Medical education through an invasion: insights from an elective programme for Ukrainian medical students at the University of Cambridge.

Medical students in Ukraine have faced extraordinary disruption to their clinical studies with both the COVID-19 pandemic and subsequent Russian military invasion forcing a majority of their learning to be conducted remotely. Over the summer of 2022, the School of Clinical Medicine, University of Cambridge hosted 20 medical students from Kharkiv National Medical University for a seven-week intensive clinical elective programme. The aim was to provide an immersive clinical placement that would help students to attain the necessary knowledge and experience to become competent and confident practising doctors. This perspective piece aims to support the development of future equivalent exchanges through outlining the placement's context, its planning and implementation, evidence of placement impact, and finally reflections and learning points.

The implications of defining obesity as a disease: a report from the Association for the Study of Obesity 2021 annual conference.

Unlike various countries and organisations, including the World Health Organisation and the European Parliament, the United Kingdom does not formally recognise obesity as a disease. This report presents the discussion on the potential impact of defining obesity as a disease on the patient, the healthcare system, the economy, and the wider society. A group of speakers from a wide range of disciplines came together to debate the topic bringing their knowledge and expertise from backgrounds in medicine, psychology, economics, and politics as well as the experience of people living with obesity. The aim of their debate was not to decide whether obesity should be classified as a disease but rather to explore what the implications of doing so would be, what the gaps in the available data are, as well as to provide up-to-date information on the topic from experts in the field. There were four topics where speakers presented their viewpoints, each one including a question-and-answer section for debate. The first one focused on the impact that the recognition of obesity could have on people living with obesity regarding the change in their behaviour, either positive and empowering or more stigmatising. During the second one, the impact of defining obesity as a disease on the National Health Service and the wider economy was discussed. The primary outcome was the need for more robust data as the one available does not represent the actual cost of obesity. The third topic was related to the policy implications regarding treatment provision, focusing on the public's power to influence policy. Finally, the last issue discussed, included the implications of public health actions, highlighting the importance of the government's actions and private stakeholders. The speakers agreed that no matter where they stand on this debate, the goal is common: to provide a healthcare system that supports and protects the patients, strategies that protect the economy and broader society, and policies that reduce stigma and promote health equity. Many questions are left to be answered regarding how these goals can be achieved. However, this discussion has set a good foundation providing evidence that can be used by the public, clinicians, and policymakers to make that happen.

Sex-specific lesion pattern of functional outcomes after stroke.

Stroke represents a considerable burden of disease for both men and women. However, a growing body of literature suggests clinically relevant sex differences in the underlying causes, presentations and outcomes of acute ischaemic stroke. In a recent study, we reported sex divergences in lesion topographies: specific to women, acute stroke severity was linked to lesions in the left-hemispheric posterior circulation. We here determined whether these sex-specific brain manifestations also affect long-term outcomes. We relied on 822 acute ischaemic patients [age: 64.7 (15.0) years, 39% women] originating from the multi-centre MRI-GENIE study to model unfavourable outcomes (modified Rankin Scale >2) based on acute neuroimaging data in a Bayesian hierarchical framework. Lesions encompassing bilateral subcortical nuclei and left-lateralized regions in proximity to the insula explained outcomes across men and women (area under the curve = 0.81). A pattern of left-hemispheric posterior circulation brain regions, combining left hippocampus, precuneus, fusiform and lingual gyrus, occipital pole and latero-occipital cortex, showed a substantially higher relevance in explaining functional outcomes in women compared to men [mean difference of Bayesian posterior distributions (men - women) = -0.295 (90% highest posterior density interval = -0.556 to -0.068)]. Once validated in prospective studies, our findings may motivate a sex-specific approach to clinical stroke management and hold the promise of enhancing outcomes on a population level.

Outcome after acute ischemic stroke is linked to sex-specific lesion patterns.

Acute ischemic stroke affects men and women differently. In particular, women are often reported to experience higher acute stroke severity than men. We derived a low-dimensional representation of anatomical stroke lesions and designed a Bayesian hierarchical modeling framework tailored to estimate possible sex differences in lesion patterns linked to acute stroke severity (National Institute of Health Stroke Scale). This framework was developed in 555 patients (38% female). Findings were validated in an independent cohort (n = 503, 41% female). Here, we show brain lesions in regions subserving motor and language functions help explain stroke severity in both men and women, however more widespread lesion patterns are relevant in female patients. Higher stroke severity in women, but not men, is associated with left hemisphere lesions in the vicinity of the posterior circulation. Our results suggest there are sex-specific functional cerebral asymmetries that may be important for future investigations of sex-stratified approaches to management of acute ischemic stroke.

High-resolution three-dimensional chromatin profiling of the Chinese hamster ovary cell genome.

Chinese hamster ovary (CHO) cell lines are the pillars of a multibillion-dollar biopharmaceutical industry producing recombinant therapeutic proteins. The effects of local chromatin organization and epigenetic repression within these cell lines result in unpredictable and unstable transgene expression following random integration. Limited knowledge of the CHO genome and its higher order chromatin organization has thus far impeded functional genomics approaches required to tackle these issues. Here, we present an integrative three-dimensional (3D) map of genome organization within the CHOK1SV® 10E9 cell line in conjunction with an improved, less fragmented CHOK1SV 10E9 genome assembly. Using our high-resolution chromatin conformation datasets, we have assigned ≈90% of sequence to a chromosome-scale genome assembly. Our genome-wide 3D map identifies higher order chromatin structures such as topologically associated domains, incorporates our chromatin accessibility data to enhance the identification of active cis-regulatory elements, and importantly links these cis-regulatory elements to target promoters in a 3D promoter interactome. We demonstrate the power of our improved functional annotation by evaluating the 3D landscape of a transgene integration site and two phenotypically different cell lines. Our work opens up further novel genome engineering targets, has the potential to inform vital improvements for industrial biotherapeutic production, and represents a significant advancement for CHO cell line development.

Cohesin-Dependent and -Independent Mechanisms Mediate Chromosomal Contacts between Promoters and Enhancers.

It is currently assumed that 3D chromosomal organization plays a central role in transcriptional control. However, depletion of cohesin and CTCF affects the steady-state levels of only a minority of transcripts. Here, we use high-resolution Capture Hi-C to interrogate the dynamics of chromosomal contacts of all annotated human gene promoters upon degradation of cohesin and CTCF. We show that a majority of promoter-anchored contacts are lost in these conditions, but many contacts with distinct properties are maintained, and some new ones are gained. The rewiring of contacts between promoters and active enhancers upon cohesin degradation associates with rapid changes in target gene transcription as detected by SLAM sequencing (SLAM-seq). These results provide a mechanistic explanation for the limited, but consistent, effects of cohesin and CTCF depletion on steady-state transcription and suggest the existence of both cohesin-dependent and -independent mechanisms of enhancer-promoter pairing.

Brain Volume: An Important Determinant of Functional Outcome After Acute Ischemic Stroke.

OBJECTIVE: To determine whether brain volume is associated with functional outcome after acute ischemic stroke (AIS). PATIENTS AND METHODS: This study was conducted between July 1, 2014, and March 16, 2019. We analyzed cross-sectional data of the multisite, international hospital-based MRI-Genetics Interface Exploration study with clinical brain magnetic resonance imaging obtained on admission for index stroke and functional outcome assessment. Poststroke outcome was determined using the modified Rankin Scale score (0-6; 0 = asymptomatic; 6 = death) recorded between 60 and 190 days after stroke. Demographic characteristics and other clinical variables including acute stroke severity (measured as National Institutes of Health Stroke Scale score), vascular risk factors, and etiologic stroke subtypes (Causative Classification of Stroke system) were recorded during index admission. RESULTS: Utilizing the data from 912 patients with AIS (mean ± SD age, 65.3±14.5 years; male, 532 [58.3%]; history of smoking, 519 [56.9%]; hypertension, 595 [65.2%]) in a generalized linear model, brain volume (per 155.1 cm3) was associated with age (ß -0.3 [per 14.4 years]), male sex (ß 1.0), and prior stroke (ß -0.2). In the multivariable outcome model, brain volume was an independent predictor of modified Rankin Scale score (ß -0.233), with reduced odds of worse long-term functional outcomes (odds ratio, 0.8; 95% CI, 0.7-0.9) in those with larger brain volumes. CONCLUSION: Larger brain volume quantified on clinical magnetic resonance imaging of patients with AIS at the time of stroke purports a protective mechanism. The role of brain volume as a prognostic, protective biomarker has the potential to forge new areas of research and advance current knowledge of the mechanisms of poststroke recovery.

Big Data Approaches to Phenotyping Acute Ischemic Stroke Using Automated Lesion Segmentation of Multi-Center Magnetic Resonance Imaging Data.

Background and Purpose- We evaluated deep learning algorithms' segmentation of acute ischemic lesions on heterogeneous multi-center clinical diffusion-weighted magnetic resonance imaging (MRI) data sets and explored the potential role of this tool for phenotyping acute ischemic stroke. Methods- Ischemic stroke data sets from the MRI-GENIE (MRI-Genetics Interface Exploration) repository consisting of 12 international genetic research centers were retrospectively analyzed using an automated deep learning segmentation algorithm consisting of an ensemble of 3-dimensional convolutional neural networks. Three ensembles were trained using data from the following: (1) 267 patients from an independent single-center cohort, (2) 267 patients from MRI-GENIE, and (3) mixture of (1) and (2). The algorithms' performances were compared against manual outlines from a separate 383 patient subset from MRI-GENIE. Univariable and multivariable logistic regression with respect to demographics, stroke subtypes, and vascular risk factors were performed to identify phenotypes associated with large acute diffusion-weighted MRI volumes and greater stroke severity in 2770 MRI-GENIE patients. Stroke topography was investigated. Results- The ensemble consisting of a mixture of MRI-GENIE and single-center convolutional neural networks performed best. Subset analysis comparing automated and manual lesion volumes in 383 patients found excellent correlation (ρ=0.92; P<0.0001). Median (interquartile range) diffusion-weighted MRI lesion volumes from 2770 patients were 3.7 cm3 (0.9-16.6 cm3). Patients with small artery occlusion stroke subtype had smaller lesion volumes ( P<0.0001) and different topography compared with other stroke subtypes. Conclusions- Automated accurate clinical diffusion-weighted MRI lesion segmentation using deep learning algorithms trained with multi-center and diverse data is feasible. Both lesion volume and topography can provide insight into stroke subtypes with sufficient sample size from big heterogeneous multi-center clinical imaging phenotype data sets.

Economic impact of musculoskeletal disorders (MSDs) on work in Europe.

Musculoskeletal disorders (MSDs) are the leading cause of work disability, sickness absence from work, 'presenteeism' and loss of productivity across all the European Union (EU) member states. It is estimated that the total cost of lost productivity attributable to MSDs among people of working age in the EU could be as high as 2% of gross domestic product (GDP). This paper examines the available evidence on the economic burden of MSDs on work across Europe and highlights areas of policy, clinical and employment practice which might improve work outcomes for individuals and families and reduce the economic and social costs of MSDs.

Genetic Factors Influencing Coagulation Factor XIII B-Subunit Contribute to Risk of Ischemic Stroke.

BACKGROUND AND PURPOSE: Abnormal coagulation has been implicated in the pathogenesis of ischemic stroke, but how this association is mediated and whether it differs between ischemic stroke subtypes is unknown. We determined the shared genetic risk between 14 coagulation factors and ischemic stroke and its subtypes. METHODS: Using genome-wide association study results for 14 coagulation factors from the population-based TwinsUK sample (N≈2000 for each factor), meta-analysis results from the METASTROKE consortium ischemic stroke genome-wide association study (12 389 cases, 62 004 controls), and genotype data for 9520 individuals from the WTCCC2 ischemic stroke study (3548 cases, 5972 controls-the largest METASTROKE subsample), we explored shared genetic risk for coagulation and stroke. We performed three analyses: (1) a test for excess concordance (or discordance) in single nucleotide polymorphism effect direction across coagulation and stroke, (2) an estimation of the joint effect of multiple coagulation-associated single nucleotide polymorphisms in stroke, and (3) an evaluation of common genetic risk between coagulation and stroke. RESULTS: One coagulation factor, factor XIII subunit B (FXIIIB), showed consistent effects in the concordance analysis, the estimation of polygenic risk, and the validation with genotype data, with associations specific to the cardioembolic stroke subtype. Effect directions for FXIIIB-associated single nucleotide polymorphisms were significantly discordant with cardioembolic disease (smallest P=5.7×10(-04)); the joint effect of FXIIIB-associated single nucleotide polymorphisms was significantly predictive of ischemic stroke (smallest P=1.8×10(-04)) and the cardioembolic subtype (smallest P=1.7×10(-04)). We found substantial negative genetic covariation between FXIIIB and ischemic stroke (rG=-0.71, P=0.01) and the cardioembolic subtype (rG=-0.80, P=0.03). CONCLUSIONS: Genetic markers associated with low FXIIIB levels increase risk of ischemic stroke cardioembolic subtype.

Polygenic overlap between kidney function and large artery atherosclerotic stroke.

BACKGROUND AND PURPOSE: Epidemiological studies show strong associations between kidney dysfunction and risk of ischemic stroke (IS), the mechanisms of which are incompletely understood. We investigated whether these associations may reflect shared heritability because of a common polygenic basis and whether this differed for IS subtypes. METHODS: Polygenic models were derived using genome-wide association studies meta-analysis results for 3 kidney traits: estimated glomerular filtration rate using serum creatinine (eGFRcrea: n=73 998), eGFR using cystatin C (eGFRcys: n=22 937), and urinary albumin to creatinine ratio (n=31 580). For each, single nucleotide polymorphisms passing 10 P value thresholds were used to form profile scores in 4561 IS cases and 7094 controls from the United Kingdom, Germany, and Australia. Scores were tested for association with IS and its 3 aetiological subtypes: large artery atherosclerosis, cardioembolism, and small vessel disease. RESULTS: Polygenic scores correlating with higher eGFRcrea were associated with reduced risk of large artery atherosclerosis, with 5 scores reaching P<0.05 (peak P=0.004) and all showing the epidemiologically expected direction of effect. A similar pattern was observed for polygenic scores reflecting higher urinary albumin to creatinine ratio, of which 3 associated with large artery atherosclerosis (peak P=0.01) and all showed the expected directional association. One urinary albumin to creatinine ratio-based score also associated with small vessel disease (P=0.03). The global pattern of results was unlikely to have occurred by chance (P=0.02). CONCLUSIONS: This study suggests possible polygenic correlation between renal dysfunction and IS. The shared genetic components may be specific to stroke subtypes, particularly large artery atherosclerotic stroke. Further study of the genetic relationships between these disorders seems merited.

Employee performance in the knowledge economy: Capturing the keys to success.

The present study examines the key determinants of employee performance in a knowledge-intensive service firm located in the UK. Using data from a pilot study, we mapped eight performance-related behaviors to two measures of global performance to isolate the strongest predictors of the latter. We also examined the degree to which these associations varied depending on whether employees or their managers reported on performance as well as according to the degree of complexity (eg, ongoing learning, multitasking, problem solving, etc.) present in workers' jobs. Findings revealed that more traditional employee performance-related behaviors (eg, dependability) as well as behaviors that have likely increased in importance in the knowledge economy (eg, sharing ideas and information) accounted for the most variance in reported global performance. Sharing ideas and information was a particularly important predictor for workers in complex jobs. When the performance-related behaviors were regressed on the organization's annual employee appraisal ratings, only dependability and time management behaviors were significantly associated with the outcome. As organizational success increasingly is dependent on intangible inputs stemming from the ideas, innovations and creativity of its workforce, organizations need to ensure that they are capturing the full range of behaviors that help to define their success. Further research with a diverse range of organizations will help define this further.

Mutations in the candidate tumour suppressor gene FLJ12973 on chromosome 15q15 are rare in colorectal cancer.

Allele imbalance at chromosome 15q14-q22 is seen in a high proportion of sporadic colorectal cancers encompassing the colorectal adenoma and carcinoma susceptibility locus. The FLJ12973 gene, which has recently been identified as a candidate tumour suppressor, maps to 15q15 and encodes a WD-repeat protein with structural similarity to the small subunit of the xeroderma pigmentosum E (XP-E) complex. To examine the proposition that FLJ12973 is involved in colorectal cancer we analysed 31 tumours for sequence variation. No missense changes or pathogenic mutations--truncating or splice site--were detected in any of the tumours. While epigenetic effects on FLJ12973 cannot be excluded, these results show that it is not a common target for mutations in colorectal cancers.

EXO1 variants occur commonly in normal population: evidence against a role in hereditary nonpolyposis colorectal cancer.

Mutations in the currently known mismatch repair genes cannot explain all cases of hereditary nonpolyposis colorectal cancer (HNPCC), and novel predisposing genes are actively sought. Recently, mutations in the DNA repair gene EXO1 have been implicated in HNPCC. One truncating and several missense changes were observed in familial colorectal cancer (CRC) cases but not in controls. We evaluated a series of European CRC patients and population controls to clarify whether EXO1 variants may indeed predispose to familial CRC. Several variants observed in patients were also observed in controls with similar frequencies, including the truncating variant proposed previously to be a disease-causing mutation. Thus, little evidence was obtained to support a major causative role of EXO1 in HNPCC, although we cannot exclude a role for EXO1 as a low penetrance cancer susceptibility or modifying gene.

Germline mutations in FH predispose to dominantly inherited uterine fibroids, skin leiomyomata and papillary renal cell cancer.

Uterine leiomyomata (fibroids) are common and clinically important tumors, but little is known about their etiology and pathogenesis. We previously mapped a gene that predisposes to multiple fibroids, cutaneous leiomyomata and renal cell carcinoma to chromosome 1q42.3-q43 (refs 4-6). Here we show, through a combination of mapping critical recombinants, identifying individuals with germline mutations and screening known and predicted transcripts, that this gene encodes fumarate hydratase, an enzyme of the tricarboxylic acid cycle. Leiomyomatosis-associated mutations are predicted to result in absent or truncated protein, or substitutions or deletions of highly conserved amino acids. Activity of fumarate hydratase is reduced in lymphoblastoid cells from individuals with leiomyomatosis. This enzyme acts as a tumor suppressor in familial leiomyomata, and its measured activity is very low or absent in tumors from individuals with leiomyomatosis. Mutations in FH also occur in the recessive condition fumarate hydratase deficiency, and some parents of people with this condition are susceptible to leiomyomata. Thus, heterozygous and homozygous or compound heterozygous mutants have very different clinical phenotypes. Our results provide clues to the pathogenesis of fibroids and emphasize the importance of mutations of housekeeping and mitochondrial proteins in the pathogenesis of common types of tumor.

Analysis of the Fanconi anaemia complementation group A gene in acute myeloid leukaemia.

Acute myeloid leukaemia (AML) is the most common acute leukaemia in adults. Around 10-15% of individuals with recessively inherited Fanconi anaemia (FA) develop AML. FA is one of a group of recessive syndromes characterized by excessive spontaneous chromosomal breakage in which heterozygote carriers appear to display an increased risk of cancer and there is some indirect evidence that FA carriers may also be at increased risk of AML. This suggests that FA genes may play a role in the development of AML in the wider context. To examine this proposition, further, we have screened samples from 79 AML patients for mutations in the major FA gene, FANCA. No truncating FANCA mutations were detected. One missense mutation previously designated as pathogenic and five novel missense mutations causing non-conservative amino acid substitutions were detected. The data suggests that while FANCA mutations are rare, FANCA mutations may contribute to the development of the disease in a subset of AML.