A novel homozygous missense TTC12 variant identified in an infertile Pakistani man with severe oligoasthenoteratozoospermia and primary ciliary dyskinesia.

TTC12 is a cytoplasmic and centromere-localized protein that plays a role in the proper assembly of dynein arm complexes in motile cilia in both respiratory cells and sperm flagella. This finding underscores its significance in cellular motility and function. However, the wide role of TTC12 in human spermatogenesis-associated primary ciliary dyskinesia (PCD) still needs to be elucidated. Whole-exome sequencing (WES) and Sanger sequencing were performed to identify potentially pathogenic variants causing PCD and multiple morphological abnormalities of sperm flagella (MMAF) in an infertile Pakistani man. Diagnostic imaging techniques were used for PCD screening in the patient. Real-time polymerase chain reaction (RT‒PCR) was performed to detect the effect of mutations on the mRNA abundance of the affected genes. Papanicolaou staining and scanning electron microscopy (SEM) were carried out to examine sperm morphology. Transmission electron microscopy (TEM) was performed to examine the ultrastructure of the sperm flagella, and the results were confirmed by immunofluorescence staining. Using WES and Sanger sequencing, a novel homozygous missense variant (c.C1069T; p.Arg357Trp) in TTC12 was identified in a patient from a consanguineous family. A computed tomography scan of the paranasal sinuses confirmed the symptoms of the PCD. RT-PCR showed a decrease in TTC12 mRNA in the patient's sperm sample. Papanicolaou staining, SEM, and TEM analysis revealed a significant change in shape and a disorganized axonemal structure in the sperm flagella of the patient. Immunostaining assays revealed that TTC12 is distributed throughout the flagella and is predominantly concentrated in the midpiece in normal spermatozoa. In contrast, spermatozoa from patient deficient in TTC12 showed minimal staining intensity for TTC12 or DNAH17 (outer dynein arms components). This could lead to MMAF and result in male infertility. This novel TTC12 variant not only illuminates the underlying genetic causes of male infertility but also paves the way for potential treatments targeting these genetic factors. This study represents a significant advancement in understanding the genetic basis of PCD-related infertility.

Improving the substrate binding of acetyl-CoA carboxylase (AccB) from Streptomyces antibioticus through computational enzyme engineering.

Malonyl-CoA serves as the main building block for the biosynthesis of many important polyketides, as well as fatty acid-derived compounds, such as biofuel. Escherichia coli, Corynebacterium gultamicum, and Saccharomyces cerevisiae have recently been engineered for the biosynthesis of such compounds. However, the developed processes and strains often have insufficient productivity. In the current study, we used enzyme-engineering approach to improve the binding of acetyl-CoA with ACC. We generated different mutations, and the impact was calculated, which reported that three mutations, that is, S343A, T347W, and S350W, significantly improve the substrate binding. Molecular docking investigation revealed an altered binding network compared to the wild type. In mutants, additional interactions stabilize the binding of the inner tail of acetyl-CoA. Using molecular simulation, the stability, compactness, hydrogen bonding, and protein motions were estimated, revealing different dynamic properties owned by the mutants only but not by the wild type. The findings were further validated by using the binding-free energy (BFE) method, which revealed these mutations as favorable substitutions. The total BFE was reported to be -52.66 ± 0.11 kcal/mol for the wild type, -55.87 ± 0.16 kcal/mol for the S343A mutant, -60.52 ± 0.25 kcal/mol for T347W mutant, and -59.64 ± 0.25 kcal/mol for the S350W mutant. This shows that the binding of the substrate is increased due to the induced mutations and strongly corroborates with the docking results. In sum, this study provides information regarding the essential hotspot residues for the substrate binding and can be used for application in industrial processes.

Percutaneous Coronary Intervention Versus Coronary Artery Bypass Grafting for Patients With Three Vessel Coronary Artery Disease: A Comparison of Centers in the Same Jurisdiction With Differing Multidisciplinary Heart Team Approaches.

OBJECTIVES: Referral patterns and outcomes of percutaneous coronary intervention (PCI) and coronary artery bypass grafting (CABG) were compared between 2 centers within 1 jurisdiction wherein only 1 center utilizes multidisciplinary review for all patients. BACKGROUND: Management of advanced coronary artery disease often involves PCI and CABG for improvements in quality of life and survival. Indications exist for PCI and CABG, with CABG demonstrating benefit in three-vessel disease (TVD). METHODS: A total of 27,961 patients underwent cardiac catheterization in 2 centers within the same single-payer health jurisdiction (Center A and B) from 2017 to 2018. Rates of PCI, CABG, and outcomes of 1-year mortality, rehospitalization, myocardial infarction, and stroke were compared. RESULTS: More patients in Center A received PCI and less received CABG compared with Center B even among patients with TVD ( P <0.001). Multivariable logistic regression identified Center B as protective for mortality for TVD patients ( P <0.001) and those undergoing PCI ( P =0.004), but not CABG ( P =0.06). Center A's 1-year mortality was increased for all patients ( P =0.004) and those with TVD ( P =0.011). CONCLUSION: Discordant outcomes exist between these 2 centers. While patients in Center A were more likely to undergo PCI than Center B and experienced decreased 1-year survival, the difference was not significant for CABG. In part, the differences are attributable to contrasting referral practices and the discrepant rates of PCI and CABG between centers. Review of all coronary artery disease patients with a multidisciplinary Heart Team including a surgical opinion may lead to a more evidence-based referral practice aligned with current clinical guidelines.

Synthesis and Biological Evaluation of Octahydroquinazolinones as Phospholipase A2, and Protease Inhibitors: Experimental and Theoretical Exploration.

Phospholipase A2 (PLA2) promotes inflammation via lipid mediators and releases arachidonic acid (AA), and these enzymes have been found to be elevated in a variety of diseases, including rheumatoid arthritis, sepsis, and atherosclerosis. The mobilization of AA by PLA2 and subsequent synthesis of prostaglandins are regarded as critical events in inflammation. Inflammatory processes may be treated with drugs that inhibit PLA2, thereby blocking the COX and LOX pathways in the AA cascade. To address this issue, we report herein an efficient method for the synthesis of a series of octahydroquinazolinone compounds (4a-h) in the presence of the catalyst Pd-HPW/SiO2 and their phospholipase A2, as well as protease inhibitory activities. Among eight compounds, two of them exhibited overwhelming results against PLA2 and protease. By using FT-IR, Raman, NMR, and mass spectroscopy, two novel compounds were thoroughly studied. After carefully examining the SAR of the investigated compounds against these enzymes, it was found that compounds (4a, 4b) containing both electron-donating and electron-withdrawing groups on the phenyl ring exhibited higher activity than compounds with only one of these groups. DFT studies were employed to study the electronic nature and reactivity properties of the molecules by optimizing at the BLYP/cc-pVDZ. Natural bond orbitals helped to study the various electron delocalizations in the molecules, and the frontier molecular orbitals helped with the reactivity and stability parameters. The nature and extent of the expressed biological activity of the molecule were studied using molecular docking with human non-pancreatic secretory phospholipase A2 (hnps-PLA2) (PDB ID: 1DB4) and protease K (PDB ID: 2PWB). The drug-ability of the molecule has been tested using ADMET, and pharmacodynamics data have been extracted. Both the compounds qualify for ADME properties and follow Lipinski's rule of five.

Testis-specific fascin component FSCN3 is dispensable for mouse spermatogenesis and fertility.

BACKGROUND: Fascins belong to a family of actin-bundling proteins that are involved in a wide range of biological functions. FSCN3, a newly identified testis-specific actin-bundling protein, is specifically expressed in elongated spermatids. However, its in vivo function in mouse spermiogenesis remains unknown. METHODS AND RESULTS: We generated Fscn3 knockout mice through CRISPR/Cas9 gene-editing technology. Fscn3-/- mice displayed normal testis morphology and testis to bodyweight ratio, and sperm concentrations did not differ significantly between Fscn3+/+ and Fscn3-/- mice. Fertility assays consistently revealed that Fscn3-/- mice are completely fertile and their reproductive status does not differ from that of wild-type. Moreover, hematoxylin and eosin staining of the testis sections of Fscn3-/- mice detected various germ cells, ranging from spermatogonia to mature spermatozoa. Furthermore, the swimming velocity of the sperm of Fscn3-/- mice was comparable to that of their wild-type littermates. Both Fscn3+/+ and Fscn3-/-mice had normal sperm morphology, indicating that the disruption of Fscn3 does not affect sperm morphology. The analysis of meiotic prophase I progression demonstrated normal prophase-I phases (leptonema to diplonema) in both Fscn3+/+ and Fscn3-/- mice, suggesting that Fscn3 is not essential for meiosis I. CONCLUSION: Our study provides the first evidence that FSCN3 is a testis-specific actin-bundling protein that is not required for mouse spermatogenesis. Our results will help reproductive biologists focus their efforts on genes that are crucial for fertility and avoid research duplication.

Surgical ventricular restoration for patients with heart failure.

On an annual basis, heart failure affects millions of people globally. Despite improvements in medications and percutaneous interventions, heart failure secondary to ischemic cardiomyopathy remains an important health issue. A large proportion of healthcare budgets are also dedicated to complications related to ischemic cardiomyopathy and heart failure. Drugs and mechanical devices have an ever-expanding role in our management of this growing patient population. However, cardiac transplantation continues to be the gold standard for treating advanced heart failure. Since there is a limited pool of suitable donor hearts, cardiac transplantation is not a viable option for many patients. Over the past five decades, various forms of surgical ventricular restoration have been proposed as an appealing option for treating heart failure in very select and specific cases. Given the pathophysiology of ischemic cardiomyopathy, literature suggests that, in those particular settings, reasonable results can be achieved by surgically restoring the ventricle to its original geometry. Herein, we explore the evidence on different operative techniques for ventricular restoration. We also present the latest findings for surgical ventricular restoration in patients with ischemic cardiomyopathy.

Recent insights into pathophysiology and management of mechanical complications of myocardial infarction.

PURPOSE OF REVIEW: Mechanical complications of myocardial infarction are a group of postischemic events and include papillary muscle rupture resulting in ischemic mitral regurgitation, ventricular septal defect, left ventricle free wall rupture, pseudoaneurysm, and true aneurysm. Advances made in management strategies, such as the institution of 'Code STEMI' and percutaneous interventions, have lowered the incidence of these complications. However, their presentation is still associated with increased morbidity and mortality. Early diagnosis and appropriate management is crucial for facilitating better clinical outcomes. RECENT FINDINGS: Although the exact timing of a curative intervention is not known, emerging percutaneous and transcatheter approaches and improving mechanical circulatory support (MCS) devices have greatly enhanced our ability to manage and treat some of the complications postinfarct. SUMMARY: Although the incidence of mechanical complications of myocardial infarction has decreased over the past few decades, these complications are still associated with high rates of morbidity and mortality. The combination of early and accurate diagnosis and subsequent appropriate management are imperative for optimizing clinical outcomes. Although more randomized clinical trials are needed, mechanical circulatory support devices and emerging therapeutic strategies can be offered to carefully selected patients.

Clinical and hemodynamic outcomes of the Dor procedure in adults with ischemic cardiomyopathy.

Ischemic cardiomyopathy continues to be a major contributor to congestive heart failure, which places a significant burden on our healthcare system. Improving medications and different coronary revascularization strategies are the mainstays in the management of ischemic cardiomyopathy. Although medications and mechanical circulatory support are playing an ever-increasing role, cardiac transplantation remains the gold standard for treating advanced heart failure. Given the small number of available and suitable donor hearts, transplantation is limited for the majority of patients. Surgical ventricular restoration has repeatedly been suggested as a viable alternative in managing heart failure in select patients, as it is believed that surgically returning the ventricle to its original dimensions is possible and associated with favorable outcomes. The purpose of this manuscript is to comprehensively review the current literature on various surgical strategies for ventricular restoration. We also contextualize the published data with respect to ventricular function, volume, structure, arrhythmias, mitral regurgitation, and clinical outcomes.

Delirium and depression in cardiac surgery: A comprehensive review of risk factors, pathophysiology, and management.

BACKGROUND: Mental health and wellbeing continue to gain more attention as they are inextricably associated with clinical outcomes, particularly quality of life. Many medical ailments and major surgeries affect patients' mental health, including depression and delirium. AIMS: The objective of this manuscript was to comprehensively review and critically examine the literature pertaining to cardiac surgery, depression, and delirium. METHODS: This is a narrative review article. We performed our search analysis by using the following key words: "Cardiac Surgery", "Depression", "Delirium", "Clinical outcomes", and "Mental Health". Search analysis was done on MedLine PubMed, accessing indexed peer-reviewed publications. RESULTS: Cardiac Surgery is a life-altering intervention indicated to improve morbidity and mortality in patients with cardiovascular diseases. Psychiatric conditions before and after cardiac surgery worsen patient prognosis and increase mortality rate. Specifically, preoperative depression increases postoperative depression and is associated with impaired functional status, slow physical recovery, and an increased readmission rate. DISCUSSION: Although the exact pathophysiology between depression and cardiovascular disease (CVD) is unknown, several pathways have been implicated. Unmanaged depression can also lead to other psychological conditions such as delirium. Like depression, the exact association between delirium and CVD is not well understood, but believed to be multifactorial. CONCLUSION: Herein, we provide a comprehensive review of the links between depression, delirium, and cardiovascular surgery. We critically examine the current data that pertains to the pathophysiology of these debilitating mental health issues in the context of cardiac surgery. Finally, we summarize the various treatment options available for managing depression and delirium in the cardiac surgery patient population.

Structural and Biochemical Insight into the Recruitment of Acyl Carrier Protein-Linked Extender Units in Ansamitocin Biosynthesis.

A few acyltransferase (AT) domains of modular polyketide synthases (PKSs) recruit acyl carrier protein (ACP)-linked extender units with unusual C2 substituents to confer functionalities that are not available in coenzyme A (CoA)-linked ones. In this study, an AT specific for methoxymalonyl (MOM)-ACP in the third module of the ansamitocin PKS was structurally and biochemically characterized. The AT uses a conserved tryptophan residue at the entrance of the substrate binding tunnel to discriminate between different carriers. A W275R mutation switches its carrier specificity from the ACP to the CoA molecule. The acyl-AT complex structures clearly show that the MOM-ACP accepted by the AT has the 2S instead of the opposite 2R stereochemistry that is predicted according to the biosynthetic derivation from a d-glycolytic intermediate. Together, these results reveal the structural basis of ATs recognizing ACP-linked extender units in polyketide biosynthesis.

Robot-assisted coronary artery bypass surgery: a systematic review and meta-analysis of comparative studies.

BACKGROUND: Robot-assisted coronary bypass (RCAB) surgery has been proposed as an alternative to conventional coronary artery bypass grafting (C-CABG) for managing coronary heart disease, but the evidence on its performance compared to other existing treatments is unclear. The aim of this study was to assess, through a systematic review of comparative studies, the safety and clinical effectiveness of RCAB compared to C-CABG and other minimally invasive approaches for the treatment of coronary heart disease. METHODS: We conducted a systematic review of primary studies in the English-language literature comparing RCAB to existing treatment options (C-CABG, minimally invasive direct coronary artery bypass [MIDCAB] and port-access coronary artery bypass [PA-CAB]) following Cochrane Collaboration guidelines. Meta-analyses were performed where appropriate. RESULTS: We reviewed 13 studies: 11 primary studies of RCAB (v. C-CABG in 7, v. MIDCAB in 3 and v. PA-CAB in 1) and 2 multicentre database studies (RCAB v. non-RCAB). The overall quality of the evidence was low. Most studies showed no significant benefit of RCAB over other treatments in a majority of outcome variables. Meta-analyses showed that RCAB had lower rates of pneumonia or wound infection than C-CABG, and shorter intensive care unit length of stay than C-CABG or MIDCAB. Individual studies showed that RCAB had some better outcomes than C-CABG (ventilation time, transfusion, postoperative pain, hospital length of stay) or MIDCAB (transfusion, postoperative pain, time to return to normal activities, physical functioning and hospital length of stay). The review of the database studies showed that RCAB was statistically superior to non-RCAB approaches in postoperative pain, renal failure, transfusion, reoperation for bleeding, stroke and hospital length of stay; however, the difference between the 2 groups in several of these outcomes was small. CONCLUSION: Although the findings from this review of comparative studies of RCAB appear promising and suggest that RCAB may offer some benefits to patients, in the absence of randomized controlled trials, these results should be interpreted cautiously.

CONTEXTE: Le pontage aortocoronarien assisté par robot (PACAR) a été proposé comme solution de rechange au pontage aortocoronarien classique (PACC) pour la prise en charge des coronaropathies, mais on manque de données probantes claires comparant son efficacité à celle d'autres traitements. La présente étude visait à évaluer, dans le cadre d'une revue systématique d'études comparatives, la sûreté et l'efficacité clinique du PACAR, comparativement à celles du PACC et d'autres interventions à effraction minimale visant le traitement des coronaropathies. MÉTHODES: Nous avons réalisé une revue systématique d'études primaires publiées en anglais comparant le PACAR à d'autres options thérapeutiques (PACC, pontage aortocoronarien direct à effraction minimale [PACDEM] et pontage aortocoronarien par voie percutanée [PACVP]) selon les lignes directrices de la Collaboration Cochrane, et avons réalisé des méta-analyses lorsque c'était approprié. RÉSULTATS: Nous avons retenu 13 études : 11 études primaires sur le PACAR (comparativement à 7 études sur le PACC, à 3 études sur le PACDEM et à 1 étude sur le PACVP) et 2 études multicentriques fondées sur des bases de données (PACAR contre tout autre type de PAC). Dans l'ensemble, les données probantes étaient considérées de faible qualité. Selon la plupart des études, le PACAR ne présentait aucun avantage significatif par rapport aux autres traitements, et ce, pour la majorité des issues. Les méta-analyses ont montré que le PACAR était associé à des taux de pneumonie et d'infection de la plaie plus faibles que le PACC, de même qu'à une durée d'hospitalisation en soins intensifs plus courte que le PACC et le PACDEM. Des études individuelles ont montré que le PACAR donnait lieu à de meilleures issues pour certains paramètres que le PACC (temps de ventilation, besoin de transfusion, douleur postopératoire et durée d'hospitalisation) et que le PACDEM (besoin de transfusion, douleur postopératoire, temps nécessaire pour la reprise des activités normales, fonctionnement physique et durée d'hospitalisation). La revue des études fondées sur des bases de données a indiqué que le PACAR était supérieur, sur le plan statistique, aux autres types de PAC en ce qui a trait à la douleur postopératoire, à l'insuffisance rénale, au besoin de transfusion, à la réalisation d'une autre chirurgie en raison de saignements, à l'accident vasculaire cérébral et à la durée d'hospitalisation; cependant, pour plusieurs de ces paramètres, les différences entre les 2 groupes étaient petites. CONCLUSION: Bien que les résultats de cette revue d'études comparatives sur le PACAR semblent prometteurs et laissent penser que cette intervention comporte des avantages pour les patients, ils devraient être interprétés avec prudence étant donné l'absence d'études cliniques randomisées.

Structural Insights into the Substrate Specificity of Acyltransferases from Salinomycin Polyketide Synthase.

Salinomycin with antibacterial and anticoccidial activities is a commercial polyether polyketide widely used in animal husbandry as a food additive. Malonyl-CoA (MCoA), methylmalonyl-CoA (MMCoA), and ethylmalonyl-CoA (EMCoA) are used as extension units in its biosynthesis. To understand how the salinomycin modular polyketide synthase (PKS) strictly discriminates among these extension units, the acyltransferase (AT) domains selecting MCoA, MMCoA, and EMCoA were structurally characterized. Molecular dynamics simulations of the AT structures helped to reveal the key interactions involved in enzyme-substrate recognitions, which enabled the engineering of AT mutants with switched specificity. The catalytic efficiencies ( kcat/ Km) of these AT mutants are comparable with those of the wild-type AT domains. These results set the stage for engineering the AT substrate specificity of modular PKSs.

Surgical Treatment for Ischemic Heart Failure (STICH) trial: A review of outcomes.

Coronary artery disease (CAD) is a significant source of morbidity and mortality in developed countries. The landmark Surgical Treatment for Ischemic Heart Failure (STICH) trial has provided greatly needed evidence in the management of patients with severe left ventricle (LV) dysfunction (LVEF ≤ 35%) and CAD amenable to revascularization. The trial investigated two primary hypotheses: (i) that coronary artery bypass grafting (CABG) with optimal medical therapy (OMT) was superior to OMT alone, and (ii) that CABG with surgical ventricular reconstruction (SVR) would be superior to CABG alone. The results of the 10-year follow-up demonstrated significant long-term benefits with the addition of CABG to OMT. However, the second hypothesis yielded controversial results as the study found no difference between CABG with SVR and SVR alone. The STICH trial, and the numerous subanalyses that followed have reinforced and challenged a number of widely held beliefs regarding the management of patients with severe LV dysfunction and ischemic heart failure. The purpose of this comprehensive review is to outline the published data from the STICH trial and its substudies while providing a balanced assessment of the evidence-based conclusions and criticisms that have followed.

Assays for Nucleotide Competitive Reversible and Irreversible Inhibitors of Ras GTPases.

Although the Ras protein has been seen as a potential target for cancer therapy for the past 30 years, there was a tendency to consider it undruggable until recently. This has changed with the demonstration that small molecules with a specificity for (disease related mutants of) Ras can indeed be found, and some of these molecules form covalent adducts. A subgroup of these molecules can be characterized as competing with binding of the natural ligands GTP and GDP. Because of the distinct properties of Ras and related GTPases, in particular the very high nucleotide affinities and associated very low dissociation rates, assays for characterizing such molecules are not trivial. This is compounded by the fact that Ras family GTPases tend to be thermally unstable in the absence of a bound nucleotide. Here, we show that instead of using the unstable nucleotide-free Ras, the protein can be isolated as a 1:1 complex with a modified nucleotide (GDP-ß-methyl ester) with low affinity to Ras. With this nucleotide analogue bound to the protein, testing of inhibitors is made experimentally more convenient and we present assays that allow the rapid assessment of the kinetic constants describing the inhibition process.

Ten-Year Outcomes After Coronary Artery Bypass Grafting According to Age in Patients With Heart Failure and Left Ventricular Systolic Dysfunction: An Analysis of the Extended Follow-Up of the STICH Trial (Surgical Treatment for Ischemic Heart Failure).

BACKGROUND: Advancing age is associated with a greater prevalence of coronary artery disease in heart failure with reduced ejection fraction and with a higher risk of complications after coronary artery bypass grafting (CABG). Whether the efficacy of CABG compared with medical therapy (MED) in patients with heart failure caused by ischemic cardiomyopathy is the same in patients of different ages is unknown. METHODS: A total of 1212 patients (median follow-up, 9.8 years) with ejection fraction ≤35% and coronary disease amenable to CABG were randomized to CABG or MED in the STICH trial (Surgical Treatment for Ischemic Heart Failure). RESULTS: Mean age at trial entry was 60 years; 12% were women; 36% were nonwhite; and the baseline ejection fraction was 28%. For the present analyses, patients were categorized by age quartiles: quartile 1, ≤54 years; quartile, 2 >54 and ≤60 years; quartile 3, >60 and ≤67 years; and quartile 4, >67 years. Older versus younger patients had more comorbidities. All-cause mortality was higher in older compared with younger patients assigned to MED (79% versus 60% for quartiles 4 and 1, respectively; log-rank P=0.005) and CABG (68% versus 48% for quartiles 4 and 1, respectively; log-rank P<0.001). In contrast, cardiovascular mortality was not statistically significantly different across the spectrum of age in the MED group (53% versus 49% for quartiles 4 and 1, respectively; log-rank P=0.388) or CABG group (39% versus 35% for quartiles 4 and 1, respectively; log-rank P=0.103). Cardiovascular deaths accounted for a greater proportion of deaths in the youngest versus oldest quartile (79% versus 62%). The effect of CABG versus MED on all-cause mortality tended to diminish with increasing age (Pinteraction=0.062), whereas the benefit of CABG on cardiovascular mortality was consistent over all ages (Pinteraction=0.307). There was a greater reduction in all-cause mortality or cardiovascular hospitalization with CABG versus MED in younger compared with older patients (Pinteraction=0.004). In the CABG group, cardiopulmonary bypass time or days in intensive care did not differ for older versus younger patients. CONCLUSIONS: CABG added to MED has a more substantial benefit on all-cause mortality and the combination of all-cause mortality and cardiovascular hospitalization in younger compared with older patients. CABG added to MED has a consistent beneficial effect on cardiovascular mortality regardless of age. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique identifier: NCT00023595.

Environment effects for earliness and grain yield traits in F1 diallel populations of maize (Zea mays L.).

BACKGROUND: Five maize inbred lines, 20 F1 diallel hybrids and two check genotypes were evaluated through genotype × environment interaction (GEI) and GGE biplot for earliness and yield traits at four locations. RESULTS: Genotype, environment and GEI showed highly significant differences for all the traits. In total sum of squares, environment and genotype played a primary role, followed by GEI. Larger effects of environment and genotype to total variation influence the earliness and yield traits. However, according to the GGE biplot, the first two principal components (PC1 and PC2) explained 95% of the variation caused by GEI. GGE biplot confirmed the differential response of genotypes across environments. F1 hybrid SWAJK-1 × FRHW-3 had better stability, with a good yield, and was considered an ideal genotype. F1 hybrid FRHW-2 × FRHW-1 showed more earliness at CCRI and Haripur, followed by PSEV3 × FRHW-2 and its reciprocal at Swat and Mansehra, respectively. F1 hybrids FRHW-1 × SWAJK-1, PSEV3 × SWAJK-1 and SWAJK-1 × FRHW-3 at Mansehra and Swat produced maximum grain yield, followed by SWAJK-1 × FRHW-1 and PSEV3 × FRHW-1 at Haripur and CCRI, respectively. CONCLUSION: Overall, maize genotypes showed early maturity in plain areas (CCRI and Haripur) but higher yield in hilly areas (Mansehra and Swat). © 2017 Society of Chemical Industry.

Effects of remote ischemic preconditioning in high-risk patients undergoing cardiac surgery (Remote IMPACT): a randomized controlled trial.

BACKGROUND: Remote ischemic preconditioning is a simple therapy that may reduce cardiac and kidney injury. We undertook a randomized controlled trial to evaluate the effect of this therapy on markers of heart and kidney injury after cardiac surgery. METHODS: Patients at high risk of death within 30 days after cardiac surgery were randomly assigned to undergo remote ischemic preconditioning or a sham procedure after induction of anesthesia. The preconditioning therapy was three 5-minute cycles of thigh ischemia, with 5 minutes of reperfusion between cycles. The sham procedure was identical except that ischemia was not induced. The primary outcome was peak creatine kinase-myocardial band (CK-MB) within 24 hours after surgery (expressed as multiples of the upper limit of normal, with log transformation). The secondary outcome was change in creatinine level within 4 days after surgery (expressed as log-transformed micromoles per litre). Patient-important outcomes were assessed up to 6 months after randomization. RESULTS: We randomly assigned 128 patients to remote ischemic preconditioning and 130 to the sham therapy. There were no significant differences in postoperative CK-MB (absolute mean difference 0.15, 95% confidence interval [CI] -0.07 to 0.36) or creatinine (absolute mean difference 0.06, 95% CI -0.10 to 0.23). Other outcomes did not differ significantly for remote ischemic preconditioning relative to the sham therapy: for myocardial infarction, relative risk (RR) 1.35 (95% CI 0.85 to 2.17); for acute kidney injury, RR 1.10 (95% CI 0.68 to 1.78); for stroke, RR 1.02 (95% CI 0.34 to 3.07); and for death, RR 1.47 (95% CI 0.65 to 3.31). INTERPRETATION: Remote ischemic precnditioning did not reduce myocardial or kidney injury during cardiac surgery. This type of therapy is unlikely to substantially improve patient-important outcomes in cardiac surgery. TRIAL REGISTRATION: ClinicalTrials.gov, no. NCT01071265.

Symptomatic graft failure and impact on clinical outcome after coronary artery bypass grafting surgery: Results from the Alberta Provincial Project for Outcome Assessment in Coronary Heart Disease registry.

BACKGROUND: In contemporary coronary artery bypass graft (CABG) surgery, the association between symptomatic graft failure (GF) and long-term clinical outcome remains unclear. We sought to identify the clinical characteristics and outcomes of GF in symptomatic patients requiring cardiac catheterization within 1 year of CABG surgery. METHODS: Using the Alberta Provincial Project for Outcomes Assessment in Coronary Heart Disease registry, 5,276 patients undergoing CABG surgery from September 2002 to August 2011 were identified. Clinical outcomes in patients with symptomatic GF were observed. Predictors of GF were analyzed at a graft level, whereas long-term survival was assessed at a patient level. A propensity score matching technique was used to adjust for baseline characteristics. RESULTS: Of our CABG cohort, 5.3% (281 patients [285 arterial and 653 vein grafts]) required symptom based coronary angiography within 1 year of CABG surgery. Acute coronary syndrome was the most common presentation (64.4%). At angiography, 27.0% (77/285) of arterial and 34.5% (225/653) of vein grafts were occluded. Respectively, arterial and vein GFs were treated as follows: percutaneous coronary intervention 61.0% versus 41.8%, re-do CABG 9.1% versus 0%, and medically without intervention 29.9% versus 58.2%. A strong trend toward reduced patient survival was noted with "arterial graft failure" (arterial ± vein GF) compared to "vein graft failure only" (no arterial GF) (adjusted hazard ratio 2.2, 95% CI 0.98-5.0, P = .056). CONCLUSION: Although the rate of cardiac catheterization within 1 year of CABG is infrequent, these patients exhibit high GF rates and commonly present with an acute coronary syndrome. In addition, "arterial graft failure" compared to "vein graft failure only" confers a higher risk of adverse long-term survival.

Coronary-artery bypass surgery in patients with left ventricular dysfunction.

BACKGROUND: The role of coronary-artery bypass grafting (CABG) in the treatment of patients with coronary artery disease and heart failure has not been clearly established. METHODS: Between July 2002 and May 2007, a total of 1212 patients with an ejection fraction of 35% or less and coronary artery disease amenable to CABG were randomly assigned to medical therapy alone (602 patients) or medical therapy plus CABG (610 patients). The primary outcome was the rate of death from any cause. Major secondary outcomes included the rates of death from cardiovascular causes and of death from any cause or hospitalization for cardiovascular causes. RESULTS: The primary outcome occurred in 244 patients (41%) in the medical-therapy group and 218 (36%) in the CABG group (hazard ratio with CABG, 0.86; 95% confidence interval [CI], 0.72 to 1.04; P=0.12). A total of 201 patients (33%) in the medical-therapy group and 168 (28%) in the CABG group died from an adjudicated cardiovascular cause (hazard ratio with CABG, 0.81; 95% CI, 0.66 to 1.00; P=0.05). Death from any cause or hospitalization for cardiovascular causes occurred in 411 patients (68%) in the medical-therapy group and 351 (58%) in the CABG group (hazard ratio with CABG, 0.74; 95% CI, 0.64 to 0.85; P<0.001). By the end of the follow-up period (median, 56 months), 100 patients in the medical-therapy group (17%) underwent CABG, and 555 patients in the CABG group (91%) underwent CABG. CONCLUSIONS: In this randomized trial, there was no significant difference between medical therapy alone and medical therapy plus CABG with respect to the primary end point of death from any cause. Patients assigned to CABG, as compared with those assigned to medical therapy alone, had lower rates of death from cardiovascular causes and of death from any cause or hospitalization for cardiovascular causes. (Funded by the National Heart, Lung, and Blood Institute and Abbott Laboratories; STICH ClinicalTrials.gov number, NCT00023595.).

Computing dominant metric dimensions of certain connected networks.

In the studies of the connected networks, metric dimension being a distance-based parameter got much more attention of the researches due to its wide range of applications in different areas of chemistry and computer science. At present its various types such as local metric dimension, mixed metric dimension, solid metric dimension, and dominant metric dimension have been used to solve the problems related to drug discoveries, embedding of biological sequence data, classification of chemical compounds, linear optimization, robot navigation, differentiating the interconnected networks, detecting network motifs, image processing, source localization and sensor networking. Dominant resolving sets are better than resolving sets because they carry the property of domination. In this paper, we obtain the dominant metric dimension of wheel, gear and anti-web wheel network in the form of integral numbers. We observe that the aforesaid networks have bounded dominant metric dimension as the order of the network increases. In particular, we also discuss the importance of the obtained results for the robot navigation networking.