The Pharmacogenomics Global Research Network Implementation Working Group: global collaboration to advance pharmacogenetic implementation.

Pharmacogenetics promises to optimize treatment-related outcomes by informing optimal drug selection and dosing based on an individual's genotype in conjunction with other important clinical factors. Despite significant evidence of genetic associations with drug response, pharmacogenetic testing has not been widely implemented into clinical practice. Among the barriers to broad implementation are limited guidance for how to successfully integrate testing into clinical workflows and limited data on outcomes with pharmacogenetic implementation in clinical practice. The Pharmacogenomics Global Research Network Implementation Working Group seeks to engage institutions globally that have implemented pharmacogenetic testing into clinical practice or are in the process or planning stages of implementing testing to collectively disseminate data on implementation strategies, metrics, and health-related outcomes with the use of genotype-guided drug therapy to ultimately help advance pharmacogenetic implementation. This paper describes the goals, structure, and initial projects of the group in addition to implementation priorities across sites and future collaborative opportunities.

Unravel the distinct effects of adiposity at different life stages on COVID-19 susceptibility and severity: A life-course Mendelian randomization study.

Childhood obesity is widely recognized as a risk factor for numerous health conditions, particularly cardiovascular disease. However, it remains unclear whether childhood adiposity directly affects the risk of COVID-19 in later life. We aimed to investigate the causal effects of early life adiposity on COVID-19 susceptibility and severity. We used genetic instruments from large-scale genome-wide association studies to examine the relationships between birth weight, childhood and adulthood adiposity indicators (including body mass index [BMI], obesity, and body size), and COVID-19 outcomes. Univariable and multivariable Mendelian randomization (MR) analyses were used to obtain the causal estimates. Univariable MR analyses found that childhood BMI and obesity were positively associated with COVID-19 risk and severity in adulthood, however, the significant associations were attenuated to null after further adjusting for adulthood adiposity indicators in multivariable MR analyses. In contrast, our analysis revealed strong evidence of a genetically predicted effect of childhood obesity on COVID-19 hospitalization (OR 1.08, 95% CI: 1.01-1.15, p = 2.12E-2), which remained robust even after adjusting for adulthood obesity and potential lifestyle confounders. Our results highlight the importance of promoting healthy weight management throughout life to reduce the risk of COVID-19.

The simultaneous addition of chitosan and peat enhanced the removals of antibiotics resistance genes during biogas residues composting.

Direct reuse of biogas residue (BR) has the potential to contribute to the dissemination of antibiotic resistance genes (ARGs). Although high-temperature composting has been demonstrated as an effective method for the harmless treatment of organic waste, there is few researches on the fate of ARGs in high-temperature composting of BR. This research examined the impact of adding 5% chitosan and 15% peat on physicochemical characteristics, microbial communities, and removal of ARGs during BR-straw composting in 12 Biolan 220L composters for 48 days. Our results showed that the simultaneous addition of chitosan and peat extended the high-temperature period, and increased the highest temperature to 74 °C and germination index. These effects could be attributed to the presence of thermophilic cellulose-decomposing genera (Thermomyces and Thermobifida). Although the microbial communities differed compositionally among temperature stages, their dissimilarity drastically reduced at final stage, indicating that the impact of different treatments on microbial community composition decreases at the end of composting. Peat had a greater impact on aerobic genera capable of cellulose degradation at thermophilic stage than chitosan. Surprisingly, despite the total copy number of ARGs significantly decreased during composting, especially in the treatment with both chitosan and peat, intI1 gene abundance significantly increased 2 logs at thermophilic stage and maintained high level in the final compost, suggesting there is still a potential risk of transmission and proliferation of ARGs. Our work shed some lights on the development of waste resource utilization and emerging contaminants removal technology.

Transforming Subdural Hematoma Treatment in the Elderly: Insights from an Endoscopic Case Series.

BACKGROUND/AIM: Subdural hematoma (SDH), a critical brain condition, significantly affects the elderly, making traditional surgeries risky due to their length and potential for blood loss. Endoscope-assisted evacuation offers a safer, less invasive alternative by reducing operation time and minimizing damage, providing an effective solution for older patients. This study evaluated six patients treated with endoscopic evacuation for different stages of SDH from August 2019 to July 2023. PATIENTS AND METHODS: Selection criteria were based on altered consciousness, lack of severe brain contusion, SDH thickness over 1 cm, or midline shift over 0.5 cm. The technique used a burr hole and rigid lens endoscope for hematoma removal, focusing on shorter surgery times and better outcomes. RESULTS: Patients aged between 63 to 84 years showed no surgical fatalities, with all recovering well by discharge. Hematoma clearance rates were 76.9% at three days, improving to 96.8% after one month. CONCLUSION: Endoscope-assisted evacuation is a safe, efficient treatment for elderly patients with various stages of SDH, offering a less invasive option with potential for better outcomes. It supports the trend towards minimally invasive neurosurgery, with further research needed to optimize patient selection and understand long-term benefits.

Targeting immune-fibroblast cell communication in heart failure.

Inflammation and tissue fibrosis co-exist and are causally linked to organ dysfunction1,2. However, the molecular mechanisms driving immune-fibroblast cell communication in human cardiac disease remain unexplored and there are at present no approved treatments that directly target cardiac fibrosis3,4. Here we performed multiomic single-cell gene expression, epitope mapping and chromatin accessibility profiling in 45 healthy donor, acutely infarcted and chronically failing human hearts. We identified a disease-associated fibroblast trajectory that diverged into distinct populations reminiscent of myofibroblasts and matrifibrocytes, the latter expressing fibroblast activator protein (FAP) and periostin (POSTN). Genetic lineage tracing of FAP+ fibroblasts in vivo showed that they contribute to the POSTN lineage but not the myofibroblast lineage. We assessed the applicability of experimental systems to model cardiac fibroblasts and demonstrated that three different in vivo mouse models of cardiac injury were superior compared with cultured human heart and dermal fibroblasts in recapitulating the human disease phenotype. Ligand-receptor analysis and spatial transcriptomics predicted that interactions between C-C chemokine receptor type 2 (CCR2) macrophages and fibroblasts mediated by interleukin-1ß (IL-1ß) signalling drove the emergence of FAP/POSTN fibroblasts within spatially defined niches. In vivo, we deleted the IL-1 receptor on fibroblasts and the IL-1ß ligand in CCR2+ monocytes and macrophages, and inhibited IL-1ß signalling using a monoclonal antibody, and showed reduced FAP/POSTN fibroblasts, diminished myocardial fibrosis and improved cardiac function. These findings highlight the broader therapeutic potential of targeting inflammation to treat tissue fibrosis and preserve organ function.

Evaluation of the Geriatric Trauma Outcome Score (GTOS) as a Prognostic Tool in Intensive Care Unit Trauma Patients.

BACKGROUND: Existing prognostic scoring systems for intensive care unit (ICU) trauma patients require extensive data collection. The Geriatric Trauma Outcome Score (GTOS), which is based on age, injury severity, and transfusion need, has been validated for predicting mortality in elderly patients with trauma; however, its utility in the general ICU trauma population remains unexplored. METHODS: This retrospective study included 2952 adult ICU trauma patients admitted between 2016 and 2021. The GTOS was calculated as follows: age + (Injury Severity Score × 2.5) + 22 (if transfused within 24 h). The area under the receiver operating characteristic curve (AUROC) was used to assess GTOS's ability to predict mortality. The optimal GTOS cutoff was determined using Youden's index. Mortality rates were compared between the high and low GTOS groups, including a propensity score-matched analysis adjusted for baseline characteristics. RESULTS: This study included 2952 ICU trauma patients, with an overall mortality rate of 11.0% (n = 325). GTOS demonstrated good predictive accuracy for mortality (AUROC 0.80). The optimal cutoff was 121.8 (sensitivity, 0.791; specificity, 0.685). Despite adjustments, patients with GTOS ≥ 121.8 had significantly higher mortality (17.4% vs. 6.2%, p < 0.001) and longer hospital stays (20.3 vs. 15.3 days, p < 0.001) compared to GTOS < 121.8. CONCLUSIONS: GTOS showed a reasonable ability to predict mortality in ICU trauma patients across all ages, although not as accurately as more complex ICU-specific models. With its simplicity, the GTOS may serve as a rapid screening tool for risk stratification in acute ICU trauma settings when combined with other data.

Investigating undiagnosed Fabry disease in young adults with ischemic stroke: A multicenter cohort study.

BACKGROUND: The global prevalence of ischemic stroke in young adults is increasing, leading to a significant social impact. Fabry disease is a recognized cause of ischemic stroke in young patients, and although disease-modifying treatments are available, further evidence is needed to confirm their effectiveness in reducing the incidence of ischemic strokes. AIMS: This study aimed to identify undiagnosed Fabry disease in young adult patients with ischemic stroke in a Taiwanese cohort. METHODS: This multicenter, prospective cohort study enrolled patients aged 20-55 years who had experienced an ischemic stroke or transient ischemic attack (TIA) within 10 days, from 1 January 2016 to 31 December 2020. Screening for Fabry disease was performed using a dry blood test to measure α-galactosidase activity in male patients and blood globotriaosylsphingosine (lyso-Gb3) levels in female patients. For patients with positive screen results, genetic diagnosis of Fabry disease was pursued through Sanger sequencing of the GLA gene, covering all exons and a segment of intron 4. RESULTS: A total of 977 patients (659 male, 68%) were enrolled from seven hospitals across Taiwan. Four patients (0.4%, all male) had positive screening results, and two patients (0.2%) were genetically diagnosed with Fabry disease. Case 1 had the GLA c.658C>T mutation and experienced ischemic stroke in the bilateral occipital regions. Case 2 had the GLA c.640-801G>A mutation and experienced an ischemic stroke in the left superficial watershed area. CONCLUSION: The prevalence of undiagnosed Fabry disease in this cohort of Taiwanese young adults with ischemic stroke or TIA was 0.3% among the young male population. Understanding the prevalence of undiagnosed Fabry disease in young adults with ischemic stroke could help shape future Fabry disease screening policies. DATA ACCESS STATEMENT: The collected data will be available upon reasonable request from the corresponding author.

MicroRNA-376a-3p sensitizes CPT-11-resistant colorectal cancer by enhancing apoptosis and reversing the epithelial-to-mesenchymal transition (EMT) through the IGF1R/PI3K/AKT pathway.

Colorectal cancer (CRC) remains the third most prevalent type of cancer worldwide contributing to an estimated 10 % of all cancer cases. CPT-11 is one of the first-line drugs for CRC treatment. Unfortunately, the development of drug resistance significantly exacerbates the adverse impact of CRC. Consequent tumor recurrences and metastasis, years after treatment are the frequently reported incidences. MicroRNAs (miRNA) are short non-coding RNA with the functionality of gene suppression. The insulin-like growth factor type 1 receptor (IGF1R) is a tyrosine kinase receptor frequently upregulated in cancers and is associated with cell survival and drug resistance. MiRNAs are frequently reported to be dysregulated in cancers including CRC. Evidence suggests that dysregulated miRNAs have direct consequences on the biological processes of their target genes. We previously demonstrated that miRNA-376a-3p is upregulated in CPT-11responsive, CRC cells upon treatment with CPT-11. We therefore aimed to investigate the involvement of miRNA-376a-3p in CPT-11 resistance and its probable association with IGF1R-mediated cancer cell survival. Our experimental approach used knockdown and overexpression experiments supplemented with western blot, RT-qPCR, flow cytometry, MTT, and migration assays to achieve our aim. Our data reveals the mechanism through which IGF1R and miRNA-376a-3p perpetrate and attenuate CPT-11 resistance respectively. MiRNA-376a-3p overexpression negatively regulated the IGF1R-induced cell survival, PI3K/AKT pathway, and reversed the epithelial-mesenchymal transition, hence sensitizing resistant cells to CPT-11. Our findings suggests that the miRNA-376a-3p/IGF1R axis holds promise as a potential target to sensitize CRC to CPT-11 in cases of drug resistance.

Therapeutic Potential of Salvia miltiorrhiza Root Extract in Alleviating Cold-Induced Immunosuppression.

The interaction between environmental stressors, such as cold exposure, and immune function significantly impacts human health. Research on effective therapeutic strategies to combat cold-induced immunosuppression is limited, despite its importance. In this study, we aim to investigate whether traditional herbal medicine can counteract cold-induced immunosuppression. We previously demonstrated that cold exposure elevated immunoglobulin G (IgG) levels in mice, similar to the effects of intravenous immunoglobulin (IVIg) treatments. This cold-induced rise in circulating IgG was mediated by the renin-angiotensin-aldosterone system and linked to vascular constriction. In our mouse model, the cold-exposed groups (4 °C) showed significantly elevated plasma IgG levels and reduced bacterial clearance compared with the control groups maintained at room temperature (25 °C), both indicative of immunosuppression. Using this model, with 234 mice divided into groups of 6, we investigated the potential of tanshinone IIA, an active compound in Salvia miltiorrhiza ethanolic root extract (SMERE), in alleviating cold-induced immunosuppression. Tanshinone IIA and SMERE treatments effectively normalized elevated plasma IgG levels and significantly improved bacterial clearance impaired by cold exposure compared with control groups injected with a vehicle control, dimethyl sulfoxide. Notably, bacterial clearance, which was impaired by cold exposure, showed an approximately 50% improvement following treatment, restoring immune function to levels comparable to those observed under normal temperature conditions (25 °C, p < 0.05). These findings highlight the therapeutic potential of traditional herbal medicine in counteracting cold-induced immune dysregulation, offering valuable insights for future strategies aimed at modulating immune function in cold environments. Further research could focus on isolating tanshinone IIA and compounds present in SMERE to evaluate their specific roles in mitigating cold-induced immunosuppression.

Evaluating the distinct effects of body mass index at childhood and adulthood on adult major psychiatric disorders.

Children with high body mass index (BMI) are at heightened risk of developing health issues in adulthood, yet the causality between childhood BMI and adult psychiatric disorders remains unclear. Using a life course Mendelian randomization (MR) framework, we investigated the causal effects of childhood and adulthood BMI on adult psychiatric disorders, including Alzheimer's disease, anxiety, major depressive disorder, obsessive-compulsive disorder (OCD), and schizophrenia, using data from the Psychiatric Genomics Consortium and FinnGen study. Childhood BMI was significantly associated with an increased risk of schizophrenia, while adulthood BMI was associated with a decreased risk of OCD and schizophrenia. Multivariable MR analyses indicated a direct causal effect of childhood BMI on schizophrenia, independent of adulthood BMI and lifestyle factors. No evidence of causal associations was found between childhood BMI and other psychiatric outcomes. The sensitivity analyses yielded broadly consistent findings. These findings highlight the critical importance of early-life interventions to mitigate the long-term consequences of childhood adiposity.

Imaging findings in suspected penile fracture: alternative diagnoses and surgical correlation.

OBJECTIVES: The primary objective is to compare the imaging and surgical findings in a cohort of patients with suspected penile fracture (PF). METHODS: Retrospective cohort study of all patients with suspected PF over an 11-year period at a tertiary referral andrology centre. All dedicated presurgical imaging with ultrasound (US) and MRI was analysed and correlated with intraoperative findings; alternative diagnoses were recorded. RESULTS: One hundred and ninety-three patients were included. One hundred and four (54%) had alternative diagnoses to PF including dorsal vein rupture and haematoma. Ninety-nine (51%) underwent surgical exploration of which 89 (46%) had PF. US correctly confirmed the presence and marked the site of fracture in 92% of cases. MRI was primarily used as a problem-solving tool (13 cases) and demonstrated a more extensive injury than US (12 cases). The reported size of tunical defect on imaging was a median of 7 mm (IQR 4-10) significantly smaller than on exploration (median 20 mm, IQR 10-30; P < .0001). CONCLUSIONS: US has a high positive predictive value in the confirmation of PF. MRI improves the detection and characterizing the extent of injury. Imaging marking informs surgical incision but defect size is under appreciated on all imaging modalities. ADVANCES IN KNOWLEDGE: Penile imaging has a high positive predictive value to not only confirm the diagnosis of PF but to stage the extent of injury and mark the skin, which impacts the surgical technique. Alternative diagnoses to fracture are common and imaging could prevent unnecessary surgical exploration.

Profiling of phenolic composition in camellia oil and its correlative antioxidant properties analysis.

Less research has been conducted on the association between camellia oil's (CO) phenolic composition and antioxidant capability. In this study, the phenolic profile of CO and its connection to antioxidant capacity were examined utilizing a combination of widely-targeted phenolic metabolomics and multivariate statistical analysis. A total of 751 phenolics were discovered. The WGCNA was used to link phenols to antioxidants, yielding 161 antioxidant-related phenols from the blue module. In response to several antioxidant assays, 59 (FRAP), 59 (DPPH), and 53 (ABTS) phenolics were identified as differential phenolic markers (DPMs). Further stepwise multiple linear regression revealed six DPMs that substantially influenced the antioxidant capacities. Nine metabolic pathways and their associated network mechanisms for the most significant phenolics were developed. This study sheds light on the phenolic content of CO, elucidates their role in antioxidant activity, and lays the groundwork for improving extraction techniques and generating improved product.

A Novel Step-Up Dosage Regimen for Enhancing the Benefit-to-Risk Ratio of Mosunetuzumab in Relapsed or Refractory Follicular Lymphoma.

Mosunetuzumab, a T-cell engaging bispecific antibody targeting CD20xCD3, is approved for treating relapsed/refractory follicular lymphoma. This research supports the approved intravenous clinical dose regimen, summarizing the exposure-response relationships for clinical safety and efficacy. A population pharmacokinetic model and Emax logistic regression exposure-response models for safety and efficacy were developed using data from 439 patients with relapsed/refractory non-Hodgkin lymphoma and 159 patients with relapsed/refractory follicular lymphoma, respectively, from a Phase I/II study (NCT02500407). Data from 0.2 to 60 mg across fixed dosing (Cohort A) and Cycle 1 step-up dosing (Cohort B) were used. Exposure-response models, using two-cycle area-under-the-concentration curve (AUC0-42) as the primary exposure endpoint, accurately depicted the complete response and objective response rate data across a 600-fold AUC0-42 range. The approved clinical dose regimen of 1/2/60/30 mg achieved near-maximal efficacy, with model-estimated CR and ORR (90% confidence interval) of 63.1% (49.7-75.0) and 79.1% (69.1-87.7), respectively. The exposure-response analysis for Grade ≥ 2 cytokine release syndrome identified receptor occupancy (%) within the first two cycles as a driver, with CRS dissipating beyond the first dosing cycle. No exposure-dependent increases were observed for other serious adverse events, including neutropenia and infections. The approved intravenous step-up dose regimen (i.e., step doses of 1 and 2 mg on Day 1 and 8, respectively) mitigated severe CRS risk, allowing safe administration of loading (60 mg) and target doses (30 mg every 3 weeks) to achieve a favorable benefit-risk profile.

Assessing spatio-temporal heterogeneity and drivers of ecosystem services to support zonal management in mountainous cities.

With complex topography and geomorphology, mountainous cities possess abundant natural resources. They are constrained by ecological environment and topographic conditions, leading to a prominent contradiction between urbanization development and ecological protection. As a result, ecosystem services (ESs) are under greater regulatory pressure. The identification of ecosystem services bundles (ESBs) can be the foundation for developing zonal ecological protection planning policies. We took Chongqing as a case study, investigated the impact mechanisms of socio-ecological factors on the level of ES supply in each ESB. The findings reveal that: (1) The quantitative assessment of ESs for 2000, 2010, and 2020 showed that ESs were temporally stable and spatially heterogeneous. Areas with high supplies of food production (FP) and water yield (WY) were predominantly found in the northwestern cropland and urban built-up regions, whereas high supply areas for the other four ESs were primarily located in the northeastern Dabashan Mountains and the southern Wuling Mountains. (2) The quantification of trade-offs and synergies between ESs showed that FP had a trade-off effect with all five other ESs, while most other ES pairs exhibited synergistic effects. It was found that the interrelationships produced changes over time. (3) Then, three types of ESBs were identified. After examining the influence mechanisms of socio-ecological factors across the three ESBs, individual ESs were found to have essentially the same types of main impact factors in three ESBs, but varies in impact. (4) Finally, with reference to changes in ES levels and interrelationships and the driving mechanisms of socio-ecological factors in each zone, this study proposed zonal strategies for managing ecosystem services and optimizing territorial space based on the geographic characteristics and socio-economic development in different ESBs, with the goal of attaining sustainable urban development and improving human welfare.

Impact of Model Spatial Resolution on Global Geophysical Satellite-Derived Fine Particulate Matter.

Global geophysical satellite-derived ambient fine particulate matter (PM2.5) inference relies upon a geophysical relationship (η) from a chemical transport model to relate satellite retrievals of aerosol optical depth (AOD) to surface PM2.5. The resolution dependence of simulated η warrants further investigation. In this study, we calculate geophysical PM2.5 with simulated η from the GEOS-Chem model in its high-performance configuration (GCHP) at cubed-sphere resolutions of C360 (∼25 km) and C48 (∼200 km) and satellite AOD at 0.01° (∼1 km). Annual geophysical PM2.5 concentrations inferred from satellite AOD and GCHP simulations at ∼25 km and ∼200 km resolutions exhibit remarkable similarity (R 2 = 0.96, slope = 1.03). This similarity in part reflects opposite resolution responses across components with population-weighted normalized mean difference (PW-NMD) increasing by 5% to 11% for primary species while decreasing by -30% to -5% for secondary species at finer resolution. Despite global similarity, our results also identify larger resolution sensitivities of η over isolated pollution sources and mountainous regions, where spatial contrast of aerosol concentration and composition is better represented at fine resolution. Our results highlight the resolution dependence of representing near-surface concentrations and the vertical distribution of chemically different species with implications for inferring ground-level PM2.5 from columnar AOD.

Perovskite Crystallization Control for Large, Oriented Grains with Residual Solvent Restrain via Hydrogen-Bonded Organic Frameworks.

Void-free perovskite films with oriented large grains are considered good performance. However, contradictory requirements on solvent volatilization arise that the growth of large grains requires slow volatilization while the residual solvent problem, which leads to difficult-handled voids at buried interface, requires quick and complete volatilization. Currently, although grain boundary additives help reach large and oriented grains, the occupation of additives in the grain boundary volatilization channel may further deteriorate the residual solvent problem. Herein, porous structures with "switchable pore" nature are constructed based on flexible hydrogen-bonded (HOF-FJU-2) in perovskite grain boundaries to meet both contradictory requirements with achieving crystallization control and residual solvent restrain. The additive molecules prolongs the perovskite crystallization through the Pb-O bond and guides the growth of (100) facet based on its strong ordered accumulation trend. The pre-embedded porous structure opens up the solvent volatilization channel for complete volatilization in annealing stage and then switches to a closed pore state via phase transformation after the solvent completely leaves, preventing the intrusion of the external environment. Combined with theoretical calculations and in situ spectrum tests, the crystallization thermodynamics and dynamics are analyzed. As expected, the target device exhibits enhanced performance (improved from 22.14% to 24.18%) and stability.

Anatomical compensation of retinal nerve fiber layer improves the detection of glaucoma between ethnicities.

The study aimed to evaluate the impact of compensating retinal nerve fiber layer (RNFL) thickness for demographic and anatomical factors on glaucoma detection in Chinese and Indian adults. A population-based study included 1995 healthy participants (1076 Chinese and 919 Indians) to construct a multivariable linear regression compensation model. This model was applied to 357 Chinese glaucoma patients, 357 healthy Chinese, and 357 healthy Indians using Cirrus spectral-domain optical coherence tomography (OCT). The compensated RNFL thickness considered age, refractive error, optic disc parameters, and retinal vessel density. Results showed that although the average RNFL thickness was significantly higher in Chinese participants compared to Indians, the compensation model reduced this difference to nonsignificance. Moreover, the compensation model significantly improved the area under the receiver operating characteristic curve (0.90 vs. 0.78; p<0.001), sensitivity (75% vs. 51%), and specificity (67% vs. 32%) in distinguishing Chinese glaucoma patients from healthy Indian individuals. The compensation model significantly enhanced the diagnostic accuracy of RNFL thickness in distinguishing glaucoma in the Chinese ethnic group compared to the OCT instrument's default values. These results suggest that modifying RNFL measurements based on individual characteristics can yield substantial benefits for glaucoma detection across ethnicities.