A Modular Approach for Accessing 3D Heterocycles via 1,2-Dicyanation of Planar N-Heteroarenes.

The rapid construction of three-dimensional (3D) heterocyclic frameworks is a key challenge in contemporary medicinal chemistry. The molecules with three-dimensional complexity hold a greater probability to improve clinical outcomes, solubility, selectivity for target proteins, and metabolic stability. However, the prevalence of flat molecules persists among new drug candidates, primarily owing to the multitude of chemical methods available for their synthesis. In principle, the dearomative functionalization of N-heteroarene allows for the conversion of readily available planar molecules into partially or fully saturated nitrogen heterocycles, which are most significant structural motifs of pharmaceuticals and natural products. Unfortunately, these reactions are very rare because of the inherent challenge imposed by heteroarenes' poor reactivity, rendering the process thermodynamically unfavorable. Herein, we report a modular approach for accessing 3D chemical space in translating planar heteroarenes into valuable 3D heterocycles via the installation of a highly versatile cyano group as a new vector. This approach is enabled by the in situ generation of reactive, non-symmetric iodane by combining cyanide anion and bench-stable PhI(OAc)2. This reaction represents a rare example of 1,2-dicyanation of N-heteroarenes that meets the numerous requirements for broad implementation in drug and agrochemical discovery.

Tandem dehydrogenation-olefination-decarboxylation of cycloalkyl carboxylic acids via multifold C-H activation.

Dehydrogenation chemistry has long been established as a fundamental aspect of organic synthesis, commonly encountered in carbonyl compounds. Transition metal catalysis revolutionized it, with strategies like transfer-dehydrogenation, single electron transfer and C-H activation. These approaches, extended to multiple dehydrogenations, can lead to aromatization. Dehydrogenative transformations of aliphatic carboxylic acids pose challenges, yet engineered ligands and metal catalysis can initiate dehydrogenation via C-H activation, though outcomes vary based on substrate structures. Herein, we have developed a catalytic system enabling cyclohexane carboxylic acids to undergo multifold C-H activation to furnish olefinated arenes, bypassing lactone formation. This showcases unique reactivity in aliphatic carboxylic acids, involving tandem dehydrogenation-olefination-decarboxylation-aromatization sequences, validated by control experiments and key intermediate isolation. For cyclopentane carboxylic acids, reluctant to aromatization, the catalytic system facilitates controlled dehydrogenation, providing difunctionalized cyclopentenes through tandem dehydrogenation-olefination-decarboxylation-allylic acyloxylation sequences. This transformation expands carboxylic acids into diverse molecular entities with wide applications, underscoring its importance.

Access to unsaturated bicyclic lactones by overriding conventional C(sp3)-H site selectivity.

Transition metal catalysis plays a pivotal role in transforming unreactive C-H bonds. However, regioselective activation of distal aliphatic C-H bonds poses a tremendous challenge, particularly in the absence of directing templates. Activation of a methylene C-H bond in the presence of methyl C-H is underexplored. Here we show activation of a methylene C-H bond in the presence of methyl C-H bonds to form unsaturated bicyclic lactones. The protocol allows the reversal of the general selectivity in aliphatic C-H bond activation. Computational studies suggest that reversible C-H activation is followed by ß-hydride elimination to generate the Pd-coordinated cycloalkene that undergoes stereoselective C-O cyclization, and subsequent ß-hydride elimination to provide bicyclic unsaturated lactones. The broad generality of this reaction has been highlighted via dehydrogenative lactonization of mid to macro ring containing acids along with the C-H olefination reaction with olefin and allyl alcohol. The method substantially simplifies the synthesis of important bicyclic lactones that are important features of natural products as well as pharmacoactive molecules.

Absence of Wee1 alters global transcriptional response to oxidative stress in Schizosaccharomyces pombe.

Stress response and checkpoint activation are the main determinants of cellular survival in adverse conditions. In Schizosaccharomyces pombe, these are controlled by the Mitogen Activated Protein Kinase Spc1 and the Cyclin dependent Kinase Cdc2 respectively. Cdc2 is regulated positively by Cdc25 and negatively by Wee1. Changes in Cdc2 activity can be sensed by Spc1 resulting in the modulation of mitotic timing by Spc1. Functional cross talks between cell cycle regulation and MAPK machinery during regulation of mitotic timing are well characterised but the presence of similar communication during stress response remains unexplored. In this study we report how the checkpoint activator kinase Wee1 can also influence the transcriptional response to oxidative stress. We show that deletion of Wee1 results in changes in gene expression of the cells, especially with respect to genes whose expression is known to be regulated by Spc1. These differences are seen in unperturbed cells as well as during oxidative stress. Moreover, such variations extend beyond what could be expected to occur due to the known enhanced Spc1 activity of these cells. This is the first depiction of the influence of Wee1 and consequently Cdc2 activity on transcriptional response to oxidative stress.

Pd-catalysed C-H functionalisation of free carboxylic acids.

Pd-catalysed C-H functionalisation of free carboxylic acids has drawn significant attention over the last few years due to the predominance of carboxylic acid moieties in pharmaceuticals and agrochemicals. But their coordinating ability was overlooked and masked by exogenous directing groups for a long time. Even other crucial roles of carboxylic acids as additives and steric inducers that directly influence the mode of a reaction have been widely neglected. This review aims to embrace all of the diverse aspects of carboxylic acids except additive and steric effects by concisely and systematically describing their versatile role in Pd-catalysed proximal and distal C-H activation reactions that could be implemented in the pharmaceutical and agrochemical industries. In addition, the mechanistic perspectives along with several recent strategies developed in the last few years discussed here will serve as educational resources for future research.

Update in perioperative cardiac medicine.

Recent studies have shed light on preoperative risk assessment, medical therapy to reduce postoperative cardiac complications (beta-blockers, statins, and angiotensin II receptor blockers [ARBs]), perioperative management of patients with coronary stents on antiplatelet therapy, and perioperative bridging anticoagulation.

Medication Adherence: Truth and Consequences.

Improving medication adherence may have a greater influence on the health of our population than in the discovery of any new therapy. Patients are nonadherent to their medicine 50% of the time. Although most physicians believe nonadherence is primarily due to lack of access or forgetfulness, nonadherence can often be an intentional choice made by the patient. Patient concealment of their medication-taking behavior is often motivated by emotions on the part of both provider and patient, leading to potentially dire consequences. A review of the literature highlights critical predictors of adherence including trust, communication and empathy, which are not easily measured by current administrative databases. Multifactorial solutions to improve medication adherence include efforts to improve patients' understanding of medication benefits, access and trust in their provider and health system. Improving providers' recognition and understanding of patients' beliefs, fears and values, as well as their own biases is also necessary to achieve increased medication adherence and population health.

Updates in perioperative medicine.

BACKGROUND: As our surgical population becomes older and more medically complex, knowledge of the most recent perioperative literature is necessary to optimize perioperative care. We aim to summarize and critique literature published over the past year with the highest potential to impact the clinical practice of perioperative medicine. METHODS: We reviewed articles published between January 2014 and April 2015, identified via MEDLINE search. The final 10 articles selected were determined by consensus among all authors, with criteria for inclusion including scientific rigor and relevance to perioperative medicine practice. RESULTS: Key findings include: long term ß-blockade should be continued prior to surgery, routine screening with postoperative troponin is not recommended, initiation/continuation of aspirin or clonidine in the perioperative period is not beneficial and may increase adverse outcomes, preoperative diagnosis and treatment of obstructive sleep apnea may reduce risk of postoperative cardiovascular complications, new pulmonary risk indices are available that accurately estimate postoperative pulmonary complications, postoperative atrial fibrillation is associated with increased long-term stroke risk, risk scores such as the CHADS2 (Congestive heart failure, Hypertension, Age ≥75 years, Diabetes Mellitus, previous stroke or transient ischemic attack) are superior to the Revised Cardiac Risk Index in predicting adverse postoperative outcomes for patients with nonvalvular atrial fibrillation, and utilization of bridging anticoagulation comes with a much higher risk of bleeding compared to patients who are not bridged. CONCLUSIONS: The body of literature reviewed provides important information for clinicians caring for surgical patients across multiple fronts, including preoperative risk assessment, medication management, and postoperative medical care.

Perioperative cardiovascular medicine: an update of the literature 2013-2014.

Perioperative medicine is an important and rapidly expanding area of interest across multiple specialties, including internal medicine, anesthesiology, surgery, cardiology, and hospital medicine. A multispecialty team approach that ensures the best possible patient outcomes has fostered collaborative strategies across the continuum of patient care. Staying current in this multidisciplinary field is difficult, because physicians interested in perioperative medicine would need to review multiple specialty journals on a regular basis. To facilitate this process, the authors performed a focused review of this literature published in 2013 and early 2014. In this update, key articles are reviewed that potentially impact clinical practice in perioperative cardiovascular risk prediction and risk management.

Risk factors for postoperative pulmonary complications: an update of the literature.

Perioperative medicine is a growing area of research that brings together internists, anesthesiologists, surgeons, and hospitalists. A medical team approach to ensure the best possible patient outcomes has fostered collaborative strategies across disciplines. Perioperative pulmonary complications are common and can be associated with significant morbidity and mortality. Effective strategies to identify and reduce risks of pulmonary complications can improve patient outcomes. We review the new literature (2013 to early 2014) in the field of perioperative pulmonary medicine that reports new strategies to improve outcomes in the area of perioperative pulmonary care.

Perioperative anticoagulation and renal disease: an update.

As our surgical population becomes older and increasingly medically complex, knowledge of the most recent perioperative literature can provide guidance for physicians across multiple specialties caring for the surgical patient. Common issues many clinicians encounter in the perioperative period relate to anticoagulation and renal disease. This article identifies gaps in knowledge for the fields of perioperative anticoagulation, acute kidney injury, and chronic kidney disease and highlights recently published studies on these topics that attempt to fill these gaps and help clinicians provide excellent care for their patients.

Update in perioperative medicine 2013.

Perioperative medicine is an important and rapidly expanding area of interest across multiple specialties, including internal medicine, anesthesiology, surgery, and hospital medicine. A multi-specialty team approach that ensures best possible patient outcomes has fostered collaborative strategies across the continuum of patient care. It is difficult to keep current in this multidisciplinary field, as physicians interested in perioperative medicine would need to review multiple specialty journals on a regular basis. To facilitate this process, we performed a focused review of this literature published in 2012. In this update, we review 9 key articles that potentially impact clinical practice in various areas of perioperative medicine including preoperative testing, cardiovascular medicine, pulmonary care, anticoagulation, and medication management.

Who's behind an HCAHPS score?

BACKGROUND: The Hospital Consumer Assessment of Health Care Providers and Systems (HCAHPS) survey asks patients how frequently their physicians treated them with courtesy and respect, listened carefully, and explained things in a way they could understand. Such summary reports may obscure differences among the types of physicians involved. A study was conducted to examine the association between ratings for different physician types and the overall HCAHPS rating of physicians. METHODS: A mixed-methods study included closed-ended surveys and in-depth interviews of patients on a hospitalist teaching service. The three HCAHPS physician communication items were used to interview patients about their communication experiences with emergency medicine (EM) physicians, hospitalists, and specialists. The association between the overall score and the scores of each physician type was examined using Spearman correlation coefficients and linear regression. Qualitative data from additional in-depth interviews were analyzed using the constant comparative method to identify recurrent themes. RESULTS: Ninety-six patients were recruited for the survey, and additional in-depth interviews were conducted with the first 30 patients. Hospitalist and specialist scores were significantly associated (p values < .05) with overall scores. Recurrent themes regarding determinants of patients' ratings were categorized in three broad domains: individual physician behavior, team communication, and system issues. The influence of each domain differed across physician types. DISCUSSION: Physician communication scores may be most strongly influenced by patient experiences with hospitalists and specialists rather than with EM physicians. Several team communication and system issues represent opportunities for improving physician communication.

Effects of sugar-sweetened and sugar-free cocoa on endothelial function in overweight adults.

BACKGROUND: Studies of cocoa suggest an array of cardiovascular benefits; however, the effects of daily intake of sugar-free and sugar-sweetened cocoa beverages on endothelial function (EF) have yet to be established. METHODS: 44 adults (BMI 25-35 kg/m2) participated in a randomized, controlled, crossover trial. Participants were randomly assigned to a treatment sequence: sugar-free cocoa beverage, sugar-sweetened cocoa beverage, and sugar-sweetened cocoa-free placebo. Treatments were administered daily for 6 weeks, with a 4-week washout period. RESULTS: Cocoa ingestion improved EF measured as flow-mediated dilation (FMD) compared to placebo (sugar-free cocoa: change, 2.4% [95% CI, 1.5 to 3.2] vs. -0.8% [95% CI, -1.9 to 0.3]; difference, 3.2% [95% CI, 1.8 to 4.6]; p<0.001 and sugar-sweetened cocoa: change, 1.5% [95% CI, 0.6 to 2.4] vs. -0.8% [95% CI, -1.9 to 0.3]; difference, 2.3% [95% CI, 0.9 to 3.7]; p=0.002). The magnitude of improvement in FMD after consumption of sugar-free versus sugar-sweetened cocoa was greater, but not significantly. Other biomarkers of cardiac risk did not change appreciably from baseline. BMI remained stable throughout the study. CONCLUSIONS: Daily cocoa ingestion improves EF independently of other biomarkers of cardiac risk, and does not cause weight gain. Sugar-free preparations may further augment endothelial function.

Daily egg consumption in hyperlipidemic adults--effects on endothelial function and cardiovascular risk.

BACKGROUND: Limiting consumption of eggs, which are high in cholesterol, is generally recommended to reduce risk of cardiovascular disease. However, recent evidence suggests that dietary cholesterol has limited influence on serum cholesterol or cardiac risk. OBJECTIVE: To assess the effects of egg consumption on endothelial function and serum lipids in hyperlipidemic adults. METHODS: Randomized, placebo-controlled crossover trial of 40 hyperlipidemic adults (24 women, 16 men; average age = 59.9 +/- 9.6 years; weight = 76.3 +/- 21.8 kilograms; total cholesterol = 244 +/- 24 mg/dL). In the acute phase, participants were randomly assigned to one of the two sequences of a single dose of three medium hardboiled eggs and a sausage/cheese breakfast sandwich. In the sustained phase, participants were then randomly assigned to one of the two sequences of two medium hardboiled eggs and 1/2 cup of egg substitute daily for six weeks. Each treatment assignment was separated by a four-week washout period. Outcome measures of interest were endothelial function measured as flow mediated dilatation (FMD) and lipid panel. RESULTS: Single dose egg consumption had no effects on endothelial function as compared to sausage/cheese (0.4 +/- 1.9 vs. 0.4 +/- 2.4%; p = 0.99). Daily consumption of egg substitute for 6 weeks significantly improved endothelial function as compared to egg (1.0 +/- 1.2% vs. -0.1 +/- 1.5%; p < 0.01) and lowered serum total cholesterol (-18 +/- 18 vs. -5 +/- 21 mg/dL; p < 0.01) and LDL (-14 +/- 20 vs. -2 +/- 19 mg/dL; p = 0.01). Study results (positive or negative) are expressed in terms of change relative to baseline. CONCLUSIONS: Egg consumption was found to be non-detrimental to endothelial function and serum lipids in hyperlipidemic adults, while egg substitute consumption was beneficial.

The prevalence of posttraumatic stress disorder among adult earthquake survivors in Peru.

OBJECTIVES: To estimate the prevalence of posttraumatic stress disorder (PTSD) and to assess the relationships between PTSD and demographic and disaster-related factors. METHODS: Five months after a magnitude 8.0 earthquake struck the city of Pisco, Peru, we conducted a cross-sectional study using demographic questions, the PTSD Checklist, and a translated version of the Harvard Trauma Questionnaire. We used stratified sampling to randomly enroll subjects in Pisco and its annexes. We then used bivariate and multivariate analyses to find correlations between PTSD and demographic and disaster-related factors. RESULTS: We interviewed 298 adult earthquake survivors and detected 75 cases of PTSD (prevalence 25.2%; 95% confidence interval, 20.2%-30.1%). In the bivariate analysis, PTSD was significantly associated with female sex, loss of church, food and water shortages immediately after the earthquake, joblessness, injuries, loss of a relative or friend, lack of clean drinking water or appropriate sleeping conditions 5 months after the earthquake, and low levels of perceived support from family and friends. In the multivariate analysis, only female sex, food and water shortages, loss of church, injuries, and low levels of perceived support from family and friends were independently associated with PTSD. CONCLUSIONS: PTSD affected about a quarter of Pisco's population. Its impact was moderate to severe when compared with other disasters worldwide and in Latin America.

Effects of walnut consumption on endothelial function in type 2 diabetic subjects: a randomized controlled crossover trial.

OBJECTIVE: To determine the effects of daily walnut consumption on endothelial function, cardiovascular biomarkers, and anthropometric measures in type 2 diabetic individuals. RESEARCH DESIGN AND METHODS: This study was a randomized, controlled, single-blind, crossover trial. Twenty-four participants with type 2 diabetes (mean age 58 years; 14 women and 10 men) were randomly assigned to one of the two possible sequence permutations to receive an ad libitum diet enriched with 56 g (366 kcal) walnuts/day and an ad libitum diet without walnuts for 8 weeks. Subjects underwent endothelial function testing (measured as flow-mediated dilatation [FMD]) and assessment of cardiovascular biomarkers before and after each 8-week treatment phase. The primary outcome measure was the change in FMD after 8 weeks. Secondary outcome measures included changes in plasma lipids, A1C, fasting glucose, insulin sensitivity, and anthropometric measures. RESULTS: Endothelial function significantly improved after consumption of a walnut-enriched ad libitum diet compared with that after consumption of an ad libitum diet without walnuts (2.2 +/- 1.7 vs. 1.2 +/- 1.6%; P = 0.04). The walnut-enriched diet increased fasting serum glucose and lowered serum total cholesterol and LDL cholesterol from baseline (10.0 +/- 20.5 mg/dl, P = 0.04; -9.7 +/- 14.5 mg/dl, P < 0.01; and -7.7 +/- 10 mg/dl, P < 0.01, respectively), although these changes were not significant compared with those for an ad libitum diet without walnuts. There were no significant changes in anthropometric measures, plasma A1C, and insulin sensitivity. CONCLUSIONS: A walnut-enriched ad libitum diet improves endothelium-dependent vasodilatation in type 2 diabetic individuals, suggesting a potential reduction in overall cardiac risk.

Acute dark chocolate and cocoa ingestion and endothelial function: a randomized controlled crossover trial.

BACKGROUND: Studies suggest cardioprotective benefits of dark chocolate containing cocoa. OBJECTIVE: This study examines the acute effects of solid dark chocolate and liquid cocoa intake on endothelial function and blood pressure in overweight adults. DESIGN: Randomized, placebo-controlled, single-blind crossover trial of 45 healthy adults [mean age: 53 y; mean body mass index (in kg/m(2)): 30]. In phase 1, subjects were randomly assigned to consume a solid dark chocolate bar (containing 22 g cocoa powder) or a cocoa-free placebo bar (containing 0 g cocoa powder). In phase 2, subjects were randomly assigned to consume sugar-free cocoa (containing 22 g cocoa powder), sugared cocoa (containing 22 g cocoa powder), or a placebo (containing 0 g cocoa powder). RESULTS: Solid dark chocolate and liquid cocoa ingestion improved endothelial function (measured as flow-mediated dilatation) compared with placebo (dark chocolate: 4.3 +/- 3.4% compared with -1.8 +/- 3.3%; P < 0.001; sugar-free and sugared cocoa: 5.7 +/- 2.6% and 2.0 +/- 1.8% compared with -1.5 +/- 2.8%; P < 0.001). Blood pressure decreased after the ingestion of dark chocolate and sugar-free cocoa compared with placebo (dark chocolate: systolic, -3.2 +/- 5.8 mm Hg compared with 2.7 +/- 6.6 mm Hg; P < 0.001; and diastolic, -1.4 +/- 3.9 mm Hg compared with 2.7 +/- 6.4 mm Hg; P = 0.01; sugar-free cocoa: systolic, -2.1 +/- 7.0 mm Hg compared with 3.2 +/- 5.6 mm Hg; P < 0.001; and diastolic: -1.2 +/- 8.7 mm Hg compared with 2.8 +/- 5.6 mm Hg; P = 0.014). Endothelial function improved significantly more with sugar-free than with regular cocoa (5.7 +/- 2.6% compared with 2.0 +/- 1.8%; P < 0.001). CONCLUSIONS: The acute ingestion of both solid dark chocolate and liquid cocoa improved endothelial function and lowered blood pressure in overweight adults. Sugar content may attenuate these effects, and sugar-free preparations may augment them.