What next for "counseling" in genetic counseling training: A reflection on how CBT and ACT approaches can contribute to the genetic counseling toolkit.

Counseling techniques are an important component of genetic counseling training and are focused on the person-centered counseling philosophy. While this has a long tradition within the profession and underpins the empowerment goal, it should not limit consideration of the potential benefits of education on other psychotherapeutic approaches such as the cognitive philosophy. The goal of empowerment in genetic counseling requires patients to receive information in a way that is accessible to them and to make sense of it in relation to their own health, lifestyle, and family information. This assimilation of new information is a complex cognitive process, and yet it is one that genetic counselors do not routinely actively facilitate. Rather the counseling component of genetic counseling has traditionally focused on emotionally supporting the patient which is driven by the person-centered philosophy that is covered in genetic counseling training. This paper argues for the potential for adopting more cognitive approaches informed by cognitive-behavioral therapy (CBT) and acceptance and commitment therapy (ACT), as these short interventions can have wide impact, including engaging patients who do not want to discuss feelings, helping people to make sense of information (not just gain knowledge), and helping people to change the relationship they have with their thoughts. This paper advocates for an introduction to CBT and ACT to be incorporated into prequalification training and for more advanced training to be available to postqualification genetic counselors.

What next for "counseling" in genetic counseling training: A co-production workshop exploring how CBT and ACT approaches can contribute to the genetic counseling toolkit.

Counseling techniques are an important part of genetic counseling, and teaching of the humanistic person-centered philosophy has been central to genetic counselor (GC) training. However, other psychotherapeutic approaches, especially cognitive approaches, may also be beneficial for the GC to have in their toolkit. This paper reports on a co-production workshop with newly qualified GCs where the potential for adopting more cognitive approaches informed by cognitive behavioral therapy (CBT) and acceptance and commitment therapy (ACT) was explored. Attendees were taught about the approaches and the rationale for their use in genetic counseling and had a chance to discuss their reactions and ideas for application. The attendees saw great potential for the approaches within their practice, feeling that these short interventions can have a wide impact, including engaging patients who do not want to discuss feelings, helping people to make sense of information (not just gain knowledge), and helping people to change the relationship they have with their thoughts. They were able to identify when they already use some cognitive approaches in their practice, and to see how they could build on this to provide better patient care. The paper advocates for an introduction to CBT and ACT to be incorporated into pre-qualification training, and for more advanced training to be available to post-qualification GCs.

Long-term effects of pulmonary endarterectomy on pulmonary hemodynamics, cardiac function, and exercise capacity in chronic thromboembolic pulmonary hypertension.

BACKGROUND: Long-term changes in exercise capacity and cardiopulmonary hemodynamics after pulmonary endarterectomy (PEA) for chronic thromboembolic pulmonary hypertension (CTEPH) have been poorly described. METHODS: We analyzed the data from 2 prospective surgical CTEPH cohorts in Hammersmith Hospital, London, and Amsterdam UMC. A structured multimodal follow-up was adopted, consisting of right heart catheterization, cardiac magnetic resonance imaging, and cardiopulmonary exercise testing before and after PEA. Preoperative predictors of residual pulmonary hypertension (PH; mean pulmonary artery pressure >20 mm Hg and pulmonary vascular resistance ≥2 WU) and long-term exercise intolerance (VO2max <80%) at 18 months were analyzed. RESULTS: A total of 118 patients (61 from London and 57 from Amsterdam) were included in the analysis. Both cohorts displayed a significant improvement of pulmonary hemodynamics, right ventricular (RV) function, and exercise capacity 6 months after PEA. Between 6 and 18 months after PEA, there were no further improvements in hemodynamics and RV function, but the proportion of patients with impaired exercise capacity was high and slightly increased over time (52%-59% from 6 to 18 months). Long-term exercise intolerance was common and associated with preoperative diffusion capacity for carbon monoxide (DLCO), preoperative mixed venous oxygen saturation, and postoperative PH and right ventricular ejection fraction (RVEF). Clinically significant RV deterioration (RVEF decline >3%; 5 [9%] of 57 patients) and recurrent PH (5 [14%] of 36 patients) rarely occurred beyond 6 months after PEA. Age and preoperative DLCO were predictors of residual PH post-PEA. CONCLUSIONS: Restoration in exercise tolerance, cardiopulmonary hemodynamics, and RV function occurs within 6 months. No substantial changes occurred between 6 and 18 months after PEA in the Amsterdam cohort. Nevertheless, long-term exercise intolerance is common and associated with postoperative RV function.

Structure-Activity Relationships for a Recently Controlled Synthetic Cathinone Dopamine Transporter Reuptake Inhibitor: α-Pyrrolidinohexiophenone (α-PHP).

α-Pyrrolidinohexiophenone (α-PHP) is the one-carbon unit α-extended homolog of the better-known and widely abused synthetic cathinone central stimulant α-PVP ("flakka"); both are now U.S. Schedule I controlled substances. Structurally, α-PVP and α-PHP possess a common terminal N-pyrrolidine moiety and differ only with respect to the length of their α-alkyl chain. Using a synaptosomal assay, we previously reported that α-PHP is at least as potent as α-PVP as a dopamine transporter (DAT) reuptake inhibitor. A systematic structure-activity study of synthetic cathinones (e.g., α-PHP) as DAT reuptake inhibitors (i.e., transport blockers), a mechanism thought responsible for their abuse liability, has yet to be conducted. Here, we examined a series of 4-substituted α-PHP analogues and found that, with one exception, all behaved as relatively (28- to >300-fold) selective DAT versus serotonin transporter (SERT) reuptake inhibitors with DAT inhibition potencies of most falling within a very narrow (i.e., <3-fold) range. The 4-CF3 analogue of α-PHP was a confirmed "outlier" in that it was at least 80-fold less potent than the other analogues and displayed reduced (i.e., no) DAT vs SERT selectivity. Consideration of various physicochemical properties of the CF3 group, relative to that of the other substituents involved here, provided relatively little insight. Unlike with DAT-releasing agents, as previously reported by us, a QSAR study was precluded because of the limited range of empirical results (with the exception of the 4-CF3 analogue) for DAT reuptake inhibition.

Subunit-selective PI3-kinase control of action strategies in the medial prefrontal cortex.

PI3-kinase (PI3K) is an intracellular signaling complex that is stimulated upon cocaine exposure and linked with the behavioral consequences of cocaine. We recently genetically silenced the PI3K p110ß subunit in the medial prefrontal cortex following repeated cocaine in mice, reinstating the capacity of these mice to engage in prospective goal-seeking behavior. In the present short report, we address two follow-up hypotheses: 1) The control of decision-making behavior by PI3K p110ß is attributable to neuronal signaling, and 2) PI3K p110ß in the healthy (i.e., drug-naïve) medial prefrontal cortex has functional consequences in the control of reward-related decision-making strategies. In Experiment 1, we found that silencing neuronal p110ß improved action flexibility following cocaine. In Experiment 2, we reduced PI3K p110ß in drug-naïve mice that were extensively trained to respond for food reinforcers. Gene silencing caused mice to abandon goal-seeking strategies, unmasking habit-based behaviors that were propelled by interactions with the nucleus accumbens. Thus, PI3K control of goal-directed action strategies appears to act in accordance with an inverted U-shaped function, with "too much" (following cocaine) or "too little" (following p110ß subunit silencing) obstructing goal seeking and causing mice to defer to habit-like response sequences.

The impact of "freedom day" on COVID-19 health protective behaviour in England: An observational study of hand hygiene, face covering use and physical distancing in public spaces pre and post the relaxing of restrictions.

Objectives: To study the prevalence of COVID-19 health protective behaviours before and after rules eased in England on the 19th July 2021. Design: Observational study pre (12th-18th July) and post (26th July-1st August) 19th July, and a cross-sectional online survey (26th to 27th July). Setting: Observations occurred in supermarkets (n = 10), train stations (n = 10), bus stops (n = 10), a coach station (n = 1) and a London Underground station (n = 1). The survey recruited a nationally representative sample. Participants: All adults entering the observed locations during a one-hour period (n = 3819 pre- and n = 2948 post-19th July). In the online survey, 1472 respondents reported having been shopping for groceries/visited a pharmacy and 566 reported having used public transport or having been in a taxi/minicab in the last week. Main outcome measures: We observed whether people wore a face covering, maintained distance from others and cleaned their hands. We investigated self-reports of wearing a face covering while in shops or using public transport. Results: In most locations observed, the proportion of people wearing face coverings, cleaning the hands and maintaining physical distance declined post 19th July. Pre 19th July, 70.2% (95% CI 68.7 to 71.7%) of people were observed to be wearing a face covering versus 55.8% (54.2 to 57.9%) post 19th July. Equivalent rates for physical distancing were 40.9% (39.0 to 42.8%) versus 29.5% (27.4 to 31.7%), and for hand hygiene were 4.4% (3.8 to 5.1%) versus 3.9% (3.2 to 4.6%). Self-reports of "always" wearing face coverings were broadly similar to observed rates. Conclusions: Adherence to protective behaviours was sub-optimal and declined during the relaxation of restrictions, despite appeals to exercise caution. Self-reports of "always" wearing a face covering in specific locations appear valid.

Utility of cardiac magnetic resonance feature tracking strain assessment in chronic thromboembolic pulmonary hypertension for prediction of REVEAL 2.0 high risk status.

Chronic thromboembolic pulmonary hypertension may be cured by pulmonary endarterectomy (PEA). Thromboembolic disease distribution/PEA success primarily determines prognosis but risk scoring criteria may be adjunctive. Right ventriculoarterial (RV-PA) and ventriculoatrial (RV-right atrium [RA]) coupling may be evaluated by cardiac MRI (CMR) feature tracking deformation/strain assessment. We characterized biatrial and biventricular CMR feature tracking (FT) strain parameters following PEA and tested the ability of CMR FT to identify REVEAL 2.0 high-risk status. We undertook a retrospective single-center cross-sectional study of patients (n = 57) who underwent PEA (2015-2020). All underwent pre and postoperative catheterization and CMR. Pulmonary arterial hypertension validated risk scores were calculated. Significant postoperative improvements were observed in mean pulmonary artery pressure (mPAP) (pre-op 45 ± 11 mmHg vs. post-op 26 ± 11 mmHg; p < 0.001) and PVR however a large proportion had residual pulmonary hypertension (45%; mPAP ≥25 mmHg). PEA augmented left heart filling with left ventricular end diastolic volume index and left atrial volume index increment. Left ventricular ejection fraction was unchanged postoperatively but LV global longitudinal strain improved (pre-op median -14.2% vs. post-op -16.0%; p < 0.001). Right ventricular (RV) geometry and function also improved with reduction in RV mass. Most had uncoupled RV-PA relationships which recovered (pre-op right ventricular free wall longitudinal strain -13.2 ± 4.8%, RV stroke volume/right ventricular end systolic volume ratio 0.78 ± 0.53 vs. post-op -16.8 ± 4.2%, 1.32 ± 0.55; both p < 0.001). Postoperatively, there were six REVEAL 2.0 high-risk patients, best predicted by impaired RA strain which was superior to traditional volumetric parameters (area under the curve [AUC] 0.99 vs. RVEF AUC 0.88). CMR deformation/strain evaluation can offer insights into coupling recovery; RA strain may be an expeditious surrogate for the more laborious REVEAL 2.0 score.

A new WHO bottle bioassay method to assess the susceptibility of mosquito vectors to public health insecticides: results from a WHO-coordinated multi-centre study.

BACKGROUND: The continued spread of insecticide resistance in mosquito vectors of malaria and arboviral diseases may lead to operational failure of insecticide-based interventions if resistance is not monitored and managed efficiently. This study aimed to develop and validate a new WHO glass bottle bioassay method as an alternative to the WHO standard insecticide tube test to monitor mosquito susceptibility to new public health insecticides with particular modes of action, physical properties or both. METHODS: A multi-centre study involving 21 laboratories worldwide generated data on the susceptibility of seven mosquito species (Aedes aegypti, Aedes albopictus, Anopheles gambiae sensu stricto [An. gambiae s.s.], Anopheles funestus, Anopheles stephensi, Anopheles minimus and Anopheles albimanus) to seven public health insecticides in five classes, including pyrethroids (metofluthrin, prallethrin and transfluthrin), neonicotinoids (clothianidin), pyrroles (chlorfenapyr), juvenile hormone mimics (pyriproxyfen) and butenolides (flupyradifurone), in glass bottle assays. The data were analysed using a Bayesian binomial model to determine the concentration-response curves for each insecticide-species combination and to assess the within-bioassay variability in the susceptibility endpoints, namely the concentration that kills 50% and 99% of the test population (LC50 and LC99, respectively) and the concentration that inhibits oviposition of the test population by 50% and 99% (OI50 and OI99), to measure mortality and the sterilizing effect, respectively. RESULTS: Overall, about 200,000 mosquitoes were tested with the new bottle bioassay, and LC50/LC99 or OI50/OI99 values were determined for all insecticides. Variation was seen between laboratories in estimates for some mosquito species-insecticide combinations, while other test results were consistent. The variation was generally greater with transfluthrin and flupyradifurone than with the other compounds tested, especially against Anopheles species. Overall, the mean within-bioassay variability in mortality and oviposition inhibition were < 10% for most mosquito species-insecticide combinations. CONCLUSION: Our findings, based on the largest susceptibility dataset ever produced on mosquitoes, showed that the new WHO bottle bioassay is adequate for evaluating mosquito susceptibility to new and promising public health insecticides currently deployed for vector control. The datasets presented in this study have been used recently by the WHO to establish 17 new insecticide discriminating concentrations (DCs) for either Aedes spp. or Anopheles spp. The bottle bioassay and DCs can now be widely used to monitor baseline insecticide susceptibility of wild populations of vectors of malaria and Aedes-borne diseases worldwide.

Observed and self-reported COVID-19 health protection behaviours on a university campus and the impact of a single simple intervention.

During the COVID-19 pandemic, most data on adherence to health protective behaviours were collected via a self-report. We quantified the discrepancy between self-report data and discretely observed behaviour in a sample of university staff and students. We assessed the prevalence of cleaning hands, wearing a face-covering and maintaining distance from others. We also tested whether additional signage reminding people that these behaviours were mandatory improved observed adherence. Prevalence estimates based on self-report were higher than those based on observations. Signage was associated with improvements for observed behaviours (all χ2 ≥ 6.0, P < 0.05). We caution that self-reported data can produce misleading adherence rates.

A systematic review of observational methods used to quantify personal protective behaviours among members of the public during the COVID-19 pandemic, and the concordance between observational and self-report measures in infectious disease health protection.

OBJECTIVES: To assess the quantity and quality of studies using an observational measure of behaviour during the COVID-19 pandemic, and to narratively describe the association between self-report and observational data for behaviours relevant to controlling an infectious disease outbreak. DESIGN: Systematic review and narrative synthesis of observational studies. DATA SOURCES: We searched Medline, Embase, PsychInfo, Publons, Scopus and the UK Health Security Agency behavioural science LitRep database from inception to 17th September 2021 for relevant studies. STUDY SELECTION: We included studies which collected observational data of at least one of three health protective behaviours (hand hygiene, face covering use and maintaining physical distance from others ('social distancing') during the COVID-19 pandemic. Studies where observational data were compared to self-report data in relation to any infectious disease were also included. DATA EXTRACTION AND SYNTHESIS: We evaluated the quality of studies using the NIH quality assessment scale for observational studies, extracted data on sample size, setting and adherence to health protective behaviours, and synthesized results narratively. RESULTS: Of 27,279 published papers on COVID-19 relevant health protective behaviours that included one or more terms relating to hand hygiene, face covering and social distancing, we identified 48 studies that included an objective observational measure. Of these, 35 assessed face covering use, 17 assessed hand hygiene behaviour and seven assessed physical distancing. The general quality of these studies was good. When expanding the search to all infectious diseases, we included 21 studies that compared observational versus self-report data. These almost exclusively studied hand hygiene. The difference in outcomes was striking, with self-report over-estimating observed adherence by up to a factor of five in some settings. In only four papers did self-report match observational data in any domains. CONCLUSIONS: Despite their importance in controlling the pandemic, we found remarkably few studies assessing protective behaviours by observation, rather than self-report, though these studies tended to be of reasonably good quality. Observed adherence tends to be substantially lower than estimates obtained via self-report. Accurate assessment of levels of personal protective behaviour, and evaluation of interventions to increase this, would benefit from the use of observational methods.

MRI Feature Tracking Strain in Pulmonary Hypertension: Utility of Combined Left Atrial Volumetric and Deformation Assessment in Distinguishing Post- From Pre-capillary Physiology.

Aims: Pulmonary hypertension (PH) is dichotomized into pre- and post-capillary physiology by invasive catheterization. Imaging, particularly strain assessment, may aid in classification and be helpful with ambiguous hemodynamics. We sought to define cardiac MRI (CMR) feature tracking biatrial peak reservoir and biventricular peak systolic strain in pre- and post-capillary PH and examine the performance of peak left atrial strain in distinguishing the 2 groups compared to TTE. Methods and Results: Retrospective cross-sectional study from 1 Jan 2015 to 31 Dec 2020; 48 patients (22 pre- and 26 post-capillary) were included with contemporaneous TTE, CMR and catheterization. Mean pulmonary artery pressures were higher in the pre-capillary cohort (55 ± 14 vs. 42 ± 9 mmHg; p < 0.001) as was pulmonary vascular resistance (median 11.7 vs. 3.7 WU; p < 0.001). Post-capillary patients had significantly larger left atria (60 ± 22 vs. 25 ± 9 ml/m2; p < 0.001). There was no difference in right atrial volumes between groups (60 ± 21 vs. 61 ± 29 ml/m2; p = 0.694), however peak RA strain was lower in post-capillary PH patients (8.9 ± 5.5 vs. 18.8 ± 7.0%; p < 0.001). In the post-capillary group, there was commensurately severe peak strain impairment in both atria (LA strain 9.0 ± 5.8%, RA strain 8.9 ± 5.5%). CMR LAVi and peak LA strain had a multivariate AUC of 0.98 (95% CI 0.89-1.00; p < 0.001) for post-capillary PH diagnosis which was superior to TTE. Conclusion: CMR volumetric and deformation assessment of the left atrium can highly accurately distinguish post- from pre-capillary PH.

Inter-individual variability amplified through breeding reveals control of reward-related action strategies by Melanocortin-4 Receptor in the dorsomedial striatum.

In day-to-day life, we often must choose between pursuing familiar behaviors or adjusting behaviors when new strategies might be more fruitful. The dorsomedial striatum (DMS) is indispensable for arbitrating between old and new action strategies. To uncover molecular mechanisms, we trained mice to generate nose poke responses for food, then uncoupled the predictive relationship between one action and its outcome. We then bred the mice that failed to rapidly modify responding. This breeding created offspring with the same tendencies, failing to inhibit behaviors that were not reinforced. These mice had less post-synaptic density protein 95 in the DMS. Also, densities of the melanocortin-4 receptor (MC4R), a high-affinity receptor for α-melanocyte-stimulating hormone, predicted individuals' response strategies. Specifically, high MC4R levels were associated with poor response inhibition. We next found that reducing Mc4r in the DMS in otherwise typical mice expedited response inhibition, allowing mice to modify behavior when rewards were unavailable or lost value. This process required inputs from the orbitofrontal cortex, a brain region canonically associated with response strategy switching. Thus, MC4R in the DMS appears to propel reward-seeking behavior, even when it is not fruitful, while moderating MC4R presence increases the capacity of mice to inhibit such behaviors.

Moral Injury as a Mediator of the Associations Between Sexual Harassment and Mental Health Symptoms and Substance Use Among Women Veterans.

Moral injury is an array of symptoms theorized to develop in response to morally injurious events, defined as events that challenge one's core moral beliefs and expectations about the self, others, and world. Recent measures of moral injury have distinguished self-directed moral injury (e.g., moral injury symptoms that emerge following the perpetration of morally injurious events) from other-directed moral injury, the symptoms of which are believed to stem from one's response to actions that others have committed (e.g., within-rank violence, failures of leadership, and acts of betrayal committed by trusted others or institutions). Using a convenience sample of 154 primarily former military women, the present study examined if other-directed moral injury symptoms (e.g., anger, betrayal, and mistrust) associated with military experience would mediate the association between military sexual harassment and mental health and substance abuse symptoms. Results demonstrated that 85.8% (n = 127) of the of this sample of women veterans reported experiencing sexual harassment during their military service. Using a single mediation model, we further demonstrated that other-directed moral injury mediated the association between sexual harassment experience and mental health symptoms. Given the percentage of women veterans who reported sexual harassment, these results suggest that additional training for military members, and particularly, military leaders, is necessary to begin to reduce sexual harassment. In addition, mental health providers who work with current and former military members should consider how other-directed moral injury may be associated with mental health symptoms among women veterans who have experienced sexual harassment while in the military.

A Strategy to Prioritize Emerging Drugs of Abuse for Analysis: Abuse Liability Testing Using Intracranial Self-Stimulation (ICSS) in Rats and Validation with α-Pyrrolidinohexanophenone (α-PHP).

Novel psychoactive substances (NPS) threaten public health and safety while also straining the limited resources of forensic laboratories. To efficiently allocate the finite resources available, we propose a new strategy for prioritizing NPS with abuse liability testing using a preclinical behavioral procedure in rats known as intracranial self-stimulation (ICSS). To validate this assay, the recently-scheduled synthetic cathinone α-PHP was compared to cocaine, a mechanistically similar drug of abuse, as a positive control and saline as a negative control. Male Sprague-Dawley rats (n=6) were implanted with electrodes targeting the medial forebrain bundle and trained to respond by lever-press for electrical brain stimulation. The rats were tested with doses of 0.32, 1.0, and 3.2 mg/kg α-PHP as well as 10 mg/kg of cocaine and saline administered by intraperitoneal injection. Neither saline nor 0.32 mg/kg α-PHP altered ICSS response rates compared to baseline levels of responding; however, doses of 1.0 and 3.2 mg/kg α-PHP and 10 mg/kg cocaine facilitated ICSS responding. This ICSS profile suggests that α-PHP has high abuse potential, with a rapid onset of effects and a long duration of action, and supports the decision to schedule this compound. This study demonstrates the ability of ICSS to distinguish between compounds of low and high potential for abuse. A strategy is proposed here to screen NPS using ICSS and classify emerging drugs into four priority categories for further analysis.

Cell adhesion factors in the orbitofrontal cortex control cue-induced reinstatement of cocaine seeking and amygdala-dependent goal seeking.

Repeated cocaine exposure causes dendritic spine loss in the orbitofrontal cortex, which might contribute to poor orbitofrontal cortical function following drug exposure. One challenge, however, has been verifying links between neuronal structural plasticity and behavior, if any. Here we report that cocaine self-administration triggers the loss of dendritic spines on excitatory neurons in the orbitofrontal cortex of male and female mice (as has been reported in rats). To understand functional consequences, we locally ablated neuronal ß1-integrins, cell adhesion receptors that adhere cells to the extracellular matrix and thus support dendritic spine stability. Degradation of ß1-integrin tone: 1) caused dendritic spine loss; 2) exaggerated cocaine-seeking responses in a cue-induced reinstatement test; and 3) impaired the ability of mice to integrate new learning into familiar routines - a key function of the orbitofrontal cortex. Stimulating Abl-related gene (Arg) kinase, over-expressing Proline-rich tyrosine kinase (Pyk2), and inhibiting Rho-associated coiled-coil containing kinase (ROCK) corrected response strategies, uncovering a ß1-integrin-mediated signaling axis that controls orbitofrontal cortical function. Finally, use of a combinatorial gene silencing/chemogenetic strategy revealed that ß1-integrins support the ability of mice to integrate new information into established behaviors by sustaining orbitofrontal cortical connections with the basolateral amygdala.SIGNIFICANCE STATEMENTCocaine degenerates dendritic spines in the orbitofrontal cortex, a region of the brain involved in interlacing new information into established behaviors. One challenge has been verifying links between cellular structural stability and behavior, if any. In this second of two related investigations, we study integrin family receptors, which adhere cells to the extracellular matrix and thereby stabilize dendritic spines (see also DePoy et al., 2019, Journal of Neuroscience). We reveal that ß1-integrins in the orbitofrontal cortex control food- and cocaine-seeking behaviors. For instance, ß1-integrin loss amplifies cocaine-seeking behavior and impairs the ability of mice to integrate new learning into familiar routines. We identify likely intracellular signaling partners by which ß1-integrins support orbitofrontal cortical function and connectivity with the basolateral amygdala.

Thymosin ß4 protects against aortic aneurysm via endocytic regulation of growth factor signaling.

Vascular stability and tone are maintained by contractile smooth muscle cells (VSMCs). However, injury-induced growth factors stimulate a contractile-synthetic phenotypic modulation which increases susceptibility to abdominal aortic aneurysm (AAA). As a regulator of embryonic VSMC differentiation, we hypothesized that Thymosin ß4 (Tß4) may function to maintain healthy vasculature throughout postnatal life. This was supported by the identification of an interaction with low density lipoprotein receptor related protein 1 (LRP1), an endocytic regulator of platelet-derived growth factor BB (PDGF-BB) signaling and VSMC proliferation. LRP1 variants have been implicated by genome-wide association studies with risk of AAA and other arterial diseases. Tß4-null mice displayed aortic VSMC and elastin defects that phenocopy those of LRP1 mutants, and their compromised vascular integrity predisposed them to Angiotensin II-induced aneurysm formation. Aneurysmal vessels were characterized by enhanced VSMC phenotypic modulation and augmented PDGFR-ß signaling. In vitro, enhanced sensitivity to PDGF-BB upon loss of Tß4 was associated with dysregulated endocytosis, with increased recycling and reduced lysosomal targeting of LRP1-PDGFR-ß. Accordingly, the exacerbated aneurysmal phenotype in Tß4-null mice was rescued upon treatment with the PDGFR-ß antagonist Imatinib. Our study identifies Tß4 as a key regulator of LRP1 for maintaining vascular health, and provides insights into the mechanisms of growth factor-controlled VSMC phenotypic modulation underlying aortic disease progression.

COVID-19 and its impact on the cardiovascular system.

OBJECTIVES: The clinical impact of SARS-CoV-2 has varied across countries with varying cardiovascular manifestations. We review the cardiac presentations, in-hospital outcomes and development of cardiovascular complications in the initial cohort of SARS-CoV-2 positive patients at Imperial College Healthcare National Health Service Trust, UK. METHODS: We retrospectively analysed 498 COVID-19 positive adult admissions to our institute from 7 March to 7 April 2020. Patient data were collected for baseline demographics, comorbidities and in-hospital outcomes, especially relating to cardiovascular intervention. RESULTS: Mean age was 67.4±16.1 years and 62.2% (n=310) were male. 64.1% (n=319) of our cohort had underlying cardiovascular disease (CVD) with 53.4% (n=266) having hypertension. 43.2%(n=215) developed acute myocardial injury. Mortality was significantly increased in those patients with myocardial injury (47.4% vs 18.4%, p<0.001). Only four COVID-19 patients had invasive coronary angiography, two underwent percutaneous coronary intervention and one required a permanent pacemaker implantation. 7.0% (n=35) of patients had an inpatient echocardiogram. Acute myocardial injury (OR 2.39, 95% CI 1.31 to 4.40, p=0.005) and history of hypertension (OR 1.88, 95% CI 1.01 to 3.55, p=0.049) approximately doubled the odds of in-hospital mortality in patients admitted with COVID-19 after other variables had been controlled for. CONCLUSION: Hypertension, pre-existing CVD and acute myocardial injury were associated with increased in-hospital mortality in our cohort of COVID-19 patients. However, only a low number of patients required invasive cardiac intervention.

Perioperative management of patients with pulmonary hypertension undergoing non-cardiothoracic, non-obstetric surgery: a systematic review and expert consensus statement.

BACKGROUND: The risk of complications, including death, is substantially increased in patients with pulmonary hypertension (PH) undergoing anaesthesia for surgical procedures, especially in those with pulmonary arterial hypertension (PAH) and chronic thromboembolic PH (CTEPH). Sedation also poses a risk to patients with PH. Physiological changes including tachycardia, hypotension, fluid shifts, and an increase in pulmonary vascular resistance (PH crisis) can precipitate acute right ventricular decompensation and death. METHODS: A systematic literature review was performed of studies in patients with PH undergoing non-cardiac and non-obstetric surgery. The management of patients with PH requiring sedation for endoscopy was also reviewed. Using a framework of relevant clinical questions, we review the available evidence guiding operative risk, risk assessment, preoperative optimisation, and perioperative management, and identifying areas for future research. RESULTS: Reported 30 day mortality after non-cardiac and non-obstetric surgery ranges between 2% and 18% in patients with PH undergoing elective procedures, and increases to 15-50% for emergency surgery, with complications and death usually relating to acute right ventricular failure. Risk factors for mortality include procedure-specific and patient-related factors, especially markers of PH severity (e.g. pulmonary haemodynamics, poor exercise performance, and right ventricular dysfunction). Most studies highlight the importance of individualised preoperative risk assessment and optimisation and advanced perioperative planning. CONCLUSIONS: With an increasing number of patients requiring surgery in specialist and non-specialist PH centres, a systematic, evidence-based, multidisciplinary approach is required to minimise complications. Adequate risk stratification and a tailored-individualised perioperative plan is paramount.

EmPHasis-10 health-related quality of life score predicts outcomes in patients with idiopathic and connective tissue disease-associated pulmonary arterial hypertension: results from a UK multicentre study.

Health-related quality of life (HRQoL) scores assess symptom burden in pulmonary arterial hypertension (PAH) but data regarding their role in prognostication and risk stratification are limited. We assessed these relationships using the emPHasis-10 HRQoL measure.1745 patients with idiopathic PAH (IPAH), drug-induced PAH (DPAH), heritable PAH (HPAH) (collectively "(I/D/H)PAH"), or connective tissue disease-associated PAH (CTD-PAH), who had completed emPHasis-10 questionnaires at one of six UK referral centres between 2014 and 2017, were identified. Correlations with exercise capacity and World Health Organization (WHO) functional class were assessed, and exploratory risk stratification thresholds were tested.Moderate correlations were seen between emPHasis-10 scores and 6-min walk distance (r=-0.546), incremental shuttle walk distance (r=-0.504) and WHO functional class (r=0.497) (all p<0.0001). Distribution of emPHasis-10 score differed significantly between each WHO functional class (all p<0.0001). On multivariate analysis, emPHasis-10 score, but not WHO functional class, was an independent predictor of mortality. In a risk stratification approach, scores of 0-16, 17-33 and 34-50 identified incident patients with 1-year mortality of 5%, 10% and 23%, respectively. Survival of patients in WHO functional class III could be further stratified using an emPHasis-10 score ≥34 (p<0.01). At follow-up, patients with improved emPHasis-10 scores had improved exercise capacity (p<0.0001) and patients who transitioned between risk groups demonstrated similar survival to patients originally in those risk groups.The emPHasis-10 score is an independent prognostic marker in patients with (I/D/H)PAH or CTD-PAH. It has utility in risk stratification in addition to currently used parameters. Improvement in emPHasis-10 score is associated with improved exercise capacity.