Paracetamol-induced hepatotoxicity after normal therapeutic doses in the Hong Kong Chinese population.

INTRODUCTION: Paracetamol is generally safe at normal therapeutic doses of ≤4 g/day in adults. However, paracetamol-induced hepatotoxicity after normal therapeutic doses use has been reported. We investigated the epidemiology of this adverse drug reaction in the Hong Kong Chinese population. METHODS: This territory-wide retrospective observational study included adult patients with suspected paracetamol-induced hepatotoxicity after normal therapeutic doses use from January 2011 to June 2022. We evaluated the demographic characteristics; paracetamol dose, duration, and reason for use; preexisting hepatotoxicity risk factors; laboratory findings; and their relationship with clinical outcomes. RESULTS: We identified 76 patients (median age: 74 years, 23 males) with suspected paracetamolinduced hepatotoxicity after normal therapeutic doses use. There were 14 cases with significant clinical outcomes (five deaths and nine cases of acute hepatic failure), with an incidence of 1.2 cases per year. For patients with significant clinical outcomes, they were significantly older (age >80 years), had a lower body weight (<50 kg), exposed to longer durations (>2 days) and higher daily doses (>3 g), and with higher proportion of malnutrition. CONCLUSION: Paracetamol-induced hepatotoxicity can occur at normal therapeutic doses in the Hong Kong Chinese population. The identified risk factors are consistent with international guidelines regarding susceptible patients. Considering the widespread local use of paracetamol and low incidence of severe hepatotoxicity, the current dosage recommendations are considered safe for the general population. For susceptible patients, a reduced maximum dose of ≤3 g/day is recommended, with liver function and serum paracetamol monitoring in place.

Expression of Chondrogenic Potential Markers in Cultured Chondrocytes from the Human Knee Joint.

OBJECTIVES: While substantial progress has been made in engineering cartilaginous constructs for animal models, further research is needed to translate these methodologies for human applications. Evidence suggests that cultured autologous chondrocytes undergo changes in phenotype and gene expression, thereby affecting their proliferation and differentiation capacity. This study was designed to evaluate the expression of chondrogenic markers in cultured human articular chondrocytes from passages 3 (P3) and 7 (P7), beyond the current clinical recommendation of P3. METHODS: Cultured autologous chondrocytes were passaged from P3 up to P7, and quantitative polymerase chain reaction (qPCR) was used to assess mRNA expression of chondrogenic markers, including collagen type I (COLI), collagen type II (COLII), aggrecan (AGG), bone morphogenetic protein 4 (BMP4), transcription factor SOX-9 (SOX9), proteoglycan 4 (PGR4), and transformation-related protein 53 (p53), between P3 and P7. RESULTS: Except for AGG, no significant differences were found in the expression of markers between passages, suggesting the maintenance of chondrogenic potential in cultured chondrocytes. Differential expression identified between SOX9 and PGR4, as well as between COLI and SOX9, indicates that differences in chondrogenic markers are present between age groups and sexes, respectively. CONCLUSIONS: Overall, expression profiles of younger and male chondrocytes exhibit conversion of mature cartilage characteristics compared to their counterparts, with signs of dedifferentiation and loss of phenotype within-group passaging. These results may have implications in guiding the use of higher passaged chondrocytes for engineering constructs and provide a foundation for clinical recommendations surrounding the repair and treatment of articular cartilage pathology in both sexes.

Descriptive analysis of poisoning cases involving attention deficit hyperactivity disorder medications in Hong Kong.

INTRODUCTION: The number of poisoning cases involving attention deficit hyperactivity disorder (ADHD) medications has reportedly risen with their increased use. However, there is limited relevant evidence from Asia. We analysed the characteristics of poisoning events involving these medications in Hong Kong. METHODS: We retrieved data regarding ADHD medication-related poisoning cases from the Hong Kong Poison Information Centre and conducted a descriptive analysis of the demographic information and poisoning information including sources of cases, exposure reason, exposure location, and outcome. The HKPIC data were linked with the Hospital Authority Clinical Data Analysis and Reporting System (CDARS) via de-identified Accident and Emergency numbers of public hospitals to investigate clinical characteristics. We also retrieved ADHD medication prescription records from the CDARS, then compared trends between poisoning cases and ADHD medication use. RESULTS: We identified 72 poisoning cases involving ADHD medications between 2009 and 2019, of which approximately 70% occurred in the affected individual's residence; most were intentional poisoning events (65.3%). No statistically significant association was observed between ADHD medication prescription trends and poisoning events involving ADHD medications. Of the 66 cases (91.7%) successfully linked to CDARS, 40 (60.6%) occurred in individuals with ADHD (median age: 14 years); 26 (39.4%) occurred in individuals who lacked ADHD (median age: 33 years) but displayed higher rates of other mental disorders including depression and anxiety. CONCLUSION: No significant correlation was evident between ADHD medication prescriptions and poisoning events involving ADHD medications. However, medication management and caregiver education must be emphasised to prevent potential poisoning events.

Aberrant inflammation in rat pregnancy leads to cardiometabolic alterations in the offspring and intrauterine growth restriction in the F2 generation.

Children of women with pre-eclampsia have increased risk of cardiovascular (CV) and metabolic disease in adult life. Furthermore, the risk of pregnancy complications is higher in daughters born to women affected by pre-eclampsia than in daughters born after uncomplicated pregnancies. While aberrant inflammation contributes to the pathophysiology of pregnancy complications, including pre-eclampsia, the contribution of maternal inflammation to subsequent risk of CV and metabolic disease as well as pregnancy complications in the offspring remains unclear. Here, we demonstrate that 24-week-old female rats (F1) born to dams (F0) exposed to lipopolysaccharide (LPS) during pregnancy (to induce inflammation) exhibited mild systolic dysfunction, increased cardiac growth-related gene expression, altered glucose tolerance, and coagulopathy; whereas male F1 offspring exhibited altered glucose tolerance and increased visceral fat accumulation compared with F1 sex-matched offspring born to saline-treated dams. Both male and female F1 offspring born to LPS-treated dams had evidence of anemia. Fetuses (F2) from F1 females born to LPS-treated dams were growth restricted, and this reduction in fetal growth was associated with increased CD68 positivity (indicative of macrophage presence) and decreased expression of glucose transporter-1 in their utero-placental units. These results indicate that abnormal maternal inflammation can contribute to increased risk of CV and metabolic disease in the offspring, and that the effects of inflammation may cross generations. Our findings provide evidence in support of early screening for CV and metabolic disease, as well as pregnancy complications in offspring affected by pre-eclampsia or other pregnancy complications associated with aberrant inflammation.

Approaching the motional ground state of a 10-kg object.

The motion of a mechanical object, even a human-sized object, should be governed by the rules of quantum mechanics. Coaxing them into a quantum state is, however, difficult because the thermal environment masks any quantum signature of the object's motion. The thermal environment also masks the effects of proposed modifications of quantum mechanics at large mass scales. We prepared the center-of-mass motion of a 10-kilogram mechanical oscillator in a state with an average phonon occupation of 10.8. The reduction in temperature, from room temperature to 77 nanokelvin, is commensurate with an 11 orders-of-magnitude suppression of quantum back-action by feedback and a 13 orders-of-magnitude increase in the mass of an object prepared close to its motional ground state. Our approach will enable the possibility of probing gravity on massive quantum systems.

Vascularized Carotid Atherosclerotic Plaque Models for the Validation of Novel Methods of Quantifying Intraplaque Neovascularization.

BACKGROUND: Intraplaque neovascularization (IPN) in advanced lesions of the carotid artery has been linked to plaque progression and risk of rupture. Quantitative measurement of IPN may provide a more powerful tool for the detection of such "vulnerable" plaque than the current visual scoring method. The aim of this study was to develop a phantom platform of a neovascularized atherosclerotic plaque within a carotid artery to assess new methods of quantifying IPN. METHODS: Ninety-two synthetic plaque models with various IPN architectures representing different ranges of IPN scoring were created and assessed using contrast-enhanced ultrasound. Intraplaque neovascularization volume was calculated from contrast infiltration in B mode. The plaque models were used to develop a testing platform for IPN quantification. A neovascularized enhancement ratio (NER) was calculated using commercially available software. The plaque model NERs were then compared to human plaque NERs (n = 42) to assess score relationship. Parametric mapping of dynamic intensity over time was used to differentiate IPN from calcified plaque regions. RESULTS: A positive correlation between NER and IPN volume (rho = 0.45; P < .0001) was found in the plaque models. Enhancement of certain plaque model types showed that they resembled human plaques, with visual grade scores of 0 (NER mean difference = 1.05 ± SE 2.45; P = .67), 1 (NER mean difference = 0.22 ± SE 3.26; P = .95), and 2 (NER mean difference = -0.84 ± SE 3.33; P = .80). An optimal cutoff for NER (0.355) identified grade 2 human plaques with a sensitivity of 95% and specificity of 91%. CONCLUSIONS: We developed a carotid artery model of neovascularized plaque and established a quantitative method for IPN using commercially available technology. We also developed an analysis method to quantify IPN in calcified plaques. This novel tool has the potential to improve clinical identification of vulnerable plaques, providing objective measures of IPN for cardiovascular risk assessment.

Pre-hospital stroke screening and notification of patients with reperfusion-eligible acute ischaemic stroke using modified Face Arm Speech Time test.

OBJECTIVES: To investigate the effects of pre-hospital stroke screening and notification on reperfusion therapy for patients with acute ischaemic stroke. METHODS: Pre-hospital stroke screening criteria were established based on a modified version of the Face Arm Speech Time (FAST) test. Screening was performed during ambulance transport by emergency medical service (EMS) personnel who completed a 2-hour training session on stroke screening. Temporal trends affecting acute ischaemic stroke investigation and intervention were compared before and after implementation of the pre-hospital screening. RESULTS: From July 2018 to October 2019, 298 patients with suspected stroke were screened by EMS personnel during ambulance transport prior to hospital arrival. Of these 298 patients, 213 fulfilled the screening criteria, 166 were diagnosed with acute stroke, and 32 received reperfusion therapy. The onset-to-door time was shortened by more than 1.5 hours (100.6 min vs 197.6 min, P<0.001). The door-to-computed tomography time (25.6 min vs 32.0 min, P=0.021), door-to-needle time (49.2 min vs 70.1 min, P=0.003), and door-to-groin puncture time for intra-arterial mechanical thrombectomy (126.7 min vs 168.6 min, P=0.04) were significantly shortened after implementation of the pre-hospital screening and notification, compared with historical control data of patients admitted from January 2018 to June 2018, before implementation of the screening system. CONCLUSION: Implementation of pre-hospital stroke screening using criteria based on a modified version of the FAST test, together with pre-arrival notification, significantly shortened the door-to-reperfusion therapy time for patients with ischaemic stroke. Pre-hospital stroke screening during ambulance transport by EMS personnel who complete a 2-hour focused training session is effective for identifying reperfusion-eligible patients with stroke.

Quantum correlations between light and the kilogram-mass mirrors of LIGO.

The measurement of minuscule forces and displacements with ever greater precision is inhibited by the Heisenberg uncertainty principle, which imposes a limit to the precision with which the position of an object can be measured continuously, known as the standard quantum limit1-4. When light is used as the probe, the standard quantum limit arises from the balance between the uncertainties of the photon radiation pressure applied to the object and of the photon number in the photoelectric detection. The only way to surpass the standard quantum limit is by introducing correlations between the position/momentum uncertainty of the object and the photon number/phase uncertainty of the light that it reflects5. Here we confirm experimentally the theoretical prediction5 that this type of quantum correlation is naturally produced in the Laser Interferometer Gravitational-wave Observatory (LIGO). We characterize and compare noise spectra taken without squeezing and with squeezed vacuum states injected at varying quadrature angles. After subtracting classical noise, our measurements show that the quantum mechanical uncertainties in the phases of the 200-kilowatt laser beams and in the positions of the 40-kilogram mirrors of the Advanced LIGO detectors yield a joint quantum uncertainty that is a factor of 1.4 (3 decibels) below the standard quantum limit. We anticipate that the use of quantum correlations will improve not only the observation of gravitational waves, but also more broadly future quantum noise-limited measurements.

Frequency-Dependent Squeezing for Advanced LIGO.

The first detection of gravitational waves by the Laser Interferometer Gravitational-Wave Observatory (LIGO) in 2015 launched the era of gravitational-wave astronomy. The quest for gravitational-wave signals from objects that are fainter or farther away impels technological advances to realize ever more sensitive detectors. Since 2019, one advanced technique, the injection of squeezed states of light, is being used to improve the shot-noise limit to the sensitivity of the Advanced LIGO detectors, at frequencies above ∼50 Hz. Below this frequency, quantum backaction, in the form of radiation pressure induced motion of the mirrors, degrades the sensitivity. To simultaneously reduce shot noise at high frequencies and quantum radiation pressure noise at low frequencies requires a quantum noise filter cavity with low optical losses to rotate the squeezed quadrature as a function of frequency. We report on the observation of frequency-dependent squeezed quadrature rotation with rotation frequency of 30 Hz, using a 16-m-long filter cavity. A novel control scheme is developed for this frequency-dependent squeezed vacuum source, and the results presented here demonstrate that a low-loss filter cavity can achieve the squeezed quadrature rotation necessary for the next planned upgrade to Advanced LIGO, known as "A+."

Mechanically-induced osteophyte in the rat knee.

OBJECTIVES: Osteophytes are common anatomical signs of advanced osteoarthritis. It remains unclear whether they develop from physio-molecular, and/or mechanical stimuli. This study examined the effects of mechanical impact on the knee joint periosteum leading to osteophyte formation. DESIGN: Eighteen mature rats received one single impact load of 53 N (30 MPa) to the periosteum of the experimental medial femoral condyles. Contralateral knees were used as controls. Animals were sacrificed at 24 h, 3, 6 and 9 weeks post-impact. Distal femurs were harvested and prepared for histology. Hematoxylin and Eosin, and Masson's trichrome stained slides were examined by light microscopy. Nuclear density was quantified to assess the tissue reaction. RESULTS: 24 h: The synovium membrane, fibrous and cambium periosteum were damaged. Blood infiltration pooled in the impacted medial collateral ligament (MCL) region. Week 3: A cartilaginous tissue spur, chondrophyte, was found in every rat at the impacted site of the MCL. Chondrophytes were composed of fibrocartilage and cartilage matrix, with signs of cartilage mineralization and remodelling activity. Week 6: Chondrophytes presented signs of more advanced mineralisation, recognized as osteophytes. Week 9: Osteophytes appeared to be more mineralized with almost no cartilage tissue. CONCLUSIONS: Osteophytes can be induced with a single mechanical impact applied to the periosteum in rat knees. These data indicate that a moderate trauma to the periosteal layer of the joint may play a role in osteophyte development.

Quantum-Enhanced Advanced LIGO Detectors in the Era of Gravitational-Wave Astronomy.

The Laser Interferometer Gravitational Wave Observatory (LIGO) has been directly detecting gravitational waves from compact binary mergers since 2015. We report on the first use of squeezed vacuum states in the direct measurement of gravitational waves with the Advanced LIGO H1 and L1 detectors. This achievement is the culmination of decades of research to implement squeezed states in gravitational-wave detectors. During the ongoing O3 observation run, squeezed states are improving the sensitivity of the LIGO interferometers to signals above 50 Hz by up to 3 dB, thereby increasing the expected detection rate by 40% (H1) and 50% (L1).

Bone mineral density from early to middle adulthood in persons with Down syndrome.

BACKGROUND: While accelerated ageing is recognised among individuals with Down syndrome (DS), the trajectory of their bone health across adulthood remains poorly understood. METHODS: This study aimed to determine the age-related loss of bone mineral density (BMD) of the lumbar spine in 128 adults with DS aged 18 to 54 years compared with 723 counterparts without DS. RESULTS: Men and women with DS had lower level of BMD than counterparts without DS across age groups. Magnitude of decrement in BMD as reflected in the z-scores was similar between younger and older men with DS. Older women with DS, on the contrary, showed greater decrement in older ages especially in their fourth decade of life. Osteopenia and osteoporosis as defined using age-specific and gender-specific T-scores affected greater number of men with DS (38% and 25%) than women (17% and 17%) aged 40-49 years. CONCLUSIONS: Findings supported adults with DS, especially men, to have early bone mineral testing.

Efficacy and safety of naltrexone for amfetamine and methamfetamine use disorder: a systematic review of randomized controlled trials.

INTRODUCTION: Amfetamine and methamfetamine abuse remains a prevalent health problem, increasing the burden on healthcare. Naltrexone, a µ-opioid receptor antagonist, has been suggested as a promising treatment for amfetamine and methamfetamine use disorder. OBJECTIVE: To review the current evidence for the efficacy and safety of naltrexone as a pharmacological treatment for amfetamine and methamfetamine use disorder. The primary outcome was defined as abstinence or reduction of use. Secondary outcomes were, attenuated "positive" subjective effects (e.g., "feel good," "craving," etc.) of amfetamine or methamfetamine after naltrexone treatment, adverse events and physiological changes (e.g., blood pressure, heart rate). METHODS: This systematic review was conducted according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement. A systematic literature search was conducted on 2 April 2017, and updated on 31 March 2018. Records were retrieved from databases including PubMed, EMBASE Classic plus EMBASE 1980 via Ovid, and the databases were searched using keywords and/or headings: (naltrexone AND amfetamine AND dependence) OR (naltrexone AND amfetamine AND craving) OR (vivitrol AND amfetamine) OR (revia AND amfetamine) OR (naltrexone AND amfetamine) OR (naltrexone AND methamfetamine dependence) OR (naltrexone AND methamfetamine AND craving) OR (vivitrol AND methamfetamine) OR (revia AND methamfetamine) OR (naltrexone AND ice) OR (naltrexone AND crystal meth) OR (naltrexone AND methamfetamine). Studies investigating the effects of naltrexone on amfetamine or methamfetamine use were eligible for inclusion. All studies were rated as low risk of bias using the Cochrane tool for risk of bias. RESULTS: Among 591 identified studies, there were four randomized controlled trials. Two studies investigated the effects of naltrexone on amfetamine use disorder and two on methamfetamine use. Compared to placebo, the abstinence rate was increased significantly (p < 0.05) by naltrexone in one of two amfetamine studies, whereas there was no statistical difference in the only study reporting methamfetamine use. In one out of two amfetamine studies, naltrexone significantly attenuated either craving levels or subjective effects (e.g., "want more," "like effect") relative to placebo (p < 0.05). Additionally, only in one of two methamfetamine studies did naltrexone produce a significant reduction (p < 0.05) in craving levels or attenuated subjective effects. Both amfetamine and methamfetamine studies showed good tolerability of naltrexone, with few adverse events seen. CONCLUSIONS: There is presently insufficient evidence to support the use of naltrexone in amfetamine and metamfetamine use disorders. There is a compelling need for high-quality studies to further evaluate the potential use of naltrexone.

Developmental origins of pregnancy-induced cardiac changes: establishment of a novel model using the atrial natriuretic peptide gene-disrupted mice.

Pregnancy evokes many challenges on the maternal cardiovascular system that may unmask predispositions for future disease. This is particularly evident for women who develop pregnancy-related disorders, for example, pre-eclampsia and gestational diabetes or hypertension. Such pregnancy-related syndromes increase the risk for cardiovascular disease (CVD) postpartum. As a result, pregnancy has been termed as a cardiovascular stress test and an indicator or marker to predict the development of CVD later in life. In addition, pregnancy-related disorders impact the development of offspring also placing them at a higher risk for disease. Utilizing pregnancy as a physiological stressor, the current investigation sought to determine whether the cardiovascular system of offspring exposed to gestational hypertension in utero would respond adversely to the stress of pregnancy. Heterozygous atrial natriuretic peptide gene-disrupted (ANP+/-) offspring were generated by either crossing male wildtype ANP+/+ with female knockout ANP-/- to produce ANP+/-KO mice or crossing female wildtype ANP+/+ with male knockout ANP-/- to produce ANP+/-WT mice. To study the cardiovascular stress induced by pregnancy, female ANP+/-WT and ANP+/-KO mice were mated with male wildtype ANP+/+ mice to initiate pregnancy. Cardiac size and molecular expression of the renin-angiotensin (RAS) and natriuretic peptide systems (NPS) were compared between offspring groups. Our data demonstrate that gestational hypertension and lack of maternal ANP did not significantly impact the progression and regression of pregnancy-induced cardiac hypertrophy over gestation and postpartum in ANP+/- offspring. Additionally, the molecular cardiac expression of the RAS and NPS did not differ between offspring groups. Future investigation should assess potential differences in cardiac function and the impact of fetal-programming on offspring cardiovascular adaptations during pregnancy in more severe models of pregnancy-related hypertensive syndrome such as angiotensin II or isoproterenol infusion.

Emergency thrombectomy for acute ischaemic stroke: current evidence, international guidelines, and local clinical practice.

Acute ischaemic stroke due to large vessel occlusion leads to grave neurological morbidity and mortality. Conventional intravenous thrombolysis is ineffective in achieving timely reperfusion in this group of patients. The publication of five positive randomised controlled trials of emergency thrombectomy for acute ischaemic stroke in 2015 provided strong evidence to support endovascular reperfusion therapy and represented a paradigm shift in acute stroke management. In this article, we review the current evidence and international guidelines, and report on the findings of a survey study of the clinical practice and opinions of local neurologists, neurosurgeons, and interventional radiologists in emergency thrombectomy. We also discuss the controversies around thrombectomy treatment, local experience, and suggestions to incorporate thrombectomy in acute stroke treatment.

Injuries and envenomation by exotic pets in Hong Kong.

INTRODUCTION: Exotic pets are increasingly popular in Hong Kong and include fish, amphibians, reptiles, and arthropods. Some of these exotic animals are venomous and may cause injuries to and envenomation of their owners. The clinical experience of emergency physicians in the management of injuries and envenomation by these exotic animals is limited. We reviewed the clinical features and outcomes of injuries and envenomation by exotic pets recorded by the Hong Kong Poison Information Centre. METHODS: We retrospectively retrieved and reviewed cases of injuries and envenomation by exotic pets recorded by the Hong Kong Poison Information Centre from 1 July 2008 to 31 March 2017. RESULTS: There were 15 reported cases of injuries and envenomation by exotic pets during the study period, including snakebite (n=6), fish sting (n=4), scorpion sting (n=2), lizard bite (n=2), and turtle bite (n=1). There were two cases of major effects from the envenomation, seven cases with moderate effects, and six cases with mild effects. All major effects were related to venomous snakebites. There were no mortalities. CONCLUSION: All human injuries from exotic pets arose from reptiles, scorpions, and fish. All cases of major envenomation were inflicted by snakes.

Ageing in individuals with intellectual disability: issues and concerns in Hong Kong.

INTRODUCTION: The increasing longevity of people with intellectual disability is testimony to the positive developments occurring in medical intervention. Nonetheless, early-onset age-related issues and concerns cause deterioration of their overall wellbeing. This paper aimed to explore the issues and concerns about individuals with intellectual disability as they age. METHODS: Articles that discussed people older than 30 years with an intellectual disability and those that identified ageing health issues and concerns were included. Only studies reported in English from 1996 to 2016 were included. We searched PubMed, Google Scholar, and Science Direct using the terms 'intellectual disability', 'ageing', 'cognitive impairment', 'health', and 'screening'. RESULTS: Apart from the early onset of age-related health problems, dementia is more likely to develop by the age of 40 years in individuals with intellectual disability. Geriatric services to people with intellectual disability, however, are only available for those aged 60 years and older. Cognitive instruments used for the general population are not suitable for people with intellectual disability because of floor effects. In Hong Kong, the Chinese version of the Dementia Screening Questionnaire for Individuals with Intellectual Disabilities is the only validated instrument for people with intellectual disability. The use of appropriate measurement tools to monitor the progression of age-related conditions in individuals with intellectual disability is of great value. CONCLUSIONS: Longitudinal assessment of cognition and function in people with intellectual disability is vital to enable early detection of significant deterioration. This allows for therapeutic intervention before substantial damage to the brain occurs such as dementia that hastens cognitive and functional decline.