Glycaemic control and microvascular complications among paediatric type 2 diabetes mellitus patients in Hong Kong at 2 years after diagnosis.

INTRODUCTION: Type 2 diabetes mellitus (T2DM) is becoming increasingly common among children and adolescents worldwide, including those in Hong Kong. This study analysed the characteristics and prevalence of microvascular complications among paediatric T2DM patients in Hong Kong at diagnosis and 2 years after diagnosis. METHODS: All patients aged <18 years who had been diagnosed with DM at public hospitals in Hong Kong were recruited into the Hong Kong Childhood Diabetes Registry. Data collected at diagnosis and 2 years after diagnosis were retrospectively retrieved from the Registry for patients diagnosed from 2014 to 2018. RESULTS: Median haemoglobin A1c (HbA1c) levels were 7.5% (n=203) at diagnosis and 6.5% (n=135) 2 years after diagnosis; 59.3% of patients achieved optimal glycaemic control (HbA1c level <7%) at 2 years. A higher HbA1c level at diagnosis was associated with worse glycaemic control at 2 years (correlation coefficient=0.39; P<0.001). The presence of dyslipidaemia (adjusted odds ratio [aOR]=3.19; P=0.033) and fatty liver (aOR=2.50; P=0.021) at 2 years were associated with suboptimal glycaemic control. Diabetic neuropathy and retinopathy were rare in our cohort, but 18.6% of patients developed microalbuminuria (MA) within 2 years after diagnosis. Patients with MA had a higher HbA1c level at 2 years (median: 7.2% vs 6.4%; P=0.037). Hypertension was a risk factor for MA at 2 years, independent of glycaemic control (aOR=4.61; P=0.008). CONCLUSION: These results highlight the importance of early diagnosis and holistic management (including co-morbidity management) for paediatric T2DM patients.

The Double-Edged Sword of ROS in Muscle Wasting and COPD: Insights from Aging-Related Sarcopenia.

An elevation in reactive oxygen species (ROS) is widely accepted to be a key mechanism that drives chronic obstructive pulmonary disease (COPD) and its major co-morbidity, skeletal muscle wasting. However, it will be perhaps a surprise to many that an elevation in ROS in skeletal muscle is also a critical process for normal skeletal muscle function and in the adaptations to physical exercise. The key message here is that ROS are not solely detrimental. This duality of ROS suggests that the mere use of a broad-acting antioxidant is destined to fail in alleviating skeletal muscle wasting in COPD because it will also be influencing critical physiological ROS-dependent processes. Here, we take a close look at this duality of ROS in skeletal muscle physiology and pathophysiology pertaining to COPD and will aim to gain critical insights from other skeletal muscle wasting conditions due to aging such as sarcopenia.

Moving Apart, Coming Together: The Formation of an LGBTQ Movement Community in South Korea.

This study examines the emergence and development of a social movement community among LGBTQ population. Drawing on the case of the LGBTQ movement in South Korea between 1993 and 2019 from a longitudinal perspective, we identify the relational dynamics of how different movement groups avoid internal frictions and successfully develop a movement community. Our findings suggest that, as a response to repeated repressive external events, LGBTQ groups have formed and maintained collaborative networks based on a common identity as "sexual minorities." By examining the networks of movement coalitions, we also identify key movement groups that played a critical role in connecting other groups with disparate sexual and gender identities within the community. These bridging actors were either the pioneering gay and lesbian groups that have collaborated since the 1990s or the new groups founded around inclusive collective identities such as "sexual minorities" or "queers." Implications for the studies on social movements and homosexuality are discussed.

Factor analysis of the Chinese version of the Autism Spectrum Quotient 10 and its association with schizotypal traits in adolescents and young adults in Hong Kong.

BACKGROUND: There is evidence suggesting that autistic traits are associated with schizotypal traits. This study examined the factor structure of the Autism Spectrum Quotient 10 (AQ-10) and its associations with schizotypal traits (measured by the Schizotypal Personality Questionnaire-Brief [SPQ-B]) in a cohort of Chinese adolescents and young adults. METHODS: Invitation letters, stratified by locations and housing types, were randomly sent to individuals aged 15 to 24 years for participation. Assessments were made using face-to-face or online interviews. Autistic traits were assessed using the Chinese version of the AQ-10. Schizotypal personality traits were assessed using the Chinese version of the 22-item SPQ-B. RESULTS: In total, 395 male and 536 female participants (mean age, 19.93 years) were recruited between July 2020 and May 2021. Exploratory factor analysis of the AQ-10 yielded three factors (theory of mind, task switching, and attention deficits) explaining 55.11% of the total variance. Autistic traits were positively correlated with schizotypal traits of disorganised features (r = 0.21, p < 0.001), interpersonal relationship deficits (r = 0.19, p < 0.001), and cognitive-perceptual deficits (r = 0.11, p = 0.001). CONCLUSION: In Chinese adolescents and young adults, autistic traits, especially task switching and attention deficits (compared with theory of mind) are more closely correlated with schizotypal personality traits. Disentangling the overlapping and diametrical structure of autistic traits and schizotypal traits may help understand their aetiologies, assessment, and interventions.

The Utility of Sirolimus Eluting Balloons in the Setting of Chronic Limb Threatening Ischaemia in Asian Patients from Singapore - 12 Months Results of the PRISTINE Registry.

PURPOSE: The aim of PRISTINE was to evaluate the 6 and 12 months safety and efficacy of the Selution Sustained Limus Release (SLR)™ sirolimus-coated balloon for treatment of complex lower limb occlusive lesions (TASC II C & D) in patients with chronic limb threatening ischemia (CLTI) from Singapore. METHODS: PRISTINE was a prospective, non-randomized, single arm, observational, multi-investigator, single-center clinical study. Complication-free survival at 30 days was the safety clinical endpoint. Immediate technical success (ability to cross and dilate the lesion and achieve residual angiographic stenosis < 30%), 6-month primary vessel patency, limb salvage, clinically driven target lesion revascularization (TLR) and amputation free survival (AFS) were the efficacy endpoints of interest. RESULTS: Seventy five patients were included. There were 50 (68.0%) males; mean age, 69.0 ± 10.7 years. CLTI severity was based on the Rutherford Scale (R5 = 51; R6 = 17). Significant co-morbidities included diabetes mellitus (n = 68; 91.0%) and end-stage renal failure (n = 28; 37.0%). 112 atherosclerotic lesions were treated (TASC II D = 58 (52%); 76 (67%) de novo). There was 100% technical success. Mean lesion length treated was 22.4 ± 13.9 cm. Primary vessel patencies at 6 and 12 months were 64/86 (74%) and 43/74 (58%) and freedom from clinically driven TLR were 72/86 (84%) and 55/74 (74%) respectively. AFS was 61/73 (84.0%; five deaths and seven major lower extremity amputation) at 6-months. Mean Rutherford score improved from 5.1 ± 0.55 at baseline to 1.1 ± 2.05 (p < 0.05) at one year and there was a wound healing rate of 38/48 (79%) at the same timepoint. CONCLUSIONS: The Selution SLR™ drug eluting balloon is safe and efficacious in treating highly complex infra-inguinal atherosclerotic lesions in an otherwise challenging frail population of CLTI patients with a high incidence of diabetes and end-stage renal failure. It is associated with highly satisfactory acute technical and clinical success, 12-month target lesion patency and AFS. LEVEL OF EVIDENCE: Level 2b, Individual Cohort Study.

Predictors of malignancy in melanocytic lesions presenting as new lesions compared to baseline total body photography: A case-control study.

BACKGROUND: Only a small per cent of new melanocytic lesions developing in adults are expected to represent melanomas. Total body photography (TBP) has been widely incorporated in clinical practice, especially for follow-up of high-risk individuals with multiple naevi. However, dynamic changes detected with TBP need to be interpreted with caution to avoid unnecessary excisions. OBJECTIVES: To identify clinical and dermoscopic predictors of malignancy in melanocytic lesions presenting clinically as new lesions on TBP. METHODS: Melanomas and melanocytic naevi excised from a high-risk cohort and presenting as new lesions on TBP were retrospectively included. Naevi were arbitrarily collected up to approximately twice the number of melanomas. Melanomas were categorized as 'unequivocal' or 'borderline' on histopathology review. RESULTS: Sixty melanomas and 110 naevi were included. Median age (range) of cases (55; 27-83) was 9 years older than controls (46; 24-77) (p < 0.0001). Median diameter (IQR) of naevi was 2.6 mm (1.8-3.8) and of melanomas 4.2 mm (2.7-7.0) (p < 0.0001). On histopathology, 40% of the melanomas were 'borderline'. A positive 7-point checklist was reported in 12.5% of 'borderline' melanomas and 33.3% of 'unequivocal' melanomas (p = 0.005), while 18.3% of melanomas were completely featureless. Blue-whitish veil, atypical vascular pattern and shiny white lines were exclusively found in melanomas. The main predictors of malignancy were (OR; 95% CI) regression structures (7.13; 1.88-27.06; p = 0.004); hypo/amelanotic colour (6.00; 1.17-30.73; p = 0.03); irregular pigmentation (3.89; 1.36-11.13; p = 0.01); asymmetrical peripheral dots/globules (3.50; 1.11-11.00; p = 0.03); and asymmetry in pattern and/or colour (2.5; 1.3-4.9; p = 0.007). All invasive melanomas detected in patients younger than 50 years presented at least one dermoscopic predictor of malignancy. CONCLUSIONS: Melanomas presenting as new lesions are frequently featureless or feature poor on dermoscopy and difficult-to-diagnose on histopathology. In high-risk patients, the presence on any of the dermoscopic predictors of malignancy identified should prompt excision; however, the remaining lesions should be closely monitored.

Mobilizing grievances in the internet age: The case of national online petitioning in South Korea, 2017-2022.

Which kinds of grievances garner support from the public on online platforms? Focusing on national online petitioning, one of the forms of direct democracy in contemporary politics, we examine the content and characteristics of petitions that succeeded in attracting public attention and support. Using our comprehensive data on online petitions that were submitted to the executive office between 2017 and 2022 in South Korea, our analysis yields three important findings. First, a mix of post-materialist topics such as human rights and gender equality and materialist topics such as safety and environment turn out to be salient among petitions that meet the signature threshold. Second, online petitions the contents of which reveal either moral emotions or Confucian attitudes are more likely to gain public support compared to others. Third, keywords that are related to moral claims asking for the apprehension of perpetrators on behalf of victims, such as 'victim,' 'perpetrator,' 'kid,' and 'punishment,' appear most frequently inside the petitions that cross the signature threshold. Such findings provide implications for understanding both the potentials and limitations of national online petitioning in contemporary democracies.

The hatred of all against all? Evidence from online community platforms in South Korea.

BACKGROUND: Over several years of recent efforts to make sense and detect online hate speech, we still know relatively little about how hateful expressions enter online platforms and whether there are patterns and features characterizing the corpus of hateful speech. OBJECTIVE: In this research, we introduce a new conceptual framework suitable for better capturing the overall scope and dynamics of the current forms of online hateful speech. METHODS: We adopt several Python-based crawlers to collect a comprehensive data set covering a variety of subjects from a multiplicity of online communities in South Korea. We apply the notions of marginalization and polarization in identifying patterns and dynamics of online hateful speech. RESULTS: Our analyses suggest that polarization driven by political orientation and age difference predominates in the hateful speech in most communities, while marginalization of social minority groups is also salient in other communities. Furthermore, we identify a temporal shift in the trends of online hate from gender to age based, reflecting the changing sociopolitical conditions within the polarization dynamics in South Korea. CONCLUSION: By expanding our understanding of how hatred shifts and evolves in online communities, our study provides theoretical and practical implications for both researchers and policy-makers.

Hong Kong consensus recommendations on the management of pancreatic ductal adenocarcinoma.

This project was undertaken to develop the first set of consensus statements regarding the management of pancreatic ductal adenocarcinoma (PDAC) in Hong Kong, with the goal of providing guidance to local clinicians. A multidisciplinary panel of experts discussed issues surrounding current PDAC management and reviewed evidence gathered in the local context to propose treatment recommendations. The experts used the Delphi approach to finalise management recommendations. Consensus was defined as ≥80% acceptance among all expert panel members. Thirty-nine consensus statements were established. These statements cover all aspects of PDAC management, including diagnosis, resectability criteria, treatment modalities according to resectability, personalised management based on molecular profiling, palliative care, and supportive care. This project fulfils the need for guidance regarding PDAC management in Hong Kong. To assist clinicians with treatment decisions based on varying levels of evidence and clinical experience, treatment options are listed in several consensus statements.

Four-year overall survival update from the phase III HIMALAYA study of tremelimumab plus durvalumab in unresectable hepatocellular carcinoma.

BACKGROUND: In the phase III HIMALAYA study (NCT03298451) in unresectable hepatocellular carcinoma (uHCC), STRIDE (Single Tremelimumab Regular Interval Durvalumab) significantly improved overall survival (OS) versus sorafenib; durvalumab monotherapy was noninferior to sorafenib for OS. Results reported herein are from a 4-year updated OS analysis of HIMALAYA. PATIENTS AND METHODS: Participants with uHCC and no previous systemic treatment were randomized to STRIDE (n = 393), durvalumab (n = 389), or sorafenib (n = 389). The updated data cut-off was 23 January 2023. OS and serious adverse events (AEs) were assessed. Additionally, baseline characteristics and subsequent therapies were analyzed in long-term survivors (≥36 months beyond randomization). RESULTS: For STRIDE, durvalumab, and sorafenib, median [95% confidence interval (CI)] follow-up was 49.12 months (46.95-50.17 months), 48.46 months (46.82-49.81 months), and 47.31 months (45.08-49.15 months), respectively. OS hazard ratio (95% CI) for STRIDE versus sorafenib was 0.78 (0.67-0.92). The 36-month OS rate for STRIDE was 30.7% versus 19.8% for sorafenib. The 48-month OS rate remained higher for STRIDE at 25.2%, versus 15.1% for sorafenib. The long-term OS benefit of STRIDE was observed across clinically relevant subgroups and was further improved in participants who achieved disease control. Long-term survivors with STRIDE (n = 103) included participants across clinically relevant subgroups, and 57.3% (59/103) had no reported subsequent anticancer therapy. No new serious treatment-related AEs occurred with STRIDE from the primary analysis (17.5%; 68/388). Durvalumab maintained OS noninferiority to sorafenib and no late-onset safety signals were identified. CONCLUSIONS: These data represent the longest follow-up to date in phase III studies in uHCC. The unprecedented 3- and 4-year OS rates reinforce the sustained long-term OS benefit of STRIDE versus sorafenib. STRIDE maintained a tolerable yet differentiated safety profile from other current uHCC therapies. Results continue to support the long-term benefits of STRIDE in a diverse population, reflective of uHCC globally.

Between ethnic diversity and immigration: Perceptions toward immigrants in a globalizing world.

This study examines how ethnic diversity and immigration at the national level influence individual perceptions toward immigrants in a cross-national context. Including both Western and non-Western countries, we specifically explore whether cumulative exposure to ethnic diversity and the current size of immigrants have dissimilar effects on individual perceptions. Results from multilevel regression analysis suggest that the level of ethnic diversity is positively associated with perceptions toward immigrants, while the number of immigrants is negatively related to immigrant perceptions. Furthermore, we find that social capital matters in reshaping these relationships: At least for individuals having high levels of social capital, the relationship between living in an ethnically diverse society and their favorable perceptions toward immigrants is strengthened while the association between observing a large number of immigrants and having negative perceptions is weakened. This research provides implications for understanding cross-national difference of individual perceptions on immigrants in our diversifying world.

Cross-sectional study to assess the psychological morbidity of women facing possible miscarriage.

INTRODUCTION: Threatened miscarriage is a common complication of pregnancy. This study aimed to assess psychological morbidity in women with threatened miscarriage, with the goal of identifying early interventions for women at risk of anxiety or depression. METHODS: Women in their first trimester attending an Early Pregnancy Assessment Clinic were recruited between July 2013 and June 2015. They were asked to complete the 12-item General Health Questionnaire (GHQ-12), the Beck Depression Inventory (BDI), Spielberger's State Anxiety Inventory State form (STAI-S), the Fatigue Scale-14 (FS-14), and the Profile of Mood States (POMS) before consultation. They were also asked to rate anxiety levels before and after consultation using a visual analogue scale (VAS). RESULTS: In total, 1390 women completed the study. The mean ± standard deviation of GHQ-12 (bi-modal) and GHQ-12 (Likert) scores were 4.04 ± 3.17 and 15.19 ± 5.30, respectively. Among these women, 48.4% had a GHQ-12 (bi-modal) score ≥4 and 76.7% had a GHQ-12 (Likert) score >12, indicating distress. The mean ± standard deviation of BDI, STAI-S, and FS-14 scores were 9.35 ± 7.19, 53.81 ± 10.95, and 2.40 ± 0.51, respectively. The VAS score significantly decreased after consultation (P<0.001). Compared with women without a history of miscarriage, women with a previous miscarriage had higher GHQ-12, BDI, and POMS scores (except for fatigue-inertia and vigour-activity subscales). A higher bleeding score was strongly positively correlated with GHQ-12 (Likert) score. There were weak correlations between pain score and the GHQ-12 (bi-modal) ≥4, BDI >12, and POMS scores (except for confusion-bewilderment subscale which showed a strong positive correlation). CONCLUSION: Women with threatened miscarriage experience a considerable psychological burden, emphasising the importance of early recognition for timely management.

Risks and impacts of thromboembolism in patients with pancreatic cancer.

INTRODUCTION: Patients with pancreatic cancer have a high risk of thromboembolism (TE), which may increase mortality. Most relevant studies have been conducted in Western populations. We investigated risk factors for TE in a predominantly Chinese population of patients with pancreatic cancer, along with effects of TE on overall survival. METHODS: This retrospective cohort study included patients diagnosed with exocrine pancreatic cancer in Prince of Wales Hospital in Hong Kong between 2010 and 2015. Data regarding patient demographics, World Health Organization performance status, stage, treatment, TE-related information, and time of death (if applicable) were retrieved from electronic medical records. Univariate and multivariable logistic regression analyses were performed to identify risk factors for TE. Survival analyses were performed using Kaplan-Meier analysis and Cox proportional hazards regression. RESULTS: In total, 365 patients were included in the study. The overall incidence of TE (14.8%) was lower than in Western populations. In univariate logistic regression analysis, stage IV disease and non-head pancreatic cancer were significantly associated with TE (both P=0.01). Multivariable logistic regression analysis showed that stage IV disease was a significant risk factor (odds ratio=1.08, 95% confidence interval [CI]=1.00-1.17; P=0.046). Median overall survival did not significantly differ between patients with and without TE (4.88 months vs 7.80 months, hazard ratio=1.08, 95% CI=0.80-1.49; P=0.58) and between patients with TE who received anticoagulation treatment or not (5.63 months vs 4.77 months, hazard ratio=0.72, 95% CI=0.40-1.29; P=0.27). CONCLUSION: The incidence of TE was low in our Chinese cohort. Stage IV disease increased the risk of TE. Overall survival was not affected by TE or its treatment.

Protocol for the Brain Health Support Program Study of the Canadian Therapeutic Platform Trial for Multidomain Interventions to Prevent Dementia (CAN-THUMBS UP): A Prospective 12-Month Intervention Study.

BACKGROUND/OBJECTIVES: CAN-THUMBS UP is designed as a comprehensive and innovative fully remote program to 1) develop an interactive and compelling online Brain Health Support Program intervention, with potential to positively influence dementia literacy, self-efficacy and lifestyle risk factors; 2) enroll and retain a community-dwelling Platform Trial Cohort of individuals at risk of dementia who will participate in the intervention; 3) support an open platform trial to test a variety of multidomain interventions that might further benefit individuals at risk of dementia. This manuscript presents the Brain Health Support Program Study protocol. DESIGN/SETTING: Twelve-month prospective multi-center longitudinal study to evaluate a fully remote web-based educational intervention. Participants will subsequently be part of a Platform Trial Cohort and may be eligible to participate in further dementia prevention clinical trials. PARTICIPANTS: Three hundred fifty older adults who are cognitively unimpaired or have mild cognitive impairment, with at least 1 well established dementia risk factor. INTERVENTION: Participants engage in the Brain Health Support Program intervention for 45-weeks and complete pre/post intervention measures. This intervention is designed to convey best available evidence for dementia prevention, consists of 181 chapters within 8 modules that are progressively delivered, and is available online in English and French. The program has been developed as a collaborative effort by investigators with recognized expertise in the program's content areas, along with input from older-adult citizen advisors. MEASUREMENTS: This study utilizes adapted remote assessments with accessible technologies (e.g. videoconferencing, cognitive testing via computer and mobile phone, wearable devices to track physical activity and sleep, self-administered saliva sample collection). The primary outcome is change in dementia literacy, as measured by the Alzheimer's Disease Knowledge Scale. Secondary outcomes include change in self-efficacy; engagement using the online program; user satisfaction ratings; and evaluation of usability and acceptance. Exploratory outcomes include changes in attitudes toward dementia, modifiable risk factors, performance on the Neuropsychological Test Battery, performance on self-administered online cognitive assessments, and levels of physical activity and sleep; success of the national recruitment plan; and the distribution of age adjusted polygenic hazard scores. CONCLUSIONS: This fully remote study provides an accessible approach to research with all study activities being completed in the participants' home environment. This approach may reduce barriers to participation, provide an easier and less demanding participant experience, and reach a broader geography with recruitment from all regions of Canada. CAN-THUMBS UP represents a Canadian contribution to the global World-Wide FINGERS program (alz.org/wwfingers).

Urbanisation and Declining Suicide Rates in China Between 2005 and 2017.

BACKGROUND: Worldwide suicide rates have declined since 2000s, with China being the primary contributor. This study aimed to investigate whether urbanisation is associated with decreasing suicide rates in China. METHODS: Suicide rates and economic indicators of 31 provinces, municipalities, and autonomous regions of China between 2005 and 2017 were analysed. Poisson random intercept models were used to determine associations between suicide rates, urbanicity, sexes, and gross regional product (GRP). RESULTS: Between 2005 and 2017, suicide rates in 31 provinces, municipalities, and autonomous regions of China continued to decrease. Urbanicity and GRP were associated with decreased suicide rates among Chinese males and females. An increase in urbanicity by 1% was associated with a 2.2% decrease in suicide rates (p < 0.001). The most urbanised and populous cities (Beijing, Shanghai, Tianjin) had the lowest suicide rates. Urbanicity was associated with a greater decline in suicide rates among females, compared with males. Association between increased urbanicity and reduced suicide rates was independent of GRP. CONCLUSION: Urbanisation was associated with declining suicide rates in China; this association was stronger among females than males.

MDF-Net: A Multi-Scale Dynamic Fusion Network for Breast Tumor Segmentation of Ultrasound Images.

Breast tumor segmentation of ultrasound images provides valuable information of tumors for early detection and diagnosis. Accurate segmentation is challenging due to low image contrast between areas of interest; speckle noises, and large inter-subject variations in tumor shape and size. This paper proposes a novel Multi-scale Dynamic Fusion Network (MDF-Net) for breast ultrasound tumor segmentation. It employs a two-stage end-to-end architecture with a trunk sub-network for multiscale feature selection and a structurally optimized refinement sub-network for mitigating impairments such as noise and inter-subject variation via better feature exploration and fusion. The trunk network is extended from UNet++ with a simplified skip pathway structure to connect the features between adjacent scales. Moreover, deep supervision at all scales, instead of at the finest scale in UNet++, is proposed to extract more discriminative features and mitigate errors from speckle noise via a hybrid loss function. Unlike previous works, the first stage is linked to a loss function of the second stage so that both the preliminary segmentations and refinement subnetworks can be refined together at training. The refinement sub-network utilizes a structurally optimized MDF mechanism to integrate preliminary segmentation information (capturing general tumor shape and size) at coarse scales and explores inter-subject variation information at finer scales. Experimental results from two public datasets show that the proposed method achieves better Dice and other scores over state-of-the-art methods. Qualitative analysis also indicates that our proposed network is more robust to tumor size/shapes, speckle noise and heavy posterior shadows along tumor boundaries. An optional post-processing step is also proposed to facilitate users in mitigating segmentation artifacts. The efficiency of the proposed network is also illustrated on the "Electron Microscopy neural structures segmentation dataset". It outperforms a state-of-the-art algorithm based on UNet-2022 with simpler settings. This indicates the advantages of our MDF-Nets in other challenging image segmentation tasks with small to medium data sizes.

Biochemical characterization of mRNA capping enzyme from Faustovirus.

The mammalian mRNA 5' cap structures play important roles in cellular processes such as nuclear export, efficient translation, and evading cellular innate immune surveillance and regulating 5'-mediated mRNA turnover. Hence, installation of the proper 5' cap is crucial in therapeutic applications of synthetic mRNA. The core 5' cap structure, Cap-0, is generated by three sequential enzymatic activities: RNA 5' triphosphatase, RNA guanylyltransferase, and cap N7-guanine methyltransferase. Vaccinia virus RNA capping enzyme (VCE) is a heterodimeric enzyme that has been widely used in synthetic mRNA research and manufacturing. The large subunit of VCE D1R exhibits a modular structure where each of the three structural domains possesses one of the three enzyme activities, whereas the small subunit D12L is required to activate the N7-guanine methyltransferase activity. Here, we report the characterization of a single-subunit RNA capping enzyme from an amoeba giant virus. Faustovirus RNA capping enzyme (FCE) exhibits a modular array of catalytic domains in common with VCE and is highly efficient in generating the Cap-0 structure without an activation subunit. Phylogenetic analysis suggests that FCE and VCE are descended from a common ancestral capping enzyme. We found that compared to VCE, FCE exhibits higher specific activity, higher activity toward RNA containing secondary structures and a free 5' end, and a broader temperature range, properties favorable for synthetic mRNA manufacturing workflows.

Non-Psychosis Symptoms of Clozapine Withdrawal: a Systematic Review.

OBJECTIVE: Clozapine is a potent antipsychotic medication with a complex receptor profile. It is reserved for treatment-resistant schizophrenia. We systematically reviewed studies of non-psychosis symptoms of clozapine withdrawal. METHODS: CINAHL, Medline, PsycINFO, PubMed, and the Cochrane Database of Systematic Reviews were searched using the keywords 'clozapine,' and 'withdrawal,' or 'supersensitivity,' 'cessation,' 'rebound,' or 'discontinuation'. Studies related to non-psychosis symptoms after clozapine withdrawal were included. RESULTS: Five original studies and 63 case reports / series were included in analysis. In 195 patients included in the five original studies, approximately 20% experienced non-psychosis symptoms following discontinuation of clozapine. In 89 patients in four of the studies, 27 experienced cholinergic rebound, 13 exhibited extrapyramidal symptoms (including tardive dyskinesia), and three had catatonia. In 63 case reports / series included, 72 patients with non-psychosis symptoms were reported, which were catatonia (n=30), dystonia or dyskinesia (n=17), cholinergic rebound (n=11), serotonin syndrome (n=4), mania (n=3), insomnia (n=3), neuroleptic malignant syndrome (NMS) [n=3, one of them had both catatonia and NMS], and de novo obsessive compulsive symptoms (n=2). Restarting clozapine appeared to be the most effective treatment. CONCLUSIONS: Non-psychosis symptoms following clozapine withdrawal have important clinical implications. Clinicians should be aware of the possible presentations of symptoms to ensure early recognition and management. Further research is warranted to better characterise the prevalence, risk factors, prognosis, and optimal drug dosing for each withdrawal symptom.