Expanded Newborn Screening for Inborn Errors of Metabolism in Hong Kong: Results and Outcome of a 7 Year Journey.

Newborn screening (NBS) is an important public health program that aims to identify pre-symptomatic healthy babies that will develop significant disease if left undiagnosed and untreated. The number of conditions being screened globally is expanding rapidly in parallel with advances in technology, diagnosis, and treatment availability for these conditions. In Hong Kong, NBS for inborn errors of metabolism (NBSIEM) began as a pilot program in October 2015 and was implemented to all birthing hospitals within the public healthcare system in phases, with completion in October 2020. The number of conditions screened for increased from 21 to 24 in April 2016 and then to 26 in October 2019. The overall recruitment rate of the NBS program was 99.5%. In the period between October 2015 and December 2022, 125,688 newborns were screened and 295 were referred back for abnormal results. The recall rate was reduced from 0.26% to 0.12% after the implementation of second-tier testing. An inherited metabolic disorder (IMD) was eventually confirmed in 47 infants, making the prevalence of IMD in Hong Kong 1 in 2674. At the time of the NBS result, 78.7% of the newborns with IMD were asymptomatic. There were two deaths reported: one newborn with methylmalonic acidemia cobalamin B type (MMACblB) died after the initial crisis and another case of carnitine palmitoyltransferase II deficiency (CPTII) died at 18 months of age after metabolic decompensation. The most common IMD noted were disorders of fatty acid oxidation metabolism (40%, 19 cases), closely followed by disorders of amino acid metabolism (38%, 18 cases), with carnitine uptake defect (19.1%, 9 cases) and citrullinemia type II (17%, 8 cases) being the two most common IMD picked up by the NBSIEM in Hong Kong. Out of the all the IMDs identified, 19.1% belonged to diverse ethnic groups. False negative cases were reported for citrullinemia type II and congenital adrenal hyperplasia during this period.

A case of G1013R FBN1 mutation: A potential genotype-phenotype correlation in severe Marfan syndrome.

Marfan Syndrome (MFS) is an autosomal dominant connective tissue disorder with a wide range of severities. Ninety-five percent of MFS probands have a mutation in the fibrillin-1 gene (FBN1); however, there are a high number of unique mutations complicating attempts at establishing any phenotype-genotype correlations for this disease (Tiecke et al., European Journal of Human Genetics, 2001, 9, 13-21). One of the few extant genotype-phenotype correlations is in exon 24-32 which have been associated with a severe pediatric presentation of neonatal MFS with predominately cardiovascular symptoms. We present a 24-year-old male patient with a heterozygous de novo variant NM_000138.4: c.3037G>A (p.G1013R) located in exon 25 of the FBN1 gene. The patient was found to have dysplastic mitral and tricuspid valves with dilated aortic root at 9 months of age. This is a notable case in that the location of this patient's mutation and his age of symptom onset would indicate a guarded prognosis. Further, this mutation, FBN1 G1013R, has been reported in the literature in four other unrelated patients all of whom presented at a young age with cardiac involvement and all of whom had relative longevity when compared to other patients with mutations in this exon 24-32 hot spot. These findings may represent a more specific genotype-phenotype correlation within this mutational hot spot.

Changes in Mortality and Cerebral Palsy in Extremely Low-Birth-Weight Infants in a Tertiary Center in Hong Kong.

Introduction. We retrospectively reviewed a cohort of extremely low-birth-weight (ELBW) babies born at Queen Mary Hospital and explored if there is any time trend in survival and short-term neurodevelopmental outcomes. Methods. We included ELBW infants born at Queen Mary Hospital between 2008 and 2015. The relationships between multiple risk factors with survival and neurodevelopmental outcomes were analyzed by either Cox regression or univariate logistic regression analysis. We also compared this birth-year period with our previous study from 1993 to 2002. Results. Two hundred seventeen ELBW infants were delivered during the study period. There was significantly higher overall survival rate (81.1%) in 2008 to 2015 compared with 71.4% in 1993 to 2002. One hundred forty-three out of 176 (81%) survivors were assessed at a corrected mean age of 18.1 months. A total of 4.2% had cerebral palsy. There were significantly lower rates of cerebral palsy in 2008 to 2015 (4.2%) compared with 1993 to 2002 (13.5%). Conclusions. We showed a temporal improvement in survival and short-term neurodevelopmental outcomes.

Rapid whole-exome sequencing facilitates precision medicine in paediatric rare disease patients and reduces healthcare costs.

BACKGROUND: Rapid whole-exome sequencing (rWES) offers the potential for early diagnosis-predicated precision medicine. Previous evidence focused predominantly on infants from the intensive care unit (ICU). This study sought to examine the diagnostic and clinical utility, and the economic impact on clinical management of rWES in patients beyond infancy and ICU setting. METHODS: rWES was performed on a prospective cohort of patients with suspected monogenic disorder referred from territory-wide paediatric ICUs and non-ICUs in Hong Kong urging for rapid genetic diagnosis. All eligible families were invited. We aimed to achieve a rapid turnaround time (TAT) of 14 days. Clinical utility and costs associated with clinical management were assessed in diagnosed cases. Actual quantitative changes in healthcare utilisation were compared with a counterfactual diagnostic trajectory and/or with matched historical control whenever possible. FINDINGS: rWES were offered to 102 families and 32/102 (31%) patients received a molecular diagnosis, with a median TAT of 11 days. Clinical management changed in 28 of 32 diagnosed patients (88%), including but not limited to modifications in treatment, avoidance of surgeries, and informing decisions on redirection of care. Cost analysis was performed in eight patients. rWES was estimated to reduce hospital length of stay by 566 days and decrease healthcare costs by HKD$8,044,250 (GBP£796,460) for these eight patients. The net cost-savings after inclusion of rWES costs were estimated to be HKD$5,325,187 (GBP£527,246). INTERPRETATION: This study replicates the diagnostic capacity and rapid TAT of rWES in predominantly Chinese patients, and demonstrates diagnosis-predicated precision medicine and net healthcare savings. Findings were corroborated by evidence from multinational cohorts, combined as part of a meta-analysis. rWES merits consideration as a first-tier diagnostic tool for patients with urgent needs in the clinical setting. FUNDING: Health and Medical Research Fund, HKU Seed Fund for Basic Research, The Society for the Relief of Disabled Children, and Edward and Yolanda Wong Fund.

Comparing the Quality of Cardiopulmonary Resuscitation Performed at the Over-the-Head Position and Lateral Position of Neonatal Manikin.

Background: Recent neonatal resuscitation guidelines suggest to perform chest compression (CC) at over-the-head (OTH) position instead of lateral position when further interventions including umbilical venous access are needed. Little information is available regarding the quality of cardiopulmonary resuscitation at different positions. Our study compared the quality of CC and ventilation at OTH position vs. lateral position in simulated neonatal resuscitation. Methods: Thirty-nine neonatal practitioners who attended the NRP®-based Provider renewal course workshop participated this study. Laerdal QCPR infant model were used to collect the data (2-miutes continuous recording) on quality of CC and ventilation of all participants at OTH position and lateral position in randomized order, both coordinated with mask ventilation or endotracheal ventilation through a Neopuff© T-piece system. The quality of CC and ventilation were compared. Participants also reported their demographics and opinions in anonymous questionnaires after the session. Results: The quality of CC and ventilation was not different when CPR was performed at OTH position and lateral position, in both mask and endotracheal ventilation. When CPR was performed with endotracheal ventilation, there were small faster frequencies of CC and ventilation at OTH position, compared with those at lateral position (p = 0.004). Most participants (87%) liked the CC performed at OTH position and had no adverse feedback. Conclusions: Performing CC at OTH position was generally well-received in simulated resuscitation; the quality of CC and ventilation at OTH position was not significantly different from that at lateral position, irrespective of mask or endotracheal ventilation.

Subthalamic nucleus deep brain stimulation for Parkinson's disease: evidence for effectiveness and limitations from 12 years' experience.

OBJECTIVE: To present the result and experience of subthalamic nucleus deep brain stimulation for Parkinson's disease. DESIGN: Case series. SETTING: Prince of Wales Hospital, Hong Kong. PATIENTS: A cohort of patients with Parkinson's disease received subthalamic nucleus deep brain stimulation from September 1998 to January 2010. Patient assessment data before and after the operation were collected prospectively. RESULTS: Forty-one patients (21 male and 20 female) with Parkinson's disease underwent bilateral subthalamic nucleus deep brain stimulation and were followed up for a median interval of 12 months. For the whole group, the mean improvements of Unified Parkinson's Disease Rating Scale (UPDRS) parts II and III were 32.5% and 31.5%, respectively (P<0.001). Throughout the years, a multidisciplinary team was gradually built. The deep brain stimulation protocol evolved and was substantiated by updated patient selection criteria and outcome assessment, integrated imaging and neurophysiological targeting, refinement of surgical technique as well as the accumulation of experience in deep brain stimulation programming. Most of the structural improvement occurred before mid-2005. Patients receiving the operation before June 2005 (19 cases) and after (22 cases) were compared; the improvements in UPDRS part III were 13.2% and 55.2%, respectively (P<0.001). There were three operative complications (one lead migration, one cerebral haematoma, and one infection) in the group operated on before 2005. There was no operative mortality. CONCLUSIONS: The functional state of Parkinson's disease patients with motor disabilities refractory to best medical treatment improved significantly after subthalamic nucleus deep brain stimulation. A dedicated multidisciplinary team building, refined protocol for patient selection and assessment, improvement of targeting methods, meticulous surgical technique, and experience in programming are the key factors contributing to the improved outcome.

Cost-effectiveness of subthalmic nucleus deep brain stimulation for the treatment of advanced Parkinson disease in Hong Kong: a prospective study.

BACKGROUND: Deep brain stimulation (DBS) is an effective but costly treatment for patients with advanced Parkinson disease (PD). This study examined the cost-effectiveness of DBS in relation to its improved effectiveness to help funding decision makers decide whether the treatment should be adopted. The incremental cost-effective ratio (ICER) per quality-adjusted life year has been benchmarked as being between US$50,000 and US$100,000 by US agencies, whereas it is less than €30,000 per quality-adjusted life year in Europe. OBJECTIVE: To provide cost-effectiveness information of subthalamic nucleus DBS for patients with advanced PD. MATERIALS: Direct medical expenses during the year before the DBS treatment were used to measure the baseline cost. Cost-effectiveness was measured by the ICER for the Unified Parkinson's Disease Rating Scale Part III and the ICER for the EuroQol Group's Health-Related Quality of Life measurement. RESULTS: Thirteen patients with advanced PD were recruited between January 2009 and January 2011. A 1-point improvement in the Unified Parkinson's Disease Rating Scale Part III score was associated with an ICER of US$926 in the first year and US$421 in the second year. A 1-point improvement on the EuroQol Group's Health-Related Quality of Life measurement was associated with an ICER of US$123,110 in the first year and US$62,846 in the second year. CONCLUSION: Cost-effectiveness of subthalamic nucleus DBS for treatment of advanced PD is greater during a 2-year period than 1 year only. These results can be used as a reference for the use of DBS for PD in a region with public health financing.

Single burr hole rigid endoscopic third ventriculostomy and endoscopic tumor biopsy: what is the safe displacement range for the foramen of Monro?

OBJECTIVE: To investigate the safe displacement range of the foramen of Monro (FM) during single burr hole rigid endoscopic third ventriculostomy (ETV) and endoscopic tumor biopsy (ETB). METHODS: Eleven patients who received ETV/ETB for third ventricular and pineal region tumor were reviewed. The burr-hole location, the size, and the virtual displacement of FM were measured using neuronavigation software. RESULTS: Hydrocephalus was resolved, and no subsequent cerebrospinal fluid (CSF) shunting was required in all cases. Histological diagnosis was established in 11 patients. Ten cases received instrumental cognitive and memory assessment postoperatively. The results were within the normal range for eight cases. The mean burr-hole location was 1.7 cm anterior to coronal suture and 3 cm from the midline. The mean diameters of FM measured on the axial, coronal, sagittal, and views were 5.7, 7.8, and 5.6 mm, respectively. The mean virtual displacements of the FM were 1.9±2.0 mm (range=0-4.8) for ETV and 2.4±2.1 mm (range=0-5.5) for ETB. The maximum displacements were 4.8 mm anteriorly for ETV and 5.5 mm posteriorly for ETB. CONCLUSION: Single burr hole rigid ETV/ETB is likely to be safe within maximum FM displacements of 4.8 mm anterior for ETV and 5.5 mm posterior for ETB. Preoperative trajectory planning using neuronavigation software is recommended.

Long-term cognitive dysfunction in patients with traumatic subarachnoid hemorrhage: prevalence and risk factors.

BACKGROUND: Cognition had recently been suggested as a supplement to traditional measures of neurological outcome. However, no data were available in the literature on long-term cognitive outcomes in patients with traumatic subarachnoid hemorrhage (tSAH). OBJECTIVE: We explored the long-term cognitive profiles of patients with tSAH who had returned to the community, and the risk factors associated with this event. METHODS: Patients with tSAH were contacted to obtain their consent to participate in the study of cognitive profiles and outcome. Forty-seven (42%) of 111 eligible patients completed all the assessments. RESULTS: Time from ictus to assessment ranged from 3 to 5 years. No difference in patient characteristics was observed between those who participated and those who did not. In patients with tSAH who had returned to the community, domain deficits and cognitive impairment were correlated with the extended Glasgow outcome scale (GOS-E), and were predicted by age and Glasgow coma scale (GCS) on admission. The accuracies of classifications were 79% and 81%, respectively. The number of domain deficits was also correlated with GOS-E, and was predicted by age, GCS on admission, and the extent of tSAH, with a total R (2) value of 50%. CONCLUSIONS: Long-term cognitive dysfunction is common after tSAH. In addition to GCS on admission and follow-up GOS-E, the extent of tSAH is an independent risk factor for the number of cognitive domain deficits that occur.

Natural history and medical treatment of cognitive dysfunction after spontaneous subarachnoid haemorrhage: review of current literature with respect to aneurysm treatment.

Aneurysmal subarachnoid haemorrhage (aSAH) has the highest mortality and morbidity among all types of stroke. Unfortunately, cognitive dysfunction remains a major problem to those who survive the acute crisis. Most studies focused on patients after microsurgical clipping, which turned out to be different from the modern patient cohorts. With the widespread introduction of endovascular surgery as the first choice of treatment, there was a hope that post-aSAH cognitive dysfunction could be markedly reduced. However, data showed that post-aSAH cognitive dysfunction remained a major burden to the survivors of our modern patient cohort that returned to the community more than nine months after the initial haemorrhage. There is, therefore, a need to further understand its pathophysiology and natural history, and to develop effective treatment strategy. The results are encouraging and further clinical studies are indicated. Collaborations between cognitive scientists, neurologists and neurosurgeons are essential to advance the understanding of the problem.

Complications of deep brain stimulation: a collective review.

BACKGROUND: Since the first deep brain stimulation (DBS) performed for movement disorder more than a decade ago, DBS has become a standard operation for advanced Parkinson's disease. Its indications are expanding to areas of dystonia, psychiatric conditions and refractory epilepsy. Additionally, a new set of DBS-related complications have arisen. Many teams found a slow learning curve from this complication-prone operation. We would like to investigate complications arising from 100 DBS electrode insertions and its prevention. METHODS: We performed an audit in all DBS patients for operation-related complications in our centre from 1997 to 2008. Complications were classified into operation-related, hardware-related and stimulation-related. Operation-related complications included intracranial haemorrhages and electrode malposition. Hardware-related complications included fracture of electrodes, electrode migration, infection and erosion. Stimulation-related complications included sensorimotor conditions, psychiatric conditions and life-threatening conditions. RESULTS: From 1997 to the end of 2008, 100 DBS electrodes were inserted in 55 patients for movement disorders, mostly for Parkinsons disease (50 patients). There was one symptomatic cerebral haemorrhage (1%) and two electrode malpositions (2%). Meticulous surgical planning, use of microdriver and a reliable electrode anchorage device would minimise this group of complications. There were two electrode fractures, one electrode migration and one pulse-generator infection which contributed to the hardware-related complication rate of 5%. There were no sensorimotor or life-threatening complications in our group. However, three patients suffered from reversible psychiatric symptoms after DBS. CONCLUSION: DBS is, on the one hand, an effective surgical treatment for movement disorders. On the other hand, it is a complication-prone operation. A dedicated "Movement Disorder Team" consisting of neurologists, neurophysiologists, functional neurosurgeons, neuropsychologists and nursing specialists is essential. Liaison among team members in peri-operative periods and postoperative care is the key to avoiding complications and having a successful patient outcome.

Clinical study on cognitive dysfunction after spontaneous subarachnoid haemorrhage: patient profiles and relationship to cholinergic dysfunction.

PURPOSE: We aimed to explore the cognitive profiles of subarachnoid haemorrhage patients who returned to the community, along with the associated risk factors. METHODS: We recruited 40 Chinese patients with spontaneous subarachnoid haemorrhage 7-27 months after the initial presentation. They had all been discharged to their homes or to care homes for the elderly. For cognitive assessment, we employed the Cognitive Subscale of the Alzheimer Disease Assessment Scale (ADAS-cog) for global cognitive function, the Frontal Assessment Battery (FAB) for frontal lobe function, and the Rivermead Behavioural Memory Test (RBMT) for everyday memory function. RESULTS: An ADAS-cog of more than 21/85 (poor global cognitive function) was noted in 14 (35%) patients. A FAB of less than 12/18 (poor frontal lobe function) was noted in 13 (27.5%) patients. An RBMT score of less than 15/26 (poor everyday memory function) was noted in 17 (43.6%) patients. Poor cognitive function was found to be associated with chronic hydrocephalus (in terms of FAB), with clinical vasospasm (in terms of RBMT), and with cerebral infarction (in terms of RBMT). CONCLUSIONS: Poor cognitive function was common and occurred in up to 43.6% of the patients, with the verbal and behavioural memory aspects predominantly affected. We did not find a significant association between cholinergic dysfunction and cognitive dysfunction. Organization of future drug trials and cognitive rehabilitation should take into account the association between frontal lobe dysfunction and chronic hydrocephalus.

Dynamic influences of culture on cooperation in the prisoner's dilemma.

This study tested whether priming of cultural symbols activates cultural behavioral scripts and thus the corresponding behaviors, and also whether the behaviors activated are context-specific. Specifically, to activate the cultural knowledge of Chinese-American bicultural participants, we primed them with Chinese cultural icons or American cultural icons. In the control condition, we showed them geometric figures. Then, the participants played the Prisoner's Dilemma game with friends or strangers (the context manipulation). As expected, participants showed more cooperation toward friends when Chinese cultural knowledge was activated than when American cultural knowledge was activated. By contrast, participants showed a similarly low level of cooperation toward strangers after both Chinese and American culture priming. These findings not only support previous evidence on culture priming of social judgment and self-construals, but also (a) provide the first evidence for the effects of culture priming on behaviors and (b) demonstrate the boundary condition of culture priming.

The developmental test of visual perception-2 normative study on the visual-perceptual function for children in Hong Kong.

This research study intended to investigate the visualperceptual performance of children in Hong Kong by comparing them to the accepted norms on the Developmental Test of Visual Perception-2nd edition. The research examined whether there was significant difference in child's gender, age, and grade. The normative study recruited two hundred and eight-nine children between the ages of 6 and 7 in normal primary schools in Hong Kong. Results indicated that there was a ceiling effect in eye-hand coordination, position in space and spatial relations subtests. Grade differences were found to be significant in all subtests except eye-hand coordination and visual-motor speed. On the other hand, there were no statistical difference in the test scores between boys and girls except on copying and figure-ground subtests. It is concluded that there is a strong need to ensure that norms for visual-perceptual tests are appropriate for the specific cultural groups being assessed.

Predicting intergroup bias: the interactive effects of implicit theory and social identity.

This research sought to integrate the implicit theory approach and the social identity approach to understanding biases in intergroup judgment. The authors hypothesized that a belief in fixed human character would be associated with negative bias and prejudice against a maligned group regardless of the perceiver's social identity. By contrast, a belief in malleable human character would allow the perceiver's social identity to guide intergroup perception, such that a common ingroup identity that includes the maligned group would be associated with less negative bias and prejudice against the maligned group than would an exclusive identity. To test these hypotheses, a correlational study was conducted in the context of the Hong Kong 1997 political transition to examine Hong Kong Chinese's perceptions of Chinese Mainlanders, and an experimental study was conducted in the United States to examine Asian Americans' perception of African Americans. Results from both studies supported the authors' predictions.

How are social identities linked to self-conception and intergroup orientation? The moderating effect of implicit theories.

Social identity approaches assume that social identification affects both self-conception and intergroup orientation. The authors contend that such social identification effects are accentuated when people hold a fixed view of human character and attribute immutable dispositions to social groups. To these individuals, social identities are immutable, concrete entities capable of guiding self-conception and intergroup orientation. Social identification effects are attenuated when people hold a malleable view of human character and thus do not view social identities as fixed, concrete entities. The authors tested and found support for this contention in three studies that were conducted in the context of the Hong Kong 1997 political transition, and discussed the findings in terms of their implications for self-conceptions and the meaning of social identification.