Wishaw General Hospital

Abstract The genetic make-up of an individual contributes to the susceptibility and response to viral infection. Although environmental, clinical and social factors have a role in the chance of exposure to SARS-CoV-2 and the severity of COVID-19 1,2 , host genetics may also be important. Identifying host-specific genetic factors may reveal biological mechanisms of therapeutic relevance and clarify causal relationships of modifiable environmental risk factors for SARS-CoV-2 infection and outcomes. We formed a global network of researchers to investigate the role of human genetics in SARS-CoV-2 infection and COVID-19 severity. Here we describe the results of three genome-wide association meta-analyses that consist of up to 49,562 patients with COVID-19 from 46 studies across 19 countries. We report 13 genome-wide significant loci that are associated with SARS-CoV-2 infection or severe manifestations of COVID-19. Several of these loci correspond to previously documented associations to lung or autoimmune and inflammatory diseases 3–7 . They also represent potentially actionable mechanisms in response to infection. Mendelian randomization analyses support a causal role for smoking and body-mass index for severe COVID-19 although not for type II diabetes. The identification of novel host genetic factors associated with COVID-19 was made possible by the community of human genetics researchers coming together to prioritize the sharing of data, results, resources and analytical frameworks. This working model of international collaboration underscores what is possible for future genetic discoveries in emerging pandemics, or indeed for any complex human disease.

BACKGROUND: Comprehensive geriatric assessment (CGA) is a multidimensional, interdisciplinary diagnostic process to determine the medical, psychological and functional capabilities of a frail elderly person in order to develop a co-ordinated and integrated plan for treatment and long-term follow up. OBJECTIVES: We sought to evaluate the effectiveness of CGA in hospital for older adults admitted as an emergency. SEARCH STRATEGY: We searched the Cochrane Effective Practice and Organisation of Care (EPOC) Group Register, the Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library), the Database of Abstracts of Reviews of Effects (DARE), MEDLINE, EMBASE, CINAHL and AARP Ageline, and handsearched high-yield journals. SELECTION CRITERIA: We searched for randomised controlled trials comparing CGA (whether by mobile teams or in designated wards) to usual care. DATA COLLECTION AND ANALYSIS: Two review authors initially assessed eligibility and trial quality and extracted published data. MAIN RESULTS: Twenty-two trials evaluating 10,315 participants in six countries were identified. Patients in receipt of CGA were more likely to be alive and in their own homes at up to six months (OR 1.25, 95% CI 1.11 to 1.42, P = 0.0002) and at the end of scheduled follow up (median 12 months) (OR 1.16, 95% CI 1.05 to 1.28, P = 0.003) when compared to general medical care. In addition, patients were less likely to be institutionalised (OR 0.79, 95% CI 0.69 to 0.88, P < 0.0001). They were less likely to suffer death or deterioration (OR 0.76, 95% CI 0.64 to 0.90, P = 0.001), and were more likely to experience improved cognition in the CGA group (OR 1.11, 95% CI 0.20 to 2.01, P = 0.02). Subgroup interaction in the primary outcomes suggests that the effects of CGA are primarily the result of CGA wards. AUTHORS' CONCLUSIONS: Comprehensive geriatric assessment increases a patient's likelihood of being alive and in their own home at up to 12 months.

OBJECTIVE: To evaluate the effectiveness of comprehensive geriatric assessment in hospital for older adults admitted as an emergency. SEARCH STRATEGY: We searched the EPOC Register, Cochrane's Controlled Trials Register, the Database of Abstracts of Reviews of Effects (DARE), Medline, Embase, CINAHL, AARP Ageline, and handsearched high yield journals. SELECTION CRITERIA: Randomised controlled trials of comprehensive geriatric assessment (whether by mobile teams or in designated wards) compared with usual care. Comprehensive geriatric assessment is a multidimensional interdisciplinary diagnostic process used to determine the medical, psychological, and functional capabilities of a frail elderly person to develop a coordinated and integrated plan for treatment and long term follow-up. DATA COLLECTION AND ANALYSIS: Three independent reviewers assessed eligibility and trial quality and extracted published data. Two additional reviewers moderated. RESULTS: Twenty two trials evaluating 10,315 participants in six countries were identified. For the primary outcome "living at home," patients who underwent comprehensive geriatric assessment were more likely to be alive and in their own homes at the end of scheduled follow-up (odds ratio 1.16 (95% confidence interval 1.05 to 1.28; P = 0.003; number needed to treat 33) at a median follow-up of 12 months versus 1.25 (1.11 to 1.42; P < 0.001; number needed to treat 17) at a median follow-up of six months) compared with patients who received general medical care. In addition, patients were less likely to be living in residential care (0.78, 0.69 to 0.88; P < 0.001). Subgroup interaction suggested differences between the subgroups "wards" and "teams" in favour of wards. Patients were also less likely to die or experience deterioration (0.76, 0.64 to 0.90; P = 0.001) and were more likely to experience improved cognition (standardised mean difference 0.08, 0.01 to 0.15; P = 0.02) in the comprehensive geriatric assessment group. CONCLUSIONS: Comprehensive geriatric assessment increases patients' likelihood of being alive and in their own homes after an emergency admission to hospital. This seems to be especially true for trials of wards designated for comprehensive geriatric assessment and is associated with a potential cost reduction compared with general medical care.

OBJECTIVE: To determine whether aspirin and antioxidant therapy, combined or alone, are more effective than placebo in reducing the development of cardiovascular events in patients with diabetes mellitus and asymptomatic peripheral arterial disease. DESIGN: Multicentre, randomised, double blind, 2x2 factorial, placebo controlled trial. SETTING: 16 hospital centres in Scotland, supported by 188 primary care groups. PARTICIPANTS: 1276 adults aged 40 or more with type 1 or type 2 diabetes and an ankle brachial pressure index of 0.99 or less but no symptomatic cardiovascular disease. INTERVENTIONS: Daily, 100 mg aspirin tablet plus antioxidant capsule (n=320), aspirin tablet plus placebo capsule (n=318), placebo tablet plus antioxidant capsule (n=320), or placebo tablet plus placebo capsule (n=318). MAIN OUTCOME MEASURES: Two hierarchical composite primary end points of death from coronary heart disease or stroke, non-fatal myocardial infarction or stroke, or amputation above the ankle for critical limb ischaemia; and death from coronary heart disease or stroke. RESULTS: No evidence was found of any interaction between aspirin and antioxidant. Overall, 116 of 638 primary events occurred in the aspirin groups compared with 117 of 638 in the no aspirin groups (18.2% v 18.3%): hazard ratio 0.98 (95% confidence interval 0.76 to 1.26). Forty three deaths from coronary heart disease or stroke occurred in the aspirin groups compared with 35 in the no aspirin groups (6.7% v 5.5%): 1.23 (0.79 to 1.93). Among the antioxidant groups 117 of 640 (18.3%) primary events occurred compared with 116 of 636 (18.2%) in the no antioxidant groups (1.03, 0.79 to 1.33). Forty two (6.6%) deaths from coronary heart disease or stroke occurred in the antioxidant groups compared with 36 (5.7%) in the no antioxidant groups (1.21, 0.78 to 1.89). CONCLUSION: This trial does not provide evidence to support the use of aspirin or antioxidants in primary prevention of cardiovascular events and mortality in the population with diabetes studied. TRIAL REGISTRATION: Current Controlled Trials ISRCTN53295293.

BACKGROUND: Carotid artery stenting (CAS) has recently emerged as a potential alternative to carotid endarterectomy. Cerebral embolization is the most devastating complication of CAS, and the echogenicity of carotid plaque has been indicated as one of the risk factors involved. This is the first study to analyze the role of a computer-assisted highly reproducible index of echogenicity, namely the gray-scale median (GSM), on the risk of stroke during CAS. METHODS AND RESULTS: The Imaging in Carotid Angioplasty and Risk of Stroke (ICAROS) registry included 418 cases of CAS collected from 11 international centers. An echographic evaluation of carotid plaque with GSM measurement was made preprocedurally. The onset of neurological deficits during the procedure and the postprocedural period was recorded. The overall rate of neurological complications was 3.6%: minor strokes, 2.2%, and major stroke, 1.4%. There were 11 of 155 strokes (7.1%) in patients with GSM < or =25 and 4 of 263 (1.5%) in patients with GSM >25 (P=0.005). Patients with severe stenosis (> or =85%) had a higher rate of stroke (P=0.03). The effectiveness of brain protection devices was confirmed in those with GSM >25 (P=0.01) but not in those with GSM < or =25. Multivariate analysis revealed that GSM (OR, 7.11; P=0.002) and rate of stenosis (OR, 5.76; P=0.010) are independent predictors of stroke. CONCLUSIONS: Carotid plaque echolucency, as measured by GSM < or =25, increases the risk of stroke in CAS. The inclusion of echolucency measured as GSM in the planning of any endovascular procedure of carotid lesions allows stratification of patients at different risks of complications in CAS.

Epilepsy is common in early childhood. In this age group it is associated with high rates of therapy-resistance, and with cognitive, motor, and behavioural comorbidity. A large number of genes, with wide ranging functions, are implicated in its aetiology, especially in those with therapy-resistant seizures. Identifying the more common single-gene epilepsies will aid in targeting resources, the prioritization of diagnostic testing and development of precision therapy. Previous studies of genetic testing in epilepsy have not been prospective and population-based. Therefore, the population-incidence of common genetic epilepsies remains unknown. The objective of this study was to describe the incidence and phenotypic spectrum of the most common single-gene epilepsies in young children, and to calculate what proportion are amenable to precision therapy. This was a prospective national epidemiological cohort study. All children presenting with epilepsy before 36 months of age were eligible. Children presenting with recurrent prolonged (>10 min) febrile seizures; febrile or afebrile status epilepticus (>30 min); or with clusters of two or more febrile or afebrile seizures within a 24-h period were also eligible. Participants were recruited from all 20 regional paediatric departments and four tertiary children's hospitals in Scotland over a 3-year period. DNA samples were tested on a custom-designed 104-gene epilepsy panel. Detailed clinical information was systematically gathered at initial presentation and during follow-up. Clinical and genetic data were reviewed by a multidisciplinary team of clinicians and genetic scientists. The pathogenic significance of the genetic variants was assessed in accordance with the guidelines of UK Association of Clinical Genetic Science (ACGS). Of the 343 patients who met inclusion criteria, 333 completed genetic testing, and 80/333 (24%) had a diagnostic genetic finding. The overall estimated annual incidence of single-gene epilepsies in this well-defined population was 1 per 2120 live births (47.2/100 000; 95% confidence interval 36.9-57.5). PRRT2 was the most common single-gene epilepsy with an incidence of 1 per 9970 live births (10.0/100 000; 95% confidence interval 5.26-14.8) followed by SCN1A: 1 per 12 200 (8.26/100 000; 95% confidence interval 3.93-12.6); KCNQ2: 1 per 17 000 (5.89/100 000; 95% confidence interval 2.24-9.56) and SLC2A1: 1 per 24 300 (4.13/100 000; 95% confidence interval 1.07-7.19). Presentation before the age of 6 months, and presentation with afebrile focal seizures were significantly associated with genetic diagnosis. Single-gene disorders accounted for a quarter of the seizure disorders in this cohort. Genetic testing is recommended to identify children who may benefit from precision treatment and should be mainstream practice in early childhood onset epilepsy.

BACKGROUND AND PURPOSE: The modified Rankin Scale (mRS) is widely used to assess global outcome after stroke. The aim of the study was to examine rater variability in assessing functional outcomes using the conventional mRS, and to investigate whether use of a structured interview (mRS-SI) reduced this variability. METHODS: Inter-rater agreement was studied among raters from 3 stroke centers. Fifteen raters were recruited who were experienced in stroke care but came from a variety of professional backgrounds. Patients at least 6 months after stroke were first assessed using conventional mRS definitions. After completion of initial mRS assessments, raters underwent training in the use of a structured interview, and patients were re-assessed. In a separate component of the study, intrarater variability was studied using 2 raters who performed repeat assessments using the mRS and the mRS-SI. The design of the latter part of the study also allowed investigation of possible improvement in rater agreement caused by repetition of the assessments. Agreement was measured using the kappa statistic (unweighted and weighted using quadratic weights). RESULTS: Inter-rater reliability: Pairs of raters assessed a total of 113 patients on the mRS and mRS-SI. For the mRS, overall agreement between raters was 43% (kappa=0.25, kappa(w)=0.71), and for the structured interview overall agreement was 81% (kappa=0.74, kappa(w)=0.91). Agreement between raters was significantly greater on the mRS-SI than the mRS (P<0.001). Intrarater reliability: Repeatability of both the mRS and mRS-SI was excellent (kappa=0.81, kappa(w) > or =0.94). CONCLUSIONS: Although individual raters are consistent in their use of the mRS, inter-rater variability is nonetheless substantial. Rater variability on the mRS is thus particularly problematic for studies involving multiple raters. There was no evidence that improvement in inter-rater agreement occurred simply with repetition of the assessment. Use of a structured interview improves agreement between raters in the assessment of global outcome after stroke.

after infection with SARS-CoV-2. The GenOMICC (Genetics of Mortality in Critical Care) study enables the comparison of genomes from individuals who are critically ill with those of population controls to find underlying disease mechanisms. Here we use whole-genome sequencing in 7,491 critically ill individuals compared with 48,400 controls to discover and replicate 23 independent variants that significantly predispose to critical COVID-19. We identify 16 new independent associations, including variants within genes that are involved in interferon signalling (IL10RB and PLSCR1), leucocyte differentiation (BCL11A) and blood-type antigen secretor status (FUT2). Using transcriptome-wide association and colocalization to infer the effect of gene expression on disease severity, we find evidence that implicates multiple genes-including reduced expression of a membrane flippase (ATP11A), and increased expression of a mucin (MUC1)-in critical disease. Mendelian randomization provides evidence in support of causal roles for myeloid cell adhesion molecules (SELE, ICAM5 and CD209) and the coagulation factor F8, all of which are potentially druggable targets. Our results are broadly consistent with a multi-component model of COVID-19 pathophysiology, in which at least two distinct mechanisms can predispose to life-threatening disease: failure to control viral replication; or an enhanced tendency towards pulmonary inflammation and intravascular coagulation. We show that comparison between cases of critical illness and population controls is highly efficient for the detection of therapeutically relevant mechanisms of disease.

OBJECTIVE: To determine neonatal outcomes (perinatal mortality and special care unit admission) and maternal outcomes (mode of delivery, delivery complications) of elective induction of labour compared with expectant management. DESIGN: Retrospective cohort study using an unselected population database. SETTING: Consultant and midwife led obstetric units in Scotland 1981-2007. PARTICIPANTS: 1,271,549 women with singleton pregnancies of 37 weeks or more gestation. INTERVENTIONS: Outcomes of elective induction of labour (induction of labour with no recognised medical indication) at 37, 38, 39, 40, and 41 weeks' gestation compared with those of expectant management (continuation of pregnancy to either spontaneous labour, induction of labour or caesarean section at a later gestation). MAIN OUTCOME MEASURES: Extended perinatal mortality, mode of delivery, postpartum haemorrhage, obstetric anal sphincter injury, and admission to a neonatal or special care baby unit. Outcomes were adjusted for age at delivery, parity, year of birth, birth weight, deprivation category, and, where appropriate, mode of delivery. RESULTS: At each gestation between 37 and 41 completed weeks, elective induction of labour was associated with a decreased odds of perinatal mortality compared with expectant management (at 40 weeks' gestation 0.08% (37/44,764) in the induction of labour group versus 0.18% (627/350,643) in the expectant management group; adjusted odds ratio 0.39, 99% confidence interval 0.24 to 0.63), without a reduction in the odds of spontaneous vertex delivery (at 40 weeks' gestation 79.9% (35,775/44,778) in the induction of labour group versus 73.7% (258,665/350,791) in the expectant management group; adjusted odds ratio 1.26, 1.22 to 1.31). Admission to a neonatal unit was, however, increased in association with elective induction of labour at all gestations before 41 weeks (at 40 weeks' gestation 8.0% (3605/44,778) in the induction of labour group compared with 7.3% (25,572/350,791) in the expectant management group; adjusted odds ratio 1.14, 1.09 to 1.20). CONCLUSION: Although residual confounding may remain, our findings indicate that elective induction of labour at term gestation can reduce perinatal mortality in developed countries without increasing the risk of operative delivery.

The relationship between the magnitude of systemic inflammatory response and the nutritional/functional parameters in patients with inoperable non-small cell lung cancer were studied. The extent of weight loss, albumin, C-reactive protein, performance status and quality of life was measured in 106 patients with inoperable non-small cell lung cancer (stages III and IV). Survival analysis was performed using the Cox proportional hazard model. The majority of patients were male and almost 80% had elevated circulating C-reactive protein concentrations (>10 mg x l(-1)). On multivariate analysis, age (P=0.012), tumour type (0.002), weight loss (P=0.056), C-reactive protein (P=0.047), Karnofsky performance status (P=0.002) and fatigue (P=0.046) were independent predictors of survival. The patients were grouped according to the magnitude of the C-reactive protein concentrations (< or =10, 11-100 and >100 mg x l(-1)). An increase in the magnitude of the systemic inflammatory response was associated with increased weight loss (P=0.004), reduced albumin concentrations (P=0.001), reduced performance status (P=0.060), increased fatigue (P=0.011) and reduced survival (HR 1.936 95%CI 1.414-2.650, P<0.001). These results indicate that the majority of patients with inoperable non-small cell lung cancer have evidence of a systemic inflammatory response. Furthermore, an increase in the magnitude of the systemic inflammatory response resulted in greater weight loss, poorer performance status, more fatigue and poorer survival.

Primary biliary cirrhosis (PBC) is a classical autoimmune liver disease for which effective immunomodulatory therapy is lacking. Here we perform meta-analyses of discovery data sets from genome-wide association studies of European subjects (n=2,764 cases and 10,475 controls) followed by validation genotyping in an independent cohort (n=3,716 cases and 4,261 controls). We discover and validate six previously unknown risk loci for PBC (Pcombined<5 × 10(-8)) and used pathway analysis to identify JAK-STAT/IL12/IL27 signalling and cytokine-cytokine pathways, for which relevant therapies exist.

Abstract Critical illness in COVID-19 is an extreme and clinically homogeneous disease phenotype that we have previously shown 1 to be highly efficient for discovery of genetic associations 2 . Despite the advanced stage of illness at presentation, we have shown that host genetics in patients who are critically ill with COVID-19 can identify immunomodulatory therapies with strong beneficial effects in this group 3 . Here we analyse 24,202 cases of COVID-19 with critical illness comprising a combination of microarray genotype and whole-genome sequencing data from cases of critical illness in the international GenOMICC (11,440 cases) study, combined with other studies recruiting hospitalized patients with a strong focus on severe and critical disease: ISARIC4C (676 cases) and the SCOURGE consortium (5,934 cases). To put these results in the context of existing work, we conduct a meta-analysis of the new GenOMICC genome-wide association study (GWAS) results with previously published data. We find 49 genome-wide significant associations, of which 16 have not been reported previously. To investigate the therapeutic implications of these findings, we infer the structural consequences of protein-coding variants, and combine our GWAS results with gene expression data using a monocyte transcriptome-wide association study (TWAS) model, as well as gene and protein expression using Mendelian randomization. We identify potentially druggable targets in multiple systems, including inflammatory signalling ( JAK1 ), monocyte–macrophage activation and endothelial permeability ( PDE4A ), immunometabolism ( SLC2A5 and AK5 ), and host factors required for viral entry and replication ( TMPRSS2 and RAB2A ).

BACKGROUND: Stigma and discrimination associated with mental illness are strongly linked to suffering, disability and poverty. In order to protect the rights of those with mental disorders and to sensitively develop services, it is vital to gain a more accurate understanding of the frequency and nature of stigma against people with mental illness. Little research about this issue has been conducted in Sub- Saharan Africa. Our study aimed to describe levels of stigma in Malawi. METHODS: A cross-sectional survey of patients and carers attending mental health and non-mental health related clinics in a general hospital in Blantyre, Malawi. Participants were interviewed using an adapted version of the questionnaire developed for the "World Psychiatric Association Program to Reduce Stigma and Discrimination Because of Schizophrenia". RESULTS: 210 participants participated in our study. Most attributed mental disorder to alcohol and illicit drug abuse (95.7%). This was closely followed by brain disease (92.8%), spirit possession (82.8%) and psychological trauma (76.1%). There were some associations found between demographic variables and single question responses, however no consistent trends were observed in stigmatising beliefs. These results should be interpreted with caution and in the context of existing research. Contrary to the international literature, having direct personal experience of mental illness seemed to have no positive effect on stigmatising beliefs in our sample. CONCLUSIONS: Our study contributes to an emerging picture that individuals in Sub-Saharan Africa most commonly attribute mental illness to alcohol/ illicit drug use and spirit possession. Our work adds weight to the argument that stigma towards mental illness is an important global health and human rights issue.

An outbreak of acute hepatitis of unknown aetiology in children was reported in Scotland1 in April 2022 and has now been identified in 35 countries2. Several recent studies have suggested an association with human adenovirus with this outbreak, a virus not commonly associated with hepatitis. Here we report a detailed case–control investigation and find an association between adeno-associated virus 2 (AAV2) infection and host genetics in disease susceptibility. Using next-generation sequencing, PCR with reverse transcription, serology and in situ hybridization, we detected recent infection with AAV2 in plasma and liver samples in 26 out of 32 (81%) cases of hepatitis compared with 5 out of 74 (7%) of samples from unaffected individuals. Furthermore, AAV2 was detected within ballooned hepatocytes alongside a prominent T cell infiltrate in liver biopsy samples. In keeping with a CD4+ T-cell-mediated immune pathology, the human leukocyte antigen (HLA) class II HLA-DRB1*04:01 allele was identified in 25 out of 27 cases (93%) compared with a background frequency of 10 out of 64 (16%; P = 5.49 × 10−12). In summary, we report an outbreak of acute paediatric hepatitis associated with AAV2 infection (most likely acquired as a co-infection with human adenovirus that is usually required as a ‘helper virus’ to support AAV2 replication) and disease susceptibility related to HLA class II status. A case–control study investigating the causes of recent cases of acute hepatitis of unknown aetiology in 32 children identifies an association between adeno-associated virus infection and host genetics in disease susceptibility.

We performed a prospective, randomised study on 57 patients older than 60 years of age with unstable, extra-articular fractures of the distal radius to compare the outcome of immobilisation in a cast alone with that using supplementary, percutaneous pinning. Patients treated by percutaneous wires had a statistically significant improvement in dorsal angulation (mean 7 degrees), radial length (mean 3 mm) and radial inclination (mean 3 mm) at one year. However, there was no significant difference in functional outcome in terms of pain, range of movement, grip strength, activities of daily living and the SF-36 score except for an improved range of movement in ulnar deviation in the percutaneous wire group. One patient developed a pin-track infection which required removal of the wires at two weeks. We conclude that percutaneous pinning of unstable, extra-articular fractures of the distal radius provides only a marginal improvement in the radiological parameters compared with immobilisation in a cast alone. This does not correlate with an improved functional outcome in a low-demand, elderly population.

PURPOSE: To determine the diagnostic accuracy of virtual histology intravascular ultrasound imaging (VH IVUS) of carotid plaque and to assess the feasibility of VH IVUS to identify plaque with embolic potential in patients undergoing carotid artery stenting (CAS). METHODS: Thirty patients (17 men; mean age 74+/-7 years) were entered nonrandomly into a single-center, prospective, 2-arm study following FDA and Institutional Review Board approval. In one arm, 15 patients underwent VH IVUS examination of carotid plaque with a cerebral protection device immediately followed by carotid endarterectomy (CEA). A comparison of "virtual" with true histology was then performed, classifying plaque type by VH IVUS and histopathology in a blinded study. In the second arm, 15 patients undergoing CAS had a preliminary VH IVUS scan performed with cerebral protection. Debris collected from the filter following stenting was examined histologically and compared with the VH IVUS data. RESULTS: The diagnostic accuracy of VH IVUS to agree with true histology in different carotid plaque types was 99.4% in thin-cap fibroatheroma, 96.1% for calcified thin-cap fibroatheroma, 85.9% in fibroatheroma, 85.5% for fibrocalcific, 83.4% in pathological intimal thickening, and 72.4% for calcified fibroatheroma. Filter debris was captured in 2 patients prior to CEA and in 4 patients undergoing CAS for restenosis; VH IVUS classification of plaque composition was consistent with the histological evaluation of filter fragments. Calcified nodules projecting into the carotid artery lumen were associated with a higher incidence of previous neurological symptoms (66.7% versus 33.3%, p<0.05), while patients on aspirin has significantly less necrotic lipid core plaque detected by VH IVUS than patients not taking aspirin (6.4%+/-4.7% versus 9.7%+/-2.8%, p<0.05). CONCLUSION: This study showed a strong correlation between VH IVUS plaque characterization and the true histological examination of the plaque following endarterectomy, particularly in "vulnerable" plaque types. The feasibility study to examine VH IVUS data and the filter debris histology in CAS patients supports a larger prospective study.

The value of an inflammation-based prognostic score (Glasgow Prognostic score, GPS) was compared with performance status (ECOG-ps) in a longitudinal study of patients (n=101) with inoperable non-small-cell lung cancer (NSCLC). At diagnosis, stratified for treatment, only the GPS (HR 2.32, 95% CI 1.52-3.54, P<0.001) was a significant predictor of survival. In contrast, neither the GPS nor ECOG-ps measured at 3-6 months follow-up were significant predictors of residual survival. This study confirms the prognostic value of the GPS, at diagnosis, in patients with inoperable NSCLC. However, the role of the GPS and ECOG-ps during follow-up has not been established.

Using the Internet to obtain health information (“online health research”, OHR) is commonplace. This paper provides a systematic narrative review of evidence concerning the relationship between OHR and health anxiety. We conclude that health anxiety is associated with more frequent self-reported OHR, heightened distress after OHR, and increased doctor visits post-OHR. Evidence suggests that OHR often has a reassurance seeking function and can relieve anxiety, but that it can also cause alarm and become a distressing, compulsive behaviour. We present a novel model that integrates these perspectives and existing research within a single explanatory framework that distinguishes between problematic OHR and compulsive OHR and describes the role of positive and negative metacognitions in their respective development.

BACKGROUND: Chronic kidney disease (CKD) is an important but under-recognized condition. Recent national guidelines have recommended that biochemistry laboratories report estimated GFR (eGFR) to improve diagnosis of CKD and facilitate disease staging and management. Previous reports have suggested that intake of large amounts of cooked meat can lead to a significant increase in serum creatinine concentration. METHODS: Participants (n = 32), consisting of 17 healthy volunteers and 15 outpatients, were recruited. Measurement of serum creatinine (kinetic Jaffe method, enzymatic, isotope-dilution mass spectrometry [IDMS]) and cystatin C, and calculation of eGFR were carried out before (i) and after a meal containing cooked meat (ii) and a meat-free meal (iii). RESULTS: Following intake of cooked meat, median serum creatinine concentration (kinetic Jaffe) increased from 80.5 micromol/L preprandially to 101.0 micromol/L 1-2 h postprandially (P<0.0001), and 99.0 micromol/L 3-4 h postprandially (P<0.0001). Median eGFR decreased from 84.0 mL/min/1.73 m2 preprandially to 59.5 mL/min/1.73 m2 1-2 h postprandially (P<0.0001), and 64.0 mL/min/1.73 m2 3-4 h postprandially (P<0.0001). Consumption of non-meat-containing meals had little impact on serum creatinine (kinetic Jaffe) and eGFR. Changes in serum creatinine were similar using all three methods, and cystatin C concentration was generally uninfluenced by food intake. CONCLUSIONS: Intake of cooked meat has a significant effect on serum creatinine concentration and eGFR. Misclassification of CKD is possible if measurements are made after meals containing cooked meat. Clinicians should ensure that CKD classification is based on samples taken in the appropriate conditions: either fasting or after avoidance of cooked meat on the day of sampling. National guidelines which overlook this factor should be revisited.

. Here we report an investigation of 38 cases, 66 age-matched immunocompetent controls and 21 immunocompromised comparator participants, using a combination of genomic, transcriptomic, proteomic and immunohistochemical methods. We detected high levels of adeno-associated virus 2 (AAV2) DNA in the liver, blood, plasma or stool from 27 of 28 cases. We found low levels of adenovirus (HAdV) and human herpesvirus 6B (HHV-6B) in 23 of 31 and 16 of 23, respectively, of the cases tested. By contrast, AAV2 was infrequently detected and at low titre in the blood or the liver from control children with HAdV, even when profoundly immunosuppressed. AAV2, HAdV and HHV-6 phylogeny excluded the emergence of novel strains in cases. Histological analyses of explanted livers showed enrichment for T cells and B lineage cells. Proteomic comparison of liver tissue from cases and healthy controls identified increased expression of HLA class 2, immunoglobulin variable regions and complement proteins. HAdV and AAV2 proteins were not detected in the livers. Instead, we identified AAV2 DNA complexes reflecting both HAdV-mediated and HHV-6B-mediated replication. We hypothesize that high levels of abnormal AAV2 replication products aided by HAdV and, in severe cases, HHV-6B may have triggered immune-mediated hepatic disease in genetically and immunologically predisposed children.