Deciphering the Lexicon of Protein Targets: A Review on Multifaceted Drug Discovery in the Era of Artificial Intelligence.

Understanding protein sequence and structure is essential for understanding protein-protein interactions (PPIs), which are essential for many biological processes and diseases. Targeting protein binding hot spots, which regulate signaling and growth, with rational drug design is promising. Rational drug design uses structural data and computational tools to study protein binding sites and protein interfaces to design inhibitors that can change these interactions, thereby potentially leading to therapeutic approaches. Artificial intelligence (AI), such as machine learning (ML) and deep learning (DL), has advanced drug discovery and design by providing computational resources and methods. Quantum chemistry is essential for drug reactivity, toxicology, drug screening, and quantitative structure-activity relationship (QSAR) properties. This review discusses the methodologies and challenges of identifying and characterizing hot spots and binding sites. It also explores the strategies and applications of artificial-intelligence-based rational drug design technologies that target proteins and protein-protein interaction (PPI) binding hot spots. It provides valuable insights for drug design with therapeutic implications. We have also demonstrated the pathological conditions of heat shock protein 27 (HSP27) and matrix metallopoproteinases (MMP2 and MMP9) and designed inhibitors of these proteins using the drug discovery paradigm in a case study on the discovery of drug molecules for cancer treatment. Additionally, the implications of benzothiazole derivatives for anticancer drug design and discovery are deliberated.

Reperfusion in Patients With ST-Segment-Elevation Myocardial Infarction With Cardiogenic Shock and Prolonged Interhospital Transport Times.

BACKGROUND: In patients with ST-segment-elevation myocardial infarction complicated by cardiogenic shock, primary percutaneous coronary intervention (pPCI) is the preferred revascularization option. Little is known about the efficacy and safety of a pharmacoinvasive approach for patients with cardiogenic shock presenting to a non-PCI hospital with prolonged interhospital transport times. METHODS: In a retrospective analysis of geographically extensive ST-segment-elevation myocardial infarction network (2006-2021), 426 patients with cardiogenic shock and ST-segment-elevation myocardial infarction presented to a non-PCI-capable hospital and underwent reperfusion therapy (53.8% pharmacoinvasive and 46.2% pPCI). The primary clinical outcome was a composite of in-hospital mortality, renal failure requiring dialysis, cardiac arrest, or mechanical circulatory support, and the primary safety outcome was major bleeding defined as an intracranial hemorrhage or bleeding that required transfusion was compared in an inverse probability weighted model. The electrocardiographic reperfusion outcome of interest was the worst residual ST-segment-elevation. RESULTS: Patients with pharmacoinvasive treatment had longer median interhospital transport (3 hours versus 1 hour) and shorter median symptom-onset-to-reperfusion (125 minute-to-needle versus 419 minute-to-balloon) times. ST-segment resolution ≥50% on the postfibrinolysis ECG was 56.6%. Postcatheterization, worst lead residual ST-segment-elevation <1 mm (57.3% versus 46.3%; P=0.01) was higher in the pharmacoinvasive compared with the pPCI cohort, but no differences were observed in the worst lead ST-segment-elevation resolution ≥50% (77.4% versus 81.8%; P=0.57). The primary clinical end point was lower in the pharmacoinvasive cohort (35.2% versus 57.0%; inverse probability weighted odds ratio, 0.44 [95% CI, 0.26-0.72]; P<0.01) compared with patients who received pPCI. An interaction between interhospital transfer time and reperfusion strategy with all-cause mortality was observed, favoring a pharmacoinvasive approach with transfer times >60 minutes. The incidence of the primary safety outcome was 10.1% in the pharmacoinvasive arm versus 18.7% in pPCI (adjusted odds ratio, 0.41 [95% CI, 0.14-1.09]; P=0.08). CONCLUSIONS: In patients with ST-segment-elevation myocardial infarction presenting with cardiogenic shock and prolonged interhospital transport times, a pharmacoinvasive approach was associated with improved electrocardiographic reperfusion and a lower rate of death, dialysis, or mechanical circulatory support without an increase in major bleeding.

Temporal Trends in in-Hospital Bleeding and Transfusion in a Contemporary Canadian ST-Elevation Myocardial Infarction Patient Population.

BACKGROUND: Although ST-elevation myocardial infarction (STEMI) management has evolved substantially over the past decade, its effect on bleeding and transfusion rates are largely unknown in a contemporary population. METHODS: Our study cohort included patients 20 years of age or older who were hospitalized for STEMI between 2007 and 2016 across all Canadian provinces, except Quebec. Unadjusted rates of bleeding and of transfusion during STEMI episodes were calculated overall and for each province according to fiscal year. Patients were stratified into 4 groups according to their bleeding/transfusion. Characteristics, treatment, and outcomes were compared between groups. Multivariate logistic regression modelling was used to assess the association between bleeding and transfusion on in-hospital mortality. RESULTS: Using 108,832 STEMI episodes, rates of in-hospital bleeding and transfusion declined between 2007 and 2016 from 3.9% to 2.8% (P < 0.0001) and 4.7% to 3.8% (P < 0.0001), respectively. However, variation in bleeding and transfusion rates were observed across Canadian provinces. Patients with bleeding or transfusion, were older, female, and had more comorbidities. Compared with patients who did not bleed or receive a transfusion, individuals who bled, were transfused, or bled and were transfused, had higher in-hospital mortality (18.6%, 30.3%, and 30.4%, respectively [P < 0.0001]). The association remained after adjustment: bleeding (odds ratio [OR], 2.0; 95% confidence interval [CI], 1.8-2.4), transfusion (OR, 4.4; 95% CI, 3.9-4.9), and bleeding and transfusion (OR, 3.8; 95% CI, 3.2-4.6). CONCLUSIONS: The proportion of Canadian STEMI patients who experienced in-hospital bleeding and transfusion has decreased over the past 9 years. However, patients with bleed or transfusion remain at higher risk of adverse outcomes.

INTRODUCTION: Bien que la prise en charge de l'infarctus du myocarde avec élévation du segment ST (STEMI) ait considérablement ait considérablement évoluée au cours de la dernière décennie, on ignore en grande partie ses répercussions sur les taux d'hémorragies et de transfusions dans la population contemporaine. MÉTHODES: Notre étude de cohorte regroupait des patients de 20 ans ou plus qui avaient été hospitalisés en raison d'un STEMI entre 2007 et 2016 dans toutes les provinces canadiennes, excepté le Québec. Nous avons calculé globalement et pour chacune des provinces les taux non ajustés d'hémorragies et de transfusions durant les épisodes de STEMI en fonction de l'année financière. Nous avons réparti les patients en quatre groupes en fonction de leurs hémorragies/transfusions. Nous avons comparé les caractéristiques, le traitement et les issues entre les groupes. Nous avons utilisé la modélisation par régression logistique multivariée pour évaluer l'association entre les hémorragies et les transfusions par rapport à la mortalité à l'hôpital. RÉSULTATS: À partir des 108 832 épisodes de STEMI, les taux d'hémorragies et de transfusions à l'hôpital ont baissé entre 2007 et 2016 de 3,9 % à 2,8 % (P < 0,0001) et de 4,7 % à 3,8 % (P < 0,0001), respectivement. Toutefois, nous avons observé la variation des taux d'hémorragies et de transfusions dans toutes les provinces canadiennes. Les patients qui avaient des hémorragies ou des transfusions, étaient plus âgés, de sexe féminin, et avaient plus de comorbidités. Comparativement aux patients qui n'avaient pas d'hémorragie ou qui ne recevaient pas de transfusion, les individus qui avaient une hémorragie, subissaient une transfusion, ou avaient une hémorragie et subissaient une transfusion étaient exposés à une mortalité à l'hôpital plus élevée (18,6 %, 30,3 % et 30,4 %, respectivement [P < 0,0001]). L'association a subsisté après l'ajustement : hémorragie (ratio d'incidence approché [RIA], 2,0; intervalle de confiance [IC] à 95 %, 1,8-2,4), transfusion (RIA, 4,4; IC à 95 %, 3,9-4,9), et hémorragie et transfusion (RIA, 3,8; IC à 95 %, 3,2-4,6). CONCLUSIONS: La proportion de patients canadiens atteints de STEMI qui subissaient des hémorragies ou des transfusions à l'hôpital a diminué au cours des 9 dernières années. Toutefois, les patients qui avaient une hémorragie ou une transfusion demeuraient exposés à un risque plus élevé d'issues défavorables.

Erratum: Critical exponents in mean-field classical spin systems [Phys. Rev. E 100, 032131 (2019)].

This corrects the article DOI: 10.1103/PhysRevE.100.032131.

Critical exponents in mean-field classical spin systems.

For mean-field classical spin systems exhibiting a second-order phase transition in the stationary state, we obtain within the corresponding phase-space evolution according to the Vlasov equation the values of the critical exponents describing power-law behavior of response to a small external field. The exponent values so obtained significantly differ from the ones obtained on the basis of an analysis of the static phase-space distribution, with no reference to dynamics. This work serves as an illustration that cautions against relying on a static approach, with no reference to the dynamical evolution, to extract critical exponent values for mean-field systems.

Trends in the Explanatory or Pragmatic Nature of Cardiovascular Clinical Trials Over 2 Decades.

Importance: Pragmatic trials test interventions using designs that produce results that may be more applicable to the population in which the intervention will be eventually applied. Objective: To investigate how pragmatic or explanatory cardiovascular (CV) randomized clinical trials (RCT) are, and if this has changed over time. Data Source: Six major medical and CV journals, including New England Journal of Medicine, Lancet, JAMA, Circulation, European Heart Journal, and Journal of the American College of Cardiology. Study Selection: All CV-related RCTs published during 2000, 2005, 2010, and 2015 were identified and included. Data Extraction and Synthesis: Included RCTs were assessed by 2 independent adjudicators with expertise in RCT and CV medicine. Main Outcomes and Measures: The outcome measure was the level of pragmatism evaluated using the Pragmatic Explanatory Continuum Index Summary (PRECIS)-2 tool, which uses a 5-point ordinal scale (ranging from very pragmatic to very explanatory) across 9 domains of trial design, including eligibility, recruitment, setting, organization, intervention delivery, intervention adherence, follow-up, primary outcome, and analysis. Results: Of 616 RCTs, the mean (SD) PRECIS-2 score was 3.26 (0.70). The level of pragmatism increased over time from a mean (SD) score of 3.07 (0.74) in 2000 to 3.46 (0.67) in 2015 (P < .001 for trend; Cohen d relative effect size, 0.56). The increase occurred mainly in the domains of eligibility, setting, intervention delivery, and primary end point. PRECIS-2 score was higher for neutral trials than those with positive results (P < .001) and in phase III/IV trials compared with phase I/II trials (P < .001) but similar between different sources of funding (public, industry, or both; P = .38). More pragmatic trials had more sites, larger sample sizes, longer follow-ups, and mortality as the primary end point. Conclusions and Relevance: The level of pragmatism increased moderately over 2 decades of CV trials. Understanding the domains of current and future clinical trials will aid in the design and delivery of CV trials with broader application.

Ivabradine in Heart Failure: The Representativeness of SHIFT (Systolic Heart Failure Treatment With the IF Inhibitor Ivabradine Trial) in a Broad Population of Patients With Chronic Heart Failure.

BACKGROUND: The sinus node inhibitor ivabradine was approved for patients with heart failure (HF) after the ivabradine and outcomes in chronic HF (SHIFT [Systolic Heart Failure Treatment With the IF Inhibitor Ivabradine Trial]) trial. Our objective was to characterize the proportion of patients with HF eligible for ivabradine and the representativeness of the SHIFT trial enrollees compared with those in the Swedish Heart Failure Registry. METHODS AND RESULTS: We examined 26 404 patients with clinical HF from the Swedish Heart Failure Registry and divided them into SHIFT type (left ventricular ejection fraction <40%, New York Heart Association class II-IV, sinus rhythm, and heart rate ≥70 beats per minute) and non-SHIFT type. Baseline characteristics and medication use were compared and change in eligibility over time was reported at 6 months and 1 year in a subset of patients. Overall, 14.2% (n=3741) of patients were SHIFT type. These patients were more likely to be younger, men, have diabetes mellitus, ischemic heart disease, lower left ventricular ejection fraction, and more recent onset HF (<6 months; all, P<0.001). Although 88.9% of SHIFT type and 88.5% of non-SHIFT type (P=0.421) were receiving selected ß-blockers, only 58.8% and 67.3% (P<0.001) were on >50% of target dose. From those patients who had repeated visits within 6 months (n=5420) and 1 year (n=6840), respectively, 10.2% (n=555) and 10.6% (n=724) of SHIFT-type patients became ineligible, 77.3% (n=4188) and 77.3% (n=5287) remained ineligible, and 4.6% (n=252) and 4.9% (n=335) of non-SHIFT-type patients became eligible for initiation of ivabradine. CONCLUSIONS: From the Swedish Heart Failure Registry, 14.2% of patients with HF were eligible for ivabradine. These patients more commonly were not receiving target ß-blocker dose. Over time, a minority of patients became ineligible and an even smaller minority became eligible.

The association between meteorological events and acute heart failure: new insights from ASCEND-HF.

INTRODUCTION: Given the rising prevalence of heart failure (HF), our objective is to explore the relationships between meteorological events and acute HF (AHF) globally. METHODS: We used data from 30 countries participating in the ASCEND-HF trial. Parameters including temperature were normalized by location for the 37 days prior to the HF event. Meteorological events were classified as a change that occurred <10% compared to baseline. The 7 days prior to the HF event was subdivided: T1: the day of and -1 day; T2: 2 and 3 days; T3: 4 and 5 days; and T4: 6 and 7 days. Results are reported as ratios of observed to expected weather events at the time of AHF presentation. RESULTS: From 7141 patients, median age was 67 (IQR 56-76) with 66% male patients and 60% of patients with ischemic cardiomyopathy. In T1, temperatures were warmer than expected with 10% fewer decreases in average [OR 0.91 95% CI (0.83-0.98)] and minimum [OR 0.90 95% CI (0.82-0.97)] temperature. In T2, temperatures were again warmer than expected with an excess number of increases in maximum [OR 1.18 95% CI (1.06-1.30)] and average [OR 1.21 95% CI (1.10-1.32)] temperature. In T4 temperatures were cooler than baseline with fewer increases [OR 0.84 95% CI (0.74-0.95)] in average temperature. CONCLUSIONS: Meteorological fluctuations appear most relevant in the 3 days (T1 and T2) prior to the HF hospitalization with temperature demonstrating a bidirectional relationship with AHF. Continued validation of biometeorological trends in HF will contribute to healthcare system planning globally.

Double aortic arch presenting in an adult with dysphagia.

Double aortic arch is a congenital anomaly that rarely presents in adults. We describe the case of a 69-year-old male who presented with a double aortic arch, right arch dominant, left arch patent, experiencing progressive dysphagia since childhood.

Baseline Q waves as a prognostic modulator in patients with ST-segment elevation: insights from the PLATO trial.

BACKGROUND: Baseline Q waves may provide additional value compared with time from the onset of symptoms in predicting outcomes for patients with ST-segment elevation. We evaluated whether baseline Q waves superseded time from symptom onset as a prognostic marker of one-year mortality in patients with ST-segment elevation acute coronary syndrome. Our study was derived from data from patients undergoing primary percutaneous coronary intervention within 24 hours in the PLATelet inhibition and patient Outcomes trial METHODS: Q waves on the baseline electrocardiogram were evaluated by a blinded core laboratory. We assessed the associations between baseline Q waves and time from symptom onset to percutaneous coronary intervention with peak biomarkers, ST-segment resolution on the discharge electrocardiogram, and one-year all-cause and vascular mortality. RESULTS: Of 4341 patients with ST-segment elevation, 46% had baseline Q waves. Compared to those without Q waves, those with baseline Q waves were older, more frequently male, had higher heart rates, more advanced Killip class and had a longer time between the onset of symptoms and percutaneous coronary intervention. They also had higher one-year all-cause mortality than patients without baseline Q waves (baseline Q waves: 4.9%; no baseline Q waves: 2.8%; hazard ratio [HR] 1.78, 95% confidence interval [CI] 1.29-2.45, p < 0.001). Complete ST-segment resolution was greatest and all-cause mortality lowest among those with symptom onset three hours or less before percutaneous coronary intervention and no baseline Q waves. After multivariable adjustment, baseline Q waves, but not time from symptom onset, were associated with a significant increase in all-cause mortality (adjusted HR 1.42, 95% CI 1.10-2.01, p = 0.046) and vascular mortality (adjusted HR 1.58, 95% CI 1.09-2.28, p = 0.02). INTERPRETATION: The presence of baseline Q waves provides useful additional prognostic insight into the clinical outcome of patients with ST-segment elevation. Clinical Trials.gov registration no. NCT00391872.