control: 6.787% (64/943), OR: 0.41, 95% CI: 0.20-0.86, P = 0.020). Based on surgical procedure, haematoma rates were similar for TXA and control groups in cancer surgery (P = 0.230). Haematoma rates reduced following TXA use in cosmetic procedures (TXA: 3.807% (15/394) vs. Control: 9.091% (34/374), OR: 0.41, 95% CI: 0.22-0.75, P = 0.004). Haematoma rates were also reduced in procedures where axillary lymph node dissection (ALND) was not performed; in the TXA group, 3.379% (22/651) developed a haematoma versus 6.623% (60/906) in the control group (OR: 0.45, 95% CI 0.27-0.77, P = 0.003). TXA administration did not impact seroma formation or infection rates. CONCLUSION: Perioperative administration of TXA may impact the incidence of haematoma in breast surgery, particularly in cosmetic procedures and procedures without ALND. Well-designed randomised studies are required to determine its true efficacy. TXA has no effect on seroma formation or infection in breast surgery.

Physiological responses to treadmill exercise in size- and fitness-matched male and female firefighter applicants.

Physiological responses during a standardised treadmill test for structural firefighting employment were compared in 41 pairs of size-matched, male and female applicants. Applicants wore personal exercise clothing, running shoes, and fire protective ensemble with self-contained breathing apparatus (added mass 21.2 ± 1.0 kg). Applicants walked at 1.56 m·s-1, completing a 5-min warm-up, 8-min at 10% grade, and then, progressive 1-min stages to exhaustion. The cut-score required completion of 13-min of exercise. Up to the cut-score, no differences in heart rate, oxygen uptake or minute ventilation were detected between sexes. At time 12:30-13:00 min, V̇O2 was 45.7 ± 0.6 vs. 44.2 ± 0.5 mL·kg-1·min-1 (body mass) for males and females, respectively. Despite similar physiological responses at minute 13, females worked at higher fractions of peak than males (p < 0.05). A second analysis compared a subset of 27 fitness-matched (V̇O2peak) male-female pairs. Fitness-matching further reduced or eliminated most observed differences in physiological responses, except small differences in breathing pattern. Practitioner Summary: Physiological responses during a standardised treadmill test for firefighter applicants were investigated in male and female applicants matched on size and fitness. Absolute responses to exercise were the same for both sexes when size-matched, but relative intensity was higher for females. Fitness-matching reduced or eliminated most previously observed differences. Abbreviations: NFPA: National Fire Protection Association; V̇O2: rate of oxygen consumption; V̇O2peak: rate of oxygen consumption at peak exercise; PAR-Q+: Physical Activity Readiness Questionnaire Plus; SCBA: self-contained breathing apparatus; ANOVA: analysis of variance; V̇E: minute ventilation; V̇Epeak: minute ventilation at peak exercise; V̇E/V̇O2: ventilatory equivalent for oxygen.

Vascular access device type for systemic anti-cancer therapies: a scoping review protocol.

INTRODUCTION: Vascular access devices (VADs) are the most common invasive procedure performed in acute medicine and cancer patients undergo multiple invasive vascular access procedures. Our aim is to identify the type of evidence available regarding the best choice of VAD for cancer patients undergoing systemic anti-cancer therapy (SACT). In this article, the authors frame the scoping review protocol used, which will systematically report all published and unpublished literature around the use of VADs for the infusion of SACT in oncology. INCLUSION CRITERIA: For studies to be included, they must focus on people or populations aged 18 years or older and report on vascular access in cancer patients. The concept is the variety of VAD use in cancer and reported insertion and post-insertion complications. The context surrounds the intravenous treatment of SACT whether in a cancer centre or non-cancer setting. METHODS: The JBI scoping review methodology framework will guide the conduct of this scoping review. Electronic databases (CINAHL, Cochrane, Medline and Embase) will be searched. Grey literature sources and the reference lists of key studies will be reviewed to identify those appropriate for inclusion. No date limits will be used in the searches and studies will be limited to the English language. Two reviewers will independently screen all titles and abstracts and full-text studies for inclusion, and a third reviewer will arbitrate disagreements. All bibliographic data, study characteristics and indicators will be collected and charted using a data extraction tool.

The amyloid concentric ß-barrel hypothesis: Models of synuclein oligomers, annular protofibrils, lipoproteins, and transmembrane channels.

Amyloid beta (Aß of Alzheimer's disease) and α-synuclein (α-Syn of Parkinson's disease) form large fibrils. Evidence is increasing however that much smaller oligomers are more toxic and that these oligomers can form transmembrane ion channels. We have proposed previously that Aß42 oligomers, annular protofibrils, and ion channels adopt concentric ß-barrel molecular structures. Here we extend that hypothesis to the superfamily of α, ß, and γ-synucleins. Our models of numerous synuclein oligomers, annular protofibrils, tubular protofibrils, lipoproteins, and ion channels were developed to be consistent with sizes, shapes, molecular weights, and secondary structures of assemblies as determined by electron microscopy and other studies. The models have the following features: (1) all subunits have identical structures and interactions; (2) they are consistent with conventional ß-barrel theory; (3) the distance between walls of adjacent ß-barrels is between 0.6 and 1.2 nm; (4) hydrogen bonds, salt bridges, interactions among aromatic side-chains, burial and tight packing of hydrophobic side-chains, and aqueous solvent exposure of hydrophilic side-chains are relatively optimal; and (5) residues that are identical among distantly related homologous proteins cluster in the interior of most oligomers whereas residues that are hypervariable are exposed on protein surfaces. Atomic scale models of some assemblies were developed.

The amyloid concentric ß-barrel hypothesis: Models of amyloid beta 42 oligomers and annular protofibrils.

Amyloid beta (Aß) peptides are a major contributor to Alzheimer's disease. They occur in differing lengths, each of which forms a multitude of assembly types. The most toxic soluble oligomers are formed by Aß42; some of which have antiparallel ß-sheets. Previously, our group proposed molecular models of Aß42 hexamers in which the C-terminus third of the peptide (S3) forms an antiparallel 6-stranded ß-barrel that is surrounded by an antiparallel barrel formed by the more polar N-terminus (S1) and middle (S2) portions. These hexamers were proposed to act as seeds from which dodecamers, octadecamers, both smooth annular protofibrils (sAPFs) and beaded annular protofibrils (bAPFs), and transmembrane channels form. Since then, numerous aspects of our models have been supported by experimental findings. Recently, NMR-based structures have been proposed for Aß42 tetramers and octamers, and NMR studies have been reported for oligomers composed of ~32 monomers. Here we propose a range of concentric ß-barrel models and compare their dimensions to image-averaged electron micrographs of both bAPFs and sAPFs of Aß42. The smaller oligomers have 6, 8, 12, 16, and 18 monomers. These beads string together to form necklace-like bAPFs. These bAPRs gradually morph into sAPFs in which a S3 ß-barrel is shielded on one or both sides by ß-barrels formed from S1 and S2 segments.

Outcomes of Saphenous Vein Intervention in the Management of Superficial Venous Incompetence: A Systematic Review and Network Meta-analysis.

OBJECTIVE: To determine the most effective modality of intervention to treat saphenous vein insufficiency. SUMMARY OF BACKGROUND DATA: Endovenous therapies have instigated a paradigm shift in the management of superficial venous incompetence. When compared with open surgery, endovenous interventions (foam sclerotherapy, radiofrequency ablation, endovenous laser ablation (EVLA), mechanochemical ablation, and CAE closure) potentially offer reduced morbidity with similar procedural efficacy. METHODS: A systematic review and series of network meta-analyses of randomized controlled trials were performed assessing risks of procedural failure (within 6-weeks) and recurrence (6-weeks to 5-years), defined by ultrasound, between the different modalities of intervention for superficial venous incompetence. Treatment comparisons addressing risks of common adverse events, venous clinical severity score, and pain were also performed. RESULTS: A systematic search identified 51 articles, describing 36 randomized controlled trials, incorporating 7576 limbs. Outcome data on 10 modalities of intervention were analyzed up to 5-year follow-up. CAE resulted in the lowest risk of procedural failure within 6-weeks. Foam sclerotherapy had the highest risk of recurrence while high ligation with stripping (HLS) and Conservatrice Hemodynamique de l'Insuffisance Veineuse en Ambulatoire were ranked best to reduce long-term recurrence. No intervention increased risks of venous thromboembolism and there was minimal difference in morbidity between treatments. All interventions improved venous clinical severity score (range -1.02 to -4.95), however, radiofrequency ablation demonstrated the greatest improvement, followed by EVLA and HLS between 2 to 5-years. EVLA was associated with the highest risk of pain, while mechanochemical ablation offered the least. CONCLUSIONS: Although CAE offered the lowest risk of initial procedural failure, HLS resulted in lower rates of long-term recurrence without considerably increasing morbidity when compared with other endovenous options.

Common genetic variants do not predict recurrent events in coronary heart disease patients.

BACKGROUND: It is unclear whether genetic variants identified from single nucleotide polymorphisms (SNPs) strongly associated with coronary heart disease (CHD) in genome-wide association studies (GWAS), or a genetic risk score (GRS) derived from them, can help stratify risk of recurrent events in patients with CHD. METHODS: Study subjects were enrolled at the close-out of the LIPID randomised controlled trial of pravastatin vs placebo. Entry to the trial had required a history of acute coronary syndrome 3-36 months previously, and patients were in the trial for a mean of 36 months. Patients who consented to a blood sample were genotyped with a custom designed array chip with SNPs chosen from known CHD-associated loci identified in previous GWAS. We evaluated outcomes in these patients over the following 10 years. RESULTS: Over the 10-year follow-up of the cohort of 4932 patients, 1558 deaths, 898 cardiovascular deaths, 727 CHD deaths and 375 cancer deaths occurred. There were no significant associations between individual SNPs and outcomes before or after adjustment for confounding variables and for multiple testing. A previously validated 27 SNP GRS derived from SNPs with the strongest associations with CHD also did not show any independent association with recurrent major cardiovascular events. CONCLUSIONS: Genetic variants based on individual single nucleotide polymorphisms strongly associated with coronary heart disease in genome wide association studies or an abbreviated genetic risk score derived from them did not help risk profiling in this well-characterised cohort with 10-year follow-up. Other approaches will be needed to incorporate genetic profiling into clinically relevant stratification of long-term risk of recurrent events in CHD patients.

COVID-19 ethnic inequalities in mental health and multimorbidities: protocol for the COVEIMM study.

PURPOSE: The COVID-19 pandemic may have exacerbated ethnic health inequalities, particularly in people with multiple long-term health conditions, the interplay with mental health is unclear. This study investigates the impact of the pandemic on the association of ethnicity and multimorbidity with mortality/service use among adults, in people living with severe mental illnesses (SMI). METHODS: This study will utilise secondary mental healthcare records via the Clinical Record Interactive Search (CRIS) and nationally representative primary care records through the Clinical Practice Interactive Research Database (CPRD). Quasi-experimental designs will be employed to quantify the impact of COVID-19 on mental health service use and excess mortality by ethnicity, in people living with severe mental health conditions. Up to 50 qualitative interviews will also be conducted, co-produced with peer researchers; findings will be synthesised with quantitative insights to provide in-depth understanding of observed associations. RESULTS: 81,483 people in CRIS with schizophrenia spectrum, bipolar or affective disorder diagnoses, were alive from 1st January 2019. Psychiatric multimorbidities in the CRIS sample were comorbid somatoform disorders (30%), substance use disorders (14%) and personality disorders (12%). In CPRD, of 678,842 individuals with a prior probable diagnosis of COVID-19, 1.1% (N = 7493) had an SMI diagnosis. People in the SMI group were more likely to die (9% versus 2% in the non-SMI sample) and were more likely to have mental and physical multimorbidities. CONCLUSION: The effect of COVID-19 on people from minority ethnic backgrounds with SMI and multimorbidities remains under-studied. The present mixed methods study aims to address this gap.

Excessive daytime sleepiness, morning tiredness and major adverse cardiovascular events in patients with chronic coronary syndrome.

BACKGROUND: Sleep-related breathing disorders (SRBDs), particularly obstructive sleep apnoea, are associated with increased cardiovascular (CV) risk. However, it is not known whether individual questions used for SRBD screening are associated with major adverse CV events (MACE) and death specifically in patients with chronic coronary syndrome (CCS). METHODS: Symptoms associated with SRBD were assessed by a baseline questionnaire in 15,640 patients with CCS on optimal secondary preventive therapy in the STABILITY trial. The patients reported the frequency (never/rarely, sometimes, often and always) of: 1) loud snoring; 2) more than one awakening/night; 3) morning tiredness (MT); 4) excessive daytime sleepiness (EDS); or 5) gasping, choking or apnoea when asleep. In adjusted Cox regression models, associations between the frequency of SRBD symptoms and CV outcomes were assessed with never/rarely as reference. RESULTS: During a median follow-up time of 3.7 years, 1,588 MACE events (541 CV deaths, 749 nonfatal myocardial infarctions [MI] and 298 nonfatal strokes) occurred. EDS was associated (hazard ratio [HR], 95% confidence interval [CI]) with increased risk of MACE (sometimes 1.14 [1.01-1.29], often 1.19 [1.01-1.40] and always 1.43 [1.15-1.78]), MI (always 1.61 [1.17-2.20]) and all-cause death (often 1.26 [1.05-1.52] and always 1.71 [1.35-2.15]). MT was associated with higher risk of MACE (often 1.23 [1.04-1.45] and always 1.46 [1.18-1.81]), MI (always 1.61 [1.22-2.14]) and all-cause death (always 1.54 [1.20-1.98]). The other SRBD-related questions were not consistently associated with worse outcomes. CONCLUSIONS: In patients with CCS, gradually higher levels of EDS and MT were independently associated with increased risk of MACE, including mortality.

Systematic review and meta-analysis of endovascular interventions for Stanford type A aortic dissection.

OBJECTIVE: The standard surgical approach to Stanford type A aortic dissection is open repair. However, up to one in four patients will be declined surgery because of prohibitive risk. Patients who are treated nonoperatively have an unacceptably high mortality. Endovascular repair of the ascending aorta is emerging as an alternative treatment for a select group of patients. The reported rates of technical success, mortality, stroke, and reintervention have varied. The objective of the study was to systematically report outcomes for acute type A dissections repaired using an endovascular approach. METHODS: The systematic review and meta-analysis was conducted in accordance with the PRISMA (preferred reporting items for systematic reviews and meta-analyses) guidelines. We performed online literature database searches through April 2020. The demographic and procedural characteristics of the individual studies were tabulated. Data on technical success, short-term mortality, stroke, and reintervention were extracted and underwent meta-analysis using a random effects model. RESULTS: Fourteen studies with 80 cases of aortic dissection (55 acute and 25 subacute) were included in the final analysis. A wide variation was found in technique and device design across the studies. The outcomes rates were estimated at 17% (95% confidence interval [CI], 10%-26%) for mortality, 15% (95% CI, 8%-23%) for technical failure, 11% (95% CI, 6%-19%) for stroke and 18% (95% CI, 9%-31%) for reintervention. The mean Downs and Black quality assessment score was 13.9 ± 3.2. CONCLUSIONS: The technique for endovascular repair of type A aortic dissection is feasible and reproducible. The results of our meta-analysis demonstrate an acceptable safety profile for inoperable patients who otherwise would have an extremely poor prognosis. Data from clinical trials are required before the technique can be introduced into routine clinical practice.

Using a quality improvement initiative to reduce acute kidney injury during on-pump coronary artery bypass grafting.

INTRODUCTION: In response to a perceived high incidence of acute kidney injury following cardiopulmonary bypass at our institution, a quality improvement initiative consisting of a systematic change to a delivered oxygen (DO2) goal-directed perfusion practice was implemented. We sought to maintain DO2 > 270 mL/min/m2 to reduce the incidence of acute kidney injury. METHODS: 'The study population included all patients receiving isolated, non-emergent, on-pump coronary artery bypass grafting from January 2015 through December 2018, excluding patients requiring preoperative hemodialysis. DO2 goal-directed perfusion was instituted in February 2017. Acute kidney injury was defined using Acute Kidney Injury Network criteria. RESULTS: The pre-goal-directed perfusion cohort included 257 patients, and the post-goal-directed perfusion cohort included 226 patients. The DO2 was significantly higher in the post-goal-directed perfusion group (p < 0.001). Postoperative change in serum creatinine and incidence of acute kidney injury were significantly lower in the post-goal-directed perfusion group (p < 0.001, p = 0.001, respectively). Estimation with probit and ordered probit models support these findings. CONCLUSION: This initiative confirms previous assertions that DO2 is a critical intraoperative parameter and should direct perfusion intervention accordingly.