High Prevalence of Late-Onset Fabry Cardiomyopathy in a Cohort of 499 Non-Selective Patients with Left Ventricular Hypertrophy: The Asian Fabry Cardiomyopathy High-Risk Screening Study (ASIAN-FAME).

Left ventricular hypertrophy (LVH) caused by cardiac variant Fabry disease (FD) is typically late-onset and may mimic LVH caused by abnormal loading conditions. We aimed to determine the prevalence of FD in a non-selective patient population of everyday practice presenting with LVH, including those with hypertension and valve disease. We measured plasma alpha-galactosidase A activity using dried blood spot tests in 499 (age = 66 ± 13 years; 336 men) Hong Kong Chinese patients with LVH defined as maximal LV septal/posterior wall thickness ≥13 mm on echocardiography. Patients with low enzyme activity underwent mutation analysis of the GLA gene. Eight (age = 53-74 years; all men) unrelated patients (1.6%) had low plasma alpha-galactosidase A activity (0.57 ± 0.27 µmol/L wb/hr) and all were confirmed to have the GLA IVS4 + 919G > A mutation. FD patients presented with heart failure (n = 5), heart block (n = 2), ventricular tachycardia (n = 1), chest pain (n = 3), and/or murmur (n = 1). Uncontrolled hypertension (n = 4) and/or severe mitral/aortic valve pathology (n = 2) were frequent. Ethnic subgroups included Teochew (n = 5), Canton (n = 2), and Wenzhou (n = 1). Endomyocardial biopsy (n = 6) revealed hypertrophic myocytes with vacuolization and dense lamellar bodies. Late-onset IVS4 + 919G > A FD is prevalent among Chinese LVH patients, and should be considered as a cause of LVH in adult patients even when hypertension and/or valve pathology are present.

Modification to Neurology Residency Training: The Toronto Neurology COVID-19 Pandemic Experience.

We describe the University of Toronto Adult Neurology Residency Program's early experiences with and response to the coronavirus disease 2019 pandemic, including modifications to the provision of neurologic care while upholding neurology education and safety. All academic and many patient-related activities were virtualized. This maintained physical distancing while creating a city-wide videoconference-based teaching curriculum, expanding the learning opportunities to trainees at all academic sites. Furthermore, we propose a novel split-team model to promote resident safety through physical distancing of teams and to establish a capacity to rapidly adapt to redeployment, service needs, and trainee illness. Finally, we developed a unique protected code stroke framework to safeguard staff and trainees during hyperacute stroke assessments in this pandemic. Our shared experiences highlight considerations for contingency planning, maintenance of education, sustainability of team members, and promotion of safe neurologic care. These interventions serve to promote trainee safety, wellness, and resiliency.

Innovation in resident education - Description of the Neurology International Residents Videoconference and Exchange (NIRVE) program.

There is considerable heterogeneity in residency education around the world. The Neurology International Residents Videoconference and Exchange (NIRVE) program aims to deliver neurology educational content to residents across different resource settings and countries through a monthly videoconferencing platform. Its purpose is to fill gaps in didactic teaching, increase exposure to a variety of cases including various practices and delivery of neurology in multiple countries, as well as integrate global health content into neurology education. NIRVE also facilitates resident exchanges among participating sites. In this descriptive article, we report NIRVE's structure and its cumulative productivity. Since its creation, NIRVE has held more than 90 videoconference rounds and has connected 16 sites in North America, South America, Europe, Asia and Africa. We describe challenges encountered since the inception of the program eleven years ago. NIRVE also fosters a culture of long-term international connection and collaboration. During global disease outbreaks, such as the current COVID-19 pandemic, videoconference rounds serve as a sustainable alternative means to deliver education. Future goals include increasing the number of sites involved, including a focus on Africa and Asia, and fostering resident-led advocacy projects.

Screening for Fabry Disease in patients with unexplained left ventricular hypertrophy.

Fabry Disease (FD) is a systemic disorder that can result in cardiovascular, renal, and neurovascular disease leading to reduced life expectancy. FD should be considered in the differential of all patients with unexplained left ventricular hypertrophy (LVH). We therefore performed a prospective screening study in Edmonton and Hong Kong using Dried Blood Spot (DBS) testing on patients with undiagnosed LVH. Participants found to have unexplained LVH on echocardiography were invited to participate and subsequently subjected to DBS testing. DBS testing was used to measure α-galactosidase (α-GAL) enzyme activity and for mutation analysis of the α-galactosidase (GLA) gene, both of which are required to make a diagnosis of FD. DBS testing was performed as a screening tool on patients (n = 266) in Edmonton and Hong Kong, allowing for detection of five patients with FD (2% prevalence of FD) and one patient with hydroxychloroquine-induced phenocopy. Left ventricular mass index (LVMI) by GLA genotype showed a higher LVMI in patients with IVS4 + 919G > A mutations compared to those without the mutation. Two patients were initiated on ERT and hydroxychloroquine was discontinued in the patient with a phenocopy of FD. Overall, we detected FD in 2% of our screening cohort using DBS testing as an effective and easy to administer screening tool in patients with unexplained LVH. Utilizing DBS testing to screen for FD in patients with otherwise undiagnosed LVH is clinically important due to the availability of effective therapies and the value of cascade screening in extended families.

CHARGE syndrome in nine patients from China.

CHARGE syndrome (CS) is a multiple congenital anomalies condition with the majority of cases caused by dominant loss-of-function mutations of the CHD7 gene. It is clinically characterized by coloboma of the eyes, heart defects, choanal atresia, retardation of growth and/or development, genital and/or urinary anomalies and ear malformations associated with deafness and vestibular disorder(s). This case series reported nine molecularly confirmed Chinese CS patients from nine unrelated families in Hong Kong. Clinical phenotype and facial features of these nine Chinese CS patients together with four previously reported Chinese patients were reviewed. Typical presentations like coloboma and choanal atresia were not universally present. The prevalence of choanal atresia in these Chinese CS patients was found to be significantly lower than that in previous cohorts of other ethnic groups. This report highlighted the existence of phenotypic variation of CS among different ethnicities and suggested that a high index of suspicion is necessary for diagnosis of CS in Chinese patients.

Genetic landscape of RASopathies in Chinese: Three decades' experience in Hong Kong.

RASopathies are a group of genetic disorders due to dysregulation of the RAS-MAPK signaling pathway, which is important in regulating cell growth, proliferation, and differentiation. These include Noonan syndrome (NS), Noonan syndrome with multiple lentigines (NSML), cardiofaciocutaneous (CFC) syndrome, and Costello syndrome (CS), clinical manifestations include growth retardation, developmental delay, cardiac defects, and specific dysmorphic features. There were abundant publications describing the genotype and phenotype from the Western populations. However, detailed study of RASopathies in Chinese population is lacking. We present here the largest cohort of RASopathies ever reported in Chinese populations, detailing the mutation spectrum and clinical phenotypes of these patients. The Clinical Genetic Service, Department of Health, and Queen Mary Hospital are tertiary referral centers for genetic disorders in Hong Kong. We retrospectively reviewed all the genetically confirmed cases of RASopathies, including NS, NSML, CFC syndrome, and CS, over the past 29 years (from 1989 to 2017). Analyses of the mutation spectrum and clinical phenotypes were performed. One hundred and ninety-one ethnic Chinese patients with genetically confirmed RASopathies were identified, including 148 patients with NS, 23 NSML, 12 CFC syndrome, and eight CS. We found a lower incidence of hypertrophic cardiomyopathy in individuals with NSML (27.3%), and NS caused by RAF1 mutations (62.5%). Another significant finding was for those NS patients with myeloproliferative disorder, the mutations fall within Exon 3 of PTPN11 but not only restricted to the well-known hotspots, that is, p.Asp61 and p.Thr731, which suggested that re-evaluation of the current tumor surveillance recommendation maybe warranted.

The effectiveness of Dietary Approaches to Stop Hypertension (DASH) counselling on estimated 10-year cardiovascular risk among patients with newly diagnosed grade 1 hypertension: A randomised clinical trial.

BACKGROUND: The Dietary Approaches to Stop Hypertension (DASH) has been shown to lower blood pressure in the West. However, the real-life impact of DASH on reducing cardiovascular (CV) risk in routine clinical setting has not been studied. METHODS: A parallel-group, open-labelled, physician-blinded, randomised controlled trial was conducted in January-June 2013 and followed up for 6- and 12-months in primary care settings in Hong Kong. Patients newly diagnosed with grade 1 hypertension (aged 40-70years) who had no concomitant medical conditions requiring dietary modifications were consecutively recruited. Subjects were randomised to standard education (usual care) (n=275), or usual care plus dietitian-delivered DASH-based dietary counselling in a single one-to-one session (intervention) (n=281). Primary outcomes were the changes in estimated 10-year CV risk. RESULTS: Outcome data were available for 504 (90.6%) and 485 (87.2%) patients at 6 and 12months, respectively. There was no difference in the reduction of 10-year CV risk between the two groups at 6months (-0.13%, 95% confidence interval [95% CI] -0.50% to 0.23%, p=0.477) and 12months (-0.08%, 95% CI -0.33% to 0.18%, p=0.568). Multivariate regression analyses showed that male subjects, younger patients, current smokers, subjects with lower educational level, and those who dined out for main meals for ≥4 times in a typical week were significantly associated with no improvements in CV risk. CONCLUSIONS: The findings may not support automatic referral of newly diagnosed grade 1 hypertensive patients for further one-to-one dietitian counselling on top of primary care physician's usual care. Patients with those risk factors identified should receive more clinical attention to reduce their CV risk. CLINICAL TRIAL REGISTRATION: ChiCTR-TRC-13003014 (http://www.chictr.org.cn/enindex.aspx).

The adoption of the Reference Framework for diabetes care among primary care physicians in primary care settings: A cross-sectional study.

The prevalence of diabetes mellitus has been increasing both globally and locally. Primary care physicians (PCPs) are in a privileged position to provide first contact and continuing care for diabetic patients. A territory-wide Reference Framework for Diabetes Care for Adults has been released by the Hong Kong Primary Care Office in 2010, with the aim to further enhance evidence-based and high quality care for diabetes in the primary care setting through wide adoption of the Reference Framework.A valid questionnaire survey was conducted among PCPs to evaluate the levels of, and the factors associated with, their adoption of the Reference Framework.A total of 414 completed surveys were received with the response rate of 13.0%. The average adoption score was 3.29 (SD 0.51) out of 4. Approximately 70% of PCPs highly adopted the Reference Framework in their routine practice. Binary logistic regression analysis showed that the PCPs perceptions on the inclusion of sufficient local information (adjusted odds ratio [aOR] = 4.748, 95%CI 1.597-14.115, P = 0.005) and reduction of professional autonomy of PCPs (aOR = 1.859, 95%CI 1.013-3.411, P = 0.045) were more likely to influence their adoption level of the Reference Framework for diabetes care in daily practices.The overall level of guideline adoption was found to be relatively high among PCPs for adult diabetes in primary care settings. The adoption barriers identified in this study should be addressed in the continuous updating of the Reference Framework. Strategies need to be considered to enhance the guideline adoption and implementation capacity.

The incidence of all-cause, cardiovascular and respiratory disease admission among 20,252 users of lisinopril vs. perindopril: A cohort study.

BACKGROUND: Major international guidelines do not offer explicit recommendations on any specific angiotensin-converting enzyme inhibitor (ACEI) agent over another within the same drug group. This study compared the effectiveness of lisinopril vs. perindopril in reducing the incidence of hospital admission due to all-cause, cardiovascular disease and respiratory disease. METHODS: Adult patients who received new prescriptions of lisinopril or perindopril from 2001 to 2005 in all public hospitals and clinics in Hong Kong were included, and followed up for ≥2years. The incidence of admissions due to all-cause, cardiovascular disease and respiratory disease were evaluated, respectively, by using Cox proportional hazard regression models. The regression models were constructed with propensity score matching to minimize indication biases. RESULTS: A total of 20,252 eligible patients with an average age of 64.5years (standard deviation 15.0) were included. The admission rate at 24months within the date of index prescription due to any cause, cardiovascular disease and respiratory disease among lisinopril vs. perindopril users was 24.8% vs. 24.8%, 13.7% vs. 14.0% and 6.9% vs. 6.3%, respectively. Lisinopril users were significantly more likely to be admitted due to respiratory diseases (adjusted hazard ratios [AHR]=1.25, 95% CI 1.08 to 1.43, p=0.002 at 12months; AHR=1.17, 95% CI 1.04 to 1.31, p=0.009 at 24months) and all causes (AHR=1.12, 95% CI 1.05 to 1.19, p<0.001 at 24months) than perindopril users. CONCLUSIONS: These findings support intra-class differences in the effectiveness of ACEIs, which could be considered by clinical guidelines when the preferred first-line antihypertensive drugs are recommended.

The concept of human dignity in the ethics of genetic research.

Despite criticism that dignity is a vague and slippery concept, a number of international guidelines on bioethics have cautioned against research that is contrary to human dignity, with reference specifically to genetic technology. What is the connection between genetic research and human dignity? In this article, I investigate the concept of human dignity in its various historical forms, and examine its status as a moral concept. Unlike Kant's ideal concept of human dignity, the empirical or relational concept takes human dignity as something that is affected by one's circumstances and what others do. I argue that the dignity objection to some forms of genetic research rests on a view of human nature that gives humans a special status in nature - one that is threatened by the potential of genetic research to reduce individuals to their genetic endowment. I distinguish two main philosophical accounts of human nature. One of these, the Aristotelian view, is compatible with the use of genetic technology to help humans realize their inherent potential to a fuller extent.

Management of patients with spontaneous intracranial hypotension causing altered level of consciousness: report of two cases and review of literature.

BACKGROUND: Decreased level of consciousness is a rare neurological manifestation of spontaneous intracranial hypotension (SIH), which typically presents with orthostatic headache. The optimal management of this uncommon presentation remains uncertain. METHODS: We analyzed the presentation, management and outcome of two patients in our institution and reviewed 22 patients reported in the literature with SIH and decreased level of consciousness, defined as any decrease in the patient's Glasgow Coma Scale score. RESULTS: There were 20 male and four female patients (M:F ratio of 5:1) with an average age of 52 years (range 37 to 68 years). There was a variable time interval of up to many months between the initial presentation of SIH and changes in the level of consciousness. An epidural autologous blood patch was eventually successful in 79% of the patients, although up to three trials were necessary in seven of these patients. Intrathecal saline infusion used as a temporizing measure resulted in excellent response within hours in five out of six patients who received this treatment. Drainage of the subdural collection either did not result in any sustained improvement or resulted in clinical deterioration in 12 out of 12 patients who received this treatment. CONCLUSIONS: In the absence of a clinical trial because of the rarity of this entity, the treatment of SIH complicated by decreased level of consciousness remained controversial in the past. However, current collective experience supports early treatment of patients with SIH and decreased level of consciousness with one or more epidural blood patches. Fibrin glue and surgical duroplasty are the next steps in the management of patients in whom epidural blood patches fail. Drainage of the subdural collections may be detrimental.

Urinary incontinence should be added to the manifestation in women with Marfan syndrome.

INTRODUCTION AND HYPOTHESIS: We aimed to compare the incidence of urinary incontinence in women with Marfan syndrome and controls, hypothesizing that connective tissue abnormality could contribute to urinary incontinence. METHODS: A cross-sectional historical cohort study was conducted on 14 premenopausal women with Marfan syndrome and 534 controls using Urogenital Distress Inventory Short Form and Incontinence Impact Questionnaire Short Form. RESULTS: Marfan subjects had significantly higher incidence of urinary symptoms, stress urinary incontinence (SUI) and urge urinary incontinence (UUI) than controls (P = 0.02, P = 0.03, P = 0.02), despite their lower parity (P = 0.01). Direct logistic regression analysis indicated that Marfan syndrome, parity and age were associated with SUI; while Marfan syndrome was the only significant predictor of UUI. CONCLUSIONS: Premenopausal women with Marfan syndrome had a higher incidence of reported urinary symptoms. Urinary incontinence should be added to the list of clinical manifestations in women with Marfan syndrome.

US and Canadian physicians' attitudes and experiences regarding disclosing errors to patients.

BACKGROUND: Patients are often not told about harmful medical errors. The malpractice environment is considered a major determinant of physicians' willingness to disclose errors to patients. Yet, little is known about the malpractice environment's actual effect on physicians' error disclosure attitudes and experiences. METHODS: Mailed survey of 2637 physicians (62.9% response rate) in the United States (Missouri and Washington) and Canada, countries with different malpractice environments. RESULTS: Physicians' error disclosure attitudes and experiences were similar across country and specialty. Of the physicians, 64% agreed that errors are a serious problem. However, 50% disagreed that errors are usually caused by system failures. Ninety-eight percent endorsed disclosing serious errors to patients and 78% supported disclosing minor errors; 74% thought disclosing a serious error would be very difficult. Fifty-eight percent had disclosed a serious error to a patient, and 85% were satisfied with the disclosure, and 66% agreed that disclosing a serious error reduces malpractice risk. Respondents' estimates of the probability of lawsuits were not associated with their support for disclosure. The belief that disclosure makes patients less likely to sue (odds ratio, 1.58), not being in private practice (odds ratio, 1.47), being Canadian (odds ratio, 1.43), and being a surgeon (odds ratio, 1.26) were independently associated with higher support for disclosing serious errors. CONCLUSIONS: US and Canadian physicians' error disclosure attitudes and experiences are similar despite different malpractice environments, and reveal mixed feelings about disclosing errors to patients. The medical profession should address the barriers to transparency within the culture of medical and surgical specialties.

How surgeons disclose medical errors to patients: a study using standardized patients.

BACKGROUND: Calls are increasing for physicians to disclose harmful medical errors to patients, but little is known about how physicians perform this challenging task. For surgeons, communication about errors is particularly important since surgical errors can have devastating consequences. Our objective was to explore how surgeons disclose medical errors using standardized patients. METHODS: Thirty academic surgeons participated in the study. Each surgeon discussed 2 of 3 error scenarios (wrong-side lumpectomy, retained surgical sponge, and hyperkalemia-induced arrhythmia) with standardized patients, yielding a total of 60 encounters. Each encounter was scored by using a scale developed to rate 5 communication elements of effective error disclosure. Half of the encounters took place face-to-face; the remainder occurred by videoconference. RESULTS: Surgeons were rated highest on their ability to explain the medical facts about the error (mean scores for the 3 scenarios ranged from 3.93 to 4.20; maximum possible score, 5). Surgeons used the word error or mistake in only 57% of disclosure conversations, took responsibility for the error in 65% of encounters, and offered a verbal apology in 47%. Surgeons acknowledged or validated patients' emotions in 55% of scenarios. Eight percent discussed how similar errors would be prevented, and 20% offered a second opinion or transfer of care to another surgeon. CONCLUSIONS: The patient safety movement calls for disclosure of medical errors, but significant gaps exist between how surgeons disclose errors and patient preferences. Programs should be developed to teach surgeons how to communicate more effectively with patients about errors.

Basilar artery stenosis mimicking the lacunar syndrome of pure motor hemiparesis.

BACKGROUND: Stereotyped, repeated transient ischemic attacks manifesting as pure motor hemiparesis are most often attributed to ischemia of the internal capsule or ventral pons resulting from in situ disease of the small penetrating arteries. CASE DESCRIPTION: We report a 61-year-old man presenting with recurrent episodes of left-sided weakness consistent with the lacunar syndrome of pure motor hemiparesis. Subsequent neuroimaging revealed infarction of the right ventral pons and a critical basilar artery stenosis as the inciting lesion. Despite maximal antithrombotic therapy, he continued to have repeated symptoms. Angioplasty and stenting were attempted but both failed due to plaque recoil and technical difficulties. After the procedure, the patient had no further ischemic episodes and remained symptom-free at two months. CONCLUSIONS: This case illustrates the imprecise and discordant relationship between the mode of presentation of a stroke syndrome and its presumed pathophysiology. The lacunar syndrome of pure motor hemiparesis should be recognized by clinicians as a mode of stroke presentation due not only to small vessel disease, but also to large artery atherosclerotic disease such as basilar artery stenosis. Prompt institution of treatment can lead to a good clinical outcome.