Correcting for library size is an essential step in bulk RNA-seq analyses, as differences in sequencing depth across samples can obscure biological signal with technical noise. While numerous normalization methods and model-based strategies have been proposed, we demonstrate here that library size-normalized counts and differential expression results obtained from such widely adopted approaches often remain strongly correlated with library size in large-scale RNA-seq experiments. Through a systematic analysis of over 100 publicly available GEO and TCGA RNA-seq datasets with raw count data, we show that library size association is observed for a substantial proportion of genes even after state-of-the-art library size correction approaches recommended by leading normalization tools. To address this issue, we propose gecco , a gene-specific exponent-corrected normalization method for RNA-seq counts that incorporates library size directly into the statistical framework via a gene-specific correction term, rather than applying a uniform adjustment factor across all genes. This formulation generalizes existing normalization approaches and yields normalized counts that are free of residual library size effects. Using both simulation studies and real large-scale RNA-seq datasets, we show that our method mitigates library size bias while preserving biological signal across a range of parameter settings. We further demonstrate that our approach leads to higher detection accuracy and more biologically meaningful pathway enrichment results in downstream differential expression and rhythmicity analyses without compromising false discovery rate control. Our method is implemented in R and is fully compatible with the widely used differential expression analysis methods DESeq2 and edgeR .
The History of Medicine Library at the Royal Australasian College of Physicians is now one of the leading comprehensive research collections on the history of medicine of Australasia. This is a far cry from the founding fellows' original proposition in 1938, when they felt the need for a 'scientific library' to ensure the academic standards of their fledgling college. The present library has been made possible by donations from many personal and corporate collections. The first was a gift from the Royal College of Physicians of London in 1954, which redirected the focus to the history of medicine, followed in 1978 by the first munificent gift from Sir Edward Ford of his personal collection of Australiana. In the concluding decades of the 20th century, the value of all traditional history of medicine libraries worldwide was brought into question. Our library has survived the threat of dispersal on several occasions. The library and the extensive heritage collection of archives, artefacts, artwork and an image library have adapted to the challenges of the digital age, with greater visibility and accessibility through digital platforms. Our library, with its own unique history, has never looked so vibrant.
X. Liu, Y. Ma, X. Wei, and T. Fan, "Neuroprotective Effect of Licochalcone a Against Oxygen-glucose Deprivation/Reperfusion in Rat Primary Cortical Neurons by Attenuating Oxidative Stress Injury and Inflammatory Response via the SIRT1/Nrf2 Pathway," Journal of Cellular Biochemistry 119, no. 4 (2018): 3210-3219, https://doi.org/10.1002/jcb.26477. The above article, published online on 6 November 2017 in Wiley Online Library (wileyonlinelibrary.com), has been retracted by agreement between the journal Editor-in-Chief, Lucie Kalvodova; and Wiley Periodicals LLC. The retraction has been agreed due to concerns raised by third parties. Specifically, multiple image elements in Figure 1 were found to have been previously published in several articles from different author groups and presented in different scientific contexts. The authors did not respond to our requests for clarification. Accordingly, the article has been retracted as the editors consider its conclusions to be invalid. The authors have been informed of the retraction decision but were not available for final confirmation.
T. Fan, H. Pi, M. Li, Z. Ren, Z. He, F. Zhu, L. Tian, M. Tu, J. Xie, M. Liu, Y. Li, M. Tan, G. Li, W. Qing, R. J. Reiter, Z. Yu, H. Wu, and Z. Zhou, "Inhibiting MT2-TFE3-Dependent Autophagy Enhances Melatonin-Induced Apoptosis in Tongue Squamous Cell Carcinoma," Journal of Pineal Research 64, no. 2 (2018): e12457, https://doi.org/10.1111/jpi.12457. The above article, published online on 08 May 2017 in Wiley Online Library (wileyonlinelibrary.com) and its corrigendum (https://doi.org/10.1111/jpi.12645), has been retracted by agreement between the journal Editor-in-Chief, Gianluca Tosini; and John Wiley & Sons Ltd. A third party brought the publisher's attention to a report on PubPeer [1] which suggested that the row of BAX bands in Figure 7E had been duplicated in Figure 8E and represented as CL-PARP following a vertical flip, while the row of GAPDH bands in Figure 7E had also likely been duplicated with further brightness changes and vertical resizing. Additionally, the row of CL-PARP bands in Figure 1B had been duplicated in Figure 2B and represented as SQSTM1 following a horizontal flip, while the row of GAPDH bands had also been duplicated between those same figures. While the corrigendum published online on 28 March 2020 corrected the duplication in Figure 2B, the corrigendum did not address how the mistake was made and did not address the duplications between Figure 7E and 8E. Further investigation by the publisher also found that most of the row of p-TFE3 bands in Figure 6A had been potentially duplicated from another article which shares one of the same authors [Chen et al. 2016 (https://doi.org/10.18632/oncotarget.12894)]. Both articles represented the data as being from different samples. Additionally, one further potential duplication between the c-TFEB and Histone H3 bands in Figure 4B was also detected. The authors responded to an inquiry by the publisher and presented original data as well as original experimental documentation. A review of these data by the publisher found that, while some of the bands in question were not duplicated, there were further discrepancies between the labeling of the original data and the data presented in the article. There were also further discrepancies between the presentation of the original data and the data included in the corrigendum. Following contact with the authors, an additional round of checks found further evidence of image duplication in the supplementary data. Part of the MT2 band in Figure S2A was potentially shared with the p-P70S6K band in Supplementary Figure S4B. Part of the GAPDH band in Figure S3A was shared with the GAPDH band in Figure S3B. A portion of the GAPDH band in Figure S4A was duplicated and represented as P70S6K in Figure S4C. Lastly, a portion of the row of GAPDH bands in Figure S3A was duplicated in Figure 6B in the main article text and represented as Histone H3 while the BAX band in Figure S5 was duplicated in Figure 4B in the main article text and represented as Histone H3. The Retraction has been agreed to because the evidence of image duplication of different samples within this work fundamentally compromises the editors' confidence in the results presented in this article. The authors were informed of the retraction. Reference 1. Phytotoma raimondii. Comments on "Inhibiting MT2-TFE3-Dependent Autophagy Enhances Melatonin-Induced Apoptosis in Tongue Squamous Cell Carcinoma," PubPeer, February 2020. https://pubpeer.com/publications/982C03B89308C90F5E87B7A19843AC.
Y. Wei, Y. Bai, X. Cheng, B. Zhu, R. J. Reiter, and H. Shi, "The Dual Roles of Melatonin Biosynthesis Enzymes in the Coordination of Melatonin Biosynthesis and Autophagy in Cassava," Journal of Pineal Research 69, no. 1 (2020): e12652, https://doi.org/10.1111/jpi.12652. The above article, published online on 23 March 2020 in Wiley Online Library (wileyonlinelibrary.com), has been retracted by agreement between the journal Editor-in-Chief, Gianluca Tosini; and John Wiley & Sons Ltd. A report on PubPeer [1] indicated that the pTRV and pTRV-MeASMT3 images in Figure 3D had been duplicated and presented as different samples in Figure 7B following rotation and further alteration. Additionally, several samples presented in Figure 4 contained overlapping or duplicated images. These concerns were confirmed by the publisher. The authors responded to an inquiry by the publisher and reported that an additional image duplication had occurred in between Figures 6C and 7C, in addition to the other errors. They reported that the duplications were due to mistakes during manuscript preparation. While the authors presented original as well as repeat data with the intention of correcting these errors, the authors did not provide a satisfactory explanation for the evidence of image rotation and alteration of images between Figures 3 and 7. Therefore, the publisher and the editor have lost confidence in the results and the conclusions, and the article must be retracted. The authors agree with the retraction.
Adults are at heightened risk of anxiety, stress, and depression; animal-assisted therapy (AAT) may serve as an effective approach to promote psychological well-being. In this study, we compared the effectiveness of AAT in improving depression, anxiety, stress, pain, and gait among adults with or without illness. We systematically searched six electronic databases (PubMed, CINAHL, Embase, Web of Science, the Cochrane Library, and Scopus) and included all studies published up to August 2024. We used comprehensive meta-analysis software to complete the quantitative synthesis. We reported pooled effect sizes as Hedges' g with corresponding 95% confidence intervals (CIs), after applying a random-effects model. Furthermore, we assessed heterogeneity using Cochran's Q test and the I2 statistic. We applied the Cochrane Risk of Bias 2.0 tool to appraise the methodological quality of the included studies. The synthesis process followed PRISMA guidelines. From the 13,345 studies identified, 35 randomised controlled trials involving 2391 adults were included. Across diverse populations, AAT was associated with reductions in depression (Hedges' g = -0.403; 95% CI = -0.536, -0.271), anxiety (Hedges' g = -0.661; 95% CI = -1.069, -0.253), and stress (Hedges' g = -1.062; 95% CI = -1.849, -0.275) at post-intervention, although substantial between-study variability was observed. We demonstrated that AAT significantly improves anxiety, depression and stress in adults, but has no meaningful effect on pain or gait. Subgroup and meta-regression analyses indicate that psychological benefits depend on population and intervention characteristics, and are not moderated by age or gender. PROSPERO: CRD42024570108.
Endodontically treated teeth are more prone to fracture due to structural loss during canal preparation and alterations in dentin biomechanics. Root canal sealers and obturation materials contribute not only to sealing ability but also to potential reinforcement of the remaining tooth structure. However, their influence on fracture resistance remains unclear due to variability in study designs and outcomes. To systematically evaluate and synthesize the available evidence on the fracture resistance of endodontically treated teeth obturated with different root canal sealers and materials. A comprehensive search was conducted across MEDLINE (via PubMed), Scopus, Web of Science, and the Cochrane Library, supplemented by grey literature from Google Scholar. A total of 549 records were identified, of which 24 studies met the eligibility criteria and were included in the qualitative synthesis. Among these, 22 were in vitro studies, one was an in vivo animal study, and one was an ex vivo study. Two independent reviewers performed study selection and data extraction. Due to methodological heterogeneity, a qualitative synthesis was performed. Obturation with root canal sealers generally improved fracture resistance compared with instrumented but unobturated controls, indicating a reinforcing effect. Epoxy resin-based and calcium silicate-based sealers demonstrated comparable performance, while zinc oxide eugenol-based sealers showed limited reinforcement. Considerable heterogeneity in tooth selection, loading conditions, and testing protocols limited direct comparisons. Root canal sealers appear to enhance the mechanical strength of endodontically treated teeth; however, no specific sealer demonstrates clear superiority. Standardized experimental models and clinical studies are needed to determine their clinical significance. Unique Identifier, CRD420251163273.
To assess the efficacy and safety of parathyroid hormone(PTH) analogs alone as compared with the conventional therapy on HypoPTH, and assess its emphasis on patients' health-related quality of life (HRQoL). Database (PubMed, Web of Science, Embase and Cochrane Library) were systematically searched until February 30, 2026. The primary outcomes were serum calcium and serum phosphate, while the secondary outcomes included 24-hour urinary calcium excretion, serum 25(OH)D, serum 1,25-dihydroxyvitamin D, calcium phosphate product, estimated glomerular filtration rate (eGFR), adverse events, and HRQoL. Meta-analysis was conducted using RevMan 5.4 and STATA 17.0. Eleven studies were included. Compared to conventional therapy, PTH analogs therapy showed no difference in serum calcium (MD = -0.02 mmol/L; 95% CI, -0.14 to 0.11 mmol/L), serum phosphorus (MD = 0.08 mmol/L; 95% CI, -0.05 to 0.20 mmol/L) and 24-hour urinary calcium excretion (MD = 1.00 mmol; 95% CI, -1.84 to 3.84 mmol). PTH analogs decreased 25(OH) vitamin D, increased 1,25(OH)2 vitamin D and eGFR. Additionally, PTH analogs therapy significantly improved HRQoL as measured by the Short Form 36 (SF-36) Health Survey Questionnaire (MD = -7.35; 95% CI, -8.37 to -6.33). In addition to the comparable control of serum calcium and serum phosphorus levels to conventional therapy, limited data indicate that PTH analogs treatment may be better in regulating the serum vitamin D and maintaining the eGFR for patients with HypoPTH. PTH analogs therapy also improves patients' HRQoL. https://www.crd.york.ac.uk/PROSPERO/, identifier CRD420251089112.
Carbon monoxide (CO) occupies an unusual position at the boundary between environmental toxicology and therapeutic pharmacology. The same molecule is regulated as an involuntary toxic exposure in public-health and occupational settings, yet it is also being explored as a controlled therapeutic agent in acute inflammation, organ preservation, wound repair and selected local-delivery indications. This critical narrative review was written to clarify three issues that have repeatedly distorted interpretation of the field: the quantitative endogenous baseline of CO (a haem-derived pool that can approach roughly 150 μmol/L in blood, far above a trace contaminant), the analytical validity of CO donor systems and the need to keep environmental exposure limits separate from drug-development risk assessment. Structured scoping searches of PubMed, Web of Science and the Cochrane Library were used to identify mechanistic, toxicological, donor chemistry, exposure metric and regulatory literature through November 2025. We place particular weight on post-2018 evidence showing that widely used ruthenium carbonyls, especially CORM-2 and CORM-3, do not behave as reliable CO donors under many physiological conditions and that several historical biological effects may reflect ruthenium reactivity rather than CO signalling. We argue that CO studies should be read through a donor-validation filter that favours gaseous CO, physiologically characterised organic donors, gas-entrapping materials and measured exposure metrics such as carboxyhaemoglobin (COHb). To make this operational, we propose a three-tier evidence scheme for grading CO biology and a minimum reporting set for CO intervention studies. The most defensible translational opportunities are short, monitored and reversible interventions in acute or localised settings; chronic systemic inhalation for diffuse disease remains less plausible because systemic COHb elevation cannot be confined to the diseased tissue. For applied toxicology, a coherent framework for CO therefore requires validated exposure metrics, explicit donor chemistry and strict separation of therapeutic benefit-risk assessment from population-protective environmental limits.
Enterovirus D68 (EV-D68) is a non-polio picornavirus that has caused increasing rates of severe respiratory illness and acute flaccid myelitis in children worldwide this century. There are no approved vaccines or antivirals for EV-D68. Thus, we conducted a crystallographic fragment screening (CFS) and a high-throughput screening (HTS) biochemical assay against the EV-D68 RNA-dependent RNA polymerase 3D (3D pol ) to identify ligandable sites and non-nucleoside compounds that can spearhead anti-enteroviral drug discovery. The CFS, involving 650 fragments, identified 68 hit compounds (~10% hit rate) distributed across 3D pol , including the functionally relevant sites RNA template channel, Active site, and RNA primer channel, and the previously unknown "Thumb site II" and "Index-middle finger pocket". Inhibition assays confirmed that compounds binding to each site can inhibit EV-D68 3D pol activity. The HTS, a fluorescence-based PicoGreen biochemical assay, permitted screening 50,000 compounds of the ChemBridge Premium Library (0.77% hit rate). After a second-round dose-response screening, we identified 5-aminoindazole as a promising scaffold that inhibits EV-D68 3D pol , including hit-to-lead compound 727590, which displayed an IC 50 value of 25 μM and preliminary structure-activity relationships. These hits offer amenable starting points for discovery and development of non-nucleoside inhibitors and provide opportunities for structure-based drug design against enteroviruses.
Osteonecrosis (ON) is a prevalent and severe complication in patients with systemic lupus erythematosus (SLE). However, the etiology and mechanism of SLE-ON have not been fully elucidated. This study aims to investigate the factors related to SLE-ON and provide a basis for early prevention and control. A comprehensive search of relevant literatures was conducted from PubMed, Ovid Medline, Web of Science, Embase, Cochrane Library, CNKI, Wanfang Data, and VIP Information databases up to 31 October 2025. According to the inclusion and exclusion criteria, 3,051 studies were examined, and quality of each study was assessed using the Newcastle-Ottawa scale (NOS). Meta-analysis methods discussed the association of the factors related to SLE-ON. A total of 64 studies were finally included in the meta-analysis. For clinical features, factors such as neuropsychiatric lupus (OR = 1.652), hyperlipidemia (OR = 1.358), oral ulcers (OR = 1.319), pleuritis (OR = 2.225), malar rash (OR = 1.311), vasculitis (OR = 2.638), serositis (OR = 1.514), hematologic involvement (OR = 1.190), Reynaud's phenomenon (OR = 1.604), thrombophlebitis (OR = 1.856), and arthritis (OR = 1.256) were positively related to SLE-ON risk. For laboratory features, proteinuria (OR = 1.635), antiphospholipid antibody (OR = 1.450), elevated ESR (OR = 1.623), leukopenia (OR = 1.317), and ACL (OR = 1.657) were positively related to SLE-ON risk as well. Interestingly, the anti-SSA antibody (OR = 0.805) and anti-SSB antibody (OR = 0.764) were negatively related to SLE-ON susceptibility. Usage of cyclophosphamide (OR = 1.869) and steroid pulse therapy (OR = 1.829) was positively correlated with occurrence of SLE-ON. Furthermore, younger age (SMD=-0.175) and the age at onset (SMD=-0.426) significantly related to developing of SLE-ON. A total of 32 factors including clinical, laboratory features, drug usage, and basic information in SLE patients were related to SLE complicated with osteonecrosis. Of note, the association between cyclophosphamide/steroid pulse therapy and SLE-ON risk may be confounded by underlying disease severity, so these results should be interpreted cautiously. Targeted monitoring and intervention of these modifiable risk factors, especially optimized steroid pulse therapy and cyclophosphamide use and early osteoporosis screening, combined with risk stratification based on anti-SSA/SSB antibody status, may help reduce SLE-ON risk and improve clinical management of SLE patients.
Acoustic droplet ejection (ADE) enables nanoliter-scale liquid handling for complex microplate assays, yet translating experimental designs into validated, instrument-ready instructions remains a bottleneck. We present PickliPy, an open-source framework that converts spreadsheet-based assay designs into validated ADE picklists. PickliPy.Assay supports combinatorial, dose-response, and multi-addition time-course dispensing, while PickliPy.Screen extends to high-throughput workflows, including library reformatting and shortlisting. Across diverse biological contexts, the framework generated reproducible, assay-ready plates and standardized execution in human cohort studies. Acoustic pre-dispensing deepened bioenergetic phenotyping of isolated human skeletal muscle mitochondria, capturing substrate switching, and sharpened dose-response precision in human pancreatic β-cells, revealing an age-associated change in succinate dehydrogenase kinetics. We benchmarked a wash-free, live-cell screen of mitochondrial function and morphology, in which deep-learning image analysis widened the assay window and ADE enabled integrative dose-response co-response analysis. Together, these tools make complex ADE experiments easier to design, reproduce, and scale from single benches to screening campaigns.
This study systematically evaluated the effects of Tai Chi on pain, functional disability, and sleep quality in patients with chronic non-specific low back pain (CNLBP). We searched CNKI, WanFang, VIP, China Biology Medicine Database, PubMed, Web of Science, Embase, and the Cochrane Library for randomized controlled trials (RCTs) of Tai Chi for CNLBP. Study quality was assessed using the Cochrane RoB 2 tool and the PEDro scale. Meta-analysis was used to pool the data. Eight RCTs involving 526 patients with CNLBP were included. Meta-analysis showed that Tai Chi significantly reduced pain, improving VAS scores (MD = -1.40, 95% CI: -2.41 to -0.40) and NRS scores. Tai Chi also significantly improved RMDQ scores (MD = -1.67, 95% CI: -2.75 to -0.59) and overall functional disability (SMD = -0.51, 95% CI: -0.90 to -0.12), but did not significantly affect ODI scores (MD = -0.62, 95% CI: -2.53 to 1.29). Moreover, improvements in PSQI scores were not statistically significant (MD = -0.18, 95% CI: -1.82 to 1.45). Tai Chi can effectively relieve pain and improve functional disability in patients with CNLBP. It is a safe and feasible non-pharmacological rehabilitation approach. However, current evidence is insufficient to confirm its effect on sleep quality. Further high-quality RCTs are needed. PROSPERO CRD420261361228.
E1A-binding protein (p300)/CREB-binding protein (CBP) bromodomains represent attractive therapeutic targets for anticancer drug development. Herein, we describe a structure-guided optimization of the lead compound UMB298 through a conformationally constrained cyclization strategy. A concise four-step synthesis (overall yield >30%), centered on a three-component reaction, was developed, enabling efficient construction of a lactam-containing imidazo[1,2-a]pyridine library for rapid screening. Among these compounds, CZL-105 emerges as a promising p300/CBP bromodomain inhibitor. It exhibits potent activity against p300 and CBP while sparing BET and demonstrates strong antiproliferative potency in OPM-2 multiple myeloma cells. Acceptable metabolic stability and pharmacokinetics support once-daily oral dosing, leading to significant tumor growth inhibition (TGI = 61%) in an OPM-2 xenograft model. These results position CZL-105 as a promising lead compound for further development. This work combines a rational design strategy and efficient chemical synthesis, accelerating the discovery of novel p300/CBP bromodomain inhibitors.
Nasopharyngeal carcinoma (NPC) is a malignant tumor with significant disease burden. Currently, radiotherapy-based multimodal therapy remains the primary treatment strategy for NPC, yet consensus on the relative efficacy of induction chemotherapy, targeted therapy, and radiotherapy remains elusive. This study aims to systematically compare the relative efficacy of induction chemotherapy, targeted therapy, and radiotherapy on overall survival and treatment response using network meta-analysis, thereby providing evidence-based guidance for clinical decision-making. Following the PRISMA-NMA and Cochrane Manual guidelines, we systematically searched six databases (PubMed, Embase, Web of Science, Cochrane Library, EBSCO, and CNKI) for relevant randomized controlled trials (RCTs) published between January 1998 and June 2025. Two researchers independently conducted literature screening, data extraction, and risk of bias assessment. A total of 12 randomized controlled trials were ultimately included. Traditional meta-analysis and heterogeneity assessment were performed using RevMan 5.3 software. A network meta-analysis was conducted using STATA 17.0 software (Stata Corp LLC, College Station, TX, USA) based on a frequency framework, with interventions ranked by cumulative ranked probability area under the curve (SUCRA). Publication bias was evaluated using a corrected funnel plot. Network meta-analysis showed that while TD ranked first in the probability of being the best treatment for OS (SUCRA = 98.1%), only IC demonstrated a statistically significant survival benefit compared to the control group (HR = 0.37, 95% CI: 0.02, 0.71). Regarding PFS, TD ranked first (SUCRA = 82.2%, HR = -0.68, 95% CI: -2.59, 1.23), although no intervention demonstrated a statistically significant benefit compared to the control group. In terms of ORR, IC had the highest probability (SUCRA = 71.6%, OR = 0.24, 95% CI: -2.18, 2.66), with no statistically significant differences among the interventions. Regarding CRR, TD showed the greatest advantage (SUCRA = 98.0%, OR = 0.26, 95% CI: 0.12, 0.58). The network meta-analysis results indicate that induction chemotherapy offers the greatest advantage in improving overall survival for nasopharyngeal carcinoma patients, while targeted drugs perform best in reducing cumulative recurrence risk. No statistically significant differences were observed among the three interventions for progression-free survival or objective response rate. Radiotherapy alone did not demonstrate significant benefit across any outcome measures. This study provides important evidence-based support for individualized treatment decisions in nasopharyngeal carcinoma. https://www.crd.york.ac.uk/prospero/, identifier CRD420251178558.
Morbid obesity (body mass index (BMI) ≥40 kg/m² or ≥35 kg/m² with comorbidities) predisposes patients to multiple urological disorders, including urinary incontinence, overactive bladder, erectile dysfunction, hypogonadism, nephrolithiasis, obesity-related kidney disease, renal cell carcinoma, and aggressive prostate cancer. Bariatric surgery is the most effective durable treatment for severe obesity. Glucagon-like peptide-1 receptor agonists, including semaglutide and tirzepatide, have revolutionised obesity pharmacotherapy. This systematic review evaluates the urological complications of morbid obesity and the effects of bariatric surgery and glucagon-like peptide-1 receptor agonists on these outcomes. We searched MEDLINE, Embase, Scopus, and the Cochrane Library (January 2000 to June 2025) for studies reporting urological outcomes in adults with BMI ≥35 kg/m². Two reviewers independently screened and extracted data. We assessed risk of bias using the A Measurement Tool to Assess Systematic Reviews (AMSTAR) version 2 and the Grading of Recommendations, Assessment, Development, and Evaluations (GRADE). Eighty-four studies (>165,000 participants) met the inclusion criteria. Obesity increases renal cell carcinoma risk (relative risk: 1.5-2.0) and prostate cancer mortality (hazard ratio: 1.19-1.24) but paradoxically reduces prostate cancer incidence. Urinary incontinence and overactive bladder improve or resolve in 50-70% of women after bariatric surgery. Erectile dysfunction and hypogonadism improve after bariatric surgery, with International Index of Erectile Function (IIEF) scores increasing 4-6 points and testosterone rising 30-50%. Glucagon-like peptide-1 receptor agonists increase testosterone (standardised mean difference: 1.39 ng/mL) and improve erectile function. Tirzepatide reduces urinary albumin-to-creatinine ratio by 19-47% and preserves estimated glomerular filtration rate. Roux-en-Y gastric bypass increases nephrolithiasis risk 2.5-4-fold via enteric hyperoxaluria, whereas sleeve gastrectomy does not. Robot-assisted surgery in obese patients achieves complication rates comparable to those of non-obese patients after comorbidity adjustment. Bariatric surgery improves obesity-related urological morbidity, but Roux-en-Y gastric bypass increases stone risk. Glucagon-like peptide-1 receptor agonists offer a promising alternative with evidence for testosterone restoration, improved erectile function, and renal protection. Preoperative urological assessment, procedure selection, and multidisciplinary care are essential.
Intrahepatic cholangiocarcinoma (ICC) is a lethal hepatic malignancy characterized by a prominent desmoplastic stroma. Here, we demonstrated that ARID1A, a core component of the SWI/SNF protein complex, is upregulated in ICC and plays an oncogenic role. Mechanistically, ARID1A stabilized NICD1 protein by inhibiting AMPK-dependent autophagy and lysosomal degradation, thereby sustaining Notch signaling. TLL1, a metalloproteinase that promotes collagen maturation, was found to be a downstream effector of ARID1A/Notch signaling. Specifically, TLL1 derived from ICC cells activated hepatic stellate cells (HSCs) and thus promoted tumor progression. Accordingly, ablation of TLL1 attenuated cancer-associated fibroblast (CAF) infiltration, collagen accumulation, and tumor progression. Moreover, virtual screening of a bioactive compound library identified acarbose, an effective medicine for glycemic control, as a potent inhibitor for TLL1. Pharmacological inhibition of TLL1 with acarbose suppressed HSC activation, collagen deposition, and tumor development. Collectively, these results establish a tumor-promoting ARID1A/Notch/TLL1 axis in ICC and reveal acarbose as a potential precision therapy for ARID1A-high ICC patients.
To synthesise nursing students' experiences of peer support during clinical practice. A qualitative meta-synthesis. We searched the Cochrane Library, Embase, PubMed, Web of Science, CNKI, Wanfang and VIP databases for qualitative studies exploring nursing students' experiences of peer support, up to 11 September 2024. The Joanna Briggs Institute Qualitative Appraisal and Review Instrument was used to assess methodological quality, and findings were synthesised using a thematic synthesis approach. Ten studies were included. From 35 extracted findings, eight categories were developed and further synthesised into two overarching themes: (1) benefits of peer support for nursing students, and (2) challenges associated with peer support experiences. Peer support in clinical practice offers meaningful benefits-including enhanced confidence, emotional support and skill development-but also presents challenges related to mentor competence, interpersonal dynamics and reduced hands-on practice. Structured programme design and mentor preparation are essential to maximise benefits while mitigating risks. The findings suggest that peer support should be formally integrated into clinical placement designs to enhance student learning and well-being. In nursing education, structured peer mentoring programmes with clear role definitions and preparatory training for mentors are recommended to improve support quality. For clinical practice settings, regular supervision and monitoring are needed to safeguard students from over-dependence on peers and to ensure that peer support complements, rather than replaces, hands-on clinical learning opportunities. No patient or public contribution.
Home mechanical ventilation (HMV) is an important form of support for the out-of-hospital management of patients with chronic respiratory failure and long-term ventilatory dependence. It plays an important role in prolonging life, relieving symptoms, and supporting home living. As the site of treatment extends from the hospital to the home, patients and caregivers must jointly face challenges related to treatment decision-making, technological adaptation, expansion of caregiving responsibilities, and insufficient support systems. Existing studies have often focused on a single disease, a single ventilation modality, or a single caregiving perspective, and a systematic synthesis of the experiences and support needs of patients receiving HMV and their caregivers remains lacking. This study aimed to systematically synthesize the experiences and support needs of patients receiving HMV and their caregivers during home treatment through a qualitative systematic review and meta-synthesis. It also explored core issues across different disease types, ventilation modalities, levels of dependence, and caregiving contexts to provide evidence for developing stratified and continuous care support pathways for the family as a unit. This study conducted a meta-synthesis using the Joanna Briggs Institute methodology for qualitative systematic reviews. PubMed, Web of Science, Embase, the Cochrane Library, and CINAHL were systematically searched from January 1, 2020, to April 30, 2026, and the reference lists of the included studies were manually searched. The methodological quality of the included studies was assessed using the JBI Critical Appraisal Checklist for Qualitative Research. Findings were categorized and synthesized using the JBI meta-aggregation approach, and confidence in the evidence for the synthesized themes was assessed using the ConQual framework. Thirteen qualitative studies were included, involving 129 patients receiving HMV and 121 family-caregiving-related participants, including family caregivers, relatives, and bereaved family members. Five synthesized themes and 17 subthemes were generated: (1) passive entry, repeated weighing, and active participation in HMV decision-making; (2) adapting to the integration of ventilation technology into everyday family life; (3) ongoing tensions among life support, quality of life, and autonomy; (4) expansion of family caregiving responsibilities and reconstruction of the boundaries of professional care; and (5) gaps in support systems and the need for continuous support for the whole family. The ConQual assessment showed that the final level of confidence was moderate for all five synthesized themes. HMV is not only a long-term respiratory support technology but also a continuous care process deeply embedded in disease progression, family life, and healthcare service systems. The experiences of patients and caregivers are jointly influenced by disease type, ventilation modality, level of ventilatory dependence, socioeconomic conditions, and healthcare system context. HMV nursing practice should shift from individual patient management and guidance on device use toward continuous support for the family as a unit. Particular attention should be given to strengthening shared decision-making, caregiver training, professional follow-up, remote monitoring and digital follow-up, psychosocial support, resource navigation, and integration of early palliative care to improve the sense of security, quality of life, and sustainability of care for both patients and caregivers.
Identification of signaling networks is an essential goal in systems biology. Here, we use CRISPR/Cas9 knockout screening (employing a whole kinome sgRNA library) to identify functionally critical protein kinases in a well-studied G α s-dependent G-protein coupled receptor (GPCR)-signaling model, namely the vasopressin V2 receptor (V2R) pathway. Screening was done using a specially-designed fluorescence-based reporter cell line with green-fluorescent protein (GFP) co-transcribed with Aqp2 , a gene whose transcription is dependent on vasopressin-mediated activation of protein kinase A (PKA). Positive regulators (n=14) included PKA-catalytic subunit α (Prkaca) and Dyrk1a ( minibrain homolog). Negative regulators (n=12) included PKA-regulatory subunit type Iα, Stk11 (catalytic subunit of liver kinase B1 [LKB1] complex), and three TGF-β receptor subunits (Tgfbr1, Tgfbr2, Tgfbr3) (see https://esbl.nhlbi.nih.gov/Databases/Kinome-CRISPR-screen/ for full list). Dyrk1a knockout cell lines failed to express AQP2 protein and exhibited a profound decrease in AQP2 mRNA. RNA-sequencing demonstrated widespread increases in cell-cycle transcripts, with a general defect in cell differentiation, accounting for AQP2 loss. TGF-β exposure to un-transformed cells results in a profound decrease in V2R and AQP2 mRNA abundance along with multiple additional transcriptional targets of V2R-PKA signaling, consistent with prior findings in TGF-β-mediated vasopressin 'escape'. Stk11/LKB1 knockout lines displayed marked increases in AQP2 protein and mRNA, even in the absence of vasopressin. RNA-sequencing showed a marked similarity between the responses to Stk11/LKB1 deletion and vasopressin exposure in untransformed cells. Phospho-proteomic data point to opposing roles of Stk11/LKB1 and PKA in the regulation of cAMP-responsive transcriptional coactivator (CRTC) proteins in the transcriptional response to V2R-PKA signaling. Cells throughout the body are regulated by extracellular signals like the hormone, vasopressin. Hormonal effects on cellular function are mediated by membrane receptors that trigger biochemical changes, often by inducing chemical modification of the amino acids making up individual proteins, such as addition of function-altering phosphate groups (phosphorylation). Protein phosphorylation is mediated by enzymes known as "protein kinases". Here, we have screened all known protein kinases using modern CRISPR/Cas9 technology to identify those involved in vasopressin action in the kidney. As expected from prior knowledge, the screen identified protein kinase A and one of its regulatory subunits, but also identified several protein kinases not previously implicated in vasopressin action in the kidney.