Comorbid psychiatric conditions with temporomandibular disorders (TMD) in a tertiary referral clinic.

Patients with chronic pain have a higher prevalence of mood disorders with depression and anxiety contributing to higher pain intensity, emotional allodynia, and neuro-anatomical changes. We sought to quantify the prevalence of psychiatric comorbidities (PCs) in a tertiary referral clinic for temporomandibular disorders (TMDs). Medical records of all patients attending clinics run by three tertiary temporomandibular joint (TMJ) surgeons for the period January to April 2022 inclusive were audited for the prevalence of concomitant psychiatric conditions. A total of 166 patients were identified with a female to male ratio of 5:1 and mean (SD) age of 45.1 (15.2) years. A total of 124 (89.9%) patients were tertiary referrals and 72 (43.4%) patients had concomitant psychiatric diagnoses, with 58 (34.9%) being on some form of psychotropic medication (PM) (patients on anticonvulsants for neuropathic pain were not included). A majority of 136 (81.9%) patients had some form of intervention (including Dysport® and minimally invasive surgery) which appeared more common in patients with co-existing psychiatric issues (p < 0.05). A higher proportion of mental health issues exist among TMD patients in a tertiary referral clinic than would be expected in the general population. We suggest a holistic approach to patients with multidisciplinary care taking into account this prevalence to ensure decision-making that contextualises the patient and not simply the pathology.

Functionality of bone marrow mesenchymal stromal cells derived from head and neck cancer patients - A FDA-IND enabling study regarding MSC-based treatments for radiation-induced xerostomia.

PURPOSE: Salivary dysfunction is a significant side effect of radiation therapy for head and neck cancer (HNC). Preliminary data suggests that mesenchymal stromal cells (MSCs) can improve salivary function. Whether MSCs from HNC patients who have completed chemoradiation are functionally similar to those from healthy patients is unknown. We performed a pilot clinical study to determine whether bone marrow-derived MSCs [MSC(M)] from HNC patients could be used for the treatment of RT-induced salivary dysfunction. METHODS: An IRB-approved pilot clinical study was undertaken on HNC patients with xerostomia who had completed treatment two or more years prior. Patients underwent iliac crest bone marrow aspirate and MSC(M) were isolated and cultured. Culture-expanded MSC(M) were stimulated with IFNγ and cryopreserved prior to reanimation and profiling for functional markers by flow cytometry and ELISA. MSC(M) were additionally injected into mice with radiation-induced xerostomia and the changes in salivary gland histology and salivary production were examined. RESULTS: A total of six subjects were enrolled. MSC(M) from all subjects were culture expanded to > 20 million cells in a median of 15.5 days (range 8-20 days). Flow cytometry confirmed that cultured cells from HNC patients were MSC(M). Functional flow cytometry demonstrated that these IFNγ-stimulated MSC(M) acquired an immunosuppressive phenotype. IFNγ-stimulated MSC(M) from HNC patients were found to express GDNF, WNT1, and R-spondin 1 as well as pro-angiogenesis and immunomodulatory cytokines. In mice, IFNγ-stimulated MSC(M) injection after radiation decreased the loss of acinar cells, decreased the formation of fibrosis, and increased salivary production. CONCLUSIONS: MSC (M) from previously treated HNC patients can be expanded for auto-transplantation and are functionally active. Furthermore IFNγ-stimulated MSC(M) express proteins implicated in salivary gland regeneration. This study provides preliminary data supporting the feasibility of using autologous MSC(M) from HNC patients to treat RT-induced salivary dysfunction.

Virtual learning in maxillofacial surgery in the post-COVID world: where are we now?

During the COVID-19 pandemic we developed a post-graduate virtual learning environment (PGVLE) in the West Midlands region for higher trainees in oral and maxillofacial surgery. We continued to develop this following the pandemic and sought to examine the trainee experience with this resource as restrictions eased. The PGVLE comprises a total of nine semesters mapping General Medical Council (GMC) learning objectives in the specialty across a total of 63 events using BigBlueButton™. Webinars are delivered on a weekly basis by subspecialty experts. Trainee feedback was sought using SurveyMonkey™ examining self-assessed confidence levels using visual analogue scores (VAS) and Likert items regarding trainers and content. A focus group was convened and the transcript analysed using grounded theory analysis (GTA). Likert items revealed overwhelmingly positive responses, with 96.2% (n = 281) of responses being positive regarding content and 97.5% (n = 475) agreeing with positive comments regarding faculty. VAS scores improved by an average of 39.0% and improvements were statistically significant for most sessions. The focus group highlighted the relevance of teaching to GMC learning objectives, the achievement of consistently high standards, the potential for conflict with clinical commitments and issues surrounding peer interaction. Satisfaction scores remain high with the PGVLE programme, which is very much here to stay in the post-graduate education of our trainees. With the easing of restrictions, we have moved to a hybrid method of learning with the potential for 'flipped classroom' methodology moving forwards.

Proteomic characterization of acute kidney injury in patients hospitalized with SARS-CoV2 infection.

BACKGROUND: Acute kidney injury (AKI) is a known complication of COVID-19 and is associated with an increased risk of in-hospital mortality. Unbiased proteomics using biological specimens can lead to improved risk stratification and discover pathophysiological mechanisms. METHODS: Using measurements of ~4000 plasma proteins in two cohorts of patients hospitalized with COVID-19, we discovered and validated markers of COVID-associated AKI (stage 2 or 3) and long-term kidney dysfunction. In the discovery cohort (N = 437), we identified 413 higher plasma abundances of protein targets and 30 lower plasma abundances of protein targets associated with COVID-AKI (adjusted p < 0.05). Of these, 62 proteins were validated in an external cohort (p < 0.05, N = 261). RESULTS: We demonstrate that COVID-AKI is associated with increased markers of tubular injury (NGAL) and myocardial injury. Using estimated glomerular filtration (eGFR) measurements taken after discharge, we also find that 25 of the 62 AKI-associated proteins are significantly associated with decreased post-discharge eGFR (adjusted p < 0.05). Proteins most strongly associated with decreased post-discharge eGFR included desmocollin-2, trefoil factor 3, transmembrane emp24 domain-containing protein 10, and cystatin-C indicating tubular dysfunction and injury. CONCLUSIONS: Using clinical and proteomic data, our results suggest that while both acute and long-term COVID-associated kidney dysfunction are associated with markers of tubular dysfunction, AKI is driven by a largely multifactorial process involving hemodynamic instability and myocardial damage.

Acute kidney injury (AKI) is a sudden, sometimes fatal, episode of kidney failure or damage. It is a known complication of COVID-19, albeit through unclear mechanisms. COVID-19 is also associated with kidney dysfunction in the long term, or chronic kidney disease (CKD). There is a need to better understand which patients with COVID-19 are at risk of AKI or CKD. We measure levels of several thousand proteins in the blood of hospitalized COVID-19 patients. We discover and validate sets of proteins associated with severe AKI and CKD in these patients. The markers identified suggest that kidney injury in COVID-19 patients involves damage to kidney cells that reabsorb fluid from urine and reduced blood flow to the heart, causing damage to heart muscles. Our findings might help clinicians to predict kidney injury in patients with COVID-19, and to understand its mechanisms.

Magnesium(I) Reduction of Aluminum(III) Hydride Complexes: Generation of Mixed Valence Aluminum (AlI /Al0 ) Hydride Cluster Compounds, [Al6 H8 (NR3 )2 {Mg(ß-diketiminate)}4 ].

Reduction of a range of amido- and aryloxy-aluminum dihydride complexes, e.g. [AlH2 (NR3 ){N(SiMe3 )2 }] (NR3 =NMe3 or N-methylpiperidine (NMP)), with ß-diketiminato dimagnesium(I) reagents, [{(Ar Nacnac)Mg}2 ] (Ar Nacnac=[HC(MeCNAr)2 ]- , Ar=mesityl (Mes) or 2,6-xylyl (Xyl)), have afforded deep red mixed valence aluminum hydride cluster compounds, [Al6 H8 (NR3 )2 {Mg(Ar Nacnac)}4 ], which have an average Al oxidation state of +0.66, the lowest for any well-defined aluminum hydride compound. In the solid-state, the clusters are shown to have distorted octahedral Al6 cores, having zero-valent Al axial sites and mono-valent AlH2 - equatorial units. Several novel by-products were isolated from the reactions that gave the clusters, including the Mg-Al bonded magnesio-aluminate complexes, [(Ar Nacnac)(Me3 N)Mg-Al(µ-H)3 [{Mg(Ar Nacnac)}2 (µ-H)]]. Computational analyses of one aluminum hydride cluster revealed its Al6 core to be electronically delocalized, and to possess one unoccupied, and six occupied, skeletal molecular orbitals.

Sociotechnical Factors Supporting Mobile Phone Use by Bus Drivers.

OCCUPATIONAL APPLICATIONSResults of a survey of drivers working for two bus companies in Norway suggest that 20% of drivers sometimes use a mobile phone while driving, even though it is not permitted. Sociotechnical analysis of the system surrounding drivers at one of the companies elicited ways in which social and technical factors combined to support mobile phone use by bus drivers. These factors were arranged under four themes: increased societal dependence on technology; developments in bus driver culture; the need for bus drivers to resolve conflicting goals; and a lack of belief in adverse consequences of using mobile phone while driving. Our findings (i) support claims that driver-centered analyses of mobile phone use or other traffic safety challenges are an insufficient basis for the development of measures and should be supplemented by sociotechnical analyses; and (ii) can inspire the design of more comprehensive measures to help reduce mobile phone use and road safety risks.

Background: Sociotechnical measures could supplement traditional risk management measures and further reduce risks of collisions involving heavy vehicles. Such measures can be identified using methods rooted in sociotechnical systems theory, which considers that people work in systems comprising multiple social and technical elements that interact to create emergent properties and conditions that influence valued system outcomes. Purpose: To investigate the potential of sociotechnical measures in helping to reduce road risks, we identified how social and technical factors combine to influence mobile phone use by bus drivers working at a company in Norway. Method: A survey of ∼600 drivers was completed, followed by focus group interviews with managers and drivers and one-on-one or group interviews with drivers. The interviews were structured using a sociotechnical analysis framework. Results: Twenty percent of drivers reported using their phone while operating a bus, even though such use was against company guidelines. Almost all drivers took their phone with them when they drove, and 40% of those who said they never used their phone while driving could still hear incoming calls and messages. Analysis from nine interviews with 26 drivers suggested that phone use by drivers operating buses is supported by interacting sociotechnical factors due to an increased societal dependence on technology, developments in bus driver culture, a need for bus drivers to resolve conflicting goals at work, and a lack of consequences for drivers using mobile phone use while driving. Conclusions: Limited consideration of the sociotechnical ecosystems surrounding bus drivers can contribute to their mobile phone use and thereby to potential problems of attention and awareness while driving. Sociotechnical approaches should be developed using participative design to reduce phone use while driving, especially to promote openness and information sharing and support bus drivers in the field as they strive to resolve conflicting goals.

Botulinum toxin in the management of myalgia in temporomandibular disorders: are all injections equal?

Botulinum toxin (BTX) is becoming widely used as an adjunct to conservative management of myalgia-predominant temporomandibular disorders (TMDs) with reports of improved quality of life. There is, however, no consensus on the optimal dosage. Based on previous studies, dose regimens vary between clinicians, and we know of no standard dose protocol for the administration of BTX for the purpose of TMD management. A survey was sent to members of the British Association of Oral and Maxillofacial Surgeons (BAOMS) Temporomandibular Joint Sub-Specialty Interest Group (TMJ SSIG) and an international mailing list of high-volume TMJ surgeons (the TMJ Internetwork) to ascertain variations in dose regimens between different clinicians. The survey found that 41 respondents offered BTX to patients. The masseter muscle group was the most commonly injected site, and the majority of respondents (34/41) used Botox® (Allergan). Brands less commonly used included Dysport® (Ipsen), and Xeomin® (Merz Pharma). Botox® doses varied between 30 and 100 units, whilst Dysport® doses ranged from 50 - 300 units/muscle. The number of injection sites/muscle also varied. This survey demonstrates the wide variation in practice amongst clinicians with respect to BTX administration. To ensure optimal dose and response titration, further studies and evidence-based research are needed to standardise its use for the treatment of TMDs.

Senior surgeons as role models in the operating theatre: a thematic analysis through the lens of aristotelian ethics.

BACKGROUND: Surgeons are commonly evaluated by surgical skills and outcomes rather than their character traits. We sought to examine role model behaviours of senior surgeons through the lens of Aristotelian (virtue) ethics. METHODS: Semi-structured focus group interviews were undertaken of anaesthetic trainees at a large university hospital NHS Foundation Trust and transcripts were subjected to thematic analysis to yield themes and subthemes. Participation of the trainees was entirely voluntary and focus groups were conducted using Zoom™. RESULTS: The overarching themes identified were 'Teamwork makes the dream work', 'Captain of the ship' and 'Strong foundations'. CONCLUSION: We hope to take lessons learnt in conjunction with our previous work to help refocus surgical training towards a process of character reformation, rather than simply imparting technical skills to trainees.

Trends, events and potential sources of Xe-detections in the German radioxenon network.

The measurement of radioxenons (133Xe, 131mXe, 133mXe, 135Xe) in the atmosphere is a keystone for the verification of the Comprehensive Nuclear-Test-Ban Treaty (CTBT). At the German Federal Office for Radiation Protection (Bundesamt für Strahlenschutz, BfS) activity concentrations of radioactive noble gases at several sites in Germany have been measured for more than 5 decades, initially to monitor nuclear facilities and since the mid-1990s also to support the development of measurement and monitoring systems and procedures for verification of the CTBT. Average 133Xe activity concentration in air measured daily at station RN33 of the International Monitoring System (IMS) of the CTBTO on Mt Schauinsland has decreased since 2008. Due to the decreasing radioxenon background in the atmosphere, laboratory measurements with less sensitive proportional counters developed in-house are increasingly replaced by an isotope specific ß-γ laboratory system for radioxenon analyses. Six years of radioxenon activity concentrations measured with the ß-γ laboratory system in weekly samples from monitoring sites in Germany are presented. Activity concentrations of 133Xe in southern Germany are now typically below 1 mBq m-3 and have decreased by an order of magnitude in the past 25 years. Magnitude and variability of 133Xe activity concentrations are generally larger in northern and western Germany compared to the south, most likely due to the prevailing wind directions in the region. Selected, but typical, periods of elevated radioxenon levels at the stations are investigated and the value of stack emission data is demonstrated.

Immunothrombosis and vascular heterogeneity in cerebral cavernous malformation.

Cerebral cavernous malformation (CCM) is a neurovascular disease that results in various neurological symptoms. Thrombi have been reported in surgically resected CCM patient biopsies, but the molecular signatures of these thrombi remain elusive. Here, we investigated the kinetics of thrombi formation in CCM and how thrombi affect the vasculature and contribute to cerebral hypoxia. We used RNA sequencing to investigate the transcriptome of mouse brain endothelial cells with an inducible endothelial-specific Ccm3 knock-out (Ccm3-iECKO). We found that Ccm3-deficient brain endothelial cells had a higher expression of genes related to the coagulation cascade and hypoxia when compared with wild-type brain endothelial cells. Immunofluorescent assays identified key molecular signatures of thrombi such as fibrin, von Willebrand factor, and activated platelets in Ccm3-iECKO mice and human CCM biopsies. Notably, we identified polyhedrocytes in Ccm3-iECKO mice and human CCM biopsies and report it for the first time. We also found that the parenchyma surrounding CCM lesions is hypoxic and that more thrombi correlate with higher levels of hypoxia. We created an in vitro model to study CCM pathology and found that human brain endothelial cells deficient for CCM3 expressed elevated levels of plasminogen activator inhibitor-1 and had a redistribution of von Willebrand factor. With transcriptomics, comprehensive imaging, and an in vitro CCM preclinical model, this study provides experimental evidence that genes and proteins related to the coagulation cascade affect the brain vasculature and promote neurological side effects such as hypoxia in CCMs. This study supports the concept that antithrombotic therapy may be beneficial for patients with CCM.

Modification of an extended total temporomandibular joint replacement (eTMJR) classification system.

The aims of this paper were to validate a modification of an extended total temporomandibular joint replacement (eTMJR) classification system and develop a classification schematic for ease of reference. High-volume TMJ surgeons were asked to score 20 separate eTMJR devices using the updated classification system, and inter-rater variability was calculated. Using the modified classification system developed, a Conger's kappa (κ) coefficient of 0.53 was returned, suggesting moderate to good levels of agreement. The final classification system was then developed in a series of standardised graphic illustrations as visual representations of the different subcategories of eTMJR devices.

Marrow-Derived Autologous Stromal Cells for the Restoration of Salivary Hypofunction (MARSH): Study protocol for a phase 1 dose-escalation trial of patients with xerostomia after radiation therapy for head and neck cancer: MARSH: Marrow-Derived Autologous Stromal Cells for the Restoration of Salivary Hypofunction.

BACKGROUND: Xerostomia, or dry mouth, is a common side effect of head and neck radiation. Current treatment options for radiation-induced xerostomia are generally supportive in nature. Adult stem cells are the ultimate source for replenishment of salivary gland tissue. Bone marrow-derived mesenchymal stromal cells (BM-MSCs) are a viable cell-based therapy for xerostomia. We have undertaken studies enabling U.S. Food and Drug Administration Investigational New Drug status, demonstrating the normal phenotype, intact functionality, and pro-growth secretome of interferon-γ (IFNγ)-stimulated BM-MSCs taken from patients with head and neck cancer who have undergone radiation ± chemotherapy. Here we present the protocol of MARSH, a first-in-human clinical trial of bone marrow-derived, IFNγ-activated BM-MSCs for the treatment of radiation-induced xerostomia. METHODS: This single-center phase 1 dose-escalation with expansion cohort, non-placebo-controlled study will assess the safety and tolerability of BM-MSCs for the treatment of radiation-induced xerostomia in patients who had head and neck cancer. The phase 1 dose-escalation study will be a 3 + 3 design with staggered enrollment. A total of 21 to 30 subjects (9 to 18 in phase 1 study, 12 in expansion cohort) will be enrolled. The primary endpoint is determining the recommended phase 2 dose (RP2D) of IFNγ-stimulated BM-MSCs to enable further studies on the efficacy of BM-MSCs. Patients' bone marrow will be aspirated, and BM-MSCs will be expanded, stimulated with IFNγ, and injected into the submandibular gland. The RP2D will be determined by dose-limiting toxicities occurring within 1 month of BM-MSC injection. Secondary outcomes of saliva amounts and composition, ultrasound of salivary glands, and quality of life surveys will be taken at 3-, 6-, 12-, and 24-month visits. DISCUSSION: Autotransplantation of IFNγ-stimulated BM-MSCs in salivary glands after radiation therapy or chemoradiation therapy may provide an innovative remedy to treat xerostomia and restore quality of life. This is the first therapy for radiation-induced xerostomia that may be curative. TRIAL REGISTRATION: World Health Organization International Clinical Trials Registry Platform: NCT04489732.

The Filipino family in a pandemic: A crosssectional study on the state of the household environment of COVID-19 patients in the Philippines / The Health Sciences Journal

INTRODUCTION@#Under COVID-19 guidelines, families are spending extended hours together within limited physical space, giving rise to a living situation that can bring families closer together and/or lead to conflicts. This study aimed to determine the current state of household cohesion and conflict among families with confirmed COVID-19 cases in the Philippines. @*METHODS@#This was a cross-sectional study using the COVID-19 Household Environment Scale (CHES) as a self-administered questionnaire among adult persons who belonged to households with at least one family member previously diagnosed or currently with COVID-19 in August and September 2021. Participants were recruited online using convenience and snowball sampling. The CHES is a 30-item tool which measures conflict and cohesion through the Conflict and Togetherness Subscales, respectively.@*RESULTS@#The composite median values of 386 participants surveyed reveal scores that were clustered to the left for the Conflict Subscale and neutrality for the Togetherness Subscale.@*CONCLUSION@#There is a general increase in household conflict and a non-significant change in togetherness among the surveyed families. The composite median values, if taken compoundly, imply the existence of more conflict and less togetherness.

Proteomic Characterization of Acute Kidney Injury in Patients Hospitalized with SARS-CoV2 Infection

Acute kidney injury (AKI) is a known complication of COVID-19 and is associated with an increased risk of in-hospital mortality. Unbiased proteomics using biological specimens can lead to improved risk stratification and discover pathophysiological mechanisms. Using measurements of [~]4000 plasma proteins in two cohorts of patients hospitalized with COVID-19, we discovered and validated markers of COVID-associated AKI (stage 2 or 3) and long-term kidney dysfunction. In the discovery cohort (N= 437), we identified 413 higher plasma abundances of protein targets and 40 lower plasma abundances of protein targets associated with COVID-AKI (adjusted p <0.05). Of these, 62 proteins were validated in an external cohort (p <0.05, N =261). We demonstrate that COVID-AKI is associated with increased markers of tubular injury (NGAL) and myocardial injury. Using estimated glomerular filtration (eGFR) measurements taken after discharge, we also find that 25 of the 62 AKI-associated proteins are significantly associated with decreased post-discharge eGFR (adjusted p <0.05). Proteins most strongly associated with decreased post-discharge eGFR included desmocollin-2, trefoil factor 3, transmembrane emp24 domain-containing protein 10, and cystatin-C indicating tubular dysfunction and injury. Using clinical and proteomic data, our results suggest that while both acute and long-term COVID-associated kidney dysfunction are associated with markers of tubular dysfunction, AKI is driven by a largely multifactorial process involving hemodynamic instability and myocardial damage.

Palmdelphin Regulates Nuclear Resilience to Mechanical Stress in the Endothelium.

BACKGROUND: PALMD (palmdelphin) belongs to the family of paralemmin proteins implicated in cytoskeletal regulation. Single nucleotide polymorphisms in the PALMD locus that result in reduced expression are strong risk factors for development of calcific aortic valve stenosis and predict severity of the disease. METHODS: Immunodetection and public database screening showed dominant expression of PALMD in endothelial cells (ECs) in brain and cardiovascular tissues including aortic valves. Mass spectrometry, coimmunoprecipitation, and immunofluorescent staining allowed identification of PALMD partners. The consequence of loss of PALMD expression was assessed in small interferring RNA-treated EC cultures, knockout mice, and human valve samples. RNA sequencing of ECs and transcript arrays on valve samples from an aortic valve study cohort including patients with the single nucleotide polymorphism rs7543130 informed about gene regulatory changes. RESULTS: ECs express the cytosolic PALMD-KKVI splice variant, which associated with RANGAP1 (RAN GTP hydrolyase activating protein 1). RANGAP1 regulates the activity of the GTPase RAN and thereby nucleocytoplasmic shuttling via XPO1 (Exportin1). Reduced PALMD expression resulted in subcellular relocalization of RANGAP1 and XPO1, and nuclear arrest of the XPO1 cargoes p53 and p21. This indicates an important role for PALMD in nucleocytoplasmic transport and consequently in gene regulation because of the effect on localization of transcriptional regulators. Changes in EC responsiveness on loss of PALMD expression included failure to form a perinuclear actin cap when exposed to flow, indicating lack of protection against mechanical stress. Loss of the actin cap correlated with misalignment of the nuclear long axis relative to the cell body, observed in PALMD-deficient ECs, Palmd-/- mouse aorta, and human aortic valve samples derived from patients with calcific aortic valve stenosis. In agreement with these changes in EC behavior, gene ontology analysis showed enrichment of nuclear- and cytoskeleton-related terms in PALMD-silenced ECs. CONCLUSIONS: We identify RANGAP1 as a PALMD partner in ECs. Disrupting the PALMD/RANGAP1 complex alters the subcellular localization of RANGAP1 and XPO1, and leads to nuclear arrest of the XPO1 cargoes p53 and p21, accompanied by gene regulatory changes and loss of actin-dependent nuclear resilience. Combined, these consequences of reduced PALMD expression provide a mechanistic underpinning for PALMD's contribution to calcific aortic valve stenosis pathology.

Synthesis of 12ß-Methyl-18-nor-bile Acids.

Decoupling the roles of the farnesoid X nuclear receptor and Takeda G-protein-coupled bile acid receptor 5 is essential for the development of novel bile acid therapeutics targeting metabolic and neurodegenerative diseases. Herein, we describe the synthesis of 12ß-methyl-18-nor-bile acids which may serve as probes in the search for new bile acid analogues with clinical applicability. A Nametkin-type rearrangement was applied to protected cholic acid derivatives, giving rise to tetra-substituted Δ13,14- and Δ13,17-unsaturated 12ß-methyl-18-nor-bile acid intermediates (24a and 25a). Subsequent catalytic hydrogenation and deprotection yielded 12ß-methyl-18-nor-chenodeoxycholic acid (27a) and its 17-epi-epimer (28a) as the two major reaction products. Optimization of the synthetic sequence enabled a chromatography-free route to prepare these bile acids at a multi-gram scale. In addition, the first cis-C-D ring-junctured bile acid and a new 14(13 → 12)-abeo-bile acid are described. Furthermore, deuteration experiments were performed to provide mechanistic insights into the formation of the formal anti-hydrogenation product 12ß-methyl-18-nor-chenodeoxycholic acid (27a).

eNOS-induced vascular barrier disruption in retinopathy by c-Src activation and tyrosine phosphorylation of VE-cadherin.

Background: Hypoxia and consequent production of vascular endothelial growth factor A (VEGFA) promote blood vessel leakiness and edema in ocular diseases. Anti-VEGFA therapeutics may aggravate hypoxia; therefore, therapy development is needed. Methods: Oxygen-induced retinopathy was used as a model to test the role of nitric oxide (NO) in pathological neovascularization and vessel permeability. Suppression of NO formation was achieved chemically using L-NMMA, or genetically, in endothelial NO synthase serine to alanine (S1176A) mutant mice. Results: Suppression of NO formation resulted in reduced retinal neoangiogenesis. Remaining vascular tufts exhibited reduced vascular leakage through stabilized endothelial adherens junctions, manifested as reduced phosphorylation of vascular endothelial (VE)-cadherin Y685 in a c-Src-dependent manner. Treatment with a single dose of L-NMMA in established retinopathy restored the vascular barrier and prevented leakage. Conclusions: We conclude that NO destabilizes adheren junctions, resulting in vascular hyperpermeability, by converging with the VEGFA/VEGFR2/c-Src/VE-cadherin pathway. Funding: This study was supported by the Swedish Cancer foundation (19 0119 Pj ), the Swedish Research Council (2020-01349), the Knut and Alice Wallenberg foundation (KAW 2020.0057) and a Fondation Leducq Transatlantic Network of Excellence Grant in Neurovascular Disease (17 CVD 03). KAW also supported LCW with a Wallenberg Scholar grant (2015.0275). WCS was supported by Grants R35 HL139945, P01 HL1070205, AHA MERIT Award. DV was supported by grants from the Deutsche Forschungsgemeinschaft, SFB1450, B03, and CRU342, P2.

Propranolol Reduces the Development of Lesions and Rescues Barrier Function in Cerebral Cavernous Malformations: A Preclinical Study.

[Figure: see text].

Bus stop design and traffic safety: An explorative analysis.

One way to prioritize public transport over private vehicle mobility, is to implement curbside rather than layby bus stop designs. There is, however, uncertainty about the consequences of implementing curbside rather than layby stops for traffic collision risks. To begin investigating this issue, we describe an exploratory analysis in which national data describing bus stops, road properties, traffic collisions and built-up areas were merged based on geographical location. Analysis of the resulting data set suggests that the relative rates of traffic collisions resulting in personal injury within 60 m of the bus stop, is higher for curbside than for layby stops in built-up areas (0.32 vs. 0.22 collisions per ten million passing vehicles, respectively). Our analyses suggest that the higher risk of nearby collisions for curbside stops is not necessarily due to bus stop design, but rather because they tend to be located closer to junctions and side roads, where collisions are more likely. Our data are not consistent with hypotheses that curbside stops are associated with greater shares of head-on or rear-end collisions than layby stops, nor that layby stops are associated with greater shares of side-on collisions than curbside stops. The limitations of this exploratory analysis, and of the use of national-level data for studying the effects of bus stop design on collision risk, are related to lack of control of bus stop design features other than curbside vs. layby, statistical power, data registration and compromises made when coupling data based on geographical location. Future work should attempt to build on our approach, and supplement database analyses with analysis of in-depth reports of bus stop collisions, observations of road user conflicts near bus stops, and before-after studies following conversion from layby to curbside stops or from curbside to layby stops.