Brighton and Sussex Medical School
  • Brighton, United Kingdom
Recent publications
Background: Multiple sclerosis (MS) and neuromyelitis optica syndrome disease (NMOSD) are inflammatory diseases of the central nervous system. The pathogenesis and treatments for these two conditions are very different. Natural killer (NK) and natural killer T (NKT) cells are immune cells with an important role in shaping the immune response. B cells are involved in antigen presentation as well as antibody and cytokine production. There is conflicting evidence of the roles of NK, NKT, and B cells in the two conditions. We aimed to compare the frequency of CD3-CD16+CD56+NK, CD3+ CD56+ NKT, and CD5+CD19+ B cells in the peripheral blood and serum Interleukin-10 (IL-10) in patients with MS and NMOSD. Methods: CD19+CD5+ B, CD3- CD16+CD56+ NK, and CD3+CD56+ NKT cells were quantitated by flow cytometry in 15 individuals with Interferon-Beta (IFN-β) treated relapsing-remitting MS (RRMS), 15 untreated RRMS, and 15 NMOSD patients as well as 30 healthy controls (HC). Serum IL-10 was measured using an enzyme-linked immunosorbent assay (ELISA). Results: The percentage of CD3-CD56+CD16+ NK cells in the peripheral blood of IFN-treated MS (1.81 ± 0.87) was significantly lower than for untreated RRMS (4.74 ± 1.80), NMOSD (4.64 ± 1.26) and HC (5.83 ± 2.19) (p < 0.0001). There were also differences for the percentage of CD3-CD16+ and CD3-CD56+ cells (p < 0.001 and p < 0.0007; respectively). IFN-treated RRMS (2.89 ± 1.51) had the lowest proportion of CD3+CD56+ among the study groups (p < 0.002). Untreated RRMS (5.56 ± 3.04) and NMOSD (5.47 ± 1.24) had higher levels of CD3+CD56+ than the HC (3.16 ± 1.98). The mean percentage of CD19+CD5+ B cells in the peripheral blood of untreated RRMS patients (1.32 ± 0.67) was higher compared to the patients with NMOSD (0.30 ± 0.20), HC (0.5 ± 0.22) and IFN-treated RRMS (0.81 ± 0.17) (p < 0.0001). Serum interleukin-10 was significantly higher in the IFN-treated RRMS (8.06 ± 5.39) and in HC (8.38 ± 2.84) compared to untreated RRMS (5.07 ± 1.44) and the patients with NMOSD (5.33 ± 2.56) (p < 0.003). Conclusions: The lower proportion of CD3-CD56+ CD16+ NK and CD3+CD56+ cells in peripheral blood of IFN-treated RRMS compared to other groups suggests the importance of immunomodulation in patients with RRMS disorder. Based on the differences in CD19+CD5+ B cells and serum IL-10 between patients and HC, supplementary assessments could be of value in clarifying their roles in autoimmunity.
SARS-CoV-2 (COVID-19) is the causative organism for a pandemic disease with a high rate of infectivity and mortality. In this study, we aimed to assess the affinity between several available small molecule and proteins, including Abl kinase inhibitors, Janus kinase inhibitor, dipeptidyl peptidase 4 inhibitors, RNA-dependent RNA polymerase inhibitors, and Papain-like protease inhibitors, using binding simulation, to test whether they may be effective in inhibiting COVID-19 infection through several mechanisms. The efficiency of inhibitors was evaluated based on docking scores using AutoDock Vina software. Strong ligand–protein interactions were predicted among some of these drugs, that included: Imatinib, Remdesivir, and Telaprevir, and this may render these compounds promising candidates. Some candidate drugs might be efficient in disease control as potential inhibitors or lead compounds against the SARS-CoV-2. It is also worth highlighting the powerful immunomodulatory role of other drugs, such as Abivertinib that inhibits pro-inflammatory cytokine production associated with cytokine release syndrome (CRS) and the progression of COVID-19 infection. The potential role of other Abl kinase inhibitors, including Imatinib in reducing SARS-CoV and MERS-CoV viral titers, immune regulatory function and the development of acute respiratory distress syndrome (ARDS), indicate that this drug may be useful for COVID-19, as the SARS-CoV-2 genome is similar to SARS-CoV.
Background: Understanding and accurately predicting the environmental limits, population at risk and burden of podoconiosis are critical for delivering targeted and equitable prevention and treatment services, planning control and elimination programs and implementing tailored case finding and surveillance activities. Methods: This is secondary analysis of a nationwide podoconiosis mapping survey in Kenya. We combined national representative prevalence survey data of podoconiosis with climate and environmental data, overlayed with population figures in a geostatistical modelling framework, to predict the environmental suitability, population living in at-risk areas and number of cases of podoconiosis in Kenya. Results: In 2020, the number of people living with podoconiosis in Kenya was estimated to be 9344 (95% uncertainty interval 4222 to 17 962). The distribution of podoconiosis varies by geography and three regions (Eastern, Nyanza and Western) represent >90% of the absolute number of cases. High environmental suitability for podoconiosis was predicted in four regions of Kenya (Coastal, Eastern, Nyanza and Western). In total, 2.2 million people live in at-risk areas and 4.2% of the total landmass of Kenya is environmentally predisposed for podoconiosis. Conclusions: The burden of podoconiosis is relatively low in Kenya and is mostly restricted to certain small geographical areas. Our results will help guide targeted prevention and treatment approaches through local planning, spatial targeting and tailored surveillance activities.
Objective: We aimed to evaluate the usability and acceptability of a co-designed mobile health (mHealth) application (PrEP-EmERGE) within a digital health pathway to support HIV pre-exposure prophylaxis (PrEP). Methods: This was a cross-sectional study to evaluate the usability and acceptability of the PrEP-EmERGE app. Data were collected via an online survey sent to all PrEP EmERGE users in September 2021. Usability was assessed with a validated usability tool, the System Usability Scale (SUS). Acceptability was assessed using modified patient-reported experience measures (PREMs). Quantitative data were analysed using descriptive and/or inferential statistics and qualitative data (free text responses) using thematic analysis. Results: In total, 81/133 (61%) active PrEP EmERGE users completed the online survey, which was available directly from their PrEP EmERGE app: 78/81 (96%) identified as cis-male, 74/81 (91%) reported their ethnicity as 'white', 69/81 (85%) reported daily PrEP use, 7/81 (9%) reported using an event-based dosing schedule, and 5/81 (6%) were switching between dosing schedules. Overall, the median SUS score was 78/100 (interquartile range: 70-92). There were no differences in median SUS scores by PrEP dosing schedules (p = 0.78) or months of experience of using the app (p = 0.31). Overall, 73/81 (90%) would recommend the PrEP EmERGE app to a friend and 78/81 (96%) rated their satisfaction of the app as excellent, good or satisfactory. The free text responses generated three key themes: accessibility (for results and information); autonomy [taking responsibility for their (sexual) health] and func-tionality (including technical recommendations for app development and the digital health pathway). Conclusions: Innovative, co-designed digital health pathways, such as PrEP EmERGE can help sexual health services to manage increasing numbers of people accessing PrEP – ensuring that they retain access for those who need to be seen face-to-face. We report high levels of acceptability and usability during the first 4 months of this novel pathway
Context: Systems Training for Emotional Predictability and Problem Solving for Emotional Intensity (STEPPS-EI), a 13-week skills-based group intervention for individuals with subthreshold borderline personality disorder (BPD) has been deemed feasible and clinically effective in primary care [1] [2]. To modernize the service, STEPPS-EI lesson content has recently built onto an eHealth platform (Minddistrict). Due to Covid-19 restrictions, group sessions were additionally delivered remotely via Zoom. This project evaluates the implementation of this digitally blended version of STEPPS-EI within two Sussex Partnership NHS Foundation Trust (SPFT) primary care services. Methods: Service users and pracitioners who participated in the first two groups from March to July 2021 were invited to take part in a feasibility evaluation investigating recruitment, retention, and attendance rates, in addition to self-reported symptoms (BSL-23, QuEST), quality of life (ReQoL), system usability, and qualitative and quantitative measures designed to shed light on the experience and opinions of service users and practitioners during the intervention. Service users participating in following groups (from July to December 2021) were invited to share their symptom and quality of life outcome data only. Results: 14 service users and 5 practitioners agreed to take part in the primary evaluation. Results suggested that 86% of these service users attended at least 75% of the group sessions, and that service users completed on average 70% of the online material. Usability ratings revealed good gradings for Zoom from all participants, yet lower gradings for Minddistrict. Further analyses revealed a generally positive attitude towards digital STEPPS-EI from all parties and practical suggestions on how to improve the intervention. 11 service users from following groups agreed to share their data. Bayesian analyses were conducted for the data of service users who provided ratings at both timepoints. Evidence was found for a decrease in BSL-23 scores and an increase in ReQoL ratings from baseline to post-intervention. Incomplete self-report data-sets limits conclusions. Conclusions: It was found that the implementation of STEPPS-EI delivered in a blended digital format was feasible. The online delivery might increase service users' engagement with the material and group sessions. Yet more training and support on the use of Minddistrict may be required to increase usability. Implications: It may be possible to effectively implement digital interventions for individuals with subthreshold BPD. However, more research on the effect of these on symptom outcomes should follow.
Background: Skin-presenting neglected tropical diseases (skin-NTDs) impose large burdens on affected people, families and communities. The NTD Roadmap 2021-2030 presents a strategic plan to guide collaborative, multisectoral action to overcome these burdens, defining targets to control, eliminate and/or eradicate skin-NTDs by 2030. One of its targets is for 40 countries to adopt integrated skin-NTD strategies. Despite this high-level support for integration, only four countries were implementing integrated skin-NTD strategies in 2020. Methods: We hosted workshops at the 2021 annual meeting of the Coalition for Operational Research on NTDs, to discuss the operationalisation of Roadmap goals into national strategies and interventions for skin-NTD control. Speakers included NTD Programme Managers from NTD-endemic countries, technical experts and researchers of different aspects of skin-NTDs. Results: Challenges include community perceptions of interventions, demonstrating the cost-effectiveness of integrated care, availability and accessibility of community-based and primary healthcare services, the quality of data on skin-NTD morbidity and changes to operational structures required for integration. Research priorities included the identification of optimal case detection platforms, evaluation of integrated care, understanding the impacts of integration on community members and community health staff and development of point-of-care diagnostics. Conclusions: The operational research priorities are intended to support the scale-up of integrated skin-NTDs programmes.
Spontaneous bacterial peritonitis (SBP) is associated with high morbidity and mortality.¹ This study aimed to assess outcomes in patients with an index presentation of SBP over a 13-year period in Southeast England.This retrospective cohort study collected data on all patients admitted with SBP from June 2006-May 2019. Patient records were reviewed and divided into period 1 (June 2006-November 2012) and period 2 (December 2012-May 2019), to assess differences, if any, in outcomes. The primary outcome was overall mortality. Cox proportional hazards regression and Kaplan-Meier survival analysis were performed. During the study period, 185 patients were hospitalised with SBP, 66%(n=123/185) being male, mean±SD age 57.9±13.3 years with alcohol being the most common cause of cirrhosis (76%, n=140/185). Mean MELD and UKELD scores were 24.0±7.1 and 59.6±7.0 respectively. In 22%(n=40/185) SBP was the index presentation of cirrhosis. Overall mortality was 85%(n=157/184), 1, 2 and 3-year survival being 34%, 28% and 25% respectively. Independent predictors of overall mortality were age (HR 1.028, 95% CI 1.011–1.045, p=0.001), serum creatinine (HR 1.003, 95% CI 1.000–1.005, p=0.018), positive ascitic fluid culture (HR 1.709, 95% CI 1.161–2.514, p=0.007) and hepatic encephalopathy (HR 1.703, 95% CI 1.040–2.789, p=0.034). Inpatient mortality was 35%(n=64/185), independent predictors being serum creatinine (HR 1.003, 95% CI 1.000–1.006, p=0.037), smoker on admission (HR 2.023, 95% CI 1.114–3.673, p=0.021) and ascitic fluid neutrophil count (HR 1.0001, 95% CI 1.0000–1.0002, p=0.006). Of those surviving hospitalisation, 78%(n=93/120) died during a median follow-up of 11.5 months (IQR 39.6). Comparing period 1 vs. period 2, follow-up duration (months, IQR) was similar (3.7, 21.8 vs. 2.2, 25.1, p=0.298). The latter however had lower serum sodium (mmol/L) (130.3±7.3 vs. 133.3±6.3, p=0.003) and ascitic fluid albumin (g/L) (6.2±3.4 vs. 10.8±5.5, p<0.001), higher ascitic fluid neutrophil count (cells/mm³, IQR) (650, 2286 vs. 400, 850, p<0.001), were more likely to receive intravenous albumin (86%(n=80/93) vs. 57%(n=52/92), p<0.001) and more likely to have hepatorenal syndrome (55%(n=51/93) vs. 33%(n=30/92), p=0.002). Prevalence of drug-resistant bacteria was 45% vs. 38% (period 1 vs. period 2 respectively) (p=0.521). Mortality overall and in those surviving hospitalisation was greater in period 1, 96%(n=87/91) vs. 75%(n=70/93), p<0.001 and 93%(n=54/58) vs. 63%(n=39/62), p<0.001 respectively. SBP continues to be associated with high mortality, serum creatinine being an independent predictor of both overall and inpatient mortality. However, mortality appears to have declined over the last 13 years, despite more severe initial presentations. Reference • Aithal G, Palaniyappan N, China L, Härmälä S, Macken L, Ryan J et al. Guidelines on the management of ascites in cirrhosis. Gut. 2020; 70 (1):9–29.
Introduction The approaches to learning students adopt when learning anatomy online could yield important lessons for educators. Dissection room teaching can encourage students to adopt a deep approach to learning anatomy. It was therefore hypothesized that the proportion of students adopting a deep approach to learning would be lower in a population learning anatomy online. This research aims to investigate the experiences of students learning anatomy online during the COVID-19 pandemic and the approaches to learning they adopted. Methods A survey was distributed to medical students at 7 universities across the UK and Ireland. The survey included two previously validated questionnaires: Approaches and Study Skills Inventory for Students and Anatomy Learning Experience Questionnaire. Results The analysis included 224 unique student responses. Students’ approach to learning mirrored reports from previous studies conducted during face-to-face tuition with 44.3% adopting deep, 40.7% strategic, 11.4% surface, and 3.6% combined learning approaches. The university (p = 0.019) and changes to formative (p = 0.016) and summative (p = 0.009) assessments significantly impacted approach to learning. Students reported that online resources were effective but highlighted the need for clearer guidance on how to find and use them successfully. Conclusion It is important to highlight that students value in-person opportunities to learn from human cadaveric material and hence dissection room sessions should remain at the forefront of anatomical education. It is recommended that future online and/or blended provisions of anatomy teaching include varied resources that maximize engagement with media featuring cadaveric specimens.
Background: Climate change has significant implications for health, yet healthcare provision itself contributes significant greenhouse gas emission. Medical students need to be prepared to address impacts of the changing environment and fulfil a key role in climate mitigation. Here we evaluate the effectiveness of an online module on climate-change and sustainability in clinical practice designed to achieve learning objectives adapted from previously established sustainable healthcare priority learning outcomes. Methods: A multi-media, online module was developed, and 3rd and 4th year medical students at Brighton and Sussex Medical School were invited to enrol. Students completed pre- and post-module questionnaires consisting of Likert scale and white space answer questions. Quantitative and qualitative analysis of responses was performed. Results: Forty students enrolled and 33 students completed the module (83% completion rate). There was a significant increase in reported understanding of key concepts related to climate change and sustainability in clinical practice (p < 0.001), with proportion of students indicating good or excellent understanding increasing from between 2 - 21% students to between 91 - 97% students. The majority (97%) of students completed the module within 90 min. All students reported the module was relevant to their training. Thematic analysis of white space responses found students commonly reported they wanted access to more resources related to health and healthcare sustainability, as well as further guidance on how to make practical steps towards reducing the environmental impact within a clinical setting. Conclusion: This is the first study to evaluate learner outcomes of an online module in the field of sustainable health and healthcare. Our results suggest that completion of the module was associated with significant improvement in self-assessed knowledge of key concepts in climate health and sustainability. We hope this approach is followed elsewhere to prepare healthcare staff for impacts of climate change and to support improving the environmental sustainability of healthcare delivery. Trial registration: Study registered with Brighton and Sussex Medical School Research Governance and Ethics Committee (BSMS RGEC). Reference: ER/BSMS3576/8, Date: 4/3/2020.
Background Iron accumulation and neuroinflammation are both pathological processes that are associated with disease progression of Huntington’s Disease (HD). However, their intercorrelation remains unclear, in both HD and other neurodegenerative diseases. Aims This study aims to investigate the correlation between altered brain iron content and altered neuroinflammatory markers in the basal ganglia of HD gene expansion carriers. Methods A total of 30 participants (11 premanifest, 7 manifest and 12 healthy controls) were scanned on a 7T MRI scanner (Philips, Netherlands), as part of a larger (EHDN seed fund) project (n=70). Quantitative susceptibility mapping (QSM) was used to quantify iron concentration in the brain. ¹H Magnetic Resonance Spectroscopy (MRS) was used to measure levels of myoinositol (Ins) and choline (Cho) in a volume-of-interest (VOI) located in the basal ganglia. Ins and Cho are two metabolites that are preferentially located in glial cells and astrocytes and can serve as neuroinflammation markers. Outcome As a first step, a subpopulation, consisting of 3 age- and sex-matched subjects per group (9 in total), will be analyzed with QSM and MRS. Magnetic susceptibility and metabolite concentrations within the MRS-VOI will be quantified and correlated. Conclusions Our unique protocol will lead us one step closer to the missing link between neuroinflammation and iron accumulation, using QSM and MRS. This could help determining the order and distribution of these pathological processes in the different stages of HD. This novel approach could create new opportunities for biomarker development and therapeutic interventions.
COVID-19 has further exacerbated trends of widening health inequalities in the UK. Shockingly, the number of years of life lived in general good health differs by over 18 years between the most and least deprived areas of England. Poor diets and obesity are established major risk factors for chronic cardiometabolic diseases and cancer, as well as severe COVID-19. For doctors to provide the best care to their patients, there is an urgent need to improve nutrition education in undergraduate medical school training. With this imperative, the Association for Nutrition established an Interprofessional Working Group on Medical Education (AfN IPG) to develop a new, modern undergraduate nutrition curriculum for medical doctors. The AfN IPG brought together expertise from nutrition, dietetic and medical professionals, representing the National Health Service (NHS), royal colleges, medical schools and universities, government public health departments, learned societies, medical students, and nutrition educators. The curriculum was developed with the key objective of being implementable through integration with the current undergraduate training of medical doctors. Through an iterative and transparent consultative process, thirteen key nutritional competencies, to be achieved through mastery of eleven graduation fundamentals, were established. The curriculum to facilitate the achievement of these key competencies is divided into eight topic areas, each underpinned by a learning objective statement and teaching points detailing the knowledge and skills development required. The teaching points can be achieved through clinical teaching and a combination of facilitated learning activities and practical skill acquisition. Therefore, the nutrition curriculum enables mastery of these nutritional competencies in a way that will complement and strengthen medical students’ achievement of the General Medical Council (GMC) Outcome for Graduates. As nutrition is an integrative science, the AfN IPG recommends that the curriculum is incorporated into initial undergraduate medical studies before specialist training. This will enable our future doctors to recognise how nutrition is related to multiple aspects of their training, from physiological systems to patient-centred care, and acquire a broad, inclusive understanding of health and disease. In addition, it will facilitate medical schools to embed nutrition learning opportunities within the core medical training, without the need to add in a large number of new components to an already crowded programme or with additional burden for teaching staff. The undergraduate nutrition curriculum for medical doctors is designed to support medical schools to create future doctors who will understand and recognise the role of nutrition in health. Moreover, it will equip frontline staff to feel empowered to raise nutrition-related issues with their patients as a fundamental part of enhanced care and to appropriately refer on for nutrition support with a registered associate nutritionist/registered nutritionist (ANutr/RNutr) or registered dietitian (RD) where this is likely to be beneficial.
Glutamatergic dysfunction is implicated in the pathoaetiology of schizophrenia, but this may vary in extent between patients. It is unclear whether inter-individual variability in glutamate is greater in schizophrenia than the general population. We conducted meta-analyses to assess (1) variability of glutamate measures in patients relative to controls, using the log coefficient of variation ratio (CVR); (2) standardised mean differences (SMD) using Hedges g; (3) modal distribution of individual-level glutamate data using Hartigan’s unimodality dip test. MEDLINE and EMBASE databases were searched from inception to October 2021 for proton magnetic resonance spectroscopy (1H-MRS) studies reporting glutamate, glutamine or Glx in schizophrenia patients compared to controls. 116 studies reporting on 7,844 patients and 7,305 controls were included. Compared with controls, patients demonstrated greater variability in glutamatergic metabolites in the medial frontal cortex (MFC, glutamate: CVR = 0.15, p < 0.001; glutamine: CVR = 0.16, p = 0.003; Glx: CVR = 0.11, p = 0.003), dorsolateral prefrontal cortex (glutamine: CVR = 0.14, p = 0.05; Glx: CVR = 0.25, p < 0.001) and thalamus (glutamate: CVR = 0.16, p = 0.008; Glx: CVR = 0.19, p = 0.008). Studies in younger, more symptomatic patients were associated with greater variability in the basal ganglia (BG glutamate with age: z=-0.03,p = 0.003, symptoms: z = 0.007,p = 0.02), MFC (glutamine with symptoms: z = 0.01,p = 0.01) and temporal lobe (glutamate with age: z=-0.03,p = 0.02). For individual patient data, most studies showed a unimodal distribution of glutamatergic metabolites. Meta-analysis of mean differences found lower MFC glutamate levels (g=-0.18,p = 0.02), higher thalamic glutamine (g = 0.53,p < 0.001) and higher BG Glx in patients relative to controls (g = 0.28,p < 0.001). Proportion of males was negatively associated with MFC glutamate (z=-0.02,p = 0.002) and frontal white matter Glx (z=-0.03,p = 0.02) in patients relative to controls. Patient PANSS total score was positively associated with glutamate SMD in patients relative to controls in BG (z = 0.01,p = 0.01) and temporal lobe (z = 0.05,p = 0.008). Further research into the mechanisms underlying greater variability in glutamatergic metabolites in schizophrenia and their clinical consequences may inform the identification of patient subgroups for future treatment strategies. Word count: 300/300
Background Oxidative stress is considered to be a contributory factor for depression, and is affected by the dietary intake of pro-and anti-oxidants. Dietary total antioxidant capacity (DTAC) is an index which is applied to estimate the cumulative power of antioxidants in the whole diet. The aim of this study was to determine the relationship between DTAC and prevalence of depression in adolescent girls. Methods A total of 741 Iranian adolescent girls aged 12–18 years were recruited into this cross-sectional study. Dietary intake and depression severity score were assessed using a food frequency questionnaire and Beck's depression inventory, respectively. To estimate the DTAC, the oxygen radical absorbance capacity method was used for selected foods. To explore the associations between DTAC and depression, logistic regression was applied using crude and adjusted models. Results Individuals in the greatest adherence to high DTAC had more intakes of whole grains, legumes, fruits, dried fruits, low fat dairy products, cruciferous vegetables, fiber, magnesium, vitamin C, folate, potassium, zinc, β-carotene, lutein, thiamin, riboflavin, niacin and vitamin B-6 and lower consumption of refined grains. Subjects in the highest quartile of DTAC had a 39% lower odds of depression compared to those in the first quartile (OR = 0.61; 95% CI: 0.38–0.97, P for trend = 0.012); these associations remained significant after adjustments in first, second and third (OR = 0.5; 95% CI: 0.28–0.92, P for trend < 0.001) adjusted models. Conclusions An inverse association was observed between the DTAC and the prevalence of depression in our population sample of adolescent girls. Further research needs to be conducted in different areas, including longitudinal studies with larger sample sizes.
Medical humanities have long been promoted as a means for trainees and doctors to gain deeper understanding of patients, illness and professionalism. In practice, teaching on medical humanities – while valuable –struggles to connect such learning to the realities of the clinical workplace and patient encounters. The solution to this shortcoming lies in recognising ‘soft’, but clinically relevant, concepts that operate within consultations. These concepts are, in fact, best revealed through literary and historic accounts of doctors, patients and illness. Such a vignette is Dickens’ parody of Victorian physicians in the shape of the doctor who visits Little Nell in his book the Old Curiosity Shop. By taking prescription and technology out of the encounter, Dicken’s parody lays bare ‘soft’ elements that constitute the art of ‘enacting the persona of the doctor’. Medical humanities in general (and literature in particular) constitute a valuable tool for teaching the place of performance and the power of human qualities in the consultation. This ‘old fashioned’ professionalism should be a foundation to every formation in clinical medicine.
Background Dengue is a neglected tropical disease, for which no therapeutic agents have shown clinical efficacy to date. Clinical trials have used strikingly variable clinical endpoints, which hampers reproducibility and comparability of findings. We investigated a delta modified Sequential Organ Failure Assessment (delta mSOFA) score as a uniform composite clinical endpoint for use in clinical trials investigating therapeutics for moderate and severe dengue. Methods We developed a modified SOFA score for dengue, measured and evaluated its performance at baseline and 48 h after enrolment in a prospective observational cohort of 124 adults admitted to a tertiary referral hospital in Vietnam with dengue shock. The modified SOFA score included pulse pressure in the cardiovascular component. Binary logistic regression, cox proportional hazard and linear regression models were used to estimate association between mSOFA, delta mSOFA and clinical outcomes. Results The analysis included 124 adults with dengue shock. 29 (23.4%) patients required ICU admission for organ support or due to persistent haemodynamic instability: 9/124 (7.3%) required mechanical ventilation, 8/124 (6.5%) required vasopressors, 6/124 (4.8%) required haemofiltration and 5/124 (4.0%) patients died. In univariate analyses, higher baseline and delta (48 h) mSOFA score for dengue were associated with admission to ICU, requirement for organ support and mortality, duration of ICU and hospital admission and IV fluid use. Conclusions The baseline and delta mSOFA scores for dengue performed well to discriminate patients with dengue shock by clinical outcomes, including duration of ICU and hospital admission, requirement for organ support and death. We plan to use delta mSOFA as the primary endpoint in an upcoming host-directed therapeutic trial and investigate the performance of this score in other phenotypes of severe dengue in adults and children.
LINKED CONTENT This article is linked to Tergast et al papers. To view these articles, visit https://doi.org/10.1111/apt.17066 and https://doi.org/10.1111/apt.17168
The QT interval is an electrocardiographic measure representing the sum of ventricular depolarization and repolarization, estimated by QRS duration and JT interval, respectively. QT interval abnormalities are associated with potentially fatal ventricular arrhythmia. Using genome-wide multi-ancestry analyses (>250,000 individuals) we identify 177, 156 and 121 independent loci for QT, JT and QRS, respectively, including a male-specific X-chromosome locus. Using gene-based rare-variant methods, we identify associations with Mendelian disease genes. Enrichments are observed in established pathways for QT and JT, and previously unreported genes indicated in insulin-receptor signalling and cardiac energy metabolism. In contrast for QRS, connective tissue components and processes for cell growth and extracellular matrix interactions are significantly enriched. We demonstrate polygenic risk score associations with atrial fibrillation, conduction disease and sudden cardiac death. Prioritization of druggable genes highlight potential therapeutic targets for arrhythmia. Together, these results substantially advance our understanding of the genetic architecture of ventricular depolarization and repolarization.
Introduction The hippocampus is an important, complex limbic structure anatomically embedded in the medial temporal lobe of each cerebral cortex, which has been implicated in the pathogenesis of neuro-inflammatory disease conditions. Few studies have focused on the characterization of the MRI neuroimaging signatures of highly physio- pathologically relevant subfields of the hippocampus (CA1, CA4-DG, CA2/CA3, SLRM). Objectives Using self-guided manually segmented, Diffusion weighted and NODDI maps created from data obtained from the Human Connectome Project (HCP) we intend to test whether Diffusion MRI-based quantitative imaging parameters (MD, FA, ODI, ISOVF, ICVF), indicative of microstructural characteristics of major hippocampal subfields (CA1, CA2/CA3, CA4-DG and SLRM), correspond to predictions for animal literature and imaging-histology correlations. We will also explore the correlations between these parameters and age. Methods We used images from the Public connectome data (updated April 2018), exploring subjects with the 3T MRI sessions obtainable from the WU-Minn HCP Data section. For the purpose of this study, we selected and downloaded 10 preliminary imaging data (6 females and 4 males) based on age variability in the following ranges (26-30, 31-35 and 36+). We manually segmented, and computed quantitative parameters. Results Converging and consistent literature allude to decreasing volumes with increasing age. Analyzing the volumes from the diffusion maps (pilot data), this was also the case, with volumes computed from CA1 and DG-CA4 sub regions. IQT also allowed for better appreciation of neuroanatomical boundaries and land marks, hence allowing more regions to be easily manually segmented (addition of CA2/CA3). Conclusions Application to Neuroinflammatory imaging data. Disclosure No significant relationships.
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716 members
Anjum Memon
  • Department of Primary Care and Public Health Medicine
Florian Kern
  • Department of Medicine
Dorina Cadar
  • Division of Clinical Neuroscience
James M Stone
  • Department of Medicine
Richard Oliver de Visser
  • Primary Care & Public Health
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Brighton, United Kingdom
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https://www.bsms.ac.uk/index.aspx