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Background: Many COVID-19 patients are left with symptoms several months after resolution of the acute illness; this syndrome is known as post-acute sequalae of COVID-19 (PASC). We aimed to determine the prevalence of objective hemodynamic cardiovascular autonomic abnormalities (CAA), explore sex differences, and assess the prevalence of CAA among hospitalized vs nonhospitalized patients with PASC., Methods: Patients with PASC (n = 70; female [F] = 56; 42 years of age; 95% confidence interval [CI], 40-48) completed standard autonomic tests, including an active stand test 399 days (338, 455) after their COVID-19 infection. Clinical autonomic abnormalities were evaluated., Results: Most patients with PASC met the criteria for at least 1 CAA (51; 73%; F = 43). The postural orthostatic tachycardia syndrome hemodynamic (POTS HR ) criterion of a heart rate increase of > 30 beats per minute within 5 to 10 minutes of standing was seen in 21 patients (30%; F = 20; P = 0.037 [by sex]). The initial orthostatic hypotension hemodynamic (IOH 40 ) criterion of a transient systolic blood pressure change of > 40 mm Hg in the first 15 seconds of standing was seen in 43 (61%) patients and equally among female and male patients (63% vs 57%; P = 0.7). Only 9 (13%) patients were hospitalized; hospitalized vs nonhospitalized patients had similar frequencies of abnormalities (67% vs 74%; P = 0.7)., Conclusions: Patients with PASC have evidence of CAA, most commonly IOH 40 , which will be missed unless an active stand test is used. Female patients have increased frequency of POTS HR , but IOH 40 is equally prevalent between sexes. Finally, even nonhospitalized "mild" infections can result in long-term CAAs., (Copyright © 2022 Canadian Cardiovascular Society. Published by Elsevier Inc. All rights reserved.)

Varicella zoster virus (VZV) establishes lifelong infection after primary disease and can reactivate. Several drugs are approved to treat VZV diseases, but new antivirals with greater potency are needed. Previously, we identified β-l-5-(( E) -2-bromovinyl)-1-((2 S ,4 S )-2-(hydroxymethyl)-1,3-(dioxolane-4-yl))uracil (l-BHDU, 1 ), which had significant anti-VZV activity. In this communication, we report the synthesis and evaluation of numerous l-BHDU prodrugs: amino acid esters ( 14 - 26 ), phosphoramidates ( 33 - 34 ), long-chain lipids (ODE-l-BHDU-MP, 38 , and HDP-l-BHDU-MP, 39 ), and phosphate ester prodrugs (POM-l-BHDU-MP, 41 , and POC-l-BHDU-MP, 47 ). The amino acid ester l-BHDU prodrugs (l-phenylalanine, 16 , and l-valine, 17 ) had a potent antiviral activity with EC 50 values of 0.028 and 0.030 μM, respectively. The phosphate ester prodrugs POM-l-BHDU-MP and POC-l-BHDU-MP had a significant anti-VZV activity with EC 50 values of 0.035 and 0.034 μM, respectively, and no cellular toxicity (CC 50 > 100 μM) was detected. Out of these prodrugs, ODE-l-BHDU-MP ( 38 ) and POM-l-BHDU-MP ( 41 ) were selected for further evaluation in future studies.

Varicella-zoster virus (VZV) is a human-restricted virus, which raises obstacles to research. The strict human tropism limits knowledge about its pathogenesis and creates challenges for evaluating antiviral treatments and vaccines. The development of humanized mouse models was driven by the need to address these challenges. Here, we summarize the humanized mouse models with xenografts of thymus/liver organoids, skin, dorsal root ganglia, and lung tissues. These models revealed VZV ORFs involved in cell tropism and pathogenesis in differentiated tissues, and made it possible to evaluate antiviral compounds in a mammalian system. Further development of skin organ culture techniques have the added benefit of lower cost and greater speed than mouse models. Human tissues, both in humanized mice and in ex vivo models, will continue to be necessary to study VZV in the tissue microenvironements to which it is adapted., (© 2022. The Author(s), under exclusive license to Springer Nature Switzerland AG.)

By suppressing gene transcription through the recruitment of corepressor proteins, B-cell lymphoma 6 (BCL6) protein controls a transcriptional network required for the formation and maintenance of B-cell germinal centres. As BCL6 deregulation is implicated in the development of Diffuse Large B-Cell Lymphoma, we sought to discover novel small molecule inhibitors that disrupt the BCL6-corepressor protein-protein interaction (PPI). Here we report our hit finding and compound optimisation strategies, which provide insight into the multi-faceted orthogonal approaches that are needed to tackle this challenging PPI with small molecule inhibitors. Using a 1536-well plate fluorescence polarisation high throughput screen we identified multiple hit series, which were followed up by hit confirmation using a thermal shift assay, surface plasmon resonance and ligand-observed NMR. We determined X-ray structures of BCL6 bound to compounds from nine different series, enabling a structure-based drug design approach to improve their weak biochemical potency. We developed a time-resolved fluorescence energy transfer biochemical assay and a nano bioluminescence resonance energy transfer cellular assay to monitor cellular activity during compound optimisation. This workflow led to the discovery of novel inhibitors with respective biochemical and cellular potencies (IC 50s ) in the sub-micromolar and low micromolar range., (© 2022. The Author(s).)

To identify new chemical series with enhanced binding affinity to the BTB domain of B-cell lymphoma 6 protein, we targeted a subpocket adjacent to Val18. With no opportunities for strong polar interactions, we focused on attaining close shape complementarity by ring fusion onto our quinolinone lead series. Following exploration of different sized rings, we identified a conformationally restricted core which optimally filled the available space, leading to potent BCL6 inhibitors. Through X-ray structure-guided design, combined with efficient synthetic chemistry to make the resulting novel core structures, a >300-fold improvement in activity was obtained by the addition of seven heavy atoms.

There is a continued need to understand varicella-zoster virus (VZV) pathogenesis and to develop more effective antivirals, as it causes chickenpox and zoster. As a human-restricted alphaherpesvirus, the use of human skin in culture and mice is critical in order to reveal the important VZV genes that are required for pathogenesis but that are not necessarily observed in the cell culture. We previously used VZV-expressing firefly luciferase (fLuc), under the control of the constitutively active SV40 promoter (VZV-BAC-Luc), to measure the VZV spread in the same sample. However, the fLuc expression was independent of viral gene expression and viral DNA replication programs. Here, we developed robust reporter VZV viruses by using bacterial artificial chromosome (BAC) technology, expressing luciferase from VZV-specific promoters. We also identified two spurious mutations in VZV-BAC that were corrected for maximum pathogenesis. VZV with fLuc driven by ORF57 showed superior growth in cells, human skin explants, and skin xenografts in mice. The ORF57-driven luciferase activity had a short half-life in the presence of foscarnet. This background was then used to investigate the roles for ORF36 (thymidine kinase (TK)) and ORF13 (thymidylate synthase (TS)) in skin. The studies reveal that VZV-∆TS had increased sensitivity to brivudine and was highly impaired for skin replication. This is the first report of a phenotype that is associated with the loss of TS.

Arboviruses such as flaviviruses and alphaviruses cause a significant human healthcare burden on a global scale. Transmission of these viruses occurs during human blood feeding at the mosquito-skin interface. Not only do pathogen immune evasion strategies influence the initial infection and replication of pathogens delivered, but arthropod salivary factors also influence transmission foci. In vitro cell cultures do not provide an adequate environment to study complex interactions between viral, mosquito, and host factors. To address this need for a whole tissue system, we describe a proof of concept model for arbovirus infection using adult human skin ex vivo with Zika virus (flavivirus) and Mayaro virus (alphavirus) . Replication of these viruses in human skin was observed up to 4 days after infection. Egressed viruses could be detected in the culture media as well. Antiviral and proinflammatory genes, including chemoattractant chemokines, were expressed in infected tissue. Immunohistochemical analysis showed the presence of virus in the skin tissue 4 days after infection. This model will be useful to further investigate: (i) the immediate molecular mechanisms of arbovirus infection in human skin, and (ii) the influence of arthropod salivary molecules during initial infection of arboviruses in a more physiologically relevant system., (© 2022 The Authors.)

Varicella zoster virus (VZV) causes chicken pox and shingles and is prevalent worldwide. Acyclovir and penciclovir (and its prodrugs) are first-line treatments for VZV infections, but they are not highly potent against VZV and resistance may arise in immunocompromised people on long-term therapy. HPMPC (cidofovir) is active against VZV, but cidofovir is not approved for treating VZV diseases, is nephrotoxic, and is not orally bioavailable. Here, we present the synthesis and evaluation of USC-373, a phosphonate prodrug of HPMPC with activity against VZV and other DNA viruses. In cultured fibroblasts, it was potent against VZV Ellen laboratory strain and was not overtly toxic, with EC 50 of 4 nM and CC 50 of 0.20 μM, producing a selectivity index of 50. In ARPE-19 cells, USC-373 was effective against VZV-ORF57-Luc wild type strain and the acyclovir-resistant isogenic strain. In human skin organ culture, USC-373 formulated in cocoa butter and applied topically prevented VZV-ORF57-Luc spread without toxicity. In NuSkin mice with human skin xenografts, one daily dose of 3 mg/kg was effective by the subcutaneous route, and one daily dose of 10 mg/kg was effective by the oral route. Remarkably, a 10 mg/kg oral dose given every other day was also effective. USC-373 was well tolerated and mice did not lose weight or show signs of distress. The prodrug modifications of USC-373 increase the potency and oral bioavailability compared to its parent nucleoside analog, HPMPC., (Copyright © 2022 The Authors. Published by Elsevier B.V. All rights reserved.)

H84T BanLec is a molecularly engineered lectin cloned from bananas with broad-spectrum antiviral activity against several RNA viruses. H84T BanLec dimers bind glycoproteins containing high-mannose N-glycans on the virion envelope, blocking attachment, entry, uncoating, and spread. It was unknown whether H84T BanLec is effective against human herpesviruses varicella-zoster virus (VZV), human cytomegalovirus (HCMV), and herpes simplex virus 1 (HSV-1), which express high-mannose N-linked glycoproteins on their envelopes. We evaluated H84T BanLec against VZV-ORF57-Luc, TB40/E HCMV-fLuc-eGFP, and HSV-1 R8411 in cells, skin organ culture, and mice. The H84T BanLec EC 50 was 0.025 µM for VZV (SI 50  = 4000) in human foreskin fibroblasts (HFFs), 0.23 µM for HCMV (SI 50  = 441) in HFFs, and 0.33 µM for HSV-1 (SI 50  = 308) in Vero cells. Human skin was obtained from reduction mammoplasties and prepared for culture. Skin was infected and cultured up to 14 days. H84T BanLec prevented VZV, HCMV and HSV-1 spread in skin at 10 µM in the culture medium, and also exhibited dose-dependent antiviral effects. Additionally, H84T BanLec arrested virus spread when treatment was delayed. Histopathology of HCMV-infected skin showed no overt toxicity when H84T BanLec was present in the media. In athymic nude mice with human skin xenografts (NuSkin mice), H84T BanLec reduced VZV spread when administered subcutaneously prior to intraxenograft virus inoculation. This is the first demonstration of H84T BanLec effectiveness against DNA viruses. H84T BanLec may have additional unexplored activity against other, clinically relevant, glycosylated viruses., (© 2022. The Author(s).)

We describe the optimization of modestly active starting points to potent inhibitors of BCL6 by growing into a subpocket, which was occupied by a network of five stably bound water molecules. Identifying potent inhibitors required not only forming new interactions in the subpocket but also perturbing the water network in a productive, potency-increasing fashion while controlling the physicochemical properties. We achieved this goal in a sequential manner by systematically probing the pocket and the water network, ultimately achieving a 100-fold improvement of activity. The most potent compounds displaced three of the five initial water molecules and formed hydrogen bonds with the remaining two. Compound 25 showed a promising profile for a lead compound with submicromolar inhibition of BCL6 in cells and satisfactory pharmacokinetic (PK) properties. Our work highlights the importance of finding productive ways to perturb existing water networks when growing into solvent-filled protein pockets.

Purpose: Effective end-organ peripheral vascular resistance responses are critical to blood pressure control while upright, and prevention of syncope (fainting). The Valsalva maneuver (VM) induces blood pressure decreases that evoke baroreflex-mediated vasoconstriction. We characterized beat-to-beat forearm vascular resistance (FVR) responses to the VM in healthy adults, evaluated the impact of age and sex on these responses, and investigated their association with orthostatic tolerance (OT; susceptibility to syncope). We hypothesized that individuals with smaller FVR responses would be more susceptible to syncope., Methods: Healthy young (N = 36; 19 women; age 25.4 ± 4.6 years) and older (N = 21; 12 women; age 62.4 ± 9.6 years) adults performed a supine 40 mmHg, 20 s VM. Graded 60° head-up-tilt with combined lower body negative pressure continued to presyncope was used to determine OT. Non-invasive beat-to-beat blood pressure and heart rate (finger plethysmography) were recorded continuously. FVR was calculated as mean arterial pressure (MAP) divided by brachial blood flow velocity (Doppler ultrasound) relative to baseline., Results: The VM produces a distinctive FVR pattern that peaks (+137.1 ± 11.6%) in phase 2B (17.5 ± 0.3 s) as the baroreflex responds to low-pressure perturbations. This response increased with age overall (p < 0.001) and within male (p = 0.030) and female subgroups (p < 0.001). Maximum FVR during the VM was significantly correlated with maximal tilt FVR (r = 0.364; p = 0.0153) and with OT when expressed relative to the MAP decrease in phase 2A (Max FVR (%)/MAP 2A-1 ; r = 0.337; p = 0.0206)., Conclusion: This is the first characterization of FVR responses to the VM. The VM elicits large baroreflex-mediated increases in FVR; small FVR responses to the VM may indicate susceptibility to syncope., (© 2021. Springer-Verlag GmbH Germany, part of Springer Nature.)

The herpesviruses varicella-zoster virus (VZV) and human cytomegalovirus (HCMV) are endemic to humans. VZV causes varicella (chicken pox) and herpes zoster (shingles), while HCMV causes serious disease in immunocompromised patients and neonates. More effective, less toxic antivirals are needed, necessitating better models to study these viruses and evaluate antivirals. Previously, VZV and HCMV models used fetal tissue; here, we developed an adult human skin model to study VZV and HCMV in culture and in vivo While VZV is known to grow in skin, it was unknown whether skin could support an HCMV infection. We used TB40/E HCMV and POka VZV strains to evaluate virus tropism in skin organ culture (SOC) and skin xenograft mouse models. Adult human skin from reduction mammoplasties was prepared for culture on NetWells or mouse implantation. In SOC, VZV infected the epidermis and HCMV infected the dermis. Specifically, HCMV infected fibroblasts, endothelial cells, and hematopoietic cells, with some infected cells able to transfer infection. VZV and HCMV mouse models were developed by subcutaneous transplantation of skin into SCID/beige or athymic nude mice at 2 independent sites. Viruses were inoculated directly into one xenograft, and widespread infection was observed for VZV and HCMV. Notably, we detected VZV- and HCMV-infected cells in the contralateral, uninoculated xenografts, suggesting dissemination from infected xenografts occurred. For the first time, we showed HCMV successfully grows in adult human skin, as does VZV. Thus, this novel system may provide a much-needed preclinical small-animal model for HCMV and VZV and, potentially, other human-restricted viruses. IMPORTANCE Varicella-zoster virus and human cytomegalovirus infect a majority of the global population. While they often cause mild disease, serious illness and complications can arise. Unfortunately, there are few effective drugs to treat these viruses, and many are toxic. To complicate this, these viruses are restricted to replication in human cells and tissues, making them difficult to study in traditional animal models. Current models rely heavily on fetal tissues, can be prohibitively expensive, and are often complicated to generate. While fetal tissue models provide helpful insights, it is necessary to study human viruses in human tissue systems to fully understand these viruses and adequately evaluate novel antivirals. Adult human skin is an appropriate model for these viruses because many target cells are present, including basal keratinocytes, fibroblasts, dendritic cells, and lymphocytes. Skin models, in culture and xenografts in immunodeficient mice, have potential for research on viral pathogenesis, tissue tropism, dissemination, and therapy., (Copyright © 2020 American Society for Microbiology.)

Deregulation of the transcriptional repressor BCL6 enables tumorigenesis of germinal center B-cells, and hence BCL6 has been proposed as a therapeutic target for the treatment of diffuse large B-cell lymphoma (DLBCL). Herein we report the discovery of a series of benzimidazolone inhibitors of the protein-protein interaction between BCL6 and its co-repressors. A subset of these inhibitors were found to cause rapid degradation of BCL6, and optimization of pharmacokinetic properties led to the discovery of 5-((5-chloro-2-((3 R ,5 S )-4,4-difluoro-3,5-dimethylpiperidin-1-yl)pyrimidin-4-yl)amino)-3-(3-hydroxy-3-methylbutyl)-1-methyl-1,3-dihydro-2 H -benzo[ d ]imidazol-2-one (CCT369260), which reduces BCL6 levels in a lymphoma xenograft mouse model following oral dosing.

Verticillium dahliae , the cause of Verticillium wilt, is a widespread pathogen that affects many crops in California and throughout the world. Cover cropping with leguminous species is often integrated into a rotation scheme for its contribution to soil nitrogen, and can contribute to management of Verticillium wilt provided the chosen crop does not support development of V. dahliae . Seven cool season legumes (faba bean, bell bean, field pea, hairy vetch, common vetch, purple vetch, and woollypod vetch), and three warm season legumes (sesbania, sunn hemp, and black-eyed pea) were evaluated as hosts for reproductive growth of V. dahliae . All 10 legumes were colonized by V. dahliae , while remaining symptomless, when subjected to a root-dip inoculation. Similar results were obtained when plants were grown in infested potting soil, albeit with a lower frequency of infection than in root-dip assays. All tested legumes were also infected in field trials, with the exception of bell bean. Overall, warm season legumes sustained higher rates of infection than cool season legumes. Common vetch was the most extensively colonized of the cool season legumes. Based on the results of this study, legumes may not be an appropriate rotation crop in fields where Verticillium wilt is a problem.

Multidrug-resistant organisms are increasing in healthcare settings, and there are few antimicrobials available to treat infections from these bacteria. Pseudomonas aeruginosa is an opportunistic pathogen in burn patients and individuals with cystic fibrosis (CF), and a leading cause of nosocomial infections. P. aeruginosa is inherently resistant to many antibiotics and can develop resistance to others, limiting treatment options. P. aeruginosa has multiple sigma factors to regulate transcription. The alternative sigma factor, RpoN (σ 54 ), regulates many virulence genes and is linked to antibiotic resistance. Recently, we described a cis-acting peptide, RpoN*, which is a "molecular roadblock", binding consensus promoters at the -24 site, blocking transcription. RpoN* reduces virulence of P. aeruginosa laboratory strains, but its effects in clinical isolates was unknown. We investigated the effects of RpoN* on phenotypically varied P. aeruginosa strains isolated from CF patients. RpoN* expression reduced motility, biofilm formation, and pathogenesis in a P. aeruginosa-C. elegans infection model. Furthermore, we investigated RpoN* effects on antibiotic susceptibility in a laboratory strain. RpoN* expression increased susceptibility to several beta-lactam-based antibiotics in strain P. aeruginosa PA19660 Xen5. We show that using a cis-acting peptide to block RpoN consensus promoters has potential clinical implications in reducing virulence and improving antibiotic susceptibility.

Background: Cardiovascular autonomic dysfunction is an early marker for cardiovascular disease. Anthracycline chemotherapy and left-sided radiation for breast cancer are associated with negative autonomic function changes. This study's objectives were to characterize changes in, and the association of exercise training with, clinical indices of cardiovascular autonomic function across the trajectory of breast cancer therapy., Subjects, Materials, and Methods: Seventy-three patients receiving adjuvant chemotherapy participated to varying degrees in supervised aerobic and resistance exercise during chemotherapy ± radiation and for 20 weeks after. Resting heart rate (HR rest ) and blood pressure were measured weekly during chemotherapy. HR rest , exercise heart rate recovery (HR recovery ), and aerobic fitness were measured at enrollment, end of chemotherapy ± radiation, and 10 and 20 weeks after treatment., Results: During chemotherapy, HR rest increased in a parabolic manner within a single treatment and with increasing treatment dose, whereas systolic and diastolic blood pressure decreased linearly across treatments. Tachycardia and hypotension were present in 32%-51% of participants. Factors associated with weekly changes during chemotherapy included receiving anthracyclines or trastuzumab, days since last treatment, hematocrit, and exercise attendance. Receipt of anthracyclines, trastuzumab, and left-sided radiation individually predicted impairments of HR rest and HR recovery during chemotherapy ± radiation; however, aerobic fitness change and at least twice-weekly exercise attendance predicted improvement. By 10 weeks after treatment, HR rest and blood pressure were not different from prechemotherapy., Conclusion: In this study, chemotherapy resulted in increased HR rest and tachycardia, as well as decreased blood pressure and hypotension. Anthracyclines, trastuzumab, and left-sided radiation were associated with HR rest elevations and impairments of HR recovery , but exercise training at least twice a week appeared to mitigate these changes., Implications for Practice: This study characterized changes in clinically accessible measures with well-established prognostic value for cardiovascular disease, and investigated associations with cardiotoxic treatments and the positive influence of exercise. The chemotherapy-related incremental increase in resting heart rate, with tachycardia occurring in one third of patients, and decrease in blood pressure, with hypotension occurring in one half of the patients, is relevant to oncology practitioners for clinical examination or patient report of related symptoms (i.e., dizziness). The weekly dose of two 60-minute sessions of moderate-intensity aerobic and resistance exercise that was identified as protective of cardiovascular autonomic impairments can easily be prescribed to patients by oncologists., Competing Interests: Disclosures of potential conflicts of interest may be found at the end of this article., (© AlphaMed Press 2018.)

Pseudomonas aeruginosa is a Gram-negative, opportunistic pathogen that infects immunocompromised and cystic fibrosis patients. Treatment is difficult due to antibiotic resistance, and new antimicrobials are needed to treat infections. The alternative sigma factor 54 (σ 54 , RpoN), regulates many virulence-associated genes. Thus, we evaluated inhibition of virulence in P. aeruginosa by a designed peptide (RpoN molecular roadblock, RpoN*) which binds specifically to RpoN consensus promoters. We expected that RpoN* binding to its consensus promoter sites would repress gene expression and thus virulence by blocking RpoN and/or other transcription factors. RpoN* reduced transcription of approximately 700 genes as determined by microarray analysis, including genes related to virulence. RpoN* expression significantly reduced motility, protease secretion, pyocyanin and pyoverdine production, rhamnolipid production, and biofilm formation. Given the effectiveness of RpoN* in vitro, we explored its effects in a Caenorhabditis elegans-P. aeruginosa infection model. Expression of RpoN* protected C. elegans in a paralytic killing assay, whereas worms succumbed to paralysis and death in its absence. In a slow killing assay, which mimics establishment and proliferation of an infection, C. elegans survival was prolonged when RpoN* was expressed. Thus, blocking RpoN consensus promoter sites is an effective strategy for abrogation of P. aeruginosa virulence.

The arterial baroreflex is crucial for short-term blood pressure control - abnormal baroreflex function predisposes to syncope and falling. Hypersensitive responses to carotid baroreflex stimulation using carotid sinus massage (CSM) are common in older adults and may be associated with syncope. The pathophysiology of this hypersensitivity is unknown, but chronic denervation of the sternocleidomastoid muscles is common in elderly patients with carotid sinus hypersensitivity (CSH), and is proposed to interfere with normal integration of afferent firing from the carotid baroreceptors with proprioceptive feedback from the sternocleidomastoids, producing large responses to CSM. We hypothesized that simulation of sternocleidomastoid "denervation" using pharmacological blockade would increase cardiovascular responses to CSM. Thirteen participants received supine and tilted CSM prior to intramuscular injections (6-8 mL distributed over four sites) of 2% lidocaine hydrochloride, and 0.9% saline (placebo) in contralateral sternocleidomastoid muscles. Muscle activation was recorded with electromyography (EMG) during maximal unilateral sternocleidomastoid contraction both pre- and postinjection. Supine and tilted CSM were repeated following injections and responses compared to preinjection. Following lidocaine injection, the muscle activation fell to 23 ± 0.04% of the preinjection value ( P  < 0.001), confirming neural block of the sternocleidomastoid muscles. Cardiac (RRI, RR interval), forearm vascular resistance (FVR), and systolic arterial pressure (SAP) responses to CSM did not increase after lidocaine injection in either supine or tilted positions (supine: ΔRRI -72 ± 31 ms, ΔSAP +2 ± 1 mmHg, ΔFVR +4 ± 4%; tilted: ΔRRI -20 ± 13 ms, ΔSAP +2 ± 2 mmHg, ΔFVR +2 ± 4%; all P  > 0.05). Neural block of the sternocleidomastoid muscles does not increase cardiovascular responses to CSM. The pathophysiology of CSH remains unknown., (© 2017 The Authors. Physiological Reports published by Wiley Periodicals, Inc. on behalf of The Physiological Society and the American Physiological Society.)

Baroreflex-mediated changes in heart rate and vascular resistance in response to variations in blood pressure are critical to maintain homeostasis. We aimed to develop time domain analysis methods to complement existing cross-spectral techniques in the investigation of the vascular resistance baroreflex response to orthostatic stress. A secondary goal was to apply these methods to distinguish between levels of orthostatic tolerance using baseline data. Eleven healthy, normotensive males participated in a graded lower body negative pressure protocol. Within individual neurogenic baroreflex cycles, the amount of muscle sympathetic nerve activity (MSNA), the diastolic pressure stimulus and response amplitudes, diastolic pressure to MSNA burst stimulus and response times, as well as the stimulus and response slopes between diastolic pressure and MSNA were computed. Coherence, gain, and frequency of highest coherence between systolic/diastolic arterial pressure (SAP/DAP) and RR-interval time series were also computed. The number of MSNA bursts per low-frequency cycle increased from 2.55 ± 0.68 at baseline to 5.44 ± 1.56 at -40 mmHg of LBNP Stimulus time decreased (3.21 ± 1.48-1.46 ± 0.43 sec), as did response time (3.47 ± 0.86-2.37 ± 0.27 sec). At baseline, DAP-RR coherence, DAP-RR gain, and the time delay between decreases in DAP and MSNA bursts were higher in participants who experienced symptoms of presyncope. Results clarified the role of different branches of the baroreflex loop, and suggested functional adaptation of neuronal pathways to orthostatic stress., (© 2017 The Authors. Physiological Reports published by Wiley Periodicals, Inc. on behalf of The Physiological Society and the American Physiological Society.)

Phosphorylated cyclopropanes, generated via the Rh(ii)-catalysed intramolecular cyclopropanation of α-(diethoxyphosphoryl)acetates, have been found to be useful precursors in the synthesis of α-alkylidene-γ-butyrolactones. These cyclopropyl intermediates undergo regioselective reductive ring-opening and subsequent Horner-Wadsworth-Emmons olefination to complete the synthesis. Total syntheses of (±)-savinin and (±)-gadain, as well as the first total synthesis of (±)-peperomin E, are all described using this method.

The Veterans Healthcare Administration (VA) has embraced patient safety and quality improvement in the quest to improve care for veterans. The New Mexico VA Health Care System introduced a new morbidity and mortality conference, called the Interdisciplinary Quality Improvement Conference (IQIC), using patient case presentations to focus on underlying systems in the clinical care environment. The revised conference design also effectively teaches the 6 Accreditation Council for Graduate Medical Education (ACGME) core requirements for resident education. A formal process was established for case selection, presentation, systems issue identification, tracking, and follow-up. The IQIC has enabled the identification of more than 20 system issues at the study institution. Outcome data show lasting improvement in system issues that were addressed by this mechanism. The VA IQIC is an effective method to both identify and correct systems issues that affect patient care and is an effective method for teaching residents the 6 ACGME requirements for residency education., (© The Author(s) 2014.)

A regio- and stereoselective one-pot C-H insertion/olefination protocol has been developed for the late stage installation of α-methylene-γ-butyrolactones into conformationally restricted cyclohexanol-derivatives. The method has been successfully applied in the total synthesis of eudesmanolide natural product frameworks, including α-cyclocostunolide.

A one-pot C-H insertion/olefination sequence for the conversion of α-diazo-α-(dialkoxyphosphoryl)acetates into α-alkylidene-γ-butyrolactones is reported. The key C-H insertion process is achieved using a catalytic amount of a dirhodium carboxylate catalyst, using operationally simple conditions. The size and electronic properties of the attached substituents were found to influence the regio- and diastereoselectivity of the process. The utility of the process is demonstrated by the synthesis of a known Staphylococcus aureus (MRSA) virulence inhibitor.

Dr. Neuro Transmitter, a psychotherapist in Paramus, New Jersey, provides services through an online, real-time consultation service known as CyberShrink, Inc., of Dallas, Texas. He is paid by the hour for his consultation services to subscribers who are billed by credit card through CyberShrink. One afternoon he logs on and is connected via private "chat channel" to a new subscriber to the service. She is Ann Hedonia of Simi Valley, California. Ten minutes into the session, Dr Transmitter recognizes that Ms. Hedonia is seriously depressed with suicidal ideation and is feeling on the edge of her ability to cope. He gently suggests that perhaps she ought to think about hospitalization near her home. Ms. Hedonia replies, "Even you don't care about me! That's it. I'm going to do it!" and disconnects. Discussion questions: Is offering psychotherapy services online ethical? What are Dr. Transmitter's obligations in general and at this particular moment to Ms. Hedonia? Suppose Ms. Hedonia has a complaint about Dr. Transmitter. From whom can she seek a remedy? Which state's laws apply regarding professional practice, confidentiality, or licensing qualifications? Must Dr. Transmitter be licensed in any state to offer this service?

The average length of stay of a difficult and dangerous mentally disordered patient and offender in conditions of maximum security is much longer in England and Wales than it is in France. This difference can be attributed to reasons of history, to national procedures relating to admission, transfer and discharge, to the differing importance attached to the gravity of the admission offence and to the time-lags involved in carrying out the transfer and discharge decisions.