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BACKGROUND: While folic acid (FA) is widely used to treat elevated total homocysteine (tHcy), promoting vascular health by reducing vascular oxidative stress and modulating endothelial nitric oxide synthase, the optimal daily dose and individual variation by MTHFR C677T genotypes have not been well studied. Therefore, this study aimed to explore the efficacy of eight different FA dosages on tHcy lowering in the overall sample and by MTHFR C677T genotypes. METHODS: This multicentered, randomized, double-blind, controlled clinical trial included 2697 eligible hypertensive adults with elevated tHcy (≥ 10 mmol/L) and without history of stroke and cardiovascular disease. Participants were randomized into eight dose groups of FA combined with 10 mg enalapril maleate, taken daily for 8 weeks of treatment. RESULTS: The intent to treat analysis included 2163 participants. In the overall sample, increasing FA dosage led to steady tHcy reduction within the FA dosing range of 0-1.2 mg. However, a plateau in tHcy lowering was observed in FA dose range of 1.2-1.6 mg, indicating a ceiling effect. In contrast, FA doses were positively and linearly associated with serum folate levels without signs of plateau. Among MTHFR genotype subgroups, participants with the TT genotype showed greater efficacy of FA in tHcy lowering. CONCLUSIONS: This randomized trial lent further support to the efficacy of FA in lowering tHcy; more importantly, it provided critically needed evidence to inform optimal FA dosage. We found that the efficacy of FA in lowering tHcy reaches a plateau if the daily dosage exceeds 1.2 mg, and only has a small gain by increasing the dosage from 0.8 to 1.2 mg. GOV IDENTIFIER: NCT03472508 (Registration Date: March 21, 2018).

BackgroundAustralia’s mental health care system has long been fragmented and under-resourced, with services falling well short of demand. In response, the World Economic Forum has recently called for the rapid deployment of smarter, digitally enhanced health services to facilitate effective care coordination and address issues of demand. The University of Sydney’s Brain and Mind Centre (BMC) has developed an innovative digital health solution that incorporates 2 components: a highly personalized and measurement-based (data-driven) model of youth mental health care and a health information technology (HIT) registered on the Australian Register of Therapeutic Goods. Importantly, research into implementation of such solutions considers education and training of clinicians to be essential to adoption and optimization of use in standard clinical practice. The BMC’s Youth Mental Health and Technology Program has subsequently developed a comprehensive education and training program to accompany implementation of the digital health solution. ObjectiveThis paper describes the protocol for an evaluation study to assess the effectiveness of the education and training program on the adoption and optimization of use of the digital health solution in service delivery. It also describes the proposed tools to assess the impact of training on knowledge and skills of mental health clinicians. MethodsThe evaluation study will use the Kirkpatrick Evaluation Model as a framework with 4 levels of analysis: Reaction (to education and training), Learning (knowledge acquired), Behavior (practice change), and Results (client outcomes). Quantitative and qualitative data will be collected using a variety of tools, including evaluation forms, pre- and postknowledge questionnaires, skill development and behavior change scales, as well as a real-time clinical practice audit. ResultsThis project is funded by philanthropic funding from Future Generation Global. Ethics approval has been granted via Sydney Local Health District’s Human Research Ethics Committee. At the time of this publication, clinicians and their services were being recruited to this study. The first results are expected to be submitted for publication in 2021. ConclusionsThe education and training program teaches clinicians the necessary knowledge and skills to assess, monitor, and manage complex needs; mood and psychotic syndromes; and trajectories of youth mental ill-health using a HIT that facilitates a highly personalized and measurement-based model of care. The digital health solution may therefore guide clinicians to help young people recover low functioning associated with subthreshold diagnostic presentations and prevent progression to more serious mental ill-health. International Registered Report Identifier (IRRID)PRR1-10.2196/24697

BackgroundThere is a growing need for cost-efficient and patient-centered approaches to support families in hospital- and community-based neurodevelopmental services. For such purposes, electronic data collection (EDC) may hold advantages over paper-based data collection. Such EDC approaches enable automated data collection for scoring and interpretation, saving time for clinicians and services and promoting more efficient service delivery. ObjectiveThis pilot study evaluated the efficacy of EDC for the Child Development Unit, a hospital-based diagnostic assessment clinic in the Sydney Children’s Hospital Network. Caregiver response rates and preference for EDC or paper-based methods were evaluated as well as the moderating role of demographic characteristics such as age, level of education, and ethnic background. MethodsFamilies were sent either a paper-based questionnaire via post or an electronic mail link for completion before attending their first on-site clinic appointment for assessment. A total of 62 families were provided a paper version of the questionnaire, while 184 families were provided the online version of the same questionnaire. ResultsCompletion rates of the questionnaire before the first appointment were significantly higher for EDC (164/184, 89.1%) in comparison to paper-based methods (24/62, 39%; P

Objective: Osteoclast (OC) over-activation is an important cause of bone loss that is strongly correlated with inflammation. Although the CD163/TWEAK/Fn14 axis has been implicated in several inflammatory pathologies, its contributions to inflammatory bone loss remain poorly understood. This study aimed to evaluate the interaction of the CD163/TWEAK/Fn14 axis with OC in inflammatory bone loss. Methods: To assess the role of CD163 in bone homeostasis, we characterized the bone phenotypes of CD163-deficient mice and their wild-type littermates. CD163 and TWEAK levels were evaluated in the bone marrow of mice with LPS-induced bone loss and individuals with rheumatoid arthritis (RA). Bone mass changes were assessed using uCT and histology following supplementation with recombinant mouse CD163 protein (rCD163) or blockade of TWEAK/Fn14 signaling in CD163-deficient mice and mice with LPS-induced bone loss. The impact of CD163/TWEAK on OC differentiation and bone resorption capacity was analyzed in vitro. Results: CD163 deficiency caused decreased bone mass and increased OC abundance. Lower CD163 expression and higher TWEAK expression were observed in the bone marrow of mice with LPS-induced bone loss and individuals with RA. TWEAK, mainly derived from CD68+ macrophages, was responsible for bone loss, and supplementing rCD163 or blocking TWEAK/Fn14 signaling contributed to rescue bone loss. TWEAK/Fn14 synergistically promoted RANKL-dependent OC differentiation and bone resorption capability through downstream mitogen-activated protein kinases (MAPK) signaling, while the pro-osteoclastic effect of TWEAK was suppressed by CD163. Conclusion: Our findings suggest that the CD163/TWEAK/Fn14 axis is a potential therapeutic target for inflammatory bone loss by regulating osteoclastogenesis.

In recent years, large language model have demonstrated outstanding capabilities across multiple natural language processing tasks, greatly aiding the development of intelligent law systems. Existing large language model in the law domain, primarily focuses on fine-tuning foundation model for simple question answering tasks in legal consultation, have not considered other application scenarios in the legal field, such as legal information extraction, judgment prediction, etc. Real world law services are far more complex than dialogues. LawLLM was proposed, a Chinese law intelligent large language model, capable of providing diverse law services for different user groups. Additionally, the application of information extraction on long-context judicial documents in the law domain was explored. The average performance of LawLLM on Lawbench outperforms all the compared large language models, being 0.19% higher than the 175 billion parameter GPT-3.5-Turbo model. LawLLM’s average performance on few-shot tasks on Lawbench is slightly lower than GPT-3.5-Turbo, by 0.02%.

BACKGROUND: Genetic variation in the human genome is a major determinant of individual disease risk, but the vast majority of missense variants have unknown etiological effects. Here, we present a robust learning framework for leveraging saturation mutagenesis experiments to construct accurate computational predictors of proteome-wide missense variant pathogenicity. RESULTS: We train cross-protein transfer (CPT) models using deep mutational scanning (DMS) data from only five proteins and achieve state-of-the-art performance on clinical variant interpretation for unseen proteins across the human proteome. We also improve predictive accuracy on DMS data from held-out proteins. High sensitivity is crucial for clinical applications and our model CPT-1 particularly excels in this regime. For instance, at 95% sensitivity of detecting human disease variants annotated in ClinVar, CPT-1 improves specificity to 68%, from 27% for ESM-1v and 55% for EVE. Furthermore, for genes not used to train REVEL, a supervised method widely used by clinicians, we show that CPT-1 compares favorably with REVEL. Our framework combines predictive features derived from general protein sequence models, vertebrate sequence alignments, and AlphaFold structures, and it is adaptable to the future inclusion of other sources of information. We find that vertebrate alignments, albeit rather shallow with only 100 genomes, provide a strong signal for variant pathogenicity prediction that is complementary to recent deep learning-based models trained on massive amounts of protein sequence data. We release predictions for all possible missense variants in 90% of human genes. CONCLUSIONS: Our results demonstrate the utility of mutational scanning data for learning properties of variants that transfer to unseen proteins.

Phylogenetic models of molecular evolution are central to numerous biological applications spanning diverse timescales, from hundreds of millions of years involving orthologous proteins to just tens of days relating to single cells within an organism. A fundamental problem in these applications is estimating model parameters, for which maximum likelihood estimation is typically employed. Unfortunately, maximum likelihood estimation is a computationally expensive task, in some cases prohibitively so. To address this challenge, we here introduce CherryML, a broadly applicable method that achieves several orders of magnitude speedup by using a quantized composite likelihood over cherries in the trees. The massive speedup offered by our method should enable researchers to consider more complex and biologically realistic models than previously possible. Here we demonstrate CherryMLs utility by applying it to estimate a general 400 × 400 rate matrix for residue-residue coevolution at contact sites in three-dimensional protein structures; we estimate that using current state-of-the-art methods such as the expectation-maximization algorithm for the same task would take >100,000 times longer.

AimTo evaluate the safety and efficacy of posterior scleral application (a modified technique) of an antimetabolite mitomycin C-soaked sponge in trabeculectomy for patients with glaucoma.MethodsThis retrospective study included 101 patients (115 eyes) with glaucoma (aged 12-83y) who underwent trabeculectomy using a modified mitomycin C-soaked sponge placement method. A piece of 3.5×10 mm2 sponge was placed vertically and posteriorly with the long side perpendicular to the limbus. The mitomycin C concentration and exposure time were 0.2-0.5 mg/mL and 1-5min, respectively. Intraocular pressure, best-corrected visual acuity, and hypotensive medications were recorded at baseline and at the final visit. Complications, interventions required, and bleb morphology were recorded postoperatively. The primary outcome was trabeculectomy safety, including complications and bleb morphology; the secondary outcome was the trabeculectomy success rate.ResultsAt the final follow-up [median 28mo, range 7-67mo and interquartile range (IQR) 13mo], the qualified (cumulative) success rate was 93.0% and the complete success rate was 60.0%. No bleb-related complications were observed. The mean height, extent, and vascularity grades were 0.6±0.9, 1.1±0.4, and 2.4±0.9, respectively. All Seidel tests were negative. The mean posteriority grade was 0.8±0.4.ConclusionTrabeculectomy with the long side of a mitomycin C-soaked sponge placed perpendicular to the corneal limbus is safe and effective.

Chimeric antigen receptor T (CAR-T) cell therapy is a new treatment for cancers, but reports on curing immune-related skin diseases are limited. We report a case of successful CAR-T-cell therapy in a patient with refractory/relapsed diffuse large B-cell lymphoma (R/R DLBCL) who was incidentally cured of chronic generalized plaque psoriasis. The patient, a 65-year-old male who had a known history of psoriasis for 45 years, did not receive immunotherapy for psoriasis during this period. Imaging, molecular biology and immunology diagnostics confirmed DLBCL. After several weeks of standard-dose R-CHOP chemotherapy, the patient achieved partial remission, but according to CT, the patient relapsed, and there was no significant improvement in her psoriasis symptoms. Subsequently, the patient was enrolled in the CD19 CAR-T-cell therapy group. Four weeks after CAR-T-cell infusion, the patient’s abdominal pain disappeared, and there was a significant improvement in overall skin lesions. One year later, follow-up results indicated complete remission of R/R DLBCL (confirmed by PET-CT), with only minimal residual psoriatic skin lesions limited to the patient’s neck. The results of using CAR-T-cell therapy to achieve an incidental cure for psoriasis highlight the potential for exploring cell-based therapies for complex autoinflammatory skin diseases.