Citations

Traditional solvents face limitations in environmental friendliness, biocompatibility, and functional tunability, which restrict their use in pharmaceuticals, biocatalysis, and biosensing.

Abstract OBJECTIVES The effect of allograft ischaemic time (AIT) on postoperative events after lung transplantation remains unclear. This study aims to assess the feasibility of extending the duration of AIT. METHODS The United Network for Organ Sharing database was queried for adult lung transplantation from 4 May 2005 to 30 June 2020. Patients were divided as per AIT into standard ischaemic time (<6 h) and prolonged ischaemic time (≥6 h) groups using propensity score matching and evaluated on a continuous scale using restricted cubic splines. The primary outcome was overall 1-year and 5-year survival. RESULTS Among 11 438 propensity-matched recipients, standard ischaemic time and prolonged ischaemic time showed no differences in overall 1-year (P = 0.29) or 5-year (P = 0.29) survival. Prolonged ischaemic time independently predicted early postoperative ventilator support for >48 h (OR = 1.33, 95% CI 1.22–1.44), dialysis (OR = 1.55, 95% CI 1.30–1.84), primary graft dysfunction (PGD; OR = 1.28, 95% CI 1.09–1.50), acute rejection (OR = 1.42, 95% CI 1.24–1.62), and interestingly, decreased 5-year bronchiolitis obliterans syndrome (HR = 0.91, 95% CI 0.85–0.97). In relative risk curves, 1-year mortality, prolonged ventilation, dialysis and PGD steadily increased per hour as AIT extended. The risk of acute rejection and 5-year bronchiolitis obliterans syndrome also showed significant changes between 5 and 8 h of AIT. In contrast, 5-year mortality remained constant despite rising AIT. CONCLUSIONS Prolonged AIT worsened early outcomes such as PGD, but improved bronchiolitis obliterans syndrome freedom at later time points. Despite this, both short- and long-term survival were similar between prolonged ischaemic time and standard ischaemic time patients. Dynamic risk changes in post-transplant events should be noted for prolonged ischaemia lung use.

Abstract Generative artificial intelligence (AI) holds immense potential for medical applications, but the lack of a comprehensive evaluation framework and methodological deficiencies in existing studies hinder its effective implementation. Standardized assessment guidelines are crucial for ensuring reliable and consistent evaluation of generative AI in healthcare. Our objective is to develop robust, standardized guidelines tailored for evaluating generative AI performance in medical contexts. Through a rigorous literature review utilizing the Web of Sciences, Cochrane Library, PubMed, and Google Scholar, we focused on research testing generative AI capabilities in medicine. Our multidisciplinary team of experts conducted discussion sessions to develop a comprehensive 32‐item checklist. This checklist encompasses critical evaluation aspects of generative AI in medical applications, addressing key dimensions such as question collection, querying methodologies, and assessment techniques. The checklist and its broader assessment framework provide a holistic evaluation of AI systems, delineating a clear pathway from question gathering to result assessment. It guides researchers through potential challenges and pitfalls, enhancing research quality and reporting and aiding the evolution of generative AI in medicine and life sciences. Our framework furnishes a standardized, systematic approach for testing generative AI's applicability in medicine. For a concise checklist, please refer to Table S or visit GenAIMed.org .

AbstractElevated blood levels of C‐reactive protein (CRP) have been linked to colorectal cancer (CRC) survival. We evaluated genetic variants associated with CRP levels and their interactions with sex and lifestyle factors in association with CRC‐specific mortality. Our study included 16 142 CRC cases from the International Survival Analysis in Colorectal Cancer Consortium. We identified 618 common single nucleotide polymorphisms (SNPs) associated with CRP levels from the NHGRI‐EBI GWAS Catalog. Cox proportional hazards regression was used to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) for associations between SNPs and CRC‐specific mortality adjusting for age, sex, genotyping platform/study and principal components. We investigated their interactions with sex and lifestyle factors using likelihood ratio tests. Of 5472 (33.9%) deaths accrued over up to 10 years of follow‐up, 3547 (64.8%) were due to CRC. No variants were associated with CRC‐specific mortality after multiple comparison correction. We observed strong evidence of interaction between variant rs1933736 at FRK gene and sex in relation to CRC‐specific mortality (corrected Pinteraction = .0004); women had higher CRC‐specific mortality associated with the minor allele (HR = 1.11, 95% CI = 1.04‐1.19) whereas an inverse association was observed for men (HR = 0.88, 95% CI = 0.82‐0.94). There was no evidence of interactions between CRP‐associated SNPs and alcohol, obesity or smoking. Our study observed a significant interaction between sex and a CRP‐associated variant in relation to CRC‐specific mortality. Future replication of this association and functional annotation of the variant are needed.

R47H- TREM2 mutation enhances AKT signaling in human AD microglia and mediates proinflammatory and synaptic toxicity in a tauopathy mouse model.

Abstract Background: A positive association between circulating C-reactive protein (CRP) and colorectal cancer survival was reported in observational studies, which are susceptible to unmeasured confounding and reverse causality. We used a Mendelian randomization approach to evaluate the association between genetically predicted CRP concentrations and colorectal cancer–specific survival. Methods: We used individual-level data for 16,918 eligible colorectal cancer cases of European ancestry from 15 studies within the International Survival Analysis of Colorectal Cancer Consortium. We calculated a genetic-risk score based on 52 CRP-associated genetic variants identified from genome-wide association studies. Because of the non-collapsibility of hazard ratios from Cox proportional hazards models, we used the additive hazards model to calculate hazard differences (HD) and 95% confidence intervals (CI) for the association between genetically predicted CRP concentrations and colorectal cancer–specific survival, overall and by stage at diagnosis and tumor location. Analyses were adjusted for age at diagnosis, sex, body mass index, genotyping platform, study, and principal components. Results: Of the 5,395 (32%) deaths accrued over up to 10 years of follow-up, 3,808 (23%) were due to colorectal cancer. Genetically predicted CRP concentration was not associated with colorectal cancer–specific survival (HD, −1.15; 95% CI, −2.76 to 0.47 per 100,000 person-years; P = 0.16). Similarly, no associations were observed in subgroup analyses by stage at diagnosis or tumor location. Conclusions: Despite adequate power to detect moderate associations, our results did not support a causal effect of circulating CRP concentrations on colorectal cancer–specific survival. Impact: Future research evaluating genetically determined levels of other circulating inflammatory biomarkers (i.e., IL6) with colorectal cancer survival outcomes is needed.

Pontocerebellar hypoplasia (PCH) is a group of neurological disorders that affect the development of the brain, in particular, the pons and cerebellum. Homozygous mutations of TBC1D23 have been found recently to lead to PCH; however, the underlying molecular mechanisms remain unclear. Here, we show that the crystal structure of the TBC1D23 C-terminal domain adopts a Pleckstrin homology domain fold and selectively binds to phosphoinositides, in particular, PtdIns(4)P, through one surface while binding FAM21 via the opposite surface. Mutation of key residues of TBC1D23 or FAM21 selectively disrupts the endosomal vesicular trafficking toward the Trans-Golgi Network. Finally, using the zebrafish model, we show that PCH patient-derived mutants, impacting either phosphoinositide binding or FAM21 binding, lead to abnormal neuronal growth and brain development. Taken together, our data provide a molecular basis for the interaction between TBC1D23 and FAM21, and suggest a plausible role for PtdIns(4)P in the TBC1D23-mediating endosome-to-TGN trafficking pathway. Defects in this trafficking pathway are, at least partially, responsible for the pathogenesis of certain types of PCH.

Abstract Graft-versus-host disease (GVHD) is one of the major obstacles for the success of allogeneic hematopoietic stem cell transplantation. In this article, we report that the interaction between OX40L and OX40 is of critical importance for both induction and progression of acute GVHD (aGVHD) driven by human T cells. Anti-human OX40L mAb (hOX40L) treatment could thus effectively reduce the disease severity in a xenogeneic-aGVHD model in both preventative and therapeutic modes. Mechanistically, blocking OX40L–OX40 interaction with an anti-hOX40L reduces infiltration of human T cells in target organs, including liver, gut, lung, and skin. It also decreases IL-21– and TNF-producing T cell responses while promoting regulatory T cell responses without compromising the cytolytic activity of CD8+ T cells. Single blockade of hOX40L was thus more effective than dual blockade of IL-21 and TNF in reducing the severity of aGVHD as well as mortality. Data from this study indicate that OX40L–OX40 interactions play a central role in the pathogenesis of aGVHD induced by human T cells. Therapeutic strategies that can efficiently interrupt OX40L–OX40 interaction in patients might have potential to provide patients with an improved clinical benefit.

Abstract Objectives Working Group 2 was convened to address topics relevant to prosthodontics and dental implants. Systematic reviews were developed according to focused questions addressing (a) the number of implants required to support fixed full‐arch restorations, (b) the influence of intentionally tilted implants compared to axial positioned implants when supporting fixed dental prostheses ( FDP s), (c) implant placement and loading protocols, (d) zirconia dental implants, (e) zirconia and metal ceramic implant supported single crowns and (f) zirconia and metal ceramic implant supported FDP s. Materials and methods Group 2 considered and discussed information gathered in six systematic reviews. Group participants discussed statements developed by the authors and developed consensus. The group developed and found consensus for clinical recommendations based on both the statements and the experience of the group. The consensus statements and clinical recommendations were presented to the plenary (gathering of all conference attendees) and discussed. Final versions were developed after consensus was reached. Results A total of 27 consensus statements were developed from the systematic reviews. Additionally, the group developed 24 clinical recommendations based on the combined expertise of the participants and the developed consensus statements. Conclusions The literature supports the use of various implant numbers to support full‐arch fixed prostheses. The use of intentionally tilted dental implants is indicated when appropriate conditions exist. Implant placement and loading protocols should be considered together when planning and treating patients. One‐piece zirconia dental implants can be recommended when appropriate clinical conditions exist although two‐piece zirconia implants should be used with caution as a result of insufficient data. Clinical performance of zirconia and metal ceramic single implant supported crowns is similar and each demonstrates significant, though different, complications. Zirconia ceramic FDP s are less reliable than metal ceramic. Implant supported monolithic zirconia prostheses may be a future option with more supporting evidence.