Circular RNA ZNF609/CKAP5 mRNA interaction regulates microtubule dynamics and tumorigenicity.

Circular RNAs (circRNAs) are widely expressed in eukaryotes and are regulated in many biological processes. Although several studies indicate their activity as microRNA (miRNA) and protein sponges, little is known about their ability to directly control mRNA homeostasis. We show that the widely expressed circZNF609 directly interacts with several mRNAs and increases their stability and/or translation by favoring the recruitment of the RNA-binding protein ELAVL1. Particularly, the interaction with CKAP5 mRNA, which interestingly overlaps the back-splicing junction, enhances CKAP5 translation, regulating microtubule function in cancer cells and sustaining cell-cycle progression. Finally, we show that circZNF609 downregulation increases the sensitivity of several cancer cell lines to different microtubule-targeting chemotherapeutic drugs and that locked nucleic acid (LNA) protectors against the pairing region on circZNF609 phenocopy such effects. These data set an example of how the small effects tuned by circZNF609/CKAP5 mRNA interaction might have a potent output in tumor growth and drug response.

Splicing dysregulation in human hematologic malignancies: beyond splicing mutations.

Splicing is a fundamental process in pre-mRNA maturation. Whereas alternative splicing (AS) enriches the diversity of the proteome, its aberrant regulation can drive oncogenesis. So far, most attention has been given to spliceosome mutations (SMs) in the context of splicing dysregulation in hematologic diseases. However, in recent years, post-translational modifications (PTMs) and transcriptional alterations of splicing factors (SFs), just as epigenetic signatures, have all been shown to contribute to global splicing dysregulation as well. In addition, the contribution of aberrant splicing to the neoantigen repertoire of cancers has been recognized. With the pressing need for novel therapeutics to combat blood cancers, this article provides an overview of emerging mechanisms that contribute to aberrant splicing, as well as their clinical potential.

Testicular niche repair after gonadotoxic treatments: Current knowledge and future directions.

The testicular niche, which includes the germ cells, somatic cells, and extracellular matrix, plays a crucial role in maintaining the proper functions of the testis. Gonadotoxic treatments, such as chemotherapy and radiation therapy, have significantly improved the survival rates of cancer patients but have also been shown to have adverse effects on the testicular microenvironment. Therefore, repairing the testicular niche after gonadotoxic treatments is essential to restore its function. In recent years, several approaches, such as stem cell transplantation, gene therapy, growth factor therapy, and pharmacological interventions have been proposed as potential therapeutic strategies to repair the testicular niche. This comprehensive review aims to provide an overview of the current understanding of testis damage and repair mechanisms. We will cover a range of topics, including the mechanism of gonadotoxic action, repair mechanisms, and treatment approaches. Overall, this review highlights the importance of repairing the testicular niche after gonadotoxic treatments and identifies potential avenues for future research to improve the outcomes for cancer survivors.

The importance of including Long COVID outcomes when developing novel treatments for acute COVID-19.

The ongoing COVID-19 pandemic continues to present surges in infections demonstrating the persistent threat posed by COVID-19. Amidst efforts to develop effective treatments for acute COVID-19, there is a growing recognition of the need to address Long COVID. This manuscript reviews the current landscape of acute COVID-19 treatments and highlights the opportunity to incorporate Long COVID as a key outcome measure in clinical trials. Our analysis includes a review of current US clinical trials investigating acute COVID-19 treatments. Of the 19 studies that met our inclusion criteria, only one study currently incorporates Long COVID measurements. In our review, we argue there are 7 compelling reasons to include Long Covid measurements, including: (1) Long COVID is not rare (2) Long COVID is debilitating to individuals and has a high societal cost (3) Those at high risk of severe COVID-19 are also at higher risk of developing Long COVID if they are infected with COVID-19 (4) Treatments for acute COVID-19 may reduce the risk of Long COVID (5) Measures exist to track Long COVID (6) Long COVID considerations are potentially important for acute COVID-19 treatment decision-making (7) Deaths and hospitalizations due to COVID-19 are increasingly rare, creating an opportunity for other important clinical endpoints to be considered In conclusion, while not every trial needs to include assessments of Long COVID, it is worth the research burden to include assessments where possible as this could facilitate the uptake of acute COVID-19 treatments that lessen the societal burden of Long COVID.

HBcrAg values may predict virological and immunological responses to pegIFN-α in NUC-suppressed HBeAg-negative chronic hepatitis B.

OBJECTIVE: Selected populations of patients with chronic hepatitis B (CHB) may benefit from a combined use of pegylated interferon-alpha (pegIFN-α) and nucleos(t)ides (NUCs). The aim of our study was to assess the immunomodulatory effect of pegIFN-α on T and natural killer (NK) cell responses in NUC-suppressed patients to identify cellular and/or serological parameters to predict better T cell-restoring effect and better control of infection in response to pegIFN-α for a tailored application of IFN-α add-on. DESIGN: 53 HBeAg-negative NUC-treated patients with CHB were randomised at a 1:1 ratio to receive pegIFN-α-2a for 48 weeks, or to continue NUC therapy and then followed up for at least 6 months maintaining NUCs. Serum hepatitis B surface antigen (HBsAg) and hepatitis B core-related antigen (HBcrAg) levels as well as peripheral blood NK cell phenotype and function and HBV-specific T cell responses upon in vitro stimulation with overlapping HBV peptides were measured longitudinally before, during and after pegIFN-α therapy. RESULTS: Two cohorts of pegIFN-α treated patients were identified according to HBsAg decline greater or less than 0.5 log at week 24 post-treatment. PegIFN-α add-on did not significantly improve HBV-specific T cell responses during therapy but elicited a significant multispecific and polyfunctional T cell improvement at week 24 post-pegIFN-α treatment compared with baseline. This improvement was maximal in patients who had a higher drop in serum HBsAg levels and a lower basal HBcrAg values. CONCLUSIONS: PegIFN-α treatment can induce greater functional T cell improvement and HBsAg decline in patients with lower baseline HBcrAg levels. Thus, HBcrAg may represent an easily and reliably applicable parameter to select patients who are more likely to achieve better response to pegIFN-α add-on to virally suppressed patients.

Mechanisms of the septic heart: From inflammatory response to myocardial edema.

Sepsis-induced myocardial dysfunction (SIMD), also known as sepsis-induced cardiomyopathy (SICM), is linked to significantly increased mortality. Despite its clinical importance, effective therapies for SIMD remain elusive, largely due to an incomplete understanding of its pathogenesis. Over the past five decades, research involving both animal models and human studies has highlighted several pathogenic mechanisms of SICM, yet many aspects remain unexplored. Initially thought to be primarily driven by inflammatory cytokines, current research indicates that these alone are insufficient for the development of cardiac dysfunction. Recent studies have brought attention to additional mechanisms, including excessive nitric oxide production, mitochondrial dysfunction, and disturbances in calcium homeostasis, as contributing factors in SICM. Emerging clinical evidence has highlighted the significant role of myocardial edema in the pathogenesis of SICM, particularly its association with cardiac remodeling in septic shock patients. This review synthesizes our current understanding of SIMD/SICM, focusing on myocardial edema's contribution to cardiac dysfunction and the critical role of the bradykinin receptor B1 (B1R) in altering myocardial microvascular permeability, a potential key player in myocardial edema development during sepsis. Additionally, this review briefly summarizes existing therapeutic strategies and their challenges and explores future research directions. It emphasizes the need for a deeper understanding of SICM to develop more effective treatments.

Anti-HLA serologic response to CD38-targeting desensitization therapy is challenged by peripheral memory B cells in highly sensitized kidney transplant candidates.

High human leukocyte antigen (HLA) sensitization limits access to compatible transplantation. New CD38-targeting agents have been shown to reduce anti-HLA antibodies, although with important interpatient variability. Thus, pretreatment identification of responder and nonresponder (NR) patients is needed for treatment decision-making. We analyzed 26 highly sensitized (HS) patients from 2 desensitization trials using anti-CD38 monoclonal antibodies. Hierarchical clustering identified 3 serologic responder groups: high responders, low responders, and NR. Spectral flow cytometry and functional HLA-specific memory B cell (mBC) assessment were first conducted on peripheral blood mononuclear cells and bone marrow samples from 16 patients treated with isatuximab (NCT04294459). Isatuximab effectively depleted bone marrow plasma cells, peripheral CD38-expressing plasmablasts, plasma cells, transitional B cells, and class-switch mBCs, ultimately reducing frequencies of HLA-specific immunoglobulin G (IgG)-producing mBCs. Multidimensional spectral flow cytometry with partial least squares discriminant analysis revealed that pretreatment abundance of specific circulating mBC phenotypes, especially CD38neg class-switch mBCs, accurately distinguished between high serologic responders and low responders or NR (AUC 0.958, 0.860-1.000, P = .009), who also displayed significantly lower frequencies of HLA-specific IgG-producing mBCs (P < .0001). This phenotypical mBC signature predicting response to therapy was validated in an external HS patient cohort (n = 10) receiving daratumumab (NCT04204980). This study identifies critical circulating mBC subset phenotypes that distinguish HS patients with successful serologic responses to CD38-targeting desensitization therapies, potentially guiding treatment decision-making.

Pre-treatment plasma retinol binding protein 4 level and its change after treatments predict systemic treatment response in psoriasis patients.

BACKGROUND: Retinol binding protein 4 (RBP4) is a mediator of inflammation and related to skin lesion formation, which suggests its engagement in psoriasis pathology and progression. This study intended to explore the change in RBP4 after systemic treatments, and its ability to predict treatment response in psoriasis patients. METHODS: This prospective study enrolled 85 psoriasis patients and 20 healthy subjects. Plasma RBP4 was detected by enzyme-linked immunosorbent assay at baseline and 12th week (W12) after systemic treatments in psoriasis patients, as well as after enrollment in healthy subjects. Psoriasis Area and Severity Index (PASI) 75 and PASI 90 were evaluated at W12 in psoriasis patients. RESULTS: RBP4 at baseline was higher in psoriasis patients than in healthy subjects [median (interquartile range): 13.39 (9.71-22.92) versus 9.59 (6.57-13.72) µg/mL] (P = 0.003). In psoriasis patients, 50 (58.8%) patients achieved PASI 75 at W12, and 25 (29.4%) patients achieved PASI 90 at W12. RBP4 was decreased at W12 compared to its level at baseline (P < 0.001). Lower RBP4 at baseline predicted achieving PASI 75 at W12 (P = 0.038). Greater RBP4 change (baseline-W12) precited achieving PASI 75 (P = 0.036) and PASI 90 (P = 0.045) at W12. Receiver operating characteristic curves suggested that after adjustment for all clinical features, RBP4 at baseline and RBP4 change (baseline-W12) had an acceptable ability to predict PASI 75 and PASI 90 at W12 with all area under curve values > 0.7. CONCLUSION: Plasma RBP4 is decreased after systemic treatments, and its low baseline level and greater decline after treatments predict good treatment response in psoriasis patients.

Cognitive impairment following breast cancer treatments: an umbrella review.

OBJECTIVES: Cancer-related cognitive impairment (CRCI) refers to a cognitive decline associated with cancer or its treatments. While research into CRCI is expanding, evidence remains scattered due to differences in study designs, methodologies, and definitions. The present umbrella review aims to provide a comprehensive overview of the current evidence regarding the impact of different breast cancer therapies on cognitive functioning, with a particular focus on the interplay among objective cognitive deficits (ie, measured with standardized tests), subjective cognitive concerns, (ie, self-reported), and other mediating psycho-physical factors. METHODS: The search was made in Pubmed, Embase, and Scopus for articles published until July 2023, following the guidelines of the Preferred Reporting Items for Systematic Reviews and Meta-analysis protocol. RESULTS: Chemotherapy and endocrine therapy appear consistently associated with CRCI in patients with breast cancer, primarily affecting memory, attention/concentration, executive functioning, and processing speed. Subjective cognitive concerns were often found weakly or not associated with neuropsychological test results, while overall CRCI seemed consistently associated with psychological distress, fatigue, sleep quality, and inflammatory and biological factors. CONCLUSION: Current evidence suggests that CRCI is common after chemotherapy and endocrine therapy for breast cancer. However, heterogeneity in study designs and the scarcity of studies on more recent treatments such as targeted therapies and immunotherapies, highlight the need for more systematic and harmonized studies, possibly taking into account the complex and multifactorial etiology of CRCI. This may provide valuable insights into CRCI's underlying mechanisms and potential new ways to treat it.

Association of Renin-Angiotensin System Inhibition With Liver-Related Events and Mortality in Compensated Cirrhosis.

BACKGROUND & AIMS: While renin-angiotensin system inhibition lowers the hepatic venous gradient, the effect on more clinically meaningful endpoints is less studied. We aimed to quantify the relationship between renin-angiotensin system inhibition and liver-related events (LREs) among adults with compensated cirrhosis. METHODS: In this national cohort study using the Optum database, we quantified the association between angiotensin-converting enzyme (ACE) inhibitor or angiotensin-receptor blocker (ARB) use and LREs (hepatocellular carcinoma, liver transplantation, ascites, hepatic encephalopathy, or variceal bleeding) among patients with cirrhosis between 2009 and 2019. Selective beta-blocker (SBB) users served as the comparator group. We used demographic and clinical features to calculate inverse-probability treatment weighting-weighted cumulative incidences, absolute risk differences, and Cox proportional hazard ratios. RESULTS: Among 4214 adults with cirrhosis, 3155 were ACE inhibitor/ARB users and 1059 were SBB users. In inverse probability treatment weighting-weighted analyses, ACE inhibitor/ARB (vs SBB) users had lower 5-year cumulative incidence (30.6% [95% confidence interval (CI), 27.8% to 33.2%] vs 41.3% [95% CI, 34.0% to 47.7%]; absolute risk difference, -10.7% [95% CI, -18.1% to -3.6%]) and lower risk of LREs (adjusted hazard ratio [aHR], 0.69; 95% CI, 0.60 to 0.80). There was a dose-response relationship: compared with SBB use, ACE inhibitor/ARB prescriptions ≥1 defined daily dose (aHR, 0.65; 95% CI, 0.56 to 0.76) were associated with a greater risk reduction compared with <1 defined daily dose (aHR, 0.87; 95% CI, 0.71 to 1.07). Results were robust across sensitivity analyses such as comparing ACE inhibitor/ARB users with nonusers and as-treated analysis. CONCLUSIONS: In this national cohort study, ACE inhibitor/ARB use was associated with significantly lower risk of LREs in patients with compensated cirrhosis. These results provide support for a randomized clinical trial to confirm clinical benefit.

Seed priming with potassium nitrate alleviates the high temperature stress by modulating growth and antioxidant potential in carrot seeds and seedlings.

Early season carrot (Daucus carota) production is being practiced in Punjab, Pakistan to meet the market demand but high temperature hampers the seed germination and seedling establishment which cause marked yield reduction. Seed priming with potassium nitrate breaks the seed dormancy and improves the seed germination and seedling growth potential but effects vary among the species and ecological conditions. The mechanism of KNO3 priming in high temperature stress tolerance is poorly understood yet. Thus, present study aimed to evaluate high temperature stress tolerance potential of carrot seeds primed with potassium nitrate and impacts on growth, physiological, and antioxidant defense systems. Carrot seeds of a local cultivar (T-29) were primed with various concentration of KNO3 (T0: unprimed (negative control), T1: hydroprimed (positive control), T2: 50 mM, T3:100mM, T4: 150 mM, T5: 200 mM, T6: 250 mM and T7: 300 mM) for 12 h each in darkness at 20 ± 2℃. Seed priming with 50 mM of KNO3 significantly enhanced the seed germination (36%), seedling growth (28%) with maximum seedling vigor (55%) and also exhibited 16.75% more carrot root biomass under high temperature stress as compared to respective control. Moreover, enzymatic activities including peroxidase, catalase, superoxidase dismutase, total phenolic contents, total antioxidants contents and physiological responses of plants were also improved in response to seed priming under high temperature stress. By increasing the level of KNO3, seed germination, growth and root biomass were reduced. These findings suggest that seed priming with 50 mM of KNO3 can be an effective strategy to improve germination, growth and yield of carrot cultivar (T-29) under high temperature stress in early cropping. This study also proposes that KNO3 may induces the stress memory by heritable modulations in chromosomal structure and methylation and acetylation of histones that may upregulate the hormonal and antioxidant activities to enhance the stress tolerance in plants.

Estrogen-modulating treatment among mid-life women and COVID-19 morbidity and mortality: a multiregister nationwide matched cohort study in Sweden.

BACKGROUND: It has been repeatedly shown that men infected by SARS-CoV-2 face a twofold higher likelihood of dying, being hospitalized or admitted to the intensive care unit compared to women, despite taking into account relevant confounders. It has been hypothesized that these discrepancies are related to sex steroid hormone differences with estrogens being negatively correlated with disease severity. The objective of this study was therefore to evaluate COVID-19-related mortality and morbidity among peri- and postmenopausal women in relation to estrogen-containing menopause hormonal treatments (MHT). METHODS: This is a national register-based matched cohort study performed in Sweden between January 1 to December 31, 2020. Study participants comprised women over the age of 53 years residing in Sweden. Exposure was defined as prescriptions of local estrogens, systemic estrogens with and without progestogens, progestogens alone, or tibolone. MHT users were then compared with a matched cohort of non-users. The primary outcome consisted of COVID-19 mortality, whereas the secondary outcomes included inpatient hospitalizations/outpatient visits and confirmed SARS-CoV-2 infection. Multivariable adjusted Cox regression-derived hazard ratios (HRs) were calculated. RESULTS: Use of systemic estrogens alone is associated with increased COVID-19 mortality among older women (aHR 4.73, 1.22 to 18.32), but the association is no longer significant when discontinuation of estrogen use is accounted for. An increased risk for COVID-19 infection is further observed for women using combined systemic estrogens and progestogens (aHR 1.06, 1.00 to 1.13) or tibolone (aHR 1.21, 1.01 to 1.45). Use of local estrogens is associated with an increased risk for COVID-19-related death (aHR 2.02,1.45 to 2.81) as well as for all secondary outcomes. CONCLUSIONS: Systemic or local use of estrogens does not decrease COVID-19 morbidity and mortality to premenopausal background levels. Excess risk for COVID-19 morbidity and mortality was noted among older women and those discontinuing systemic estrogens. Higher risk for death was also noted among women using local estrogens, for which non-causal mechanisms such as confounding by comorbidity or frailty seem to be the most plausible underlying explanations. TRIAL REGISTRATION DETAILS: Not applicable.

Optoelectronic control of cardiac rhythm: Toward shock-free ambulatory cardioversion of atrial fibrillation.

Atrial fibrillation (AF) is the most prevalent cardiac arrhythmia, progressive in nature, and known to have a negative impact on mortality, morbidity, and quality of life. Patients requiring acute termination of AF to restore sinus rhythm are subjected to electrical cardioversion, which requires sedation and therefore hospitalization due to pain resulting from the electrical shocks. However, considering the progressive nature of AF and its detrimental effects, there is a clear need for acute out-of-hospital (i.e., ambulatory) cardioversion of AF. In the search for shock-free cardioversion methods to realize such ambulatory therapy, a method referred to as optogenetics has been put forward. Optogenetics enables optical control over the electrical activity of cardiomyocytes by targeted expression of light-activated ion channels or pumps and may therefore serve as a means for cardioversion. First proof-of-principle for such light-induced cardioversion came from in vitro studies, proving optogenetic AF termination to be very effective. Later, these results were confirmed in various rodent models of AF using different transgenes, illumination methods, and protocols, whereas computational studies in the human heart provided additional translational insight. Based on these results and fueled by recent advances in molecular biology, gene therapy, and optoelectronic engineering, a basis is now being formed to explore clinical translations of optoelectronic control of cardiac rhythm. In this review, we discuss the current literature regarding optogenetic cardioversion of AF to restore normal rhythm in a shock-free manner. Moreover, key translational steps will be discussed, both from a biological and technological point of view, to outline a path toward realizing acute shock-free ambulatory termination of AF.

Hofmann-Type Cyanide Bridged Coordination Polymers for Advanced Functional Nanomaterials.

Since the discovery of Hofmann clathrates of inorganic cyanide bridged coordination polymers (Hofmann-type CN-CPs), extensive research is done to understand their behavior during spin transitions caused by guest molecules or external stimuli. Lately, research on their nanoscale architectures for sensors and switching devices is of interest. Their potential is reported for producing advanced functional inorganic materials in two-dimensional (2D) morphology using a scalable solid-state thermal treatment method. For instance, but not restricted to, alloys, carbides, chalcogenides, oxides, etc. Simultaneously, their in situ crystallization at graphene oxide (GO) nanosheet surfaces, followed by a subsequent self-assembly to build layered lamellar structures, is reported providing hybrid materials with a variety of uses. Hence, an overview of the most recent developments is presented here in the synthesis of nanoscale structures, including thin films and powders, using Hofmann-type CN-CPs. Also thoroughly demonstrated are the most recent synthetic ideas with the modest control over the size and shape of nanoscale particles. Additionally, in order to create new functional hybrid materials for electrical and energy applications, their thermal decomposition in various environments and hybridization with GO and other guest molecules is examined. This review article also conveyed their spin transition, astounding innovative versatile adhesives, and structure features.

Cs-treatments in Kesterite Thin-Film Solar Cells for Efficient Perovskite Tandems.

Cu2ZnSn(S,Se)4 (CZTSSe) thin film solar cells are an attractive choice for a bottom cell of the low-cost and environmental tandem solar cells with perovskite. However, the progress in developing efficient perovskite/CZTSSe tandem solar cells has been hindered by the lack of high performance of the CZTSSe bottom cell. Here, an efficient CZTSSe bottom cell is demonstrated by adopting a facile and effective CsF treatment process. It is found that the CsF treatment not only facilitates grain growth and improves phase homogeneity by suppressing the detrimental deep-level defects and secondary phases, but also induces larger band bending and stronger drift force at the P-N junction. As a result, the carrier extraction/transport can be effectively accelerated, while reducing the interfacial recombination. These combined effects eventually result in a significant performance enhancement from 8.38% to 10.20%. The CsF-treated CZTSSe solar cell is finally applied to the mechanically-stacked perovskite/CZTSSe 4-terminal tandem cell by coupling a semi-transparent perovskite top cell, which exhibits the highest reported tandem efficiency of 23.01%.

Association of sex with in-hospital management and outcomes of patients with heart failure: data from the REAL-HF registry: The impact of sex in patients hospitalized for heart failure.

BACKGROUND: There are sex differences in HF patients. It is not clear whether such differences mainly reflect cultural behaviours and clinical inertia, and the role of sex on clinical outcomes is still controversial. We aimed to investigate the association of sex with in-hospital management and outcomes in patients with HF. METHODS: We analyzed data of 4016 adult patients hospitalized for HF in 2020-2021 and enrolled in a multicentre national registry. RESULTS: Women (n=1818[45%]) were older than men (83vs77 years, p<0.0001), with a higher prevalence of arterial hypertension (73%vs69%, p=0.011) and atrial fibrillation. Women presented more frequently with HF and preserved ejection fraction -HFpEF (55%vs32%, p<0.001). They were more often hospitalized in internal medicine departments (71%vs51%), and men in highly specialized cardiology units (49%vs29%). When considering HF pharmacological treatments at discharge in the subgroup with reduced ejection fraction -HFrEF (n=1525), there were no significant differences (49% of women treated with GDMT [guideline-directed medical therapy] vs 52% of men, p=0.197). Sex was not associated either with hospital readmissions (30-days OR[95%CI]=0.89[0.71-1.11], p=0.304; 1-year OR[95%CI]=1.02[0.88-1.19], p=0.777) or with mortality (in-hospital OR[95%CI]=1.14[0.73-1.78], p=0.558; 1-year OR[95%CI]=1.08[0.87-1.33], p=0.478). Similar results were obtained when considering different HF categories based on left ventricular ejection fraction. CONCLUSIONS: Women and men exhibited distinct clinical profiles. Although this may have had an impact on hospital pathways (non-cardiology/cardiology units) and pharmacological prescriptions, sex per se did not appear as an independent determinant of clinical choices. Moreover, when considering homogeneous groups, women were not undertreated. Finally, female sex was not associated with worse clinical outcomes.

Bacterial community composition of wheat aboveground compartments correlates with yield during the reproductive phase.

Plant-associated microbial communities play important roles in agricultural productivity, and their composition has been shown to vary across plant compartments and developmental stages. However, the response of microbial communities within different plant compartments and at different developmental stages to diverse long-term fertilization treatments, as well as their linkages with crop yields, remains underexplored. This study analyzed wheat-associated bacterial communities within various soil and plant compartments under three fertilization treatments throughout the vegetative and reproductive phases. The variance in bacterial community was primarily attributed to compartments, followed by fertilization treatments and developmental stages. The composition of belowground bacterial communities (bulk soil, rhizosphere soil, and root) exhibited stronger responses to fertilization treatments than aboveground compartments (stem and leaf). The composition of belowground bacterial communities responded to fertilization treatments at all developmental stages, and it was significantly correlated with crop yields during the vegetative phase, whereas the aboveground community composition only showed a response to fertilization during the reproductive phase, at which point it was significantly correlated with crop yields. Moreover, during this reproductive phase, the co-occurrence network of aboveground bacterial communities exhibited enhanced complexity, and it contained an increased number of keystone species associated with crop yields, such as Sphingomonas spp., Massilia spp., and Frigoribacterium spp. Structural equation modeling indicated that augmenting total phosphorus levels in aboveground compartments could enhance crop yields by increasing the relative abundance of these keystone species during the reproductive phase. These findings highlight the pivotal role of aboveground bacterial communities in wheat production during the reproductive phase. IMPORTANCE: The developmental stage significantly influences crop-associated bacterial communities, but the relative importance of bacterial communities in different compartments to crop yields across various stages is still not well understood. This study reveals that belowground bacterial communities during the vegetative phase are significantly correlated with crop yields. Notably, during the reproductive phase, the composition of aboveground bacterial communities was significantly correlated with crop yields. During this phase, the complexity and enriched keystone species within the aboveground co-occurrence network underscore their role in boosting crop production. These results provide a foundation for developing microbiome-based products that are phase-specific and promote sustainable agricultural practices.

Total Margin Control Is Superior to Traditional Margin Assessment for Treatment of Low-Stage Penile Squamous Cell Carcinoma.

PURPOSE: Penile cancer is rare, with significant morbidity and limited literature assessing utility of peripheral and deep en face margin assessment (PDEMA) vs traditional margin assessment (vertical sections) on treatment outcomes. MATERIALS AND METHODS: This was a 32-year retrospective multicenter cohort study at 3 academic tertiary care centers. The cohort consisted of 189 patients with histologic diagnosis of in situ or T1a cutaneous squamous cell carcinoma of the penis at Brigham and Women's, Massachusetts General Hospital (1988-2020), and Memorial Sloan Kettering Cancer Center (1995-2020) treated with PDEMA surgical excision, excision/circumcision, or penectomy/glansectomy. Local recurrence, metastasis, and disease-specific death were assessed via multivariable Cox proportional hazard models. RESULTS: The cohort consisted of 189 patients. Median age at diagnosis was 62 years. Median tumor diameter was 1.3 cm. The following outcomes of interest occurred: 30 local recurrences, 13 metastases, and 5 disease-specific deaths. Primary tumors were excised with PDEMA (N = 30), excision/circumcision (N = 110), or penectomy/glansectomy (N = 49). Of patients treated with traditional margin assessment (non-PDEMA), 12% had narrow or positive margins. Five-year proportions were as follows with respect to local recurrence-free survival, metastasis-free survival, and disease-specific survival/progression-free survival, respectively: 100%, 100%, and 100% following PDEMA; 82%, 96%, and 99% following excision/circumcision; 83%, 91%, and 95% following penectomy/glansectomy. A limitation is that this multi-institutional cohort study was not externally validated. CONCLUSIONS: Initial results are encouraging that PDEMA surgical management effectively controls early-stage penile squamous cell carcinoma.

Comparative Effects of GLP-1 Receptor Agonists and Metformin on Glaucoma Risk in Type 2 Diabetes Patients.

PURPOSE: To compare effects of glucagon-like peptide-1 (GLP-1) receptor agonists and metformin on the risk of primary open-angle glaucoma (POAG), ocular hypertension, and the need for first-line glaucoma treatments in patients with type 2 diabetes. DESIGN: A retrospective cohort study was conducted using electronic medical records (EMR) data from the from an international electronic health record network, covering a period from May 2006 to May 2024. PARTICIPANTS: Patients diagnosed with type 2 diabetes mellitus (T2DM) who were treated with either GLP-1 receptor agonists or metformin. METHODS: Data from 120 healthcare organizations across 17 countries were analyzed. Patient outcomes were assessed at 1, 2, and 3 years. Propensity score matching (PSM) was used to balance covariates such as demographics, comorbidities, and medication usage. Risk ratios (RR) with 95% confidence intervals (CI) were calculated. MAIN OUTCOME MEASURES: Incidence of POAG, ocular hypertension, and the need for first-line treatments including beta-blockers, prostaglandin analogues, brimonidine, brinzolamide, dorzolamide, netarsudil, and laser trabeculoplasty. RESULTS: After PSM, both groups included 61,998 patients at the 1-year follow-up, 27,414 at the 2-year follow-up, and 14,100 at the 3-year follow-up. Patients treated with GLP-1 receptor agonists had a significantly decreased risk of developing POAG compared to those on metformin at 1 year (RR 0.59, 95% CI 0.39-0.88), 2 years (RR 0.50, 95% CI 0.32-0.78), and 3 years (RR 0.59, 95% CI 0.37-0.94). Similar protective effects were observed for ocular hypertension with risk reductions of 56% at 1 year (RR 0.44, 95% CI 0.31-0.62), 57% at 2 years (RR 0.43, 95% CI 0.30-0.62), and 49% at 3 years (RR 0.51, 95% CI 0.34-0.75). The risk of first-line therapy initiation was also lower in the GLP-1 receptor agonists group at 1 year (RR 0.63, 95% CI 0.53-0.74), 2 years (RR 0.71, 95% CI 0.59-0.85), and 3 years (RR 0.75, 95% CI 0.62-0.91). CONCLUSIONS: GLP-1 receptor agonists are associated with a significantly lower incidence of POAG, ocular hypertension, and the need for first-line glaucoma treatments compared to metformin in patients with type 2 diabetes. These findings highlight the potential ocular benefits of GLP-1 receptor agonists and their expanding role in the clinical management of diabetic patients.

Applying a simplified economic evaluation approach to evaluate infertility treatments in clinical practice.

IVF is the backbone of infertility treatment, but due to its costs, it is not affordable for everyone. The cost of IVF is further escalated by interventions added to the routine treatment, which are claimed to boost pregnancy rates, so-called add-ons. Consequently, it is critical to offset the increased costs of an intervention against a potentially higher benefit. Here, we propose using a simplified framework considering the cost of a standard IVF procedure to create one live-born baby as a benchmark for the cost-effectiveness of other fertility treatments, add-ons inclusive. This framework is a simplified approach to a formal economic evaluation, enabling a rapid assessment of cost effectiveness in clinical settings. For a 30-year-old woman, assuming a 44.6% cumulative live birth rate and a cost of $12 000 per complete cycle, the cost to create one live-born baby would be ∼$27 000 (i.e. willingness to pay). Under this concept, the decision whether to accept or reject a new treatment depends from an economic perspective on the incremental cost per additional live birth from the new treatment/add-on, with the $27 000 per live-born baby as a reference threshold. This threshold can vary with women's age, and other factors such as the economic perspective and risk of side effects can play a role. If a new add-on or treatment costs >$27 000 per live birth, it might be more rational to invest in a new IVF cycle rather than spending on the add-on. With the increasing number of novel technologies in IVF and the lack of a rapid approach to evaluate their cost-effectiveness, this simplified framework will help with a more objective assessment of the cost-effectiveness of infertility treatments, including add-ons.