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Sympathetic nervous system activity (SNSA) is believed to participate in the genesis of ventricular tachyarrhythmias (VTA) but understanding has been impeded by the number and complexity of effects and the paucity of data from humans. New information from studies of genetic disorders, animal models, and spontaneous human arrhythmias indicates the importance of the temporal pattern of SNSA in arrhythmia development. The proarrhythmic effects of short-term elevations of SNSA are exemplified by genetic disorders and include enhancement of early and delayed afterdepolarizations and increased dispersion of repolarization. The role of long-term elevations of SNSA is suggested by animal models of enhanced SNSA signaling that results in apoptosis, hypertrophy, and fibrosis, and sympathetic nerve sprouting caused by infusion of nerve growth factor. Processes that overlap short- and long-term effects are suggested by changes in R-R interval variability (RRV) that precede VTA in patients by several hours. SNSA-mediated alterations in gene expression of ion channels may account for some intermediate-term effects. The propensity for VTA is highest when short-, intermediate, and long-term changes are superimposed. Because the proarrhythmic effects are related to the duration and intensity of SNSA, normal regulatory processes such as parasympathetic activity that inhibits SNSA, and oscillations that continuously vary the intensity of SNSA may provide vital antiarrhythmic protection that is lost in severe heart failure and other disorders. These observations may have therapeutic implications. The recommended use of beta-adrenergic receptor blockers to achieve a constant level of inhibition does not take into account the temporal patterns and regional heterogeneity of SNSA, the proarrhythmic effects of alpha-adrenergic receptor stimulation, or the potential proarrhythmic effects of beta-adrenergic receptor blockade. Further research is needed to determine if other approaches to SNSA modulation can enhance the antiarrhythmic effects. [ABSTRACT FROM AUTHOR]

Introduction: We hypothesized that autonomic activity preceding spontaneous sustained monomorphic ventricular tachycardia (VTsm) as assessed by heart rate (HR) and RR interval variability (RRV) differs between type 1 VTsm which is initiated by morphologically distinct, early cycle, possibly triggering premature ventricular complexes (PVCs) and type 2 VTsm in which the initial complex has a QRS waveform identical to subsequent complexes. Methods and Results: Baseline Holter tapes (1,646) from a clinical trial were scanned for VTsm. QRS complexes of VTsm were compared by two-lead cross-correlation to distinguish type 1 and type 2 VTsm. Frequency domain RRV index were estimated over 5 minutes, 15 minutes, and 24 hours. Type 1 and type 2 VTsm were present in 15 (group 1) and 33 (group 2) of 48 patients, respectively. HR did not change in group 1 (88.4 ± 15.2 to 89.7 ± 13.0 beats/min, P = 0.89), but Increased before the onset of VTsm in group 2 (74.3 ± 16.3 to 81.2 ± 18.0 beats/mm, P < 0.001). RRV index were severely depressed In both groups. No RRV index changed significantly before the onset of type 1 VTsm, whereas significant changes occurred before type 2 VTsm from 24-hour average to 30 minutes before VTsm in very low (very low-frequency power [VLFP]: 6.62 ± 1.53 to 6.20 ± 2.07 ln msec², P = 0.036), low (Iow-frequency power [LFP]: 5.61 ± 1.43 to 528 ± 1.59 in msec², P = 0.004), normalized low (normalized low-frequency power [LFPn]: -0.48 ± 0.58 to -0.55 ± 0.64 normalized units [nu], P = 0.05) and the ratio of LFP to high-frequency power (HFP) (LFP/HFP: 4.20 ± 3.47 to 3.45 ± 2.53, P = 0.017). Declines in RRV index between 2 hours to the 30-minute period before VTsm occurred in group 2 but not group 1 in LFP (5.85 ± 1.42 to 5.28 ± 1.59 in msec, P = 0.043) and HFP (4.94 ± 5.14 to 3.46 ± 2.52 ln msec², P = 0.008), with a downward trend in LFP/HFP (4.94 ± 5.14 to 3.45 ± 2.53, P = 0.127) and LFPn (-0.38 ± 0.36 to -0.55 ± 0.64, P = 0.15), while HFPn tended to rise (-1.47 ± 0.65 to -1.27 ± 0.64, P = 0.15). Conclusions: HR and RRV did not change before type 1 VTsm, suggesting that short-term changes in autonomic activity were not essential to initiation of apparent PVC-triggered VTsm. In contrast, RR Interval dynamics before type 2 VTsm suggested that short-term changes in neurohormonal activity contributed to arrhythmia initiation. Heterogeneities in arrhythmia onset may reflect distinct triggers and substrate properties that could provide a basis for effective therapeutic targets. [ABSTRACT FROM AUTHOR]

The total photon economy of a chromophore molecular species represents a study of how absorbed photons partition among various electronic states and ultimately dissipate their excited energy into the environment. A complete accounting of these rates and pathways would allow one to optimize chromophores and their environments for applications. We describe a technique, fluorescent optical cycling (FOC), which allows for simultaneous observation of prompt and delayed emission during and after multiple pulsed excitation, ultimately granting access to multi-state photophysical rates. We exercise control over the excitation pulse train, which allows us to "optically shelve" long-lived intermediate states without the use of diode or flashlamp excitation. By recording all photon arrival times in the visible and shortwave infrared, we can simultaneously resolve fluorescence, phosphorescence, and singlet oxygen sensitization in a single experiment. We use FOC to examine the photophysics of dual emitting bis(di- R -phosphino)alkanethiophene-pyridine-platinum ([Pt(thpy)(dppm)] + ) under different solvation conditions, revealing changes in intersystem crossing and phosphorescent rates induced by the external heavy atom effect. Coupling FOC with decay associated Fourier spectroscopy (DAFS), we demonstrate simultaneous correlated spectral and lifetime data in this dual emitting complex. Finally, FOC combined with superconducting nanowire single photon detectors (SNSPDs) allows us to observe the shortwave infrared region (SWIR) phosphorescence of singlet oxygen sensitized by Rose Bengal. Overall, FOC provides a powerful tool to simultaneously study multiple photophysics across timescales, even in weakly populated electronic states.

Age-related myelin damage induces inflammatory responses, yet its involvement in Alzheimer's disease remains uncertain, despite age being a major risk factor. Using a mouse model of Alzheimer's disease, we found that amyloidosis itself triggers age-related oligodendrocyte and myelin damage. Mechanistically, CD8 + T cells promote the progressive accumulation of abnormally interferon-activated microglia that display myelin-damaging activity. Thus, our data suggest that immune responses against myelinating oligodendrocytes may contribute to neurodegenerative diseases with amyloidosis., (© 2024. The Author(s).)

Purpose: With increasing utilization of genetic testing, sharing genetic information can become part of general family health communication while providing biological relatives with important information about their own genetic risk. Importantly, little is known about motivations for and barriers to family communication of genetic information in historically underserved populations., Methods: Using mixed methods, we explored patient experiences with family communication in a study population of English- and Spanish-speaking adults aged 18 to 49 years, enriched for participants from historically underserved backgrounds. Risk screening for hereditary cancer guided genetic testing for cancer risk genes and other medically actionable findings., Results: Most participants overall (91%), including most with normal findings (89%), shared or planned to share their results with relatives. Common motivations for sharing results were to give relatives information about their genetic risk and because the participant thought the results were interesting. Reasons for not sharing were limited contact with relatives, perceptions of limited clinical utility for relatives, and concern that discussion of genetic information was stigmatized or taboo., Conclusion: Results demonstrate high rates of sharing genetic information, indicate motivations for sharing go beyond facilitating genetic testing for relatives, and suggest general willingness to share genetic information as part of family health communication., Competing Interests: Conflict of Interest Laura Amendola is an employee and shareholder of Illumina. The remaining authors have no conflict of interest to disclose., (Copyright © 2023 American College of Medical Genetics and Genomics. Published by Elsevier Inc. All rights reserved.)

Underserved patients face substantial barriers to receiving cancer genetic services. The Cancer Health Assessments Reaching Many (CHARM) study evaluated ways to increase access to genetic testing for individuals in underserved populations at risk for hereditary cancer syndromes (HCS). Here, we report the successful implementation of CHARM in a low-resource environment and the development of sustainable processes to continue genetic risk assessment in this setting. The research team involved key clinical personnel and patient advisors at Denver Health to provide input on study methods and materials. Through iterative and collaborative stakeholder engagement, the team identified barriers and developed solutions that would both facilitate participation in CHARM and be feasible to implement and sustain long term in clinical care. With a focus on infrastructure building, educational modules were developed to increase awareness among referring providers, and standard methods of identifying and managing HCS patients were implemented in the electronic medical record. Three hundred sixty-four DH patients successfully completed the risk assessment tool within the study, and we observed a sustained increase in referrals to genetics for HCS (from 179 in 2017 to 427 in 2021 post-intervention). Implementation of the CHARM study at a low-resourced safety net health system resulted in sustainable improvements in access to cancer genetic risk assessment and services that continue even after the study ended.Trial registration NCT03426878., (© 2023. The Author(s).)

Introduction: Research on the perceived utility of genomic sequencing has focused primarily on pediatric populations and on individuals and families with rare genetic diseases. Here, we evaluate how well a multifaceted perceived utility model developed with these populations applies to a diverse, adult population aged 18-49 at risk for hereditary cancer and propose new considerations for the model., Methods: Participants received clinical genomic sequencing in the Cancer Health Assessments Reaching Many (CHARM) study. Semi-structured qualitative interviews were conducted with a subset of participants at 1 and 6 months after results disclosure. We used an approach influenced by grounded theory to examine perceptions of the utility of genomic sequencing and analyzed how utility in CHARM mapped to the published multifaceted perceived utility model, noting which domains were represented or absent and which were most salient to our population., Results: Participants' discussions of utility often involved multiple domains and revealed the variety of ways in which receiving sequencing results can impact one's life. Results demonstrated that an individual's perception of utility can change over the life course when sequenced at a relatively young age and may be influenced by the resources available to them to act on the results., Conclusion: Our findings demonstrate the relevance of a multifaceted perceived utility model for a diverse adult population at risk for hereditary cancer. We identified refinements that could make the model more robust, including emphasizing the overlapping nature of the domains and the importance of life stage and personal resources to the perception of utility., (© 2023 The Author(s). Published by S. Karger AG, Basel.)

Purpose: Effective approaches to communicate genomic information are needed to ensure equitable care. In a randomized controlled superiority trial, we tested a novel practice model that aims to make genetic counseling inclusive, by making the communication accessible, relational, and actionable (ARIA)., Methods: In total, 696 English- and Spanish-speaking patients aged 18 to 49 years, enriched for individuals from historically underserved backgrounds, were randomized in 1:1 ratio to ARIA or usual care. Primary outcomes were accuracy of recall, communication satisfaction, and perceived understanding. In total, 33 participants completed qualitative interviews., Results: Recall and understanding were high for all participants. ARIA participants scored higher on the relationship scale of communication satisfaction (mean difference = 0.09, 95% CI = <0.01 to 0.17). Moderator analyses of communication satisfaction showed that those with lower health literacy reported less communication difficulty in ARIA and those using medical interpreters reported greater communication ease in ARIA. No significant difference was found on other primary and secondary outcomes. Qualitative data enhanced understanding of how and why ARIA can be effective., Conclusion: This study provides evidence that a genetic counseling intervention that focuses on specific communication skills to enhance relationship-building, patient engagement, and comprehension can be effective with all patients and may be especially valuable for patients of lower health literacy and Spanish-speakers who use a medical interpreter., Competing Interests: Conflict of Interest One of the coauthors, L.M.A., is an employee at Illumina, Inc. All other authors declare no conflicts of interest., (Copyright © 2022 American College of Medical Genetics and Genomics. All rights reserved.)

In this work, two pathways of reactivity are investigated to generate site-specific substitutions at the B7 vertex of the luminescent boron cluster, anti -B 18 H 22 . First, a palladium-catalyzed cross-coupling reaction utilizing the precursor 7-I-B 18 H 21 and a series of model nucleophiles was developed, ultimately producing several B-N- and B-O-substituted species. Interestingly, the B-I bond in this cluster can also be substituted in an uncatalyzed fashion, leading to the formation of various B-N, B-O, and B-S products. This work highlights intricate differences corresponding to these two reaction pathways and analyzes the role of solvents and additives on product distributions. As a result of our synthetic studies, seven new B 18 -based clusters were synthesized, isolated, and characterized by mass spectrometry and nuclear magnetic resonance (NMR) spectroscopy. The photoluminescence properties of two structurally similar ether and thioether products were further investigated, with both exhibiting blue fluorescence in solution at 298 K and long-lived green or yellow phosphorescence at 77 K. Overall, this work shows, for the first time, the ability to perform substitution of a boron-halogen bond with nucleophiles in a B 18 -based cluster, resulting in the formation of photoluminescent molecules.

In this work, we discuss the synthesis and characterization of a 2D coordination polymer composed of a dianionic perhydroxylated boron cluster, [B 12 (OH) 12 2- ], coordinated to Zn(II)-the first example of a transition metal-coordinated [B 12 (OH) 12 ] 2- compound. This material was synthesized via cation exchange from the starting cesium salt and then subjected to rigorous characterization prior to and after thermal activation. Numerous techniques, including XRD, FTIR, SEM, TGA, and solid-state NMR revealed a 2D coordination polymer composed of sheets of Zn(II) ions intercalated between planes of boron clusters. The as-synthesized material was then evacuated of solvent via thermal treatment, and atomic-level changes from this transformation were elucidated through a combination of 1D and 2D solid-state NMR analyses of 11 B and 1 H nuclei, suggesting the full removal of coordinated solvent molecules. Evidence also suggested that [B 12 (OH) 12 2- ] can adjust its coordination to Zn(II) in the solid-state through hemilability of its numerous -OH ligands.

The dynamic photoluminescence properties, and potential quenching mechanisms, of anti -B 18 H 22 , 4,4'-Br 2 - anti -B 18 H 20 , and 4,4'-I 2 - anti -B 18 H 20 are investigated in solution and polymer films. UV stability studies of the neat powders show no decomposition occurring after intense 7 day light soaking. In contrast, clusters incorporated into polymer films are found to degrade into smaller borane fragments under the same irradiation conditions. To highlight the utility of these compounds, we leverage their favorable optical properties in a prototype UV imaging setup.

Purpose: There is a critical need for genomic medicine research that reflects and benefits socioeconomically and ancestrally diverse populations. However, disparities in research populations persist, highlighting that traditional study designs and materials may be insufficient or inaccessible to all groups. New approaches can be gained through collaborations with patient/community stakeholders. Although some benefits of stakeholder engagement are recognized, routine incorporation into the design and implementation of genomics research has yet to be realized., Methods: The National Institutes of Health-funded Clinical Sequencing Evidence-Generating Research (CSER) consortium required stakeholder engagement as a dedicated project component. Each CSER project planned and carried out stakeholder engagement activities with differing goals and expected outcomes. Examples were curated from each project to highlight engagement strategies and outcomes throughout the research lifecycle from development through dissemination., Results: Projects tailored strategies to individual study needs, logistical constraints, and other challenges. Lessons learned include starting early with engagement efforts across project stakeholder groups and planned flexibility to enable adaptations throughout the project lifecycle., Conclusion: Each CSER project used more than 1 approach to engage with relevant stakeholders, resulting in numerous adaptations and tremendous value added throughout the full research lifecycle. Incorporation of community stakeholder insight improves the outcomes and relevance of genomic medicine research., Competing Interests: Conflict of Interest The authors declare no conflict of interest., (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)

Lynch syndrome (LS) is the most common inherited cause of colorectal and endometrial cancers. Identifying individuals at risk for LS without personal cancer history requires detailed collection and assessment of family health history. However, barriers exist to family health history collection, especially in historically underserved populations. To improve LS risk assessment in historically underserved populations, we adapted the provider-facing PREdiction Model for gene Mutations (PREMM 5 ™ model), a validated LS risk assessment model, into a patient-facing electronic application through an iterative development process involving expert and patient stakeholders. We report on preliminary findings based on the first 500 individuals exposed to the adapted application in a primary care population enriched for low-literacy and low-resource patients. Major adaptations to the PREMM 5 ™ provider module included reduction in reading level, addition of interactive literacy aids, incorporation of family history assessment for both maternal and paternal sides of the family, and inclusion of questions about individual relatives or small groups of relatives to reduce cognitive burden. In the first 500 individuals, 90% completed the PREMM 5 ™ independently; of those, 94% did so in 5 min or less (ranged from 0.2 to 48.8 min). The patient-facing application was able to accurately classify 84% of patients as having clinically significant or not clinically significant LS risk. Our preliminary results suggest that in this diverse study population, most participants were able to rapidly, accurately, and independently complete an interactive application collecting family health history assessment that accurately assessed for Lynch syndrome risk., (© 2021. The Author(s).)

Within-study comparisons (WSCs) compare quasi-experimental results to an experimental benchmark and assess the extent to which quasi-experiments (QEs) sacrifice internal validity for external validity. WSCs inform decisions about when to use experiments or QEs, as well as methodological decisions (e.g., covariate selection) about how to implement QEs when they are necessary or preferred. We review the methodological literature on WSCs and present the findings from a WSC of a school voucher program as an example of the use of WSCs to inform policy debates involving the third sector. Prior literature and our results suggest that QE evaluations of third-sector institutions can produce low levels of bias, but only if analytic models include key proxy variables for voluntary self-selection into programs., Competing Interests: Conflict of interestThere are no conflicts of interest to disclose. We are in full compliance with all Institutional Review Board and Institute for Education Sciences standards., (© The Author(s) 2022.)

Competing Interests: Sapna Syngal Consulting or Advisory Role: Myriad Genetics, DC Health Patents, Royalties, Other Intellectual Property: Dana-Farber Cancer Institute has a registered service mark for the PREMM5 model and holds copyrights for the PREMM questionnaires; Myriad Genetics (through Dana-Farber Cancer Institute) paid an inventor share of the IP (license issue fee) No other potential conflicts of interest were reported. Sapna Syngal Consulting or Advisory Role: Myriad Genetics, DC Health Patents, Royalties, Other Intellectual Property: Dana-Farber Cancer Institute has a registered service mark for the PREMM5 model and holds copyrights for the PREMM questionnaires; Myriad Genetics (through Dana-Farber Cancer Institute) paid an inventor share of the IP (license issue fee) No other potential conflicts of interest were reported.

Advances in the application of genomic technologies in clinical care have the potential to increase existing healthcare disparities. Studies have consistently shown that only a fraction of eligible patients with a family history of cancer receive recommended cancer genetic counseling and subsequent genetic testing. Care delivery models using pre-test and post-test counseling are not scalable, which contributes to barriers in accessing genetics services. These barriers are even more pronounced for patients in historically underserved populations. We have designed a multimodal intervention to improve subsequent cancer surveillance, by improving the identification of patients at risk for familial cancer syndromes, reducing barriers to genetic counseling/testing, and increasing patient understanding of complex genetic results. We are evaluating this intervention in two large, integrated healthcare systems that serve diverse patient populations (NCT03426878). The primary outcome is the number of diagnostic (hereditary cancer syndrome) findings. We are examining the clinical and personal utility of streamlined pathways to genetic testing using electronic medical record data, surveys, and qualitative interviews. We will assess downstream care utilization of individuals receiving usual clinical care vs. genetic testing through the study. We will evaluate the impacts of a literacy-focused genetic counseling approach versus usual care genetic counseling on care utilization and participant understanding, satisfaction, and family communication. By recruiting participants belonging to historically underserved populations, this study is uniquely positioned to evaluate the potential of a novel genetics care delivery program to reduce care disparities., (Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Transcatheter aortic valve replacement (TAVR) is a rapidly evolving treatment for severe aortic stenosis. However, uncertainties exist for optimal valve selection as there are few long-term studies comparing patient survival by valve type. Objective: We hypothesized that self-expandable valves (SEV) would provide a survival advantage over balloon expandable valves (BEV), as SEV continue to expand and might better accommodate to the anatomy of the aortic valve over time. Methods: We examined outcomes according to valve type from a rural tertiary referral center between 2012 and 2017. Results: Out of 269 patients, 77 deaths (28.6%) occurred over the study period with 6 deaths by 1 month post-TAVR and 37 deaths by 1 year post-TAVR. The median observation time for survivors was 21.5 months. The probability of survival at 3 years was 60.7% and 61.9% for patients who underwent treatment with SEV and BEV, respectively. There was no statistically significant difference in overall patient survival with or without adjustment for factors such as age, sex, race, and aortic valve area. Additionally, in a secondary analysis restricted to those patients treated in later years (2015-2017) survival among patients with BEV appeared superior (HR=0.456, P=0.015). Conclusion: Patients who underwent TAVR at a rural medical center with SEV showed similar survival compared to those who received a BEV. Superior survival was observed among those who received BEV versus SEV between 2015 and 2017., (Copyright © 2021 Marshfield Clinic Health System.)

Bromination of the luminescent borane, anti-B18H22, via electrophilic substitution using AlCl3 and Br2, yields the monosubstituted derivative 4-Br-anti-B18H21 as an air-stable crystalline solid. In contrast to the unsubstituted parent compound, 4-Br-anti-B18H21 possesses dual emission upon excitation with UV light and exhibits fluorescence at 410 nm and phosphorescence at 503 nm, with Φtotal = 0.07 in oxygen-free cyclohexane. Increased oxygen content in cyclohexane solution quenches the phosphorescence signal. The fluorescent signal intensity remains unaffected by oxygen, suggesting that this molecule could be used as a ratiometric oxygen probe.

Objective: The aim of this randomized controlled trial with a parallel design was to evaluate the effect of brief, cognitive remediation therapy (CRT) for anorexia nervosa (AN) on set-shifting., Method: Two hundred seventy-five inpatient adults and adolescents with AN (mean age = 23.1; SD = 12.7) were randomly assigned (using simple randomization procedures) to either a CRT or control condition. All participants received treatment as usual; however, the CRT condition completed five CRT group sessions in lieu of other group therapies provided on the unit. Set-shifting abilities were evaluated by: (a) neuropsychological measures and (b) experimental cognitive behavior therapy thought records. Blinding of group assignment occurred during baseline assessment and ended following group commencement., Results: Data from 135 CRT and 140 control condition participants were analyzed. On all neuropsychological measures, results revealed no between group condition effects, but did show statistically significant time effects, with medium to large effect sizes. Thought record analysis revealed a significant condition by age interaction effect where adults in the CRT condition generated significantly more alternative thoughts and had stronger believability of alternative thoughts than children, a trend that was not found in the control condition. This yielded moderate to large effect sizes of.0.56 and 0.72, respectively., Discussion: Based on traditional neuropsychological measures, these findings do not suggest a differential effect of CRT for AN in the format applied. However, results suggest that CRT may have some increased beneficial cognitive effect for adults, as compared to children, based on thought record analysis., (© 2019 Wiley Periodicals, Inc.)

The delivery of teletherapy is an important advancement in clinical care for the treatment of eating disorders (EDs). Specifically, it seems to improve access to highly specialized ED treatment. Research on the application of videoconferencing-based psychotherapy services for EDs is minimal; however, results suggest that this treatment format leads to significant improvements in clinical symptoms and is well accepted by patients. General telemedicine guidelines and administrative and clinical recommendations specific to the treatment of ED patients have been identified. With careful planning and thoughtful application, Internet-based therapy seems to be a valuable resource for practitioners seeking to disseminate specialized ED treatments., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Aim: There are minimal data to guide the continuing medical education (CME) of general paediatricians working in non-tertiary hospitals. The aim of this study was to determine the procedural and resuscitation skills required by non-tertiary paediatricians and the frequency with which these skills are utilised., Methods: Over a 12-month period (December 2012 to December 2013), each of the 11 paediatricians involved in acute inpatient care at University Hospital Geelong (UHG) completed a weekly online survey regarding their inpatient clinical experience. This included procedures performed or directly supervised as well as their resuscitation involvement., Results: Each of the 11 paediatricians who managed inpatients on a regular or semi-regular basis during the study period agreed to participate, and each completed all of the weekly surveys. There were seven UHG paediatricians with an inpatient appointment (each with a 0.27 full-time equivalent (FTE) paediatrician workload) and four paediatricians providing inpatient cover on a locum basis. Over the course of 12 months, each 0.27 FTE paediatrician was, on average, involved in 11.3 neonatal, 1.7 infant and 2.4 child resuscitations and performed 0.9 intubations., Conclusions: Paediatricians working at non-tertiary hospitals are required to perform and supervise critical procedural and resuscitation skills but have limited opportunities to maintain proficiency in such skills. General paediatric training and consultant paediatrician CME programmes should ensure the acquisition and maintenance of the procedural and resuscitation skills required for the management of seriously ill children in non-tertiary acute care settings., (© 2018 Paediatrics and Child Health Division (The Royal Australasian College of Physicians).)

Carboranes are boron-rich molecular clusters possessing electronic characteristics that allow for orthogonal approaches to vertex-selective modifications. We report improved functionalization methods utilizing orthogonal chemistry to achieve efficient substitution at electron-rich B-vertices and electron-poor C-vertices of carborane. Functionalization of B-vertices with alkyl and (hetero)aryl groups using the corresponding Grignard reagents has been improved through the use of a Pd-based precatalyst featuring an electron-rich biaryl phosphine ligand, resulting in reduced reaction times. Importantly, this method is tolerant towards alkyl-based Grignard reagents containing β-hydrogens. Furthermore, a transition metal-free approach to the substitution of carborane C-vertices with (hetero)aryl substrates has been developed under nucleophilic aromatic substitution (S N Ar) conditions. The selective substitution of carboranes afforded by these methods holds potential for the rational synthesis of heterofunctionalized boron clusters with substituents on both boron and carbon-based vertices.

Responding to a major disaster requires coordination and communication across all critical infrastructure sectors, including emergency management and drinking water and wastewater. This paper describes how in planning for an earthquake in the Cascadia Subduction Zone, the various bureaus in the City of Portland developed robust relationships by participating in joint exercises and events, coordinating on damage assessments and collaborating on planning efforts. The paper also describes the various tools and resources provided by the US Environmental Protection Agency to help water utilities and emergency management agencies to strengthen their relationships.

Background: The clinical significance of left bundle branch block (LBBB) has recently expanded with the discovery of a strong association with better outcomes in patients receiving cardiac resynchronization therapy., Methods: Several milestones have contributed to the current understanding on the role of LBBB in clinical practice., Result: Sunao Tawara described the arrangement of components of what he called the cardiac conduction system from the atrioventricular node to the terminal Purkinje fibers that connect to the working myocardium, and his hypotheses on how it functions remain current. Mauricio Rosenbaum and colleagues developed the bifascicular model of the left-sided conduction system that explains the characteristic electrocardiographic changes associated with propagation disturbances in its components. Andrés Ricardo Pérez-Riera and others have disputed the bifascicular model as oversimplified and have emphasized the role of the left septal fascicle. Marcelo Elizari and colleagues have explained the importance of masquerading bundle branch block. Elena Sgarbossa and colleagues developed a scheme to recognize ST elevation myocardial infarction in patients with left bundle branch block which remains current after more than 20 years. Enrique Cabrera and others identified electrocardiographic signs of remote myocardial infarction., Conclusion: Substantial progress has been made in the understanding of LBBB, yet its role in clinical practice continues to evolve and important gaps remain to which research should be directed.

Spinal muscular atrophy (SMA) is a neurodegenerative disorder that results from mutations in the SMN1 gene, leading to survival motor neuron (SMN) protein deficiency. One therapeutic strategy for SMA is to identify compounds that enhance the expression of the SMN2 gene, which normally only is a minor contributor to functional SMN protein production, but which is unaffected in SMA. A recent high-throughput screening campaign identified a 3,4-dihydro-4-phenyl-2(1H)-quinolinone derivative (2) that increases the expression of SMN2 by 2-fold with an EC 50  = 8.3 µM. A structure-activity relationship (SAR) study revealed that the array of tolerated substituents, on either the benzo portion of the quinolinone or the 4-phenyl, was very narrow. However, the lactam ring of the quinolinone was more amenable to modifications. For example, the quinazolinone (9a) and the benzoxazepin-2(3H)-one (19) demonstrated improved potency and efficacy for increase in SMN2 expression as compared to 2., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

Aim: Data regarding temporal trends in per capita paediatric hospital presentations and admissions are required to inform health system and workforce planning., Methods: Emergency Department (ED) presentations and admissions to the University Hospital Geelong among patients aged 0 to 16 years over a 12-month period (2012-2013) were determined by review of hospital records and then compared with similar data collected during 1996/1997. 1 During each period, the Geelong region was serviced by a single ED, enabling us to estimate per capita presentation and admission rates., Results: Since 1996/1997, per capita paediatric presentations to the ED increased from 643 to 1837 per 10 000 (186%; 95% confidence interval 181% to 191%). Moreover, the proportion of paediatric ED presentations resulting in hospital admission increased from 12.3% to 18.3% (49%; 95% confidence interval 39% to 59%)., Conclusions: There has been a substantial absolute and per capita increase in paediatric ED presentations and hospital admissions since the 1990s. These trends place an increasing burden on the public hospital system, and strategies are required to promote paediatric acute care in the ambulatory setting., (© 2016 Paediatrics and Child Health Division (The Royal Australasian College of Physicians).)

Purpose: The goal of this study was to develop a technology-based strategy to identify patients with undiagnosed hypertension in 23 primary care practices and integrate this innovation into a continuous quality improvement initiative in a large, integrated health system., Methods: In phase 1, we reviewed electronic health records (EHRs) using algorithms designed to identify patients at risk for undiagnosed hypertension. We then invited each at-risk patient to complete an automated office blood pressure (AOBP) protocol. In phase 2, we instituted a quality improvement process that included regular physician feedback and office-based computer alerts to evaluate at-risk patients not screened in phase 1. Study patients were observed for 24 additional months to determine rates of diagnostic resolution., Results: Of the 1,432 patients targeted for inclusion in the study, 475 completed the AOBP protocol during the 6 months of phase 1. Of the 1,033 at-risk patients who remained active during phase 2, 740 (72%) were classified by the end of the follow-up period: 361 had hypertension diagnosed, 290 had either white-coat hypertension, prehypertension, or elevated blood pressure diagnosed, and 89 had normal blood pressure. By the end of the follow-up period, 293 patients (28%) had not been classified and remained at risk for undiagnosed hypertension., Conclusions: Our technology-based innovation identified a large number of patients at risk for undiagnosed hypertension and successfully classified the majority, including many with hypertension. This innovation has been implemented as an ongoing quality improvement initiative in our medical group and continues to improve the accuracy of diagnosis of hypertension among primary care patients., (© 2014 Annals of Family Medicine, Inc.)

eXtension (pronounced e-extension) is an online resource transforming how faculty can collaborate and deliver equine education. As the first Community of Practice launched from eXtension, HorseQuest (HQ) offers free, interactive, peer-reviewed, online resources on a variety of equine-related topics at http://www.extension.org. This group has adapted traditional educational content to the online environment to maximize search engine optimization, to be more discoverable and relevant in the online world. This means that HQ resources are consistently being found on the first page of search results. Also, by researching key words searched by Internet users, HQ has guided new content direction and determined potential webcast topics based on relevance and frequency of those searches. In addition to establishing good search engine optimization, HQ has been utilizing the viral networking aspect of YouTube by uploading clips of existing equine educational videos to YouTube. HorseQuest content appears in mainstream media, is passed on by the user, and helps HQ effectively reach their community of interest (horse enthusiasts). HorseQuest partners with My Horse University to produce webcasts that combine concise knowledge exchange via a scripted presentation with viewer chat and incoming questions. HorseQuest has produced and published content including 12 learning modules, 8 webchats, 21 webcasts, and 572 videos segments. After the official public launch, there was a steady increase in average number of visits/mo and average page views/mo over the 26-mo period. These regressions show a statistically significant increase in visits (P < 0.001) of approximately 450 visits per month and a significant increase in page views (P = 0.004) of about 373 page views per month. HorseQuest is a resource for several state 4-H advancement and competition programs and will continue to be incorporated into traditional extension programs, while reaching and affecting global audiences.

Investigations of the impact of ventricular arrhythmias in populations have focused primarily on two aspects, ventricular ectopic activity and sudden cardiac death (SCD). The observation that coronary heart disease (CHD) is an important background of death due to ventricular tachyarrhythmia (VTA) remains the dominant belief today. The evidence supports the principle that reduction of deaths due to VTA is multifactorial and results from improved primary prevention, treatment of CHD complications, and secondary prevention. Recent evidence for unfavorable trends for SCD and CHD mortality raises the specter of a reversal in the gains made against fatal VTA in recent decades.

Patients with sickle cell disease exhibit both acute and chronic activation of the coagulation and fibrinolytic systems. To test the relationship between sickle cell pathology and activation of the hemostatic system, mice with targeted deletions of plasminogen (Plg) or fibrinogen (Fib) were crossed with transgenic mice expressing Hb SAD [beta(6Glu-Val) (HbS), beta(23Val-Ile) (HbAntilles), and beta(121Glu-Gln) (HbD-Punjab)]. Fibrinogen deficiency dramatically reduced the survival of mice with Hb SAD to a much greater degree than mice with normal hemoglobin. The combination of Hb SAD and fibrinogen deficiency had a greater effect on mortality than that obtained by adding the mortality risks of each defect alone. The deleterious effect of the combination of Hb SAD and fibrinogen deficiency on mortality was accelerated by hypoxia. The excess mortality associated with plasminogen deficiency was identical in SAD and control mice. The adverse effect of fibrinogen deficiency on mortality in SAD mice is not consistent with the simple hypothesis that fibrin deposition is uniformly deleterious in the context of vaso-occlusive sickle cell disease. Rather, our findings suggest that the contribution of fibrinogen to tissue repair may in some contexts limit sickle cell disease pathophysiology.