(C5H6N)Pb2X5 (X = Cl, Br): Hybrid Lead Halides Based on Seven-Coordinate Pb(II).

Hybrid lead halides are a diverse family of compounds, of interest for their optoelectronic properties, that vary in the dimensionality and connectivity of their inorganic substructures. The great majority of these compounds are based on lead-centered octahedra, with few examples featuring inorganic architectures containing higher coordination numbers. Here, we report the synthesis and characterization of a pyridinium lead bromide phase that is based on seven-coordinate Pb(II) centers. Through edge- and face-sharing, the polyhedra form a corrugated, two-dimensional inorganic substructure. Electronic structure calculations were used to examine the band structure and the role of the stereoactive lone pair in the inherently asymmetric, seven-coordinate Pb(II) geometry. For reference, we have visualized the role of the lone pair in the binary halide PbBr2, which also has a seven-coordinate inner ligand sphere. A comparison of the new structure with the limited number of existing hybrid lead halides with similar inorganic architectures highlights the templating role of the organic cation for these compounds. We also contribute characterization and discussion of isomorphic pyridinium lead chloride, which had been deposited in the Cambridge Structural Database but never, to our knowledge, addressed in the literature. The compounds were synthesized using solution conditions and structures determined with single-crystal X-ray diffraction. The materials were also characterized via powder X-ray diffraction, combustion elemental analysis, and diffuse reflectance UV-vis spectroscopy. While the structures reported here are centrosymmetric, the seven-coordinate, capped trigonal prismatic geometry that we have identified is a source of local asymmetry that could be used as a component in designing globally noncentrosymmetric structures.

Outcomes in Patients Stratified by PRECISE-DAPT Versus DAPT Scores After Percutaneous Coronary Interventions.

The optimal length of dual antiplatelet therapy (DAPT) after percutaneous coronary intervention (PCI) remains debated. Current guidelines recommend individualized treatment with consideration of risk scores. We sought to evaluate the degree of agreement in treatment recommendations and the ability to predict ischemic and bleeding complications of the PRECISE-DAPT (predicting bleeding complications in patients undergoing stent implantation and subsequent dual antiplatelet therapy) and DAPT scores. Consecutive patients receiving 12 months of DAPT were grouped based on score treatment recommendation at the time of PCI: PRECISE-DAPT prolonged or shortened (PRECISE DAPT <25 vs ≥25) and DAPT prolonged or shortened (DAPT ≥2 vs <2). One-year ischemic and bleeding outcomes were compared for each group. In 451 patients, the PRECISE-DAPT and DAPT score recommendations were concordant in 56.7% of patients (Cohen's kappa for agreement of k = 0.139, 95% confidence interval 0.065 to 0.212). There was no difference in composite major adverse cardiovascular and cerebrovascular events between patients with high versus low PRECISE-DAPT or DAPT scores. In patients with a high PRECISE-DAPT score versus a low score, there was an increased incidence of 1-year all-cause mortality (2.13% vs 0%, p = 0.04) and an increase in bleeding (Bleeding Academic Research Consortium ≥3a: 17.0% vs 2.8%; p <0.001; Bleeding Academic Research Consortium 3b/c and 5: 8.5% vs 1.4%; p = 0.001). There were no differences in rates of mortality or bleeding for patients with high versus low DAPT scores. In conclusion, when applied at the baseline, the PRECISE-DAPT and DAPT scores frequently make discordant DAPT duration recommendations. The PRECISE-DAPT, but not the DAPT score, demonstrated associations with all-cause mortality and bleeding in patients prescribed 12 months of DAPT after PCI.

De-escalation of P2Y12 Inhibitor Use After Percutaneous Coronary Intervention and Acute Coronary Syndromes.

BACKGROUND: De-escalation from potent platelet P2Y12 inhibitors to clopidogrel is common. Despite having a clinical rationale, non-bleeding-related de-escalation when a lateral change between potent agents is an option may put patients at increased ischemic risk. We set out to define the scope of P2Y12 inhibitor de-escalation in a large clinical registry and evaluate the potential impact of non-bleeding-related de-escalation on clinical outcomes. METHODS: : A retrospective cohort study was performed on consecutive patients in the Cardiovascular Percutaneous Intervention Trial (CAPITAL) registry to identify those who underwent a switch in therapy within 1 year of percutaneous coronary intervention. The de-escalations were categorized as bleeding-related or non-bleeding-related. The primary outcome was major adverse cardiovascular events, a composite of death, myocardial infarction, and stroke. Secondary outcomes included individual components of major adverse cardiovascular events and a safety endpoint of thrombolysis in myocardial infarction bleeding. RESULTS: Of 1854 patients, 209 (11.3%) underwent de-escalation: 24.9% of cases were bleeding-related, 37.8% were non-bleeding-related, and 37.3% were for unknown reasons. All patients with non-bleeding-related de-escalation were switched from ticagrelor to clopidogrel. The primary outcome occurred in 14 (6.7%) patients, of which 50% underwent non-bleeding-related de-escalation (P = 0.430). Among those with non-bleeding-related de-escalation, 7.6% were hospitalized for myocardial infarction, compared to 1.9% and 3.8% among those with a bleeding-related and unknown rationale, respectively (P = 0.293). CONCLUSIONS: De-escalation, particularly non-bleeding-related de-escalation, of P2Y12 inhibitors is common. A substantial proportion of such de-escalation may be avoidable. Given the potential risk of ischemic complications, strategies should be considered to encourage both the upfront use of potent P2Y12 inhibitors and alternative strategies to de-escalation.

CONTEXTE: La désescalade thérapeutique consistant à passer d'un inhibiteur puissant du récepteur plaquettaire P2Y12 au clopidogrel est pratique courante. En dépit de son fondement clinique, la désescalade non liée aux saignements lorsqu'une substitution d'inhibiteurs puissants est possible peut entraîner une augmentation du risque d'ischémie chez les patients. L'objectif de notre étude était d'analyser, dans un vaste registre clinique, l'amplitude du recours à la désescalade à partir d'un inhibiteur du récepteur P2Y12 et d'évaluer les conséquences possibles de la désescalade non liée aux saignements sur les résultats cliniques. MÉTHODOLOGIE: Une étude de cohorte rétrospective a été effectuée sur une série de patients consécutifs inscrits au registre CAPITAL ( Ca rdiovascular P ercutaneous I ntervention T ri al ) afin de recenser ceux qui avaient fait l'objet d'un changement de traitement au cours de l'année suivant leur intervention coronarienne percutanée. Les désescalades ont été classées en deux catégories selon qu'elles étaient liées ou non liées aux saignements. Le critère d'évaluation principal, soit la survenue d'un événement cardiovasculaire indésirable majeur (ECIM), était un critère composite regroupant le décès, l'infarctus du myocarde et l'accident vasculaire cérébral. Les critères d'évaluation secondaires comprenaient chaque composante individuelle du critère composite et un critère d'évaluation de l'innocuité mesuré par le score TIMI (thrombolyse dans l'infarctus du myocarde) relatif aux saignements. RÉSULTATS: Sur 1854 patients, 209 (11,3 %) avaient fait l'objet d'une désescalade, qui était liée aux saignements dans 24,9 % des cas, non liée aux saignements dans 37,8 % des cas et sans raison indiquée dans 37,3 % des cas. Tous les patients ayant fait l'objet d'une désescalade non liée aux saignements étaient passés du ticagrélor au clopidogrel. Le critère d'évaluation principal a été observé chez 14 (6,7 %) patients, dont 50 % avaient fait l'objet d'une désescalade non liée aux saignements (p = 0,430). Parmi les patients ayant fait l'objet d'une désescalade non liée aux saignements, 7,6 % avaient été hospitalisés pour un infarctus du myocarde, comparativement à 1,9 % et 3,8 % des patients chez qui la désescalade était liée aux saignements ou n'avait pas de raison connue, respectivement (p = 0,293). CONCLUSIONS: La désescalade à partir d'inhibiteurs du récepteur P2Y12, et particulièrement la désescalade non liée aux saignements, est pratique courante, alors qu'elle pourrait être évitée dans une proportion élevée de cas. Compte tenu du risque de complications ischémiques d'une telle pratique, des stratégies devraient être envisagées afin d'encourager à la fois le recours dès le départ à des inhibiteurs puissants du récepteur P2Y12 et l'adoption de stratégies de remplacement de la désescalade.

Development of succinimide-based inhibitors for the mitochondrial rhomboid protease PARL.

While the biochemistry of rhomboid proteases has been extensively studied since their discovery two decades ago, efforts to define the physiological roles of these enzymes are ongoing and would benefit from chemical probes that can be used to manipulate the functions of these proteins in their native settings. Here, we describe the use of activity-based protein profiling (ABPP) technology to conduct a targeted screen for small-molecule inhibitors of the mitochondrial rhomboid protease PARL, which plays a critical role in regulating mitophagy and cell death. We synthesized a series of succinimide-containing sulfonyl esters and sulfonamides and discovered that these compounds serve as inhibitors of PARL with the most potent sulfonamides having submicromolar affinity for the enzyme. A counterscreen against the bacterial rhomboid protease GlpG demonstrates that several of these compounds display selectivity for PARL over GlpG by as much as two orders of magnitude. Both the sulfonyl ester and sulfonamide scaffolds exhibit reversible binding and are able to engage PARL in mammalian cells. Collectively, our findings provide encouraging precedent for the development of PARL-selective inhibitors and establish N-[(arylsulfonyl)oxy]succinimides and N-arylsulfonylsuccinimides as new molecular scaffolds for inhibiting members of the rhomboid protease family.

Coronary CT Angiography Guided Medical Therapy in Subclinical Atherosclerosis.

The goals of primary prevention in coronary atherosclerosis are to avoid sudden cardiac death, myocardial infarction or the need for revascularization procedures. Successful prevention will rely on accurate identification, effective therapy and monitoring of those at risk. Identification and potential monitoring can be achieved using cardiac computed tomography (CT). Cardiac CT can determine coronary artery calcification (CAC), a useful surrogate of coronary atherosclerosis burden. Cardiac CT can also assess coronary CT angiography (CCTA). CCTA can identify arterial lumen narrowing and highlight mural atherosclerosis hitherto hidden from other anatomical approaches. Herein we consider the role of CCTA and CAC-scoring in subclinical atherosclerosis. We explore the use of these modalities in screening and discuss data that has used CCTA for guiding primary prevention. We examine therapeutic trials using CCTA to determine the effects of plaque-modifying therapies. Finally, we address the role of CCTA and CAC to guide therapy as defined in current primary prevention documents. CCTA has emerged as an essential tool in the detection and management of clinical coronary artery disease. To date, its role in subclinical atherosclerosis is less well defined, yet with modern CT scanners and continued pharmacotherapy development, CCTA is likely to achieve a more prominent place in the primary prevention of coronary atherosclerosis.

Prognostic importance of coincidental coronary artery calcification on FDG-PET/CT oncology studies.

Coronary artery calcification (CAC) on body CT imaging is considered a coincidental finding in cancer patients. In order to determine the significance of CAC in cancer patients we evaluated the prognostic utility of CAC detected on oncology FDG-PET/CT studies. A retrospective study was performed of consecutive FDG-PET/CT studies from January to March 2011. CAC was identified on the CT portion of FDG/PET-CT studies. Chart review documented statin use, the Framingham risk score (FRS) (includes age, diabetes, hypertension, dyslipidemia and smoking), the primary malignancy and metastases. The primary end point was a composite of death and cardiovascular (CV) events (non-fatal myocardial infarction (MI), PCI or coronary artery bypass surgery (CABG)). 266 patients had a median follow up of 41 months (95% CI 31-56 months). CAC was noted in 140 patients. Based on CAC, potentially 84 patients would have had a change in statin prescribing (p < 0.01). CAC was associated with the primary end point on univariable and multivariable analysis (OR 2.6 (95% CI 1.42-4.77) (p < 0.01). On univariable Kaplan-Meier survival analysis, CAC was associated with decreased survival only in the absence of metastases (p < 0.01). Cox proportional hazard modelling demonstrated CAC was associated with mortality and cardiac events in patients without metastases, whereas FRS was not (For CAC: HR 1.69 (95% CI 1.22-2.35), p = 0.002). CAC is commonly detected with oncology FDG-PET/CT. In cancer patients CAC was associated with an increased risk of clinical events. CAC reduced survival free time in patients without metastases. CAC might therefore be considered more than a coincidentaloma in patients without metastases.

Delays in ST-Elevation Myocardial Infarction Care During the COVID-19 Lockdown: An Observational Study.

BACKGROUND: Management of ST-elevated myocardial infarction (STEMI) necessitates rapid reperfusion. Delays prolong myocardial ischemia and increase the risk of complications, including death. The COVID-19 pandemic may have impacted STEMI management. We evaluated the relative volume of hospitalizations and clinical time intervals within a regional STEMI system. METHODS: 494 patients with STEMI were grouped into pre-lockdown, lockdown and re-opening cohorts. Clinical, temporal and outcome data were collected and compared between groups for both urban and rural patients, receiving primary percutaneous coronary intervention (PCI) and pharmacoinvasive revascularization, respectively. Data was compared to a 10-year historical comparator. RESULTS: During pre-lockdown there was 238 cases versus 193 in lockdown; a 19.0% reduction in volume. When lockdown was compared to the median caseload from a 10-year historical cohort, a 19.8% reduction was observed. For patients treated with primary PCI during lockdown, median symptom-to-balloon time increased by 44-minutes [217 (IQR 157-387) vs. 261 (160-659) minutes; p=0.03]; driven by an increase in median symptom-to-door time of 41-minutes [136 (IQR 80-267) vs. 177 (IQR 90-569) minutes; p<0.01]. Only patients transferred from non-PCI facilities demonstrated an increase in door-to-reperfusion time [116 (IQR 93-150) vs. 139 (IQR 100-199) minutes; p<0.01]. More patients had left ventricular dysfunction during the lockdown [35% vs. 44%; p=0.04], but there was no difference in mortality. CONCLUSION: During the COVID-19 lockdown, fewer patients presented with STEMI. Time-to-reperfusion was significantly prolonged and appeared driven predominantly by patient-level and transfer delays. Public education and systems-level changes will be integral to STEMI care during the second wave of COVID-19.