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The evolution of bisindolyl maleimides and indolyl maleimide derivatives and their unique biological activities have stimulated great interest in medicinal chemistry programs. Bisindolylmaleimide (BIM)-type compounds arise from natural sources such as arcyriarubin and are biosynthetically related to indolocarbazoles. BIMs are commonly the immediate synthetic precursors of indolocarbazoles, lacking a central bond between the two aromatic units and making them more flexible and drug-like. Synthetic endeavours within this class of compounds are broad and have led to the development of both remarkably potent and selective protein kinase inhibitors. Clinical BIM examples include ruboxistaurin and enzastaurin, which are highly active inhibitors of protein kinase C-β. While BIMs are widely recognised as protein kinase inhibitors, other modes of activity have been reported, including the inhibition of calcium signalling and antimicrobial activity. Critically, structural differences can be used to exploit new bioactivity and therefore it is imperative to discover new chemical entities to address new targets. BIMs can be highly functionalised or chemically manipulated, which provides the opportunity to generate new derivatives with unique biological profiles. This review will collate new synthetic approaches to BIM-type compounds and their associated bioactivities with a focus on clinical applications.

The synthesis and biological evaluation of a series of novel heterocyclic indole derivatives is described. The consolidation of the combretastatin and bisindolylmaleimide templates towards the inclusion of a novel heterocyclic ring proffered a versatile pharmacophore with which to pursue chemical diversification. Given literature precedent, maleimide was initially investigated in this role and the bioactivity assessed by measurement of NCI-60 cell panel growth. Subsequently, a range of 5-aminopyrazoles was designed and developed to explore the specific effect of heterocycle hydrogen bonding on cell growth. The unique electronic nature of the 5-aminopyrazole moiety allowed for regiospecific monosubstitution on different sites of the ring, such as thiourea substitution at the N(1) position for derivative 45 or trifluoroacetylation on the 5-amino position for 43. Further derivatisation led to the ultimate development of bicyclic pyrazolotriazinedione 41 and pyrimidine 42 systems. The antiproliferative activities of these 3,4-diaryl-5-aminopyrazoles were assessed using the NCI-60 cell screen, disclosing the discovery of distinct selectivity profiles towards a number of cell lines, such as SNB-75 CNS cancer, UO-31 and CAKI-1 renal cancer cells. A series of DNA topological assays discounted the interaction with topoisomerase II as a putative mechanism of action.

Proximal humeral fractures (PHFs) are a common type of fracture, particularly in older adults, accounting for approximately 5-6% of all fractures. This article provides a comprehensive review of PHFs, focusing on epidemiology, injury mechanism, clinical and radiographic assessment, classification systems, and treatment options. The incidence of PHFs varies across regions, with rates ranging from 45.7 to 60.1 per 100,000 person-years. Females are more susceptible to PHFs than males, and the incidence is highest in women over the age of 85. The injury mechanism of PHFs is typically bimodal, with high-energy injuries predominant in younger individuals and low-energy injuries in the elderly. Clinical assessment of PHFs involves obtaining a thorough history, physical examination, and evaluation of associated injuries, particularly neurovascular injuries. Radiographic imaging helps assess fracture displacement and plan for treatment. The Neer classification system is the most commonly used classification for PHFs, although other systems, such as AO/OTA, Codman-Hertel, and Resch classifications, also exist. The choice of treatment depends on factors such as patient age, activity level, fracture pattern, and surgeon expertise. Nonoperative management is typically preferred for elderly patients with minimal displacement, while operative fixation is considered for more complex fractures. Nonoperative treatment involves sling immobilization followed by physiotherapy, with good outcomes reported for certain fracture patterns. Operative management options include closed reduction and percutaneous pinning (CRPP), open reduction and internal fixation (ORIF), or arthroplasty. CRPP is suitable for specific fracture patterns, but the quality of reduction is crucial for favorable outcomes. ORIF is used when CRPP is not feasible, and various surgical approaches are available, each with its advantages and potential complications. PHFs are a significant clinical challenge due to their prevalence and complexity. Treatment decisions should be patient centered based on patient factors and fracture severity., Competing Interests: The authors report no conflicts of interest in this work., (© 2023 Baker et al.)

Objective: The purpose of this study was to investigate the injury rate in NBA players following return to play during the post-COVID-19 shutdown 2019-2020 NBA season., Methods: This study was a retrospective review of all NBA players who were placed on the injury report during the preseason and first 4 weeks of the regular season as well as playoffs from the 2017-2018 through 2020-2021 NBA seasons. The data were compiled using publicly available injury reports. All injuries were recorded, and injury rates were calculated per 1000 athletic exposures. Risk ratio with 95% confidence intervals compared injury rates between the 2 cohorts., Results: Over the course of the study period, 399 injuries were reported. The highest injury rate per athletic exposure was observed to have occurred during the first month of the regular season in the 2 seasons prior to the COVID-19 pandemic. There was no significant difference in the average number of games missed before and after the pandemic for the preseason (P = .95), first month of regular season (P = .62), and playoffs (P = .69). There was no significant difference in the rate of injury when comparing injury rates before and after the pandemic for the preseason (P = .25), first month of the regular season (P = .11), and playoffs (P = .3)., Conclusion: The rate of injury in NBA players following the COVID-19 pandemic was not significantly higher than 2 recent past NBA seasons.

Purpose: To investigate the injury rate in National Football League (NFL) athletes during the first 4 weeks of the 2020 NFL season., Methods: This study was a retrospective review of all NFL players who were placed on the injury report during the preseason and the first 4 weeks of the regular season from the 2016-2017 through the 2020-2021 NFL regular seasons. Players' dates of injury were cross-referenced with an absence of statistics from the respective games for which they were ruled out so as to ensure accuracy. Injury rates were calculated per 1,000 athletic exposures. Relative risk with 95% confidence intervals compared injury rates between the 2 cohorts., Results: Over the course of the study period of 4 NFL seasons, 3,025 injuries were reported. Of the 3,025 injuries reported, 582 (19%) occurred during weeks 1-4 of the 2020-2021 regular season, whereas 1,292 (53%) occurred during preseason weeks 1-4, and 1,151 (38%) occurred during regular-season weeks 1-4 of NFL seasons 2016-2017, 2018-2019, and 2019-2020. There was a significant increase in the injury rate during weeks 1-4 of the 2020-2021 regular season for all comparisons with the injury rate both during the preseasons and the regular seasons of 3 recent past NFL seasons., Conclusions: The rate of injury in NFL players during weeks 1-4 of the 2020-2021 regular seasons was significantly higher than during 3 recent past NFL preseasons and regular seasons., Level of Evidence: Level IV, diagnostic case series., (© 2021 by the Arthroscopy Association of North America. Published by Elsevier Inc.)

Major depressive disorder (MDD) is a leading cause of disease burden worldwide. While the incidence, symptoms and treatment of MDD all point toward major sex differences, the molecular mechanisms underlying this sexual dimorphism remain largely unknown. Here, combining differential expression and gene coexpression network analyses, we provide a comprehensive characterization of male and female transcriptional profiles associated with MDD across six brain regions. We overlap our human profiles with those from a mouse model, chronic variable stress, and capitalize on converging pathways to define molecular and physiological mechanisms underlying the expression of stress susceptibility in males and females. Our results show a major rearrangement of transcriptional patterns in MDD, with limited overlap between males and females, an effect seen in both depressed humans and stressed mice. We identify key regulators of sex-specific gene networks underlying MDD and confirm their sex-specific impact as mediators of stress susceptibility. For example, downregulation of the female-specific hub gene Dusp6 in mouse prefrontal cortex mimicked stress susceptibility in females, but not males, by increasing ERK signaling and pyramidal neuron excitability. Such Dusp6 downregulation also recapitulated the transcriptional remodeling that occurs in prefrontal cortex of depressed females. Together our findings reveal marked sexual dimorphism at the transcriptional level in MDD and highlight the importance of studying sex-specific treatments for this disorder.

Background: Individuals with cardiac sarcoidosis have an increased risk of ventricular arrhythmia and death. Several small cohort studies have evaluated the ability of late gadolinium enhancement (LGE) by cardiac magnetic resonance imaging (MRI) to predict adverse cardiovascular events. However, studies have yielded inconsistent results, and some analyses were underpowered. Therefore, we sought to systematically review and perform meta-analysis of the prognostic value of cardiac MRI for patients with known or suspected cardiac sarcoidosis., Methods and Results: We systematically searched for cohort studies of patients with known sarcoidosis with suspected cardiac involvement who underwent cardiac MRI with LGE with at least 12 months of either prospective or retrospective follow-up data regarding post-MRI adverse cardiovascular outcomes. We identified 7 studies of 694 subjects (mean age 53; 42% men).One hundred and ninety-nine patients (29%) were LGE positive. All-cause mortality occurred in 19 LGE-positive versus 17 LGE-negative subjects (annualized incidence, 3.1% versus 0.6%). The pooled relative risk was 3.38 (95% confidence interval, 1.07-10.7; P=0.04). Cardiovascular mortality occurred in 10 LGE-positive versus 2 LGE-negative subjects (annualized incidence, 1.9% versus 0.3%; relative risk 10.7 [95% confidence interval, 1.34-86.3]; P=0.03). Ventricular arrhythmia occurred in 41 LGE-positive versus 0 LGE-negative subjects (annualized incidence, 5.9% versus 0%; relative risk 19.5 [95% confidence interval, 2.68-143]; P=0.003). A combined end point of death or ventricular arrhythmia occurred in 64 LGE-positive versus 18 LGE-negative subjects (annualized incidence, 8.8% versus 0.6%; relative risk 6.20 [95% confidence interval, 2.47-15.6]; P<0.001). There was no significant heterogeneity for any outcomes., Conclusions: LGE is associated with future cardiovascular death and ventricular arrhythmia among patients referred to MRI for known or suspected cardiac sarcoidosis., (© 2016 American Heart Association, Inc.)

Tomatoes, members of the Solanaceae plant family, produce biologically active secondary metabolites, including glycoalkaloids, which may have both adverse and beneficial biological effects. Using the linear ion trap (LIT) mass spectrometry, multi-stage collision induced dissociation (CID) experiments (MSn) were performed to elucidate characteristic fragmentation pathways of the glycoalkaloid, tomatidine and of β1-hydroxytomatine. High resolution with high accuracy mass analysis using an Orbitrap fourier transform MS with higher-energy collisional induced dissociation (HCD) was used to produce mass spectra data across a wide spectral range for confirmation of proposed ion structures and formulae.

Acute chest pain in the emergency department (ED) is a common and costly public health challenge. The traditional strategy of evaluating acute chest pain by hospital or ED observation over a period of several hours, serial electrocardiography and cardiac biomarkers, and subsequent diagnostic testing such as physiologic stress testing is safe and effective. Yet this approach has been criticized for being time intensive and costly. This review evaluates the current medical evidence which has demonstrated the potential for coronary CT angiography (CTA) assessment of acute chest pain to safely reduce ED cost, time to discharge, and rate of hospital admission. These benefits must be weighed against the risk of ionizing radiation exposure and the influence of ED testing on rates of downstream coronary angiography and revascularization. Efforts at radiation minimization have quickly evolved, implementing technology such as prospective electrocardiographic gating and high pitch acquisition to significantly reduce radiation exposure over just a few years. CTA in the ED has demonstrated accuracy, safety, and the ability to reduce ED cost and crowding although its big-picture effect on total hospital and health care system cost extends far beyond the ED. The net effect of CTA is dependent also on the prevalence of coronary artery disease (CAD) in the population where CTA is used, which significantly influences rates of post-CTA invasive procedures such as angiography and coronary revascularization. These potential costs and benefits will warrant careful consideration and prospective monitoring as additional hospitals continue to implement this important technology into their diagnostic regimen., (Published by Elsevier Inc.)

We apply the item-order theory of list composition effects in free recall to the orthographic distinctiveness effect. The item-order account assumes that orthographically distinct items advantage item-specific encoding in both mixed and pure lists, but at the expense of exploiting relational information present in the list. Experiment 1 replicated the typical free recall advantage of orthographically distinct items in mixed lists and the elimination of that advantage in pure lists. Supporting the item-order account, recognition performances indicated that orthographically distinct items received greater item-specific encoding than did orthographically common items in mixed and pure lists (Experiments 1 and 2). Furthermore, order memory (input-output correspondence and sequential contiguity effects) was evident in recall of pure unstructured common lists, but not in recall of unstructured distinct lists (Experiment 1). These combined patterns, although not anticipated by prevailing views, are consistent with an item-order account.

Historically, executive coaching has been reserved only for the c-suite in healthcare organizations. Expanding this resource to directors and managers has been assumed to be cost-prohibitive. The authors describe an intervention whereby executive coaching was expanded beyond the c-suite, during a critical transition time for the organization in an attempt to positively impact management turnover, staff turnover, and employee satisfaction.

It is becoming increasingly clear that the interactions of targets and biomarkers, drug modes of action and molecular mechanisms of side-effects and toxic effects are much more complex than previously anticipated, basically due to physiological compensation and cross-talk. Single genes often lead to hundreds or even thousands of functional protein molecules, modified at the post-translational level. Thus, the comprehensive analysis of proteins (proteomics) teaches us that physiological activity means dynamic, multidimensional processes among many thousands of different proteins within higher systems of organisation and correlation. Crucial for control and relevant reduction of this enormous complexity, which will enable new kinds of molecular drug screening, as well as a new type of molecular toxicology, is a consequently differential and quantitative protein analysis. Precise knowledge of key protein isoforms with specific post-translational modifications within kinetic and contextual relationships is accessible by powerful new technologies, which have emerged to analyse the surprisingly ambiguous world of proteins, where single molecular modules are involved in a diversity of often opposing signal transduction pathways in a most flexible way.

We offer simple solutions to three kinematic problems that occur in the folding of proteins. We show how to construct suitably local elementary Monte Carlo moves, how to close a loop, and how to fold a loop without breaking the bond that closes it., (Copyright 2003 Wiley Periodicals, Inc.)

We propose an algorithmic strategy for improving the efficiency of Monte Carlo searches for the low-energy states of proteins. Our strategy is motivated by a model of how proteins alter their shapes. In our model, when proteins fold under physiological conditions, their backbone dihedral angles change synchronously in groups of four or more to avoid steric clashes and respect the kinematic conservation laws. They wriggle; they do not thrash. We describe a simple algorithm that can be used to incorporate wriggling in Monte Carlo simulations of protein folding. We have tested this wriggling algorithm against a code in which the dihedral angles are varied independently (thrashing). Our standard of success is the average root-mean-square distance (rmsd) between the alpha-carbons of the folding protein and those of its native structure. After 100,000 Monte Carlo sweeps, the relative decrease in the mean rmsd, as one switches from thrashing to wriggling, rises from 11% for the protein 3LZM with 164 amino acids (aa) to 40% for the protein 1A1S with 313 aa and 47% for the protein 16PK with 415 aa. These results suggest that wriggling is useful and that its utility increases with the size of the protein. One may implement wriggling on a parallel computer or a computer farm.