Hillingdon 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: The COPD Assessment Test (CAT) is responsive to change in patients with chronic obstructive pulmonary disease (COPD). However, the minimum clinically important difference (MCID) has not been established. We aimed to identify the MCID for the CAT using anchor-based and distribution-based methods. METHODS: We did three studies at two centres in London (UK) between April 1, 2010, and Dec 31, 2012. Study 1 assessed CAT score before and after 8 weeks of outpatient pulmonary rehabilitation in patients with COPD who were able to walk 5 m, and had no contraindication to exercise. Study 2 assessed change in CAT score at discharge and after 3 months in patients admitted to hospital for more than 24 h for acute exacerbation of COPD. Study 3 assessed change in CAT score at baseline and at 12 months in stable outpatients with COPD. We focused on identifying the minimum clinically important improvement in CAT score. The St George's Respiratory Questionnaire (SGRQ) and Chronic Respiratory Questionnaire (CRQ) were measured concurrently as anchors. We used receiver operating characteristic curves, linear regression, and distribution-based methods (half SD, SE of measurement) to estimate the MCID for the CAT; we included only patients with paired CAT scores in the analysis. FINDINGS: In Study 1, 565 of 675 (84%) patients had paired CAT scores. The mean change in CAT score with pulmonary rehabilitation was -2·5 (95% CI -3·0 to -1·9), which correlated significantly with change in SGRQ score (r=0·32; p<0·0001) and CRQ score (r=-0·46; p<0·0001). In Study 2, of 200 patients recruited, 147 (74%) had paired CAT scores. Mean change in CAT score from hospital discharge to 3 months after discharge was -3·0 (95% CI -4·4 to -1·6), which correlated with change in SGRQ score (r=0·47; p<0·0001). In Study 3, of 200 patients recruited, 164 (82%) had paired CAT scores. Although no significant change in CAT score was identified after 12 months (mean 0·6, 95% CI -0·4 to 1·5), change in CAT score correlated significantly with change in SGRQ score (r=0·36; p<0·0001). Linear regression estimated the minimum clinically important improvement for the CAT to range between -1·2 and -2·8 with receiver operating characteristic curves consistently identifying -2 as the MCID. Distribution-based estimates for the MCID ranged from -3·3 to -3·8. INTERPRETATION: The most reliable estimate of the minimum important difference of the CAT is 2 points. This estimate could be useful in the clinical interpretation of CAT data, particularly in response to intervention studies. FUNDING: Medical Research Council and UK National Institute of Health Research.

OBJECTIVE: To determine the efficacy of a probiotic drink containing Lactobacillus for the prevention of any diarrhoea associated with antibiotic use and that caused by Clostridium difficile. DESIGN: Randomised double blind placebo controlled study. PARTICIPANTS: 135 hospital patients (mean age 74) taking antibiotics. Exclusions included diarrhoea on admission, bowel pathology that could result in diarrhoea, antibiotic use in the previous four weeks, severe illness, immunosuppression, bowel surgery, artificial heart valves, and history of rheumatic heart disease or infective endocarditis. INTERVENTION: Consumption of a 100 g (97 ml) drink containing Lactobacillus casei, L bulgaricus, and Streptococcus thermophilus twice a day during a course of antibiotics and for one week after the course finished. The placebo group received a longlife sterile milkshake. PRIMARY OUTCOME: occurrence of antibiotic associated diarrhoea. Secondary outcome: presence of C difficile toxin and diarrhoea. RESULTS: 7/57 (12%) of the probiotic group developed diarrhoea associated with antibiotic use compared with 19/56 (34%) in the placebo group (P=0.007). Logistic regression to control for other factors gave an odds ratio 0.25 (95% confidence interval 0.07 to 0.85) for use of the probiotic, with low albumin and sodium also increasing the risk of diarrhoea. The absolute risk reduction was 21.6% (6.6% to 36.6%), and the number needed to treat was 5 (3 to 15). No one in the probiotic group and 9/53 (17%) in the placebo group had diarrhoea caused by C difficile (P=0.001). The absolute risk reduction was 17% (7% to 27%), and the number needed to treat was 6 (4 to 14). CONCLUSION: Consumption of a probiotic drink containing L casei, L bulgaricus, and S thermophilus can reduce the incidence of antibiotic associated diarrhoea and C difficile associated diarrhoea. This has the potential to decrease morbidity, healthcare costs, and mortality if used routinely in patients aged over 50. TRIAL REGISTRATION: National Research Register N0016106821.

The clinical and neuroendocrine response to diuretic treatment was assessed at rest and on exercise in 12 patients with heart failure. Before treatment all patients were limited by breathlessness on exercise; one was oedematous. Plasma renin activity and aldosterone were normal but plasma noradrenaline was raised both at rest and on exercise. After one month's treatment with frusemide (40 mg) and amiloride (5 mg) weight was significantly reduced by a mean of 3.5 kg and exercise capacity had doubled. Plasma noradrenaline fell to normal at rest but remained abnormally raised on exercise. Plasma renin activity and aldosterone increased significantly both at rest and on exercise. Diuretics bring about a considerable clinical improvement in patients with chronic heart failure but they stimulate the renin-angiotensin system. Activation of the renin-angiotensin system in moderate heart failure occurs as a response to diuretic treatment rather than as a result of the disease process itself.

BACKGROUND: Evidence from systematic reviews demonstrates that multi-disciplinary rehabilitation is effective in the stroke population, in which older adults predominate. However, the evidence base for the effectiveness of rehabilitation following acquired brain injury (ABI) in younger adults has not been established, perhaps because this scenario presents different methodological challenges in research. OBJECTIVES: To assess the effects of multi-disciplinary rehabilitation following ABI in adults 16 to 65 years of age. SEARCH METHODS: We ran the most recent search on 14 September 2015. We searched the Cochrane Injuries Group Specialised Register, The Cochrane Library, Ovid MEDLINE(R), Ovid MEDLINE(R) In-Process & Other Non-Indexed Citations, Ovid MEDLINE(R) Daily and Ovid OLDMEDLINE(R), Embase Classic+Embase (OvidSP), Web of Science (ISI WOS) databases, clinical trials registers, and we screened reference lists. SELECTION CRITERIA: Randomised controlled trials (RCTs) comparing multi-disciplinary rehabilitation versus routinely available local services or lower levels of intervention; or trials comparing an intervention in different settings, of different intensities or of different timing of onset. Controlled clinical trials were included, provided they met pre-defined methodological criteria. DATA COLLECTION AND ANALYSIS: Three review authors independently selected trials and rated their methodological quality. A fourth review author would have arbitrated if consensus could not be reached by discussion, but in fact, this did not occur. As in previous versions of this review, we used the method described by Van Tulder 1997 to rate the quality of trials and to perform a 'best evidence' synthesis by attributing levels of evidence on the basis of methodological quality. Risk of bias assessments were performed in parallel using standard Cochrane methodology. However, the Van Tulder system provided a more discriminative evaluation of rehabilitation trials, so we have continued to use it for our primary synthesis of evidence. We subdivided trials in terms of severity of brain injury, setting and type and timing of rehabilitation offered. MAIN RESULTS: We identified a total of 19 studies involving 3480 people. Twelve studies were of good methodological quality and seven were of lower quality, according to the van Tulder scoring system. Within the subgroup of predominantly mild brain injury, 'strong evidence' suggested that most individuals made a good recovery when appropriate information was provided, without the need for additional specific interventions. For moderate to severe injury, 'strong evidence' showed benefit from formal intervention, and 'limited evidence' indicated that commencing rehabilitation early after injury results in better outcomes. For participants with moderate to severe ABI already in rehabilitation, 'strong evidence' revealed that more intensive programmes are associated with earlier functional gains, and 'moderate evidence' suggested that continued outpatient therapy could help to sustain gains made in early post-acute rehabilitation. The context of multi-disciplinary rehabilitation appears to influence outcomes. 'Strong evidence' supports the use of a milieu-oriented model for patients with severe brain injury, in which comprehensive cognitive rehabilitation takes place in a therapeutic environment and involves a peer group of patients. 'Limited evidence' shows that specialist in-patient rehabilitation and specialist multi-disciplinary community rehabilitation may provide additional functional gains, but studies serve to highlight the particular practical and ethical restraints imposed on randomisation of severely affected individuals for whom no realistic alternatives to specialist intervention are available. AUTHORS' CONCLUSIONS: Problems following ABI vary. Consequently, different interventions and combinations of interventions are required to meet the needs of patients with different problems. Patients who present acutely to hospital with mild brain injury benefit from follow-up and appropriate information and advice. Those with moderate to severe brain injury benefit from routine follow-up so their needs for rehabilitation can be assessed. Intensive intervention appears to lead to earlier gains, and earlier intervention whilst still in emergency and acute care has been supported by limited evidence. The balance between intensity and cost-effectiveness has yet to be determined. Patients discharged from in-patient rehabilitation benefit from access to out-patient or community-based services appropriate to their needs. Group-based rehabilitation in a therapeutic milieu (where patients undergo neuropsychological rehabilitation in a therapeutic environment with a peer group of individuals facing similar challenges) represents an effective approach for patients requiring neuropsychological rehabilitation following severe brain injury. Not all questions in rehabilitation can be addressed by randomised controlled trials or other experimental approaches. For example, trial-based literature does not tell us which treatments work best for which patients over the long term, and which models of service represent value for money in the context of life-long care. In the future, such questions will need to be considered alongside practice-based evidence gathered from large systematic longitudinal cohort studies conducted in the context of routine clinical practice.

Clinicians used to observing individual patients, and epidemiologists trained to observe the course of disease, may be forgiven for misunderstanding the term observational method as used in qualitative research. In contrast to the clinician or epidemiologist, the qualitative researcher systematically watches people and events to find out about behaviours and interactions in natural settings. Observation, in this sense, epitomises the idea of the researcher as the research instrument. It involves "going into the field"--describing and analysing what has been seen. In health care settings this method has been insightful and illuminating, but it is not without pitfalls for the unprepared researcher.

BACKGROUND: The coronavirus disease (COVID-19) global pandemic has resulted in unprecedented public health measures. This has impacted the UK education sector with many universities halting campus-based teaching and examinations. The aim of this study is to identify the impact of COVID-19 on final year medical students' examinations and placements in the United Kingdom (UK) and how it might impact their confidence and preparedness going into their first year of foundation training. METHODS: A 10-item online survey was distributed to final year medical students across 33 UK medical schools. The survey was designed by combining dichotomous, multiple choice and likert response scale questions. Participants were asked about the effect that the COVID-19 global pandemic had on final year medical written exams, electives, assistantships and objective structured clinical examinations (OSCEs). The survey also explored the student's confidence and preparedness going into their first year of training under these new unprecedented circumstances. RESULTS: Four hundred forty students from 32 UK medical schools responded. 38.4% (n = 169) of respondents had their final OSCEs cancelled while 43.0% (n = 189) had already completed their final OSCEs before restrictions. 43.0% (n = 189) of assistantship placements were postponed while 77.3% (n = 340) had electives cancelled. The impact of COVID-19 on OSCEs, written examinations and student assistantships significantly affected students' preparedness (respectively p = 0.025, 0.008, 0.0005). In contrast, when measuring confidence, only changes to student assistantships had a significant effect (p = 0.0005). The majority of students feel that measures taken during this pandemic to amend their curricula was necessary. Respondents also agree that assisting in hospitals during the outbreak would be a valuable learning opportunity. CONCLUSIONS: The impact on medical student education has been significant, particularly affecting the transition from student to doctor. This study showed the disruptions to student assistantships had the biggest effect on students' confidence and preparedness. For those willing to assist in hospitals to join the front-line workforce, it is crucial to maintain their wellbeing with safeguards such as proper inductions, support and supervision.

This study is based on observations made on boys at birth, during infancy, and throughout early child-hood. Its purpose was to find out how often the testes were in the scrotum at birth and what happened in later years to those that were not. An analysis of the position of the testes was made in over 3,500 infant boys at birth. Those in whom one or both testes were not in the scrotum at the age of 1 month were followed up. To this number a further 40 cases of failure of descent in early infancy have been added in order to obtain, as nearly as possible, a true incidence of the various types of failure. Criteria of Descent At birth in the full-term baby boy the testis is

Ulcerative colitis is a relapsing and remitting disease that is increasing in incidence and prevalence. Management aims to achieve rapid resolution of symptoms, mucosal healing and improvement in a patient's quality of life. 5-aminosalicylate acid medications remain the first-line treatment for mild to moderate disease. In the event of suboptimal response to these medications, escalation to immunosuppressive medications and biologics may be necessary. Importantly, despite best medical therapy, surgery may be required in a proportion of patients. The future will likely see an array of new therapeutic options for those with ulcerative colitis with the potential for a more personalised treatment approach.

Sarcopenia and frailty are geriatric syndromes characterized by multisystem decline, which are related to and reflected by markers of skeletal muscle dysfunction. In older people, sarcopenia and frailty have been used for risk stratification, to predict adverse outcomes and to prompt intervention aimed at preventing decline in those at greatest risk. In this review, we examine sarcopenia and frailty in the context of chronic respiratory disease, providing an overview of the common assessments tools and studies to date in the field. We contrast assessments of sarcopenia, which consider muscle mass and function, with assessments of frailty, which often additionally consider social, cognitive and psychological domains. Frailty is emerging as an important syndrome in respiratory disease, being strongly associated with poor outcome. We also unpick the relationship between sarcopenia, frailty and skeletal muscle dysfunction in chronic respiratory disease and reveal these as interlinked but distinct clinical phenotypes. Suggested areas for future work include the application of sarcopenia and frailty models to restrictive diseases and population-based samples, prospective prognostic assessments of sarcopenia and frailty in relation to common multidimensional indices, plus the investigation of exercise, nutritional and pharmacological strategies to prevent or treat sarcopenia and frailty in chronic respiratory disease.

INTRODUCTION: We propose that the increase in TNF-alpha and IL-6 in the brain in idiopathic parkinsonism is in response to a peripheral immune/ inflammatory process, so ubiquitous as to be responsible for the resemblance between ageing and parkinsonism. METHODS: Circulating cytokine was measured in 78 subjects with idiopathic parkinsonism and 140 without, aged 30 to 90 years, all obeying inclusion/exclusion criteria. RESULTS: Serum TNF-alpha increased (P<0.0001) by 1.37 (95% CI 0.75, 2.00)% x y(-1), IL-6 by 2.63 (1.75, 3.52) (P<0.0005). TNF-alpha appeared elevated in parkinsonians whose postural and psychomotor responses were abnormal, being suppressed where they were normal: trends which contrasted with those in controls (P = 0.015 and 0.05, respectively). Parkinsonism appeared (P = 0.08) to have an effect on IL-6, equivalent to that of >10 years of ageing (28(-3, 69)%), but was not immediately related to between-subject differences in performance. CONCLUSION: Ageing and pathogenetic insult may be confounded, age being a progression, not a risk, factor.

BACKGROUND: Frailty is an important clinical syndrome that is consistently associated with adverse outcomes in older people. The relevance of frailty to chronic respiratory disease and its management is unknown. OBJECTIVES: To determine the prevalence of frailty among patients with stable COPD and examine whether frailty affects completion and outcomes of pulmonary rehabilitation. METHODS: % predicted 48.9 (21.0)) were recruited between November 2011 and January 2015. Frailty was assessed using the Fried criteria (weight loss, exhaustion, low physical activity, slowness and weakness) before and after pulmonary rehabilitation. Predictors of programme non-completion were identified using multivariate logistic regression, and outcomes were compared using analysis of covariance, adjusting for age and sex. RESULTS: 209/816 patients (25.6%, 95% CI 22.7 to 28.7) were frail. Prevalence of frailty increased with age, Global Initiative for Chronic Obstructive Lung Disease (GOLD) stage, Medical Research Council (MRC) score and age-adjusted comorbidity burden (all p≤0.01). Patients who were frail had double the odds of programme non-completion (adjusted OR 2.20, 95% CI 1.39 to 3.46, p=0.001), often due to exacerbation and/or hospital admission. However, rehabilitation outcomes favoured frail completers, with consistently better responses in MRC score, exercise performance, physical activity level and health status (all p<0.001). After rehabilitation, 71/115 (61.3%) previously frail patients no longer met case criteria for frailty. CONCLUSIONS: Frailty affects one in four patients with COPD referred for pulmonary rehabilitation and is an independent predictor of programme non-completion. However, patients who are frail respond favourably to rehabilitation and their frailty can be reversed in the short term.

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.

OBJECTIVE: To investigate whether distractions in the operating room (OR) are associated with higher mental workload and stress, and poorer teamwork among OR personnel. BACKGROUND: Engaging in multiple tasks can affect performance. There is little research on the effect of distractions on surgical team members' behavior and cognitive processes. METHODS: Ninety general surgery cases were observed in real time. Cases were assessed by a surgeon and a behavioral scientist using 4 validated tools: OR Distractions Assessment Form, the Observational Teamwork Assessment for Surgery tool, NASA-Task Load Index, and short form of the State Trait Anxiety Inventory. Analysis of variance was performed to evaluate significant differences between teamwork, workload, and stress level among team members. Correlations (Pearson r) were computed to evaluate associations between variables. RESULTS: The most prevalent distractions were those initiated by external staff, followed by case-irrelevant conversations. Case-irrelevant conversations were associated with poorer team performance. Irrelevant conversations initiated by surgeons were associated with lower teamwork in surgeons (across team skills: r = -0.44 to -0.58, P < 0.05 to 0.01) and anesthesiologists (r = -0.38 and r = -0.40, for coordination and leadership; P < 0.05). Equipment-related distractions correlated with higher stress (r = 0.48, P < 0.05) and lower teamwork (across team skills: r = -0.42 to -0.50, P < 0.05) in nurses. Acoustic distractions correlated with higher stress in surgeons (r = 0.32, P < 0.05) and higher workload in anesthesiologists (r = 0.30, P < 0.05). CONCLUSIONS: Although some distractions may be inevitable in the OR, they can also be detrimental to the team. A deeper understanding of the effect of distractions on teams and their outcomes can lead to targeted quality improvement.

OBJECTIVES: To establish the effect of preoperative smoking cessation on the risk of postoperative complications, and to identify the effect of the timing of preoperative cessation. DATA SOURCES: The Cochrane Library Database, PsycINFO, EMBASE, Medline, and CINAHL databases were searched, using the terms: "smoking", "smoking-cessation", "tobacco-use", "tobacco-abstinence", "cigarett$", "complication$", "postoperative-complication$", "preoperative", "perioperative" and "surg$". Further articles were obtained from reference lists. The search was limited to articles on adults, written in English and published up to November 2005. STUDY SELECTION: Prospective cohort designs exploring the effects of preoperative smoking cessation on postoperative complications were included. Two reviewers independently scanned abstracts of relevant articles to determine eligibility. Lack of agreement was resolved through discussion and consensus. Twelve studies met the inclusion criteria. DATA EXTRACTION: Methodological quality was assessed by both reviewers, exploring validation of smoking status, clear definition of the period of smoking cessation, control for confounding variables and length of follow-up. DATA SYNTHESIS: Only four of the studies specified the exact period of smoking cessation, with six studies specifying the length of the follow-up period. Five studies revealed a lower risk or incidence of postoperative complications in past smokers than current smokers or reported that there was no significant difference between past smokers and non-smokers. CONCLUSIONS: Longer periods of smoking cessation appear to be more effective in reducing the incidence/risk of postoperative complications; there was no increased risk in postoperative complications from short term cessation. An optimal period of preoperative smoking cessation could not be identified from the available evidence.

PURPOSE: Lamotrigine is an effective add-on therapy against a range of epileptic seizure types. Comparative studies with carbamazepine (CBZ) as monotherapy in newly diagnosed epilepsy suggest similar efficacy. In this study, lamotrigine (LTG) and phenytoin (PHT) are compared. METHODS: In a double-blind parallel-groups study, 181 patients with newly diagnosed untreated partial seizures or secondarily or primary generalised tonic-clonic seizures were randomised to two treatment groups. One group (n = 86) received LTG titrated over 6 weeks from a starting dose of 100 mg/day. The other (n = 95) received PHT titrated from 200 mg/day. Treatment continued for < or =48 weeks. RESULTS: The percentages of patients remaining on each treatment and seizure free during the last 24 and 40 weeks of the study, and times to first seizure after the first 6 weeks of treatment (dose-titration period), did not differ significantly between the treatment groups. These were measures of efficacy. Time to discontinuation, a composite index of efficacy and safety, likewise did not distinguish between treatments. Adverse events led to discontinuation of 13 (15%) patients from LTG and 18 (19%) from PHT. The adverse-event profile for LTG was dominated by skin rash [discontinuation of 10 (11.6%) patients compared with five (5.3%) from PHT] rather than central nervous system side effects: asthenia, somnolence, and ataxia were each significantly more frequent in the PHT group. The high rate of rash with LTG was probably due to the high starting dose and may be avoidable. A quality-of-life instrument, the SEALS inventory, favoured LTG. Patients taking PHT showed the biochemical changes expected of an enzyme-inducing drug, whereas those taking LTG did not. CONCLUSIONS: LTG and PHT monotherapy were similarly effective against these seizure types in patients with newly diagnosed epilepsy. LTG was better tolerated, more frequently causing rash, but with a lower incidence of central nervous system side effects.

Phantom limb pain may appear in up to 85% of patients after amputation. There is no effective treatment. Perioperative epidural infusion of morphine and bupivacaine, alone or in combination, is effective in preventing phantom limb pain in patients with pre-existing limb pain. Serious side-effects, however, make them difficult to manage on a general ward. Clonidine has been shown to be an effective postoperative analgesia when applied epidurally. To mitigate the potentially serious side-effects of all these drugs, we have studied their combined efficiency in preventing phantom limb pain in a prospective controlled study of 24 patients undergoing lower limb amputation. In the study group (n = 13), an epidural infusion containing bupivacaine 75 mg, clonidine 150 micrograms and diamorphine 5 mg in 60 ml normal saline was given at 1-4 ml/h 24-48 h preoperatively and maintained for at least 3 days postoperatively. The control group (n = 11) received on-demand opioid analgesia. Pain was assessed by visual analogue scale at 7 days, 6 months and 1 year. At 1 year follow-up, one patient in the study group and eight patients in the control group had phantom pain (P < 0.002) and two patients in the study group versus eight patients in the control group had phantom limb sensation (P < 0.05). There was no significant improvement in stump pain. We conclude that perioperative epidural infusion of diamorphine, clonidine and bupivacaine is safe and effective in reducing the incidence of phantom pain after amputation.

is possible because of proximity to others with contagious diseases (ie, resulting from direct person-to-person transmission).

The amyloidoses are a group of diseases in which amyloid, a proteinaceous substance, deposits in one or more organs. As many as 23 different precursor proteins to the formation of amyloid have been described in man. These may deposit themselves in a fibrillar matrix within selected tissues. Fibrils are formed when normally soluble constituents undergo transformational change and misfold to become relatively insoluble. A variety of mechanisms promote these changes, which result in the final common pathway of the deposition of non-branching fibrils that can be visualised by electron microscopy and which are seen on light microscopy as a homogenous extracellular material (figure 1). Figure 1 Myocardial biopsy from a patient with congestive cardiac failure and echocardiographic appearances of amyloid deposition. The myocytes appear yellow with the amyloid staining turquoise (sulfated Alcian blue stain). Immunostaining subsequently confirmed transthyretin as the constituent protein. In the developed world, cardiologists predominantly encounter three main types of amyloidosis that affect the heart; light chain (AL) amyloidosis, senile systemic amyloidosis (SSA), and familial amyloidosis (FAP); the latter most commonly results from a mutation in transthyretin. In the developing world, secondary amyloid (AA) is more prevalent, due to chronic infections and inadequately treated inflammatory conditions. Occurring worldwide and later in life, a further amyloid type to affect the heart is isolated atrial amyloid (IAA).w1 w2 Finally, and much less common, are the non-transthyretin variants, including mutations of fibrinogen, apoprotein, and gelsolin. These rarer types can cause significant cardiac compromise. Cardiac involvement in amyloidosis is usually part of a systemic disease. The heart is frequently the predominant organ affected but, in some forms of the disease, isolated heart involvement can occur. In patients with a non-cardiac biopsy showing amyloid deposition, cardiac involvement has been defined—by a consensus opinion from the 10th International Symposium on Amyloidosis1—as …

BACKGROUND: Some young children reared in profoundly depriving institutions have been found to show autistic-like patterns, but the developmental significance of these features is unknown. METHODS: A randomly selected, age-stratified, sample of 144 children who had experienced an institutional upbringing in Romania and who were adopted by UK families was studied at 4, 6, and 11 years, and compared with a non-institutionalised sample of 52 domestic adoptees. Twenty-eight children, all from Romanian institutions, for whom the possibility of quasi-autism had been raised, were assessed using the Autism Diagnostic Interview-Revised (ADI-R) and the Autism Diagnostic Observation Schedule (ADOS) at the age of 12 years. RESULTS: Sixteen children were found to have a quasi-autistic pattern; a rate of 9.2% in the Romanian institution-reared adoptees with an IQ of at least 50 as compared with 0% in the domestic adoptees. There were a further 12 children with some autistic-like features, but for whom the quasi-autism designation was not confirmed. The follow-up of the children showed that a quarter of the children lost their autistic-like features by 11. Disinhibited attachment and poor peer relationships were also present in over half of the children with quasi-autism. CONCLUSIONS: The findings at age 11/12 years confirmed the reality and clinical significance of the quasi-autistic patterns seen in over 1 in 10 of the children who experienced profound institutional deprivation. Although there were important similarities with 'ordinary' autism, the dissimilarities suggest a different meaning.