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Hong Kong has been severely affected by severe acute respiratory syndrome (SARS). Contact in households and healthcare settings is thought to be important for transmission, putting children at particular risk. Most data so far, however, have been for adults. We prospectively followed up the first ten children with SARS managed during the early phase of the epidemic in Hong Kong. All the children had been in close contact with infected adults. Persistent fever, cough, progressive radiographic changes of chest and lymphopenia were noted in all patients. The children were treated with high-dose ribavirin, oral prednisolone, or intravenous methylprednisolone, with no short-term adverse effects. Four teenagers required oxygen therapy and two needed assisted ventilation. None of the younger children required oxygen supplementation. Compared with adults and teenagers, SARS seems to have a less aggressive clinical course in younger children.

Serial blood tests showed mild thrombocytopenia (trough 110 [x] 109/L), and raised erythrocyte sedimentation rate (peak 60 mm/Hr), C-reactive protein (peak 102 mg/L; range, [lesser than]5.0), lactate dehydrogenase (270 U/L; range, [lesser than]270), ferritin (1568 pmol/L; range, 31-279), highly sensitive troponin I (peak 643 ng/L; range, [lesser than]21), N-terminal prohormone of brain natriuretic peptide (peak 3213 ng/L; range, [lesser than]112), and interleukin-6 (IL-6) (peak 480.9 pg/mL; range, [lesser than]4). Since he had been infected with COVID-19 approximately 4 weeks previously, he was suspected to have PIMS-TS (paediatric multisystem inflammatory syndrome temporally associated with SARS-CoV-2).2Other differential diagnoses were excluded but included streptococcal and staphylococcal infection, Epstein[-]Barr virus infection and infection-related myocarditis. A recent observational study demonstrated that patients who received IVIG and methylprednisolone together were less likely to require second-line biological agents, and were at lower risk of secondary acute left ventricular dysfunction and need for haemodynamic support with a shorter length of stay in the intensive care unit.5 Interleukin-1 and IL-6 receptor monoclonal antibodies have been used as second-line biological agents and have been shown to achieve remission when first-line therapies fail.2 5Short-term outcomes of PIMS-TS are generally good. Analysis or interpretation of data: D Mak, NC Fong, D Leung, WHS Wong, MHK Ho, SSL Tsao, CS Wong, JC Yam, WWY Tso, KKW To, PKH Tam, GCF Chan, WH Leung, KY Yuen, V Novelli, N Klein, M Levin, E Whitaker, YL Lau. The funding source was not involved in the study design, collection, analysis or interpretation of data; in the writing of the manuscript; or in the decision to submit the manuscript for publication.

Sudden arrhythmia death syndrome (SADS) accounts for about 30% of causes of sudden cardiac death (SCD) in young people. In Hong Kong, there are scarce data on SADS and a lack of experience in molecular autopsy. We aimed to investigate the value of molecular autopsy techniques for detecting SADS in an East Asian population. This was a two-part study. First, we conducted a retrospective 5-year review of autopsies performed in public mortuaries on young SCD victims. Second, we conducted a prospective 2-year study combining conventional autopsy investigations, molecular autopsy, and cardiac evaluation of the first-degree relatives of SCD victims. A panel of 35 genes implicated in SADS was analysed by next-generation sequencing. There were 289 SCD victims included in the 5-year review. Coronary artery disease was the major cause of death (35%); 40% were structural heart diseases and 25% were unexplained. These unexplained cases could include SADS-related conditions. In the 2-year prospective study, 21 SCD victims were examined: 10% had arrhythmogenic right ventricular cardiomyopathy, 5% had hypertrophic cardiomyopathy, and 85% had negative autopsy. Genetic analysis showed 29% with positive heterozygous genetic variants; six variants were novel. One third of victims had history of syncope, and 14% had family history of SCD. More than half of the 11 first-degree relatives who underwent genetic testing carried related genetic variants, and 10% had SADS-related clinical features. This pilot feasibility study shows the value of incorporating cardiac evaluation of surviving relatives and next-generation sequencing molecular autopsy into conventional forensic investigations in diagnosing young SCD victims in East Asian populations. The interpretation of genetic variants in the context of SCD is complicated and we recommend its analysis and reporting by qualified pathologists.

Hereditary channelopathies and cardiomyopathies are potentially lethal and are clinically and genetically heterogeneous, involving at least 90 genes. Genetic testing can provide an accurate diagnosis, guide treatment, and enable cascade screening. The genetic basis among the Hong Kong Chinese population is largely unknown. We aimed to report on 28 unrelated patients with positive genetic findings detected from January 2006 to December 2015. Sanger sequencing was performed for 28 unrelated patients with a clinical diagnosis of channelopathies or cardiomyopathies, testing for the following genes: and for long QT syndrome; for Brugada syndrome; for catecholaminergic polymorphic ventricular tachycardia; and for hypertrophic cardiomyopathy; for dilated cardiomyopathy; and and for arrhythmogenic right ventricular dysplasia/cardiomyopathy. There were 17 males and 11 females; their mean age at diagnosis was 39 years (range, 1-80 years). The major clinical presentations included syncope, palpitations, and abnormal electrocardiography findings. A family history was present in 13 (46%) patients. There were 26 different heterozygous mutations detected, of which six were novel-two in (NM_198056.2:c.429del and c.2024-11T>A), two in (NM_000256.3:c.906-22G>A and c.2105_2106del), and two in (NM_170707.3:c.73C>A and c.1209_1213dup). We have characterised the genetic heterogeneity in channelopathies and cardiomyopathies among Hong Kong Chinese patients in a 10-year case series. Correct interpretation of genetic findings is difficult and requires expertise and experience. Caution regarding issues of non-penetrance, variable expressivity, phenotype-genotype correlation, susceptibility risk, and digenic inheritance is necessary for genetic counselling and cascade screening.

Frontotemporal dementia is a heterogenous neurodegenerative disorder, with about a third of cases being genetic. Most of this genetic component is accounted for by mutations in GRN, MAPT, and C9orf72. In this study, we aimed to complement previous phenotypic studies by doing an international study of age at symptom onset, age at death, and disease duration in individuals with mutations in GRN, MAPT, and C9orf72. In this international, retrospective cohort study, we collected data on age at symptom onset, age at death, and disease duration for patients with pathogenic mutations in the GRN and MAPT genes and pathological expansions in the C9orf72 gene through the Frontotemporal Dementia Prevention Initiative and from published papers. We used mixed effects models to explore differences in age at onset, age at death, and disease duration between genetic groups and individual mutations. We also assessed correlations between the age at onset and at death of each individual and the age at onset and at death of their parents and the mean age at onset and at death of their family members. Lastly, we used mixed effects models to investigate the extent to which variability in age at onset and at death could be accounted for by family membership and the specific mutation carried. Data were available from 3403 individuals from 1492 families: 1433 with C9orf72 expansions (755 families), 1179 with GRN mutations (483 families, 130 different mutations), and 791 with MAPT mutations (254 families, 67 different mutations). Mean age at symptom onset and at death was 49·5 years (SD 10·0; onset) and 58·5 years (11·3; death) in the MAPT group, 58·2 years (9·8; onset) and 65·3 years (10·9; death) in the C9orf72 group, and 61·3 years (8·8; onset) and 68·8 years (9·7; death) in the GRN group. Mean disease duration was 6·4 years (SD 4·9) in the C9orf72 group, 7·1 years (3·9) in the GRN group, and 9·3 years (6·4) in the MAPT group. Individual age at onset and at death was significantly correlated with both parental age at onset and at death and with mean family age at onset and at death in all three groups, with a stronger correlation observed in the MAPT group (r=0·45 between individual and parental age at onset, r=0·63 between individual and mean family age at onset, r=0·58 between individual and parental age at death, and r=0·69 between individual and mean family age at death) than in either the C9orf72 group (r=0·32 individual and parental age at onset, r=0·36 individual and mean family age at onset, r=0·38 individual and parental age at death, and r=0·40 individual and mean family age at death) or the GRN group (r=0·22 individual and parental age at onset, r=0·18 individual and mean family age at onset, r=0·22 individual and parental age at death, and r=0·32 individual and mean family age at death). Modelling showed that the variability in age at onset and at death in the MAPT group was explained partly by the specific mutation (48%, 95% CI 35–62, for age at onset; 61%, 47–73, for age at death), and even more by family membership (66%, 56–75, for age at onset; 74%, 65–82, for age at death). In the GRN group, only 2% (0–10) of the variability of age at onset and 9% (3–21) of that of age of death was explained by the specific mutation, whereas 14% (9–22) of the variability of age at onset and 20% (12–30) of that of age at death was explained by family membership. In the C9orf72 group, family membership explained 17% (11–26) of the variability of age at onset and 19% (12–29) of that of age at death. Our study showed that age at symptom onset and at death of people with genetic frontotemporal dementia is influenced by genetic group and, particularly for MAPT mutations, by the specific mutation carried and by family membership. Although estimation of age at onset will be an important factor in future pre-symptomatic therapeutic trials for all three genetic groups, our study suggests that data from other members of the family will be particularly helpful only for individuals with MAPT mutations. Further work in identifying both genetic and environmental factors that modify phenotype in all groups will be important to improve such estimates. UK Medical Research Council, National Institute for Health Research, and Alzheimer's Society.

SummaryCommunity-based screening and treatment of women aged 70–85 years at high fracture risk reduced fractures; moreover, the screening programme was cost-saving. The results support a case for a screening programme of fracture risk in older women in the UK.IntroductionThe SCOOP (screening for prevention of fractures in older women) randomized controlled trial investigated whether community-based screening could reduce fractures in women aged 70–85 years. The objective of this study was to estimate the long-term cost-effectiveness of screening for fracture risk in a UK primary care setting compared with usual management, based on the SCOOP study.MethodsA health economic Markov model was used to predict the life-time consequences in terms of costs and quality of life of the screening programme compared with the control arm. The model was populated with costs related to drugs, administration and screening intervention derived from the SCOOP study. Fracture risk reduction in the screening arm compared with the usual management arm was derived from SCOOP. Modelled fracture risk corresponded to the risk observed in SCOOP.ResultsScreening of 1000 patients saved 9 hip fractures and 20 non-hip fractures over the remaining lifetime (mean 14 years) compared with usual management. In total, the screening arm saved costs (£286) and gained 0.015 QALYs/patient in comparison with usual management arm.ConclusionsThis analysis suggests that a screening programme of fracture risk in older women in the UK would gain quality of life and life years, and reduce fracture costs to more than offset the cost of running the programme.

•HPV vaccines were first licensed with 3-dose schedules and can now be administered as 2 doses in young adolescents.•We showed immunological superiority of 2D of AS04-HPV-16/18v vs. 2D or 3D of 4vHPV.•Higher circulating antibodies may be indicative of a longer duration of protection.•2D of AS04-HPV-16/18v safety is in line with known profiles of both vaccines. This observer-blind study (clinicaltrials.gov NCT01462357) compared the immunogenicity and safety of two doses (2D) of the HPV-16/18 AS04-adjuvanted vaccine (2D of AS04-HPV-16/18) vs. two or three doses of the 4vHPV vaccine [2D or 3D of 4vHPV] in 1075 healthy girls aged 9–14 years. Girls were randomized (1:1:1) to receive 2D of AS04-HPV-16/18 at months (M) 0, 6 (N = 359), 2D of 4vHPV at M0, 6 (N = 358) or 3D of 4vHPV at M0, 2, 6 (N = 358). 351, 339 and 346 girls, respectively, returned for the concluding visit at M36. Superiority was demonstrated at M7 and M12; comparison of the immune response to both vaccine antigens was made between 2D of AS04-HPV-16/18 and 2D or 3D of 4vHPV at subsequent time points in the according-to-protocol immunogenicity cohort (ATP-I; N = 958 at M36) and the total vaccinated cohort (TVC: N = 1036 at M36). HPV-16/18-specific T-cell- and B-cell-mediated immune responses and safety were also investigated. At M36, anti-HPV-16/18 ELISA responses in the 2D AS04-HPV-16/18 group remained superior to those of the 2D and 3D 4vHPV groups. In the M36 TVC, geometric mean titers were 2.78-fold (HPV-16) and 6.84-fold (HPV-18) higher for 2D of AS04-HPV-16/18 vs. 2D of 4vHPV and 2.3-fold (HPV-16) and 4.14-fold (HPV-18) higher vs. 3D of 4vHPV. Results were confirmed by vaccine pseudovirion-based neutralisation assay. Numbers of circulating CD4+ T cells and B cells appeared similar across groups. Safety was in line with the known safety profiles of both vaccines. In conclusion, superior HPV-16/18 antibody responses were elicited by 2D of the AS04-HPV-16/18 compared with 2D or 3D of the 4vHPV vaccine in girls aged 9–14 years. Clinical Trial Registration: NCT0146235.

Partial monosomy of the short arm of chromosome 1 is the most consistent cytogenetic abnormality found in human neuroblastomas, but its overall frequency and significance are unclear. Using a panel of chromosome-1-specific DNA probes that identify restriction fragment length polymorphisms, we demonstrate that 13 of 47 human neuroblastomas (28%) have somatic loss of heterozygosity (LOH) at one or more loci on the distal short arm of chromosome 1. The chromosomal region that shows LOH most consistently is between 1p36.1 and 1p36.3; loss of a gene or genes in this region may be critical for the development or progression of neuroblastomas. The region of LOH in human neuroblastoma may resemble that described for pheochromocytoma, medullary thyroid carcinoma, and melanoma, which are also tumors of neural-crest origin. Although LOH for distal chromosome 1p can occur in early stages of neuroblastoma, the loss usually occurs in tumors of advanced clinical stages. LOH for the short arm of chromosome 1 correlates significantly with N-myc amplification, suggesting that these two genetic events are related. Indeed, these two lesions appear to characterize a genetically distinct subset of particularly aggressive neuroblastomas.

Let X,YX,Y be locally compact Hausdorff spaces and M{\\mathcal M}, N{\\mathcal N} be Banach algebras. Let θ:C0(X,M)→C0(Y,N)\\theta : C_0(X,{\\mathcal M}) \\to C_0(Y, {\\mathcal N}) be a zero product preserving bounded linear map with dense range. We show that θ\\theta is given by a continuous field of algebra homomorphisms from M{\\mathcal M} into N{\\mathcal N} if N{\\mathcal N} is irreducible. As corollaries, such a surjective θ\\theta arises from an algebra homomorphism, provided that M{\\mathcal M} is a W∗W^*-algebra and N{\\mathcal N} is a semi-simple Banach algebra, or both M{\\mathcal M} and N{\\mathcal N} are C∗C^*-algebras.