Development of Somaliland national harmonised medical curriculum.

BACKGROUND AND OBJECTIVES: The rational for the Somaliland national harmonised curriculum (NHC) was driven by shared concern about the quality of medical education. PROCESS: The Ministry of Education and Science and the Ministry of Health Development produced a Medical Education Policy 2018. Policy objectives included the development of the NHC and accreditation for medical schools that met the standards of the World Federation for Medical Education (WFME). Two bodies were asked to oversee these aims: the National Health Professions' Commission (NHPC) and the National Commission of Higher Education (NCHE). Between 2018 and 2020, a collaborative approach between the Somaliland government, medical school stakeholders, King's Global Health Partnership's (KGHP) volunteers and the Tropical Health Education Trust (THET) team was used to design the 6-years NHC. The NHC structure, content and delivery were grounded by WFME standards, health needs of the local population, student focused and active learning methods, and feasibility of implementation in medical schools. OUTCOMES: The NHC comprises details about the educational outcomes, curriculum model and framework, educational principles, instructional and learning methods, core as well as optional content, and assessment strategy. CONCLUSIONS: The approach used to develop the NHC ensured it is bespoken for Somaliland. Ongoing evaluation of patient and population needs, each medical school's review of programme implementation and outcomes will inform continuous revision and renewal.

Atropisomerism in Drug Discovery: A Medicinal Chemistry Perspective Inspired by Atropisomeric Class I PI3K Inhibitors.

Atropisomerism is a type of axial chirality resulting from hindered rotation about a σ bond that gives rise to nonsuperimposable stereoisomers (termed "atropisomers"). The inversion of chirality of an atropisomeric axis is a time- and temperature-dependent dynamic process occurring by simple bond rotation. For this reason, the rotational energy barrier (ΔErot) and the interconversion rate between an atropisomeric pair of biologically active molecules are important parameters to consider in drug discovery.Many compounds with atropisomeric axes advance into development every year. The vast majority of them have low rotational energy barriers (ΔErot lower than 20 kcal/mol), meaning they are rapidly equilibrating conformers and considered achiral (class 1 atropisomers). Compounds in class 2 (ΔErot = 20 to 30 kcal/mol) can be challenging to develop given that the stereochemical integrity of the atropisomeric axes can be compromised over time. It has been recommended that small molecule drug candidates containing one or more atropisomeric axes with rotational energy barriers greater than 30 kcal/mol (class 3 atropisomers) should be developed as single atropisomers.In medicinal chemistry, a σ bond with restricted rotation is engineered into a bioactive molecule primarily to limit its number of accessible conformations, thereby minimizing entropic and/or enthalpic energy penalties associated with biological target binding. In addition to enhanced pharmacology, potential positive outcomes of introducing atropisomerism include improved physicochemical properties and superior pharmacokinetics/ADME profiles. The application of atropisomerism in medicinal chemistry has become increasingly enabled due to recent advances in synthesis, purification, and analysis, as described in this special issue and recent review articles.Herein, we discuss two case studies from our own work in which restricting rotation about axes of atropisomerism led to significant improvements in pharmacological, physicochemical, and ADME properties for different series of PI3K inhibitors. In the first instance, a restricted axis of rotation was designed to mitigate an acid-mediated hydrolytic degradation pathway observed in a series of PI3Kδ inhibitors. The conformational constraint disrupts conjugation between a quinazolinone and a pyridine, leading to improved chemical stability under acidic conditions. In the second case study, introduction of a restricted axis of rotation between two heteroaromatic systems in a series of PI3Kß inhibitors generated pairs of atropisomeric compounds with significantly different biological activities. Advanced profiling also demonstrated clear substrate stereospecificity in regard to metabolism by aldehyde oxidase. Gratifyingly, the eutomer (more active atropisomer) shows significantly less susceptibility for oxidative metabolism relative to the distomer (less active atropisomer). The improvements in potency, selectivity, chemical stability, and metabolic stability discussed in this manuscript are all directly related to the concept of atropisomerism.

The Utilisation of Hydrogels for iPSC-Cardiomyocyte Research.

Cardiac fibroblasts' (FBs) and cardiomyocytes' (CMs) behaviour and morphology are influenced by their environment such as remodelling of the myocardium, thus highlighting the importance of biomaterial substrates in cell culture. Biomaterials have emerged as important tools for the development of physiological models, due to the range of adaptable properties of these materials, such as degradability and biocompatibility. Biomaterial hydrogels can act as alternative substrates for cellular studies, which have been particularly key to the progression of the cardiovascular field. This review will focus on the role of hydrogels in cardiac research, specifically the use of natural and synthetic biomaterials such as hyaluronic acid, polydimethylsiloxane and polyethylene glycol for culturing induced pluripotent stem cell-derived cardiomyocytes (iPSC-CMs). The ability to fine-tune mechanical properties such as stiffness and the versatility of biomaterials is assessed, alongside applications of hydrogels with iPSC-CMs. Natural hydrogels often display higher biocompatibility with iPSC-CMs but often degrade quicker, whereas synthetic hydrogels can be modified to facilitate cell attachment and decrease degradation rates. iPSC-CM structure and electrophysiology can be assessed on natural and synthetic hydrogels, often resolving issues such as immaturity of iPSC-CMs. Biomaterial hydrogels can thus provide a more physiological model of the cardiac extracellular matrix compared to traditional 2D models, with the cardiac field expansively utilising hydrogels to recapitulate disease conditions such as stiffness, encourage alignment of iPSC-CMs and facilitate further model development such as engineered heart tissues (EHTs).

Rapid scale-up of COVID-19 training for frontline health workers in 11 African countries.

BACKGROUND: The global spread of the SARS-CoV-2 virus highlights both the importance of frontline healthcare workers (HCW) in pandemic response and their heightened vulnerability during infectious disease outbreaks. Adequate preparation, including the development of human resources for health (HRH) is essential to an effective response. ICAP at Columbia University (ICAP) partnered with Resolve to Save Lives and MOHs to design an emergency training initiative for frontline HCW in 11 African countries, using a competency-based backward-design approach and tailoring training delivery and health facility selection based on country context, location and known COVID-19 community transmission. METHODS: Pre- and post-test assessments were conducted on participants completing the COVID-19 training. Parametric and non-parametric methods were used to examine average individual-level changes from pre- to post-test, and compare performance between countries, cadres, sex and facility types. A post-evaluation online training survey using Qualtrics was distributed to assess participants' satisfaction and explore training relevance and impact on their ability to address COVID-19 in their facilities and communities. RESULTS: A total of 8797 HCW at 945 health facilities were trained between June 2020 and October 2020. Training duration ranged from 1 to 8 days (median: 3 days) and consisted of in person, virtual or self guided training. Of the 8105 (92%) HCW working at health facilities, the majority (62%) worked at secondary level facilities as these were the HF targeted for COVID-19 patients. Paired pre- and post-test results were available for 2370 (25%) trainees, and 1768 (18%) participants completed the post-evaluation training survey. On average, participants increased their pre- to post-test scores by 15 percentage points (95% CI 0.14, 0.15). While confidence in their ability to manage COVID-19 was high following the training, respondents reported that lack of access to testing kits (55%) and PPE (50%), limited space in the facility to isolate patients (45%), and understaffing (39%) were major barriers. CONCLUSION: Ongoing investment in health systems and focused attention to health workforce capacity building is critical to outbreak response. Successful implementation of an emergency response training such as this short-term IPC training initiative in response to the COVID-19 pandemic, requires speed, rigor and flexibility of its design and delivery while building on pre-existing systems, resources, and partnerships.

Development of a simple and effective online training for health workers: results from a pilot in Nigeria.

BACKGROUND: Health workers (HWs) in Africa face challenges accessing and learning from existing online training opportunities. To address these challenges, we developed a modular, self-paced, mobile-ready and work-relevant online course covering foundational infection prevention and control (IPC) concepts. Here, we evaluate the first pilot of this course, conducted with HWs in Nigeria. METHODS: We used a learner-centered design and prototyping process to create a new approach to delivering online training for HWs. The resulting course comprised 10 self-paced modules optimized for use on mobile devices. Modules presented IPC vignettes in which learning was driven by short assessment questions with feedback. Learners were recruited by distributing a link to the training through Nigeria-based email lists, WhatsApp groups and similar networks of HWs, managers and allied professionals. The course was open to learners for 8 weeks. We tracked question responses and time on task with platform analytics and assessed learning gains with pre- and post-testing. Significance was evaluated with the Wilcoxon signed-rank test, and effect size was calculated using Cohen's d. RESULTS: Three hundred seventy-two learners, with roles across the health system, enrolled in the training; 59% completed all 10 modules and earned a certificate. Baseline knowledge of foundational IPC concepts was low, as measured by pre-test scores (29%). Post-test scores were significantly higher at 54% (effect size 1.22, 95% confidence interval 1.00-1.44). Learning gains were significant both among learners with low pre-test scores and among those who scored higher on the pre-test. We used the Net Promoter Score (NPS), a common user experience metric, to evaluate the training. The NPS was + 62, which is slightly higher than published scores of other self-paced online learning experiences. CONCLUSIONS: High completion rates, significant learning gains and positive feedback indicate that self-paced, mobile-ready training that emphasizes short, low-stakes assessment questions can be an effective, scalable way to train HWs who choose to enroll. Low pre-test scores suggest that there are gaps in IPC knowledge among this learner population.

Small-molecule agents for the treatment of inflammatory bowel disease.

Inflammatory bowel disease (IBD) is a chronic, debilitating condition with a significant impact on quality of life. In spite of recent advances with antibody therapies, there remains a significant unmet medical need in IBD. Ongoing research and development efforts aim to identify new therapies that will increase remission rates beyond those achieved with current standard-of-care, while maintaining a high safety margin. This review will provide an overview of the small-molecule agents that are being explored in this regard.

Patterns and frequency of renal abnormalities in Fanconi anaemia: implications for long-term management.

BACKGROUND: Fanconi anaemia (FA) is an inherited disease with bone marrow failure, variable congenital and developmental abnormalities, and cancer predisposition. With improved survival, non-haematological manifestations of FA become increasingly important for long-term management. While renal abnormalities are recognized, detailed data on patterns and frequency and implications for long-term management are sparse. METHODS: We reviewed clinical course and imaging findings of FA patients with respect to renal complications in our centre over a 25-year period to formulate some practical suggestions for guidelines for management of renal problems associated with FA. RESULTS: Thirty patients including four sibling sets were reviewed. On imaging, 14 had evidence of anatomical abnormalities of the kidneys. Two cases with severe phenotype, including renal abnormalities, had chronic kidney disease (CKD) at diagnosis. Haematopoietic stem cell transplantation was complicated by significant acute kidney injury (AKI) in three cases. In three patients, there was CKD at long-term follow-up. All patients had normal blood pressure. CONCLUSIONS: Evaluation of renal anatomy with ultrasound imaging is important at diagnostic workup of FA. While CKD is uncommon at diagnosis, our data suggests that the incidence of CKD increases with age, in particular after haematopoietic stem cell transplantation. Monitoring of renal function is essential for management of FA. Based on these long-term clinical observations, we formulate some practical guidelines for assessment and management of renal abnormalities in FA.

Mumps Outbreak Among a Highly Vaccinated University Community-New York City, January-April 2014.

Background: On 14 January 2014, a vaccinated student presented with parotitis. Mumps immunoglobulin M (IgM) testing was negative and reverse-transcription polymerase chain reaction (RT-PCR) testing was not performed, resulting in a missed diagnosis and the start of an outbreak at a New York City (NYC) university. Methods: Mumps case investigations included patient interviews, medical records review, and laboratory testing including mumps serology and RT-PCR. Case patients were considered linked to the outbreak if they attended or had epidemiologic linkage to the university. Epidemiologic, clinical, and laboratory data for outbreak cases residing in NYC were analyzed. Results: Fifty-six NYC residents with mumps were identified with onset between 12 January and 30 April 2014. Fifty-three cases (95%) were university students, 1 (2%) was a staff member, and 2 (4%) had epidemiologic links to the university. The median age was 20 years (range 18-37 years). All cases had parotitis. Three cases were hospitalized, including 1 of 2 cases with orchitis. Fifty-four (96%) cases had received ≥1 mumps-containing vaccine, 1 (2%) was unvaccinated due to religious exemption, and 1 (2%) had unknown vaccination status. Two of the 44 (5%) cases tested by serology were mumps IgM positive, and 27 of the 40 (68%) tested by RT-PCR were positive. Conclusions: Mumps outbreaks can occur in highly vaccinated populations. Mumps should be considered in patients with parotitis regardless of vaccination status. RT-PCR is the preferred testing method; providers should not rely on IgM testing alone. High vaccination coverage and control measures likely limited the extent of the outbreak.

Value of supervised learning events in predicting doctors in difficulty.

CONTEXT: In the UK, supervised learning events (SLE) replaced traditional workplace-based assessments for foundation-year trainees in 2012. A key element of SLEs was to incorporate trainee reflection and assessor feedback in order to drive learning and identify training issues early. Few studies, however, have investigated the value of SLEs in predicting doctors in difficulty. This study aimed to identify principles that would inform understanding about how and why SLEs work or not in identifying doctors in difficulty (DiD). METHODS: A retrospective case-control study of North West Foundation School trainees' electronic portfolios was conducted. Cases comprised all known DiD. Controls were randomly selected from the same cohort. Free-text supervisor comments from each SLE were assessed for the four domains defined in the General Medical Council's Good Medical Practice Guidelines and each scored blindly for level of concern using a three-point ordinal scale. Cumulative scores for each SLE were then analysed quantitatively for their predictive value of actual DiD. A qualitative thematic analysis was also conducted. RESULTS: The prevalence of DiD in this sample was 6.5%. Receiver operator characteristic curve analysis showed that Team Assessment of Behaviour (TAB) was the only SLE strongly predictive of actual DiD status. The Educational Supervisor Report (ESR) was also strongly predictive of DiD status. Fisher's test showed significant associations of TAB and ESR for both predicted and actual DiD status and also the health and performance subtypes. None of the other SLEs showed significant associations. Qualitative data analysis revealed inadequate completion and lack of constructive, particularly negative, feedback. This indicated that SLEs were not used to their full potential. CONCLUSIONS: TAB and the ESR are strongly predictive of DiD. However, SLEs are not being used to their full potential, and the quality of completion of reports on SLEs and feedback needs to be improved in order to better identify and manage DiD.

Medical planning for very large events: Special Olympics World Games Los Angeles 2015.

Mass gathering events that involve special populations have challenges that require unique medical planning. The key to a successful mass event is in the preparation, planning, and communication. Concerns in communication such as language barriers, age of participants, and intellectual disability should be addressed early in the planning. In the event of a mass casualty disaster, there should be a clear chain of command and escalation policy. The primary concern of the sports medicine team is to ensure safety for the participation of an athlete. The risk of injury to an athlete varies depending on the event and venue. The sporting venue may require special consideration for access to athletes, crowd control, and ingress/egress of medical personnel and transports. In order to ensure safety and efficient care, it is paramount to have the necessary medical planning and preparedness to manage a large-scale sporting event.

Acquired Esotropia in Cerebellar Disease: A Case Series Illustrating Misdiagnosis as Isolated Lateral Rectus Paresis and Progression Over Time.

We highlight an under-recognised cause of acquired esotropia with this prospective observational case series of adults with diplopia secondary to cerebellar dysfunction. We also show deterioration of cerebellar esotropia over time, which has not been previously described. Seven adults (four women) developed diplopia at a median age of 63 years (range: 31-75 years), as the initial manifestation of the underlying cerebellar disorder. Causes of cerebellar dysfunction were familial cerebellar ataxia of unknown mutation (two patients), idiopathic cerebellar ataxia (four patients), and spinocerebellar ataxia 3 (one patient). At onset, three patients had unilateral and four had bilateral lateral rectus under-action. These were initially diagnosed as lateral rectus paresis, but the diagnosis was revised, as our examination showed no slowing of abducting saccades assessed clinically and full abduction with gaze-evoked nystagmus. Esotropia was concomitant and worse for distance, although at onset one patient's esotropia was equal for near and distance. There was a trend of worsening esotropia over time, following a median interval follow-up of 4 years (range: 1-18). All patients were first observed to have cerebellar eye signs after a median interval of 5 years (range: 1-30) from presentation, i.e., impaired pursuit (7/7 patients), gaze-evoked nystagmus (7/7), hypometric saccades (3/7), downbeat nystagmus (2/7), and skew deviation (4/7). Only two patients have not developed non-ocular cerebellar eye signs, after 5 and 8 years from diplopia onset, respectively; the other five patients had gait ataxia, which could be mild. The patients were successfully treated with prisms (7/7), botulinum toxin injections (1/7), and strabismus surgery (1/7).

The in vitro pharmacology of GS-5759, a novel bifunctional phosphodiesterase 4 inhibitor and long acting ß2-adrenoceptor agonist.

Inhaled long-acting ß(2)-adrenoceptor agonists (LABA) that act as bronchodilators and the oral anti-inflammatory phosphodiesterase 4 (PDE4) inhibitor roflumilast are both approved therapies for chronic obstructive pulmonary disease (COPD). Here we describe the activity of a novel, inhaled, bifunctional, small molecule (R)-6-[(3-{[4-(5-{[2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethyl]amino}pent-1-yn-1-yl)phenyl]carbamoyl}phenyl)sulfonyl]-4-[(3-methoxyphenyl)amino]-8-methylquinoline-3-carboxamide (GS-5759), which has specific ß(2) agonist and PDE4 inhibitory activity. GS-5759 demonstrated potent and full agonist activity at ß(2) adrenoceptors (EC(50) = 8 ± 4 nM) and is a potent inhibitor of the PDE4 enzyme (IC(50) = 5 ± 3 nM). In cell assays, GS-5759 inhibited lipopolysaccharide (LPS)-induced tumor necrosis factor α (TNFα) production in human peripheral mononuclear cells (PBMC) with an IC(50) = 0.3 nM [confidence interval (CI) 0.1-0.6] and in human neutrophils formyl-methionyl-leucyl-phenylalanine (fMLP)-induced super oxide anion production with an IC(50) = 3 nM (CI 0.8-8). The addition of the ß(2) antagonist ICI 118551 shifted the IC(50) in these cell assays to 4 and 38 nM, respectively, demonstrating the contribution of both ß(2) agonist and PDE4 inhibitory activity to GS-5759. GS-5759 was also a potent inhibitor of profibrotic and proinflammatory mediator release from human lung fibroblasts. GS-5759 relaxed guinea pig airway smooth muscle strips precontracted with carbachol in a concentration-dependent manner with an EC(50) = 0.5 µM (CI 0.2-2) and had slow dissociation kinetics with an Off T(1/2) > 720 minutes at an EC(80) concentration of 3 µM. GS-5759 is a novel bifunctional molecule with both potent ß(2) agonist and PDE4 inhibitor activity that could provide inhaled bronchodilator and anti-inflammatory therapy for COPD.

The effects of adenosine A2B receptor inhibition on VEGF and nitric oxide axis-mediated renal function in diabetic nephropathy.

Diabetic nephropathy (DN) is the most common cause of end-stage renal disease worldwide. The pathophysiologic mechanisms of diabetic nephropathy are incompletely understood but include overproduction of various growth factors and cytokines. Upregulation of vascular endothelial growth factor (VEGF) is a pathogenic event occurring in most forms of podocytopathy; however, the mechanisms that regulate this growth factor induction are not clearly identified. A2B receptors have been found to regulate VEGF expression under hypoxic environment in different tissues. One proposed hypothesis in mediating diabetic nephropathy is the modulation of VEGF-NO balance in renal tissue. We determined the role of adenosine A2B receptor in mediating VEGF overproduction and nitrite in diabetic nephropathy. The renal content of A2B receptors and VEGF was increased after 8 weeks of diabetes induction. The renal and plasma nitrite levels were also reduced in these animals. In vivo administration of A2B adenosine receptor antagonist (MRS1754) inhibited the renal over expression of VEGF and adverse renal function parameters. The antagonist administration also improved the kidney tissue nitrite levels. In conclusion, we demonstrated that VEGF induction via adenosine signaling might be the critical event in regulating VEGF-NO axis in diabetic nephropathy.

The effect of different types of oral or intravenous corticosteroids on capillary blood glucose levels in hospitalized inpatients with and without diabetes.

PURPOSE: This study investigated: (1) the type of corticosteroid associated with the greatest degree of hyperglycemia, assessed using bedside capillary blood glucose monitoring, in hospitalized patients; and (2) the pattern of hyperglycemia throughout the day with the use of each type of corticosteroid. METHODS: This single-center, retrospective study used data from 964 adult inpatients receiving oral or IV corticosteroids. Data on capillary blood glucose concentrations and time taken over 7 days were collected. A mixed model for repeated measures was applied to investigate changes in glucose concentration over time with the use of four different corticosteroids. An autoregressive covariance structure was used to model correlations between repeated measurements. FINDINGS: Across all 7 days, the mean blood glucose concentration was greater with dexamethasone compared to that with hydrocortisone (mean difference, 16.6 mg/dL [95% CI, 8.1-24.8] [0.92 mmol/L (95% CI, 0.45-1.38)]) or prednisolone (mean difference, 20.0 mg/dL [95% CI, 14.2-25.7] [1.11 mmol/L (95% CI, 0.79-1.43)]). The mean blood glucose concentration was greater with methylprednisolone compared to that with hydrocortisone (mean difference, 23.9 mg/dL [95% CI, 11.3-36.4] [1.33 mmol/L (95% CI, 0.63-2.02)]), and with methylprednisolone versus prednisolone (mean difference, 27.4 mg/dL [95% CI, 16.4-38.3] [1.52 mmol/L (95% CI, 0.91-2.13)]). There were no significant differences in the patterns of hyperglycemia at six time points of the day with each type of corticosteroid. IMPLICATIONS: Treatment with oral or IV dexamethasone or methylprednisolone was associated with greater hyperglycemia in comparison to prednisolone and hydrocortisone. More vigorous monitoring and intervention, when necessary, are suggested in adult inpatients receiving corticosteroids, in particular dexamethasone and methylprednisolone.

Phenoage and longitudinal changes on transthoracic echocardiography in Alström syndrome: a disease of accelerated ageing?

Alström syndrome (AS) is an ultra-rare disorder characterised by early-onset multi-organ dysfunction, such as insulin resistance, obesity, dyslipidaemia, and renal and cardiovascular disease. The objective is to explore whether AS is a disease of accelerated ageing and whether changes over time on echocardiography could reflect accelerated cardiac ageing. Cross-sectional measurement of Phenoage and retrospective analysis of serial echocardiography were performed between March 2012 and November 2022. The setting is a single national tertiary service jointly run by health service and patient charity. Forty-five adult patients aged over 16 years were included, 64% were male and 67% of White ethnicity. The median Phenoage was 48 years (interquartile range [IQR]: 35-72) in the 34 patients for whom this was calculable, which was significantly higher than the median chronological age of 29 years (IQR: 22-39, p<0.001). Phenoage was higher than chronological age in 85% (N=29) of patients, with a median difference of +18 years (IQR: +4, +34). On echocardiography, significant decreases were observed over time in left ventricular (LV) size at end-diastole (average of 0.046 cm per year, p<0.001) and end-systole (1.1% per year, p=0.025), with significant increase in posterior wall thickness at end-diastole (0.009 cm per year, p=0.008). LV systolic function measured by global longitudinal strain reduced (0.34 percentage points per year, p=0.020) and E/e'lat increased (2.5% per year, p=0.019). Most AS patients display a higher Phenoage compared to chronological age. Cardiac changes in AS patients were also reflective of accelerated ageing, with a reduction in LV size and increased wall thickening. AS may be a paradigm disease for premature ageing.

Defining the cardiovascular phenotype of adults with Alström syndrome.

BACKGROUND: >40% of infants with Alström Syndrome (AS) present with a transient, severe cardiomyopathy in the first months of life, with apparent recovery in survivors. One in five individuals then develop a later-onset cardiomyopathy but wide clinical variability is observed, even within the same family. The rationale for this study is to provide a comprehensive evaluation of the cardiovascular phenotype in adults with AS. METHODS: Adults attending the National Centre for AS in England were studied. All patients underwent biochemical, 12- lead electrocardiography, echocardiography, and cardiovascular magnetic resonance imaging. RESULTS: 47 adults with AS (64% male; mean age 33 years; 66% white British) were studied. Seven (15%) survived infantile cardiomyopathy and 23 (49%) developed adult-onset cardiomyopathy. Conventional risk factors for cardiovascular disease were present in 39 (83%). Abnormalities were present on biomarkers in 16 (34%), ECG 30 (64%), echocardiography 19 (40%) and CMR 31 (66%). Coronary artery imaging was performed in six (13%), with abnormalities in two. Cardiac, renal, and liver markers were more often impaired in older patients, with impaired left ventricular ejection fraction, reduced global longitudinal strain and late enhancement. 6 (13%) had severe pulmonary hypertension (mean pulmonary artery pressure 46 mmHg) due to left heart disease on invasive testing. CONCLUSION: Cardiomyopathy is common in adults with AS, complicated in a significant proportion by atherosclerotic coronary artery disease and restrictive cardiomyopathy, confirmed on CMR and invasive testing. With advancing age, cardiovascular complications are compounded by contemporaneous renal and liver disease.

National service evaluation of the quality of care for children and young people with congenital adrenal hyperplasia in the United Kingdom: survey responses from patients and clinicians.

INTRODUCTION: Quantifying differences in service provision for children and young people (CYP) living with Congenital Adrenal Hyperplasia (CAH) across the United Kingdom. METHODS: A national service evaluation using online questionnaires circulated to patients and clinicians from secondary and tertiary UK centres managing CYP with CAH, and via the "Living with CAH" support group mailing list. RESULTS: Total of 195 responses relating to patients aged 0-20 years attending 33 clinics (43 patients, 152 carers), as well as 34 clinicians from 18 trusts working across the 33 clinics. Only 12% of clinicians were 'completely satisfied' with the service provided, compared to 68% of carers and 76% of patients. Whilst 94% of clinicians reported providing formal training to families with CAH, over 80% of both patients and carers reported not attending what they considered formal training. Appetite for further training was higher in carers (86%) than patients (55%), although further 'unsure' responses suggested formal training sessions would likely be well attended. Access to psychological services was difficult for 44% of clinicians. Biochemical monitoring of treatment was broadly in keeping with international guidelines, with 67% of clinicians reporting regular use of dried blood spots, and 12% regular urinary steroid metabolites. CONCLUSION: While there is overall good satisfaction with care provision among patients and carers with CAH in the UK, extra resources addressing the psychological and educational needs about the disease and its management would benefit patients and carers. Improved access to allied health professionals and psychologists will help support families and improve patient outcomes.

Defining the key pharmacophore elements of PF-04620110: discovery of a potent, orally-active, neutral DGAT-1 inhibitor.

DGAT-1 is an enzyme that catalyzes the final step in triglyceride synthesis. mRNA knockout experiments in rodent models suggest that inhibitors of this enzyme could be of value in the treatment of obesity and type II diabetes. The carboxylic acid-based DGAT-1 inhibitor 1 was advanced to clinical trials for the treatment of type 2 diabetes, despite of the low passive permeability of 1. Because of questions relating to the potential attenuation of distribution and efficacy of a poorly permeable agent, efforts were initiated to identify compounds with improved permeability. Replacement of the acid moiety in 1 with an oxadiazole led to the discovery of 52, which possesses substantially improved passive permeability. The resulting pharmacodynamic profile of this neutral DGAT-1 inhibitor was found to be similar to 1 at comparable plasma exposures.

QDOT MICRO™ versus THERMOCOOL® SMARTTOUCH™ and THERMOCOOL SMARTTOUCH® Surround Flow in radiofrequency ablation of paroxysmal atrial fibrillation.

Aim: The objective of this study was to indirectly compare QDOT MICRO™ (QDOT), Thermocool® SmartTouch™ (ST) and Thermocool® SmartTouch® Surround Flow (STSF) to treat paroxysmal atrial fibrillation. Methods: Differences in baseline characteristics between study cohorts were reduced by reweighting patients using inverse probability of treatment weighting. The primary outcome was procedure time. Secondary outcomes were fluoroscopy time, clinical success at 12 months, and rhythm monitoring-adjusted recurrence. Results: QDOT was associated with significantly faster mean procedure and fluoroscopy time, and significant improvement in the rate of recurrence compared with pooled ST/STSF. No difference was observed for clinical success at 12 months. Conclusion: QDOT was associated with greater efficiency, greater effectiveness in rhythm monitoring-adjusted recurrence and similar effectiveness in clinical success at 12 months compared with pooled ST/STSF.