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Familial AD accounts for less than 0.5% of early-onset AD cases.1 It is caused by mutations in the PSEN1, PSEN2 or APP gene, resulting in early deposition of amyloid plaques due to overproduction and deposition of Aβ42 leading to early neurodegeneration (the amyloid hypothesis).1Nonetheless a newer presenilin hypothesis suggests alternative mechanisms, eg, loss-of-function of PSEN1 with suppressed γ-secretase activity and increased Aβ42/Aβ40 ratios, resulting in neurodegeneration.2 Presenilin-1 mutations account for up to 71.5% of Asian cases of familial AD.1 These patients may have an atypical presentation such as parkinsonism or spastic paraparesis.1 With a few exceptions, familial AD mutations are considered fully penetrant with the development of dementia at a predictable age. Author contributions All authors contributed to the concept or design of the study, acquisition of the data, analysis or interpretation of the data, drafting of the manuscript, and critical revision of the manuscript for important intellectual content. Whitney CT Ip 1; YF Shea 1; TK Ling; MHKCPath2; CY Law 2; CW Lam 2,3; Patrick KC Chiu 1 1 Department of Medicine, Queen Mary Hospital, The University of Hong Kong, Hong Kong SAR, China 2 Division of Chemical Pathology, Department of Pathology, Queen Mary Hospital, Hong Kong SAR, China 3 Department of Pathology, The University of Hong Kong, Hong Kong SAR, China

Pedigree of the patient's family showing the autosomal dominant inheritance pattern of disease transmission Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy is caused by cysteine-altering pathogenic variants in the NOTCH3 gene, with consequent vasculopathic changes, predominantly involving small penetrating arteries, arterioles, and brain capillaries.1 2 The mutation leads to an odd number of cysteine residues with deposition of osmiophilic material and progressive degeneration of vascular smooth muscle cells.1 2 The key to diagnosis includes a strong family history of young-onset stroke, an absence of strong vascular risk factors, and salient findings on brain magnetic resonance imaging, especially extensive white matter abnormalities and subcortical infarcts involving external capsules. Genetic testing for the NOTCH3 gene can be arranged after consultation with chemical pathologists in major public hospitals.3 4 The principle of management for symptomatic patients is similar to that of other patients with stroke, ie, antiplatelet therapy, lipid-lowering agents, and blood pressure control. Whitney CT Ip 1; YF Shea 1; HF Tong 2,3; CY Law 2; CW Lam 2,4; Patrick KC Chiu 1 1 Department of Medicine, Queen Mary Hospital, The University of Hong Kong, Hong Kong SAR, China 2 Division of Chemical Pathology, Department of Pathology, Queen Mary Hospital, Hong Kong SAR, China 3 Department of Pathology, Princess Margaret Hospital, Hong Kong SAR, China 4 Department of Pathology, The University of Hong Kong, Hong Kong SAR, China

The management of inflammatory bowel diseases (IBDs; Crohn's disease, ulcerative colitis) is increasingly complex. Specialized care has been associated with improved ambulatory IBD outcomes.AimsTo examine if the implementation of specialized inpatient IBD care modified short-term and long-term clinical outcomes in IBD-related hospitalizations.MethodsThis retrospective cohort study included IBD patients hospitalized between July 2013 and April 2015 at a single tertiary referral center where a specialized inpatient IBD care model was implemented in July 2014. In-hospital medical and surgical outcomes as well as postdischarge outcomes at 30 and 90 days were analyzed along with measures of quality of in-hospital care. Effect of specialist IBD care was examined on multivariate analysis.ResultsA total of 408 IBD-related admissions were included. With implementation of specialized IBD inpatient care, we observed increased frequency of use of high-dose biologic therapy for induction (26% versus 9%, odds ratio 5.50, 95% confidence interval 1.30–23.17) and higher proportion of patients in remission at 90 days after discharge (multivariate odds ratio 1.60, 95% confidence interval 0.99–2.69). Although there was no difference in surgery by 90 days, among those who underwent surgery, early surgery defined as in-hospital or within 30 days of discharge, was more common in the study period (71%) compared with the control period (46%, multivariate odds ratio 2.73, 95% confidence interval 1.22–6.12). There was no difference in length of stay between the 2 years.ConclusionsImplementation of specialized inpatient IBD care beneficially impacted remission and facilitated early surgical treatment.

Study objectives: Minimal-access thymectomy has become increasingly popular as surgical treatment for patients with nonthymomatous myasthenia gravis (NTMG) because of its comparable efficacy, safety, and lesser degree of tissue trauma compared with conventional open surgery. We reviewed and analyzed our data on video-assisted thoracic surgery (VATS) thymectomy and present the clinical outcomes according to the Myasthenia Gravis Foundation of America classification. Design: A retrospective review of VATS thymectomy for NTMG in a university hospital over a 12-year period. Data were collected from the medical records and supplemented with telephone surveys. The impact of surgery and other variables potentially affecting complete stable remission (CSR) were calculated using Kaplan-Meier survival curves; comparisons between survival curves was performed using the log-rank test. Results: A total of 38 consecutive patients underwent VATS thymectomy for NTMG. Median postoperative stay was 3 days. Pathologic examination revealed thymic hyperplasia in 61.1% of cases, normal thymus in 22.2%, and thymic atrophy in 16.6%. There was no perioperative mortality; complications occurred in four patients. After a median follow-up of 69 months, 91.6% of patients experienced improvement, with crude CSR achieved in 22.2%. Kaplan-Meier survival curve demonstrated a 75% CSR rate at 10-year follow-up. On univariate analysis, only disease duration ≤ 12 months (p = 0.03) was associated with a statistically significant improvement in CSR. Conclusions: VATS thymectomy for NTMG results in symptomatic improvement in the vast majority of patients, with a high rate of CSR. The procedure is associated with low morbidity and no perioperative mortality. Future studies on thymectomy for myasthenia gravis should be reported in a standardized manner to allow accurate comparisons between results in the absence of randomized prospective trials.

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.

Mutational analysis for PRRT2 gene Exons of PRRT2 were amplified using polymerase chain reaction, of which its conditions and primer sequences for PRRT2 are available upon request. Mutational analysis for patient with paroxysmal kinesigenic dyskinesia for family 6Heterozygous NM_145239.2:c.379delG (NP_660282.2: p.Glu127Serfs*49) in exon 2 shown in the forward (sense) direction Discussion Familial PKD (OMIM#128200) is the most common type of paroxysmal movement disorder. The disease is caused by mutation of the PRRT2 gene (proline-rich transmembrane protein 2; OMIM*614386).2 3 PRRT2 mutation can also cause PKD/IC, paroxysmal exercise[-]induced dyskinesia, paroxysmal non-kinesigenic dyskinesia, benign familial infantile epilepsy, episodic ataxia, hemiplegic migraine, intellectual disability, and benign paroxysmal torticollis of infancy.4 5 Patients with PKD can be misdiagnosed with epilepsy or psychogenic illness6; an aetiological diagnosis will require genetic analysis of PRRT2 gene, the most common disease-causing gene for PKD. Most (79%) PKD patients had a distinctive phenotype.1 Atypical features have been reported, for example, long duration of attack,2 attacks triggered by stress/anxiety,3 and painful dystonia.14 This explains the unusual features observed in family 1 (painful dystonia, attacks precipitated by stress) and family 2 (attacks up to 3 minutes).

Cholesterol levels were also elevated with total cholesterol level of 23.1 mmol/L (reference value, [lesser than]5.2), high-density lipoprotein-cholesterol (HDL-C) level 0.5 mmol/L (reference value, [greater than]1.6), and high triglycerides (TG) level 11.8 mmol/L (reference value, [lesser than]1.7). Low-density lipoprotein cholesterol (LDL-C) level could not be calculated based on indirect quantitation with the Friedewald equation as per usual practice since TG level was [greater than]4.5 mmol/L; hence, it was measured directly and was normal at 0.2 mmol/L (reference value, [lesser than]4.1). Lipoprotein electrophoresis showed chylomicron and very low[-]density lipoprotein bands, and an additional beta-lipoprotein band that had migrated to cathode was detected, compatible with lipoprotein-X (Lp-X) [Fig a]. Unlike LDL-C, Lp-X does not contain Apo B, the most important ligand to the hepatic LDL-C receptor. Since Lp-X hypercholesterolaemia is not due to overproduction by hepatocytes, use of medications such as statins to downregulate cholesterol synthesis is ineffective.3 In addition, since Lp-X does not contain Apo B, which is the major component of LDL and one of the most important factors in the pathogenesis of atherosclerotic plaques, it is not atherogenic.4 Neither of our cases reported here had any complications of hypercholesterolaemia including exanthemata, retinal thromboembolism and pulmonary cholesteroloma.

Subclinical vascular impairment can be exacerbated in individuals who experience sustained inflammation after COVID-19 infection. Our study explores the prevalence and impact of autoantibodies on vascular dysfunction in healthy COVID-19 survivors, an area that remains inadequately investigated. Focusing on autoantibodies against the atypical chemokine receptor 1 (ACKR1), COVID-19 survivors demonstrated significantly elevated anti-ACKR1 autoantibodies, correlating with systemic cytokines, circulating damaged endothelial cells, and endothelial dysfunction. An independent cohort linked these autoantibodies to increased vascular disease outcomes during a median 6.7-yr follow-up. We analyzed a single-cell transcriptome atlas of endothelial cells from diverse mouse tissues, identifying enriched Ackr1 expressions in venous regions of the brain and soleus muscle vasculatures, which holds intriguing implications for tissue-specific venous thromboembolism manifestations reported in COVID-19. Functionally, purified immunoglobulin G (IgG) extracted from patient plasma did not trigger cell apoptosis or increase barrier permeability in human vein endothelial cells. Instead, plasma IgG enhanced antibody-dependent cellular cytotoxicity mediated by patient PBMCs, a phenomenon alleviated by blocking peptide or liposome ACKR1 recombinant protein. The blocking peptide uncovered that purified IgG from COVID-19 survivors possessed potential epitopes in the N-terminal extracellular domain of ACKR1, which effectively averted antibody-dependent cellular cytotoxicity. Our findings offer insights into therapeutic development to mitigate autoantibody reactivity in blood vessels in chronic inflammation.

Newborn screening is important for early diagnosis and effective treatment of inborn errors of metabolism (IEM). In response to a 2008 coroners' report of a 14-year-old boy who died of an undiagnosed IEM, the OPathPaed service model was proposed. In the present study, we investigated the feasibility of the OPathPaed model for delivering expanded newborn screening in Hong Kong. In addition, health care professionals were surveyed on their knowledge and opinions of newborn screening for IEM. The present prospective study involving three regional hospitals was conducted in phases, from 1 October 2012 to 31 August 2014. The 10 steps of the OPathPaed model were evaluated: parental education, consent, sampling, sample dispatch, dried blood spot preparation and testing, reporting, recall and counselling, confirmation test, treatment and monitoring, and cost-benefit analysis. A fully automated online extraction system for dried blood spot analysis was also evaluated. A questionnaire was distributed to 430 health care professionals by convenience sampling. In total, 2440 neonates were recruited for newborn screening; no true-positive cases were found. Completed questionnaires were received from 210 respondents. Health care professionals supported implementation of an expanded newborn screening for IEM. In addition, there is a substantial need of more education for health care professionals. The majority of respondents supported implementing the expanded newborn screening for IEM immediately or within 3 years. The feasibility of OPathPaed model has been confirmed. It is significant and timely that when this pilot study was completed, a government-led initiative to study the feasibility of newborn screening for IEM in the public health care system on a larger scale was announced in the Hong Kong Special Administrative Region Chief Executive Policy Address of 2015.