Aim
Hong Kong's existing mental health services are inadequate in addressing young people's needs. The LevelMind@JC project established an early intervention platform of community‐based ...youth‐specific mental health centres involving youth workers, cross‐disciplinary professionals, and young people. The project intends to (1) pilot a community platform that incorporates a youth‐friendly early screening tool with preventative intervention capabilities, (2) set up a state‐of‐the‐art training system for youth mental health workers, (3) establish a community clinical support team and (4) develop a timely evaluation system to monitor the service and evaluate its outcome and cost‐effectiveness against generic youth services.
Methods
Six hundred LevelMind@JC service users will be assessed alongside 600 young people visiting generic youth centres and 100 young people in the community. Participants will be matched according to age, gender, years of education, socioeconomic status, and level of distress. Assessments, administered at baseline and at 3, 6 and 12 months, will cover demographic characteristics, psychological distress, quality of life, depressive and anxiety symptoms, functioning, physical health and lifestyle, personality and social measures, cognitive measures and health economics. Mixed‐model ANOVAs will be used to indicate interactions between services and between time points.
Conclusion
Built upon a community‐based support model, LevelMind@JC aims to promote positive mental health in young people through the collaboration of cross‐disciplinary mental health professionals. If efficacy and cost‐effectiveness are established, the project could be scaled up, implicating a wider reach of care. We anticipate its success to be critical in combatting mental health issues stemming from both personal and population‐level stressors.
The artemisinin (ART)-based antimalarials have contributed significantly to reducing global malaria deaths over the past decade, but we still do not know how they kill parasites. To gain greater ...insight into the potential mechanisms of ART drug action, we developed a suite of ART activity-based protein profiling probes to identify parasite protein drug targets in situ. Probes were designed to retain biological activity and alkylate the molecular target(s) of Plasmodium falciparum 3D7 parasites in situ. Proteins tagged with the ART probe can then be isolated using click chemistry before identification by liquid chromatography–MS/MS. Using these probes, we define an ART proteome that shows alkylated targets in the glycolytic, hemoglobin degradation, antioxidant defense, and protein synthesis pathways, processes essential for parasite survival. This work reveals the pleiotropic nature of the biological functions targeted by this important class of antimalarial drugs.
Restrictive COVID-19 measures can have significant mental health impacts, particularly on young people. How such measures may influence day-to-day momentary affect, nonetheless, remains to be ...explored. Experience sampling data were collected from 165 young people (aged 15–24) as part of a larger epidemiological youth mental health study in Hong Kong. We examined the impact of one of the most stringent COVID-19 measures – dine-in restrictions – on momentary positive and negative affect and current contexts and activities of these young people. The effects of a milder form of COVID-19 measure – school suspension – were separately examined. Multilevel analysis revealed that those in the dine-in ban group, compared to dining-as-usual, showed significantly reduced momentary positive affect (
β
= −0.17,
SE
= 0.06,
p
= 0.003). Its effect remained significant even when accounting for baseline depressive and anxiety symptoms and socioeconomic status (
β
= −0.15,
SE
= 0.05,
p
= 0.008). The effect of dine-in ban on reduced momentary positive affect was found specifically when participants were in indoor locations (e.g., home, office), alone, and engaged in passive leisure activities. This pattern was not observed when participants were at school or at other outdoor locations, with friends, or engaged in active leisure activities. No significant effect of school suspension on momentary affect was observed. More severe COVID-19 measures, such as dine-in ban, can have significant impacts on the momentary positive affect of young people. Certain contexts and activities may offer protection against the consequences of COVID-19 measures. The current findings may help to inform future designs of mental health interventions and public health policies.
Summary Background Head and neck cancers positive for human papillomavirus (HPV) are exquisitely radiosensitive. We investigated whether chemoradiotherapy with reduced-dose radiation would maintain ...survival outcomes while improving tolerability for patients with HPV-positive oropharyngeal carcinoma. Methods We did a single-arm, phase 2 trial at two academic hospitals in the USA, enrolling patients with newly diagnosed, biopsy-proven stage III or IV squamous-cell carcinoma of the oropharynx, positive for HPV by p16 testing, and with Zubrod performance status scores of 0 or 1. Patients received two cycles of induction chemotherapy with 175 mg/m2 paclitaxel and carboplatin (target area under the curve of 6) given 21 days apart, followed by intensity-modulated radiotherapy with daily image guidance plus 30 mg/m2 paclitaxel per week concomitantly. Complete or partial responders to induction chemotherapy received 54 Gy in 27 fractions, and those with less than partial or no responses received 60 Gy in 30 fractions. The primary endpoint was progression-free survival at 2 years, assessed in all eligible patients who completed protocol treatment. This study is registered with ClinicalTrials.gov , numbers NCT02048020 and NCT01716195. Findings Between Oct 4, 2012, and March 3, 2015, 45 patients were enrolled with a median age of 60 years (IQR 54–67). One patient did not receive treatment and 44 were included in the analysis. 24 (55%) patients with complete or partial responses to induction chemotherapy received 54 Gy radiation, and 20 (45%) with less than partial responses received 60 Gy. Median follow-up was 30 months (IQR 26–37). Three (7%) patients had locoregional recurrence and one (2%) had distant metastasis; 2-year progression-free survival was 92% (95% CI 77–97). 26 (39%) of 44 patients had grade 3 adverse events, but no grade 4 events were reported. The most common grade 3 events during induction chemotherapy were leucopenia (17 39%) and neutropenia (five 11%), and during chemoradiotherapy were dysphagia (four 9%) and mucositis (four 9%). One (2%) of 44 patients was dependent on a gastrostomy tube at 3 months and none was dependent 6 months after treatment. Interpretation Chemoradiotherapy with radiation doses reduced by 15–20% was associated with high progression-free survival and an improved toxicity profile compared with historical regimens using standard doses. Radiotherapy de-escalation has the potential to improve the therapeutic ratio and long-term function for these patients. Funding University of California.
Bacterial biofilms are associated with numerous human infections. The predominant protein expressed in enteric biofilms is the amyloid curli, which forms highly immunogenic complexes with DNA. ...Infection with curli-expressing bacteria or systemic exposure to purified curli-DNA complexes triggers autoimmunity via the generation of type I interferons (IFNs) and anti-double-stranded DNA antibodies. Here, we show that DNA complexed with amyloid curli powerfully stimulates Toll-like receptor 9 (TLR9) through a two-step mechanism. First, the cross beta-sheet structure of curli is bound by cell-surface Toll-like receptor 2 (TLR2), enabling internalization of the complex into endosomes. After internalization, the curli-DNA immune complex binds strongly to endosomal TLR9, inducing production of type I IFNs. Analysis of wild-type and TLR2-deficient macrophages showed that TLR2 is the major receptor that drives the internalization of curli-DNA complexes. Suppression of TLR2 internalization via endocytosis inhibitors led to a significant decrease in Ifnβ expression. Confocal microscopy analysis confirmed that the TLR2-bound curli was required for shuttling of DNA to endosomal TLR9. Structural analysis using small-angle X-ray scattering revealed that incorporation of DNA into curli fibrils resulted in the formation of ordered curli-DNA immune complexes. Curli organizes parallel, double-stranded DNA rods at an inter-DNA spacing that matches up well with the steric size of TLR9. We also found that production of anti-double-stranded DNA autoantibodies in response to curli-DNA was attenuated in TLR2- and TLR9-deficient mice and in mice deficient in both TLR2 and TLR9 compared to wild-type mice, suggesting that both innate immune receptors are critical for shaping the autoimmune adaptive immune response. We also detected significantly lower levels of interferon-stimulated gene expression in response to purified curli-DNA in TLR2 and TLR9 deficient mice compared to wild-type mice, confirming that TLR2 and TLR9 are required for the induction of type I IFNs. Finally, we showed that curli-DNA complexes, but not cellulose, were responsible elicitation of the immune responses to bacterial biofilms. This study defines the series of events that lead to the severe pro-autoimmune effects of amyloid-expressing bacteria and suggest a mechanism by which amyloid curli acts as a carrier to break immune tolerance to DNA, leading to the activation of TLR9, production of type I IFNs, and subsequent production of autoantibodies.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
The potential benefits of aquatic environments for public health have been understudied in Asia. We investigated the relationships between blue space exposures and health outcomes among a sample of ...predominantly older adults in Hong Kong. Those with a view of blue space from the home were more likely to report good general health, while intentional exposure was linked to greater odds of high wellbeing. Visiting blue space regularly was more likely for those within a 10–15 min walk, and who believed visit locations had good facilities and wildlife present. Longer blue space visits, and those involving higher intensity activities, were associated with higher recalled wellbeing. Our evidence suggests that, at least for older citizens, Hong Kong's blue spaces could be an important public health resource.
•A view of blue space from the home was related to good self-reported health.•Visiting blue spaces regularly was associated with high wellbeing.•Presence of wildlife and good facilities at blue spaces related to visiting regularly.•Safety and presence of wildlife related to recalled wellbeing from a single visit.•Vigorous activity and longer visit durations associated with recalled wellbeing.
In most animals, the brain controls the body via a set of descending neurons (DNs) that traverse the neck. DN activity activates, maintains or modulates locomotion and other behaviors. Individual DNs ...have been well-studied in species from insects to primates, but little is known about overall connectivity patterns across the DN population. We systematically investigated DN anatomy in
and created over 100 transgenic lines targeting individual cell types. We identified roughly half of all
DNs and comprehensively map connectivity between sensory and motor neuropils in the brain and nerve cord, respectively. We find the nerve cord is a layered system of neuropils reflecting the fly's capability for two largely independent means of locomotion -- walking and flight -- using distinct sets of appendages. Our results reveal the basic functional map of descending pathways in flies and provide tools for systematic interrogation of neural circuits.
ABSTRACT The Hubble 2020: Outer Planet Atmospheres Legacy program is generating new yearly global maps for each of the outer planets. This report focuses on Jupiter results from the first year of the ...campaign. The zonal wind profile was measured and is in the same family as the Voyager and Cassini era profiles, showing some variation in mid- to high-latitude wind jet magnitudes, particularly at +40° and −35° planetographic latitude. The Great Red Spot continues to maintain an intense orange coloration, but also shows new internal structures, including a reduced core and new filamentary features. Finally, a wave that was not previously seen in Hubble images was also observed and is interpreted as a baroclinic instability with associated cyclone formation near 16° N latitude. A similar feature was observed faintly in Voyager 2 images, and is consistent with the Hubble feature in location and scale.
Primaquine (PQ) is an essential antimalarial drug but despite being developed over 70 years ago, its mode of action is unclear. Here, we demonstrate that hydroxylated-PQ metabolites (OH-PQm) are ...responsible for efficacy against liver and sexual transmission stages of Plasmodium falciparum. The antimalarial activity of PQ against liver stages depends on host CYP2D6 status, whilst OH-PQm display direct, CYP2D6-independent, activity. PQ requires hepatic metabolism to exert activity against gametocyte stages. OH-PQm exert modest antimalarial efficacy against parasite gametocytes; however, potency is enhanced ca.1000 fold in the presence of cytochrome P450 NADPH:oxidoreductase (CPR) from the liver and bone marrow. Enhancement of OH-PQm efficacy is due to the direct reduction of quinoneimine metabolites by CPR with the concomitant and excessive generation of H
O
, leading to parasite killing. This detailed understanding of the mechanism paves the way to rationally re-designed 8-aminoquinolines with improved pharmacological profiles.
Abstract
Background
Chronic hepatitis B (CHB) and fatty liver (FL) are common, natural history data on concurrent FL and CHB (FL-CHB) are limited. This study aimed to evaluate the effect of FL on ...cirrhosis, hepatocellular carcinoma (HCC), and hepatitis B surface antigen (HBsAg) seroclearance incidence in CHB patients.
Methods
In a retrospective cohort study of 6786 adult CHB patients, we used propensity score matching (PSM) to balance the FL-CHB and non-FL CHB groups. Kaplan-Meier methods were used to compare cumulative cirrhosis, HCC, and HBsAg seroclearance rates between subgroups.
Results
Before PSM, compared to non-FL CHB, FL-CHB patients had lower 10-year cumulative rates of cirrhosis, HCC, and a higher HBsAg seroclearance rate. Similar results were found in the matched FL-CHB and non-FL CHB patients, as well as in the antiviral-treated PSM cohort. Cox proportional hazards model indicated FL to remain significantly and strongly associated with lower risk of cirrhosis and HCC (hazard ratio HR, 0.19 95% confidence interval {CI}, .12–.33, P < .001 and HR, 0.21 95% CI, .09–.51, P = .001, respectively) in antiviral-treated patients but not in untreated patients.
Conclusions
FL was significantly associated with lower cirrhosis and HCC risk and higher HBsAg seroclearance. Further studies are needed to confirm our funding and investigate the mechanisms underlying the impact of FL on CHB.
In this retrospective cohort study of 6786 adult patients with chronic hepatitis B (CHB), we observed a consistently lower incidence of cirrhosis, hepatocellular carcinoma, and higher incidence of hepatitis B surface antigen seroclearance in CHB patients’ concurrent fatty liver (FL), compared to non-FL CHB patients.
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