Safety and efficacy of enclomiphene and clomiphene for hypogonadal men.

Background: Both clomiphene citrate and its isomer, enclomiphene, have become widespread within urologic practice; thus, understanding these medications' comparative benefits and risks is crucial for optimizing treatment and providing improved therapeutic options. We sought to investigate the longitudinal benefits and risks associated with enclomiphene, compared to clomiphene, and to provide valuable insights for clinicians when making treatment decisions in the management of hypogonadism. Methods: We retrospectively studied patients at our academic center who had been prescribed clomiphene and, later, enclomiphene for hypogonadism. Baseline laboratory values were documented for each patient before being prescribed clomiphene, followed by subsequent values for each variable in the most recent visit before stopping clomiphene and any noted adverse effects experienced during this time. The same process was repeated for enclomiphene, using the clomiphene levels as an updated baseline. Two-tailed t-tests were employed using R to analyze the longitudinal impacts of clomiphene and enclomiphene on serum hormone values as well as a regression analysis to estimate the odds ratio (OR) for adverse events between the two therapies. Results: Among 66 patients, enclomiphene exhibited a median testosterone increase of 166 (vs. 98 ng/dL, P=0.20) with lower estradiol change than clomiphene (-5.92 vs. 17.50 pg/mL, P=0.001). Adverse effects were statistically significantly less frequent with enclomiphene, including decreased libido (P=0.001), reduced energy (P=0.044), and mood changes (P=0.03). Regression analysis confirmed lower odds of adverse events with enclomiphene [OR: 0.18; 95% confidence interval (CI): 0.07-0.44, P=0.02]. Conclusions: Our findings demonstrate that enclomiphene provides improvement in testosterone levels with a lower rate of documented adverse events. These findings support enclomiphene as a comparable treatment option for hypogonadal men while minimizing the risk of adverse effects. Further research and more extensive studies are warranted to validate these conclusions and explore the additional long-term effects of enclomiphene to guide future patient counseling regarding these medications.

Effective xanthine oxidase inhibitor urate lowering therapy in gout is linked to an emergent serum protein interactome of complement and inflammation modulators.

Urate-lowering treatment (ULT) to target with xanthine oxidase inhibitors (XOIs) paradoxically causes early increase in gouty arthritis flares. Because delayed reduction in flare burden is mechanistically unclear, we tested for ULT inflammation responsiveness markers. Unbiased proteomics analyzed blood samples (baseline, 48 weeks ULT) in two, independent ULT out trial cohorts (n = 19, n = 30). STRING-db and multivariate analyses supplemented determinations of altered proteins via Wilcoxon matched pairs signed rank testing in XOI ULT responders. Mechanistic studies characterized proteomes of cultured XOI-treated murine bone marrow macrophages (BMDMs). At 48 weeks ULT, serum urate normalized in all gout patients, and flares declined in association with significantly altered proteins (p < 0.05) in clustering and proteome networks in sera and peripheral blood mononuclear cells. Sera demonstrated altered complement activation and regulatory gene ontology biologic processes. In both cohorts, a treatment-emergent serum interactome included key gouty inflammation mediators (C5, IL-1B, CXCL8, IL6). Last, febuxostat treatment decreased complement activation biologic process proteins in cultured BMDMs. Reduced gout flares are linked with a XOI treatment-emergent serum protein interactome that includes inflammation regulators, associated with altered complement activation and regulatory biologic processes. Serum and leukocyte proteomics could help identify when gouty inflammatory processes begin to subside in response to ULT.Trial Registration: ClinicalTrials.gov Identifier NCT02579096, posted October 19, 2015.

Comparative Analysis of the Intrinsic Disorder Within the Layers of the Human Cornea.

PURPOSE: The human cornea is essential for vision, providing structural integrity and refractive power to the eye. Recent advancements have deepened our understanding of the corneal molecular composition, yet the role of intrinsically disordered proteins within the cornea is unexplored. METHODS: We analyzed 3,250 corneal proteins identified by Dyrlund et al, focusing on the epithelium, stroma, and endothelium layers. We performed a bioinformatics analysis to characterize the amino acid composition, the propensity for intrinsic protein disorder, and the distribution of protein types in 3 corneal layer proteome. RESULTS: Our study demonstrates that each corneal layer exhibited unique patterns in amino acid composition related to protein disorder. Order-promoting amino acids were generally depleted except for leucine, whereas disorder-promoting amino acids like arginine and glutamic acid were enriched across all layers. Significant variations were observed in the levels of intrinsic disorder among the different corneal layers, with substantial proportions of highly disordered proteins present in each. Analysis of protein class type in each layers revealed that no significant differences were detected in the distribution of protein classifications across the layers, suggesting a consistent population of the protein types across all corneal layers. CONCLUSIONS: Our findings reveal a sophisticated landscape of protein structures where intrinsic disorder varies across layers, suggesting an adaptation of the corneal proteome to the unique physiological demands of each layer. These structural variations may reflect the intricate requirements for corneal transparency, biomechanical stability, and environmental responsiveness.

Oncologic outcomes of pelvic organ-preserving radical cystectomy vs. Standard radical cystectomy: A systematic review and meta-analysis.

BACKGROUND AND OBJECTIVE: Radical Cystectomy is indicated in muscle-invasive bladder cancer and select cases of nonmuscle invasive bladder cancer. Women often undergo additional reproductive organ removal, greatly impacting sexual function and quality of life. Pelvic organ-preserving radical cystectomy aims to mitigate these effects, but its oncologic outcomes are not well-defined. This presents a meta-analysis of available literature on oncological outcomes of pelvic organ-preserving radical cystectomy in women with muscle invasive disease. METHODS: A systematic search across PubMed, Web of Science, Scopus, and Google Scholar was performed to identify studies comparing oncological outcomes between pelvic organ-preserving radical cystectomy and standard radical cystectomy in women with muscle-invasive bladder cancer or high-risk or recurrent nonmuscle invasive cancer. The search included English or Spanish studies, statistically comparing overall survival, cancer-specific survival, and recurrence-free survival. Statistical analysis used Review Manager, employing fixed or random-effects models based on heterogeneity. KEY FINDINGS AND LIMITATIONS: Six retrospective studies met inclusion criteria, totaling 597 patients of which 303 received pelvic organ-preserving radical cystectomy and 294 received standard radical cystectomy. Overall Survival was not different between the 2 groups (HR 1.05 [0.77, 1.43]; P = 0.77). Cancer-Specific Survival also was found to be not different between the 2 groups (HR 1.27 [0.86, 1.87]; P = 0.22). Additionally, recurrence-free survival was not different between the 2 groups (HR 0.85 [0.41, 1.75]; P = 0.65. Four of the included studies exhibited a moderate risk of bias, with 1 study demonstrating low risk and the remaining study manifesting a serious risk of bias. CONCLUSION: The comparison showed no significant differences in overall survival, cancer-specific survival, or recurrence-free survival rates.

Regenerative therapies for erectile dysfunction: a systematic review, Bayesian network meta-analysis, and meta-regression.

BACKGROUND: Current guidelines advocate a shared decision-making process approach to erectile dysfunction management, and while there is growing interest in regenerative therapies such as stem cell therapy, platelet-rich plasma injections, and low-intensity shockwave therapy for erectile dysfunction, comparative data on the efficacy of these modalities are limited. AIM: This systematic review and network meta-analysis aims to compare stem cell therapy, platelet-rich plasma injections, and low-intensity shockwave therapy for managing erectile dysfunction and quantify their impact on the International Index of Erectile Function (IIEF). METHODS: In January 2024, a systematic search of online databases was performed to identify randomized clinical trials related to stem cell therapy, platelet-rich plasma injections, and low-intensity shockwave therapy in erectile dysfunction. Eligible articles reported outcomes using the IIEF score. Data were inputted into Review Manager 5.4 for pairwise meta-analysis. Data were then used to build a network in R Studio. These networks were used to model 200 000 Markov Chains via MonteCarlo sampling. The results are expressed as standardized mean difference (SMD) with 95% credible intervals (CrI). Meta-regression was used to adjust for PDE5is use. OUTCOMES: Impact on the International Index of Erectile Function. RESULTS: A total of 16 studies involving 907 patients were analyzed. The standardized mean difference (SMD) vs control for stem cell therapy was 0.92 [95% CrI -0.49, 2.3]. For platelet-rich plasma, the SMD vs control was 0.83 [95% CrI 0.15, 1.5], and for low-intensity shockwave therapy, the SMD vs control was 0.84 [95% CrI 0.49, 1.2]. When stratifying low-intensity shockwave therapy by dose, the SMD vs control at 0.15 mJ/mm2 was 1.1 [95% CrI 0.36, 1.9], while at 0.09 mJ/mm2, it was 0.75 [95% CrI 0.26, 1.2]. Meta-regression adjusting for the administration of PDE5 inhibitors yielded non-significant results. CLINICAL IMPLICATIONS: The findings suggest that stem cells, platelet-rich plasma, and low intensity shockwave therapy, particularly at 0.15 and 0.09 mJ/mm2, may offer improvements in erectile function. STRENGTHS AND LIMITATIONS: The strength is the robust statistical methods. Limitations are in heterogeneity in control groups and follow-up durations among included studies. CONCLUSION: Shockwave therapy and platelet-rich plasma demonstrated statistically significant improvements, though the clinical relevance and extent of their impact remain questionable. Further research is necessary to determine the efficacy of stem cell therapies for erectile function.

The Alzheimer's Disease Neuroimaging Initiative-4 (ADNI-4) Engagement Core: A culturally informed, community-engaged research (CI-CER) model to advance brain health equity.

INTRODUCTION: The Alzheimer's Disease Neuroimaging Initiative-4 (ADNI-4) Engagement Core was launched to advance Alzheimer's disease (AD) and AD-related dementia (ADRD) health equity research in underrepresented populations (URPs). We describe our evidence-based, scalable culturally informed, community-engaged research (CI-CER) model and demonstrate its preliminary success in increasing URP enrollment. METHODS: URPs include ethnoculturally minoritized, lower education (≤ 12 years), and rural populations. The CI-CER model includes: (1) culturally informed methodology (e.g., less restrictive inclusion/exclusion criteria, sociocultural measures, financial compensation, results disclosure, Spanish Language Capacity Workgroup) and (2) inclusive engagement methods (e.g., the Engagement Core team; Hub Sites; Community-Science Partnership Board). RESULTS: As of April 2024, 60% of ADNI-4 new in-clinic enrollees were from ethnoculturally or educationally URPs. This exceeds ADNI-4's ≥ 50% URP representation goal for new enrollees but may not represent final enrollment. DISCUSSION: Findings show a CI-CER model increases URP enrollment in AD/ADRD clinical research and has important implications for clinical trials to advance health equity. HIGHLIGHTS: The Alzheimer's Disease Neuroimaging Initiative-4 (ADNI-4) uses a culturally informed, community-engaged research (CI-CER) approach. The CI-CER approach is scalable and sustainable for broad, multisite implementation. ADNI-4 is currently exceeding its inclusion goals for underrepresented populations.

Erectile dysfunction as a holistic indicator of well-being: a narrative review.

INTRODUCTION: Erectile dysfunction (ED), affecting around 52% of men aged 40-70, is a significant marker of overall health and a potential warning sign of multiple conditions like cardiovascular diseases (CVDs), diabetes, and mental health disorders. Recognizing and addressing ED through a holistic approach involving nutrition, physical activity, sleep, and stress management can improve both erectile and overall health outcomes. AIMS: To provide a narrative review of the available literature on the relationship between ED and overall health, elaborate on the possible mechanisms explaining this association, and discuss the effects of lifestyle on ED. METHODS: A search of the medical literature was carried out in PubMed and Medline, focusing on original research and systematic reviews of original research on ED and overall health. RESULTS: Due to shared pathophysiological mechanisms like endothelial dysfunction, ED is a significant indicator of overall health, particularly related to CVD and diabetes mellitus. Multiple studies have shown that ED frequently precedes cardiovascular events and is associated with increased cardiovascular risk, especially in younger men and those with diabetes. It also has a profound, bidirectional relationship with mental health conditions like depression and anxiety, creating a vicious cycle where each exacerbates the other. The four health pillars of nutrition, physical activity, sleep, and stress management play significant roles in erectile function and overall sexual health. CONCLUSION: ED is not just a condition affecting sexual function but a critical indicator of broader health issues. By adopting an integrative approach that combines nutrition, physical activity, sleep, and stress management, healthcare providers can offer holistic and effective management strategies for this condition.

Iliotibial-Band and Gluteus Medius Percutaneous Ultrasound Tenotomy for Refractory Trochanteric Pain Syndrome: A Longitudinal Observational Study with One-Year Durability Results.

BACKGROUND: Greater trochanteric pain syndrome (GTPS) is a common cause of lateral hip pain that affects patients' quality of life and functioning. The condition is often associated with tightness of the iliotibial band (ITB) and tendinopathy of the gluteus medius (GMed) tendon, which are subjected to excessive stress and inflammation. A traditional treatment for GTPS is conservative medical management (CMM), which includes but is not limited to physiotherapy, oral anti-inflammatory medication, and/or local steroid injections. Surgery is performed when these treatments fail. The failure of these techniques indicates that some treatments classified as CMM may not be feasible for some patients. OBJECTIVES: This study aimed to evaluate the efficacy and safety of combined GMed and ITB injections for a cohort of CMM-refractory GTPS patients. STUDY DESIGN: A retrospective chart review. SETTING: Single-center, academic hospital. METHODS: Between 01/01/2022 and 12/31/2022, a retrospective analysis of 68 hips that underwent combination GMed-ITB percutaneous ultrasound tenotomy (PUT) was performed. The primary outcome measure was a numeric rating scale (NRS) for hip pain, and the secondary outcome measures were VISA-G (Victorian Institute of Sports Assessment-Gluteal Tendinopathy) scores, sitting-to-standing and walking tolerance, and side-lying tolerance. RESULTS: The patients' NRS scores decreased, and the VISA-G scores and all functional measures increased one year after the procedure, indicating significant improvement in pain and functioning (P < 0.001). Treatment success, defined as 50% reduction in pain and side-lying tolerance, was achieved by 83% of the patients. No major complications were reported. LIMITATIONS: The lack of a comparable cohort reduces the data's interpretative significance. Having a control arm would have enabled a statistical comparison between treated and untreated patients to provide a valid assessment of the procedure's benefit. CONCLUSIONS: This study demonstrated the feasibility and efficacy of combined GMed-ITB PUT as a novel treatment for GTPS in patients who failed CMM. The results showed significant and durable improvement in pain, function, and quality of life at the one-year follow-up. Our study suggests that both ITB and GMed tendons are involved in the pathogenesis of GTPS. The present study compared favorably with previous studies that reported outcomes of either ITB PUT or GMed PUT alone, implying that combining the approaches may offer superior benefits. Furthermore, the study had several strengths, such as the use of a validated outcome measure (VISA-G), the elimination of bias by independent practitioners, and the inclusion of a difficult population with severe pain.

Technology-based instrumental activities of daily living in persons with Alzheimer's disease and related disorders.

INTRODUCTION: Instrumental activities of daily living (iADLs) increasingly involve technology (e.g., making payments online, texting). The current study examined the applicability and diagnostic accuracy of technology-based iADLs in those evaluated for Alzheimer's disease and related dementias (ADRD). METHODS: A total of 264 care partners of persons undergoing comprehensive interdisciplinary evaluations completed the Functional Activities Questionnaire and 11 technology-based iADL items. RESULTS: Technology-based iADLs applied to more than 80% of patients. Average dependence on technology-based items was overall less than for traditional iADLs. The addition of technology-based items to traditional iADL items slightly improved the ability to identify individuals with dementia. When considered separately, technology-based iADL items demonstrated comparable ability to distinguish between diagnostic stages. DISCUSSION: Technology use is common in older adults with ADRD for a range of daily activities. Accounting for technology use increases the content validity of existing iADL measures for the modern context and yields comparable diagnostic accuracy. Highlights: Technology use is often integral to daily activity performance for individuals with Alzheimer's disease and related dementias (ADRD).Daily technologies, such as smartphones, were used frequently by those with ADRD.Many individuals were less dependent on technology activities than traditional activities.Adding technology questions slightly increased diagnostic accuracy for detecting dementia.

Relationship between renal pelvis pressure and post-ureteroscopy infection in a live swine model.

OBJECTIVE: To evaluate the relationship between renal pelvis pressure and infection after ureteroscopy, using a live swine model. MATERIALS AND METHODS: In anaesthetised pigs, a 1-h ureteroscopy was performed using a pressure-sensing guidewire, with renal pelvis pressure maintained at either 37 mmHg or 75 mmHg for the entire procedure and infusion with saline alone or with a standardised concentration of uropathogenic Escherichia coli strain CFT073 (1.5 × 107 colony-forming units [CFU]/mL). Venous blood sampling was performed during and after the procedure. Vital signs, inflammatory biomarkers, and renal tissue and blood cultures were assessed. RESULTS: In 21 pig kidneys, study groups were: 37 mmHg with saline irrigation (n = 3); 75 mmHg with saline irrigation (n = 4); 37 mmHg with saline irrigation with 1.5 × 107 CFU/mL E. coli (n = 7); and 75 mmHg with saline irrigation with 1.5 × 107 CFU/mL E. coli (n = 7). Statistically significant changes in inflammatory biomarkers were most pronounced in the group with 75 mmHg saline irrigation + E. coli and were significantly elevated compared with the control group and the group receiving E. coli irrigation at 37 mmHg. Positive blood cultures were noted in 5/7 animals treated with E. coli at 75 mmHg; no others developed bacteraemia. CONCLUSION: In this swine model of ureteroscopy, irrigation with saline + E. coli at a renal pelvis pressure of 75 mmHg resulted in bacteraemia and inflammatory biomarker elevations significantly greater than both E. coli irrigation with renal pelvis pressure maintained at 37 mmHg and the control.

Transient Notch Activation Converts Pluripotent Stem Cell-Derived Cardiomyocytes Towards a Purkinje Fiber Fate.

Cardiac Purkinje fibers form the most distal part of the ventricular conduction system. They coordinate contraction and play a key role in ventricular arrhythmias. While many cardiac cell types can be generated from human pluripotent stem cells, methods to generate Purkinje fiber cells remain limited, hampering our understanding of Purkinje fiber biology and conduction system defects. To identify signaling pathways involved in Purkinje fiber formation, we analyzed single cell data from murine embryonic hearts and compared Purkinje fiber cells to trabecular cardiomyocytes. This identified several genes, processes, and signaling pathways putatively involved in cardiac conduction, including Notch signaling. We next tested whether Notch activation could convert human pluripotent stem cell-derived cardiomyocytes to Purkinje fiber cells. Following Notch activation, cardiomyocytes adopted an elongated morphology and displayed altered electrophysiological properties including increases in conduction velocity, spike slope, and action potential duration, all characteristic features of Purkinje fiber cells. RNA-sequencing demonstrated that Notch-activated cardiomyocytes undergo a sequential transcriptome shift, which included upregulation of key Purkinje fiber marker genes involved in fast conduction such as SCN5A, HCN4 and ID2, and downregulation of genes involved in contractile maturation. Correspondingly, we demonstrate that Notch-induced cardiomyocytes have decreased contractile force in bioengineered tissues compared to control cardiomyocytes. We next modified existing in silico models of human pluripotent stem cell-derived cardiomyocytes using our transcriptomic data and modeled the effect of several anti-arrhythmogenic drugs on action potential and calcium transient waveforms. Our models predicted that Purkinje fiber cells respond more strongly to dofetilide and amiodarone, while cardiomyocytes are more sensitive to treatment with nifedipine. We validated these findings in vitro, demonstrating that our new cell-specific in vitro model can be utilized to better understand human Purkinje fiber physiology and its relevance to disease.

Should Military Veterans Be Classified as High Risk for Prostate Cancer Screening? A Systematic Review and Meta-analysis.

OBJECTIVE: To assess the unique risks of prostate cancer among U.S. veterans, and to advocate for improved care by raising awareness of the gaps in current AUA guidelines that do not address the specific needs of military personnel and veterans. METHODS: Ovid interface, Google Scholar, PubMed, and Medline were searched for studies investigating prostate cancer in veterans published between 1975 and 2023. Search terms: "veteran", "military", "molecular markers", "prostate cancer", "prostate cancer risk", and "military exposure" were used. Articles meeting inclusion criteria underwent analysis, data synthesis, and meta-analysis where applicable. RESULTS: Results from 45 articles indicate a significant increase in prostate cancer risk associated with exposure to Agent Orange (OR 1.97 [95% CI: 1.64-2.37], P <.00001), aromatic hydrocarbons (OR 1.14 [95% CI: 1.01-1.28], P = .03), and a slight increase with cadmium exposure (OR 1.03 [95% CI: 0.96-1.09], P = .42). While some evidence suggests an association between Camp Lejeune and prostate cancer risk in retrospective cohort studies, logistical regression analysis study did not entirely substantiate this relationship. CONCLUSION: This review identifies several exposures that elevate prostate cancer risk. Military veterans should be further questioned about their exposures and potentially treated as a high-risk screening group. Further research is warranted to strengthen these associations, as the current evidence remains limited.

Pelargonic acid's interaction with the auxin transporter PIN1: A potential mechanism behind its phytotoxic effects on plant metabolism.

Pelargonic acid (PA) is a saturated fatty acid commonly found in several organisms, that is known for its phytotoxic effect and its use as bioherbicide for sustainable weed management. Although PA is already commercialised as bioherbicide, its molecular targets and mode of action is unknown according to the Herbicide Resistance Action Committee. Therefore, the aim of this work was focusing on the way this natural active substance impacts the plant metabolism of the model species Arabidopsis thaliana. PA caused increase of secondary and adventitious roots, as well as torsion, loss of gravitropism and phytotoxic effects. Moreover, PA altered the cellular arrangement and the PIN proteins activity. Computational simulations revealed that the intermolecular interactions between PA and the polar auxin transporter protein PIN1 are very similar to those established between the natural auxin IAA and PIN1. However, under intracellular conditions, the PA-PIN1 binding is more energetically stable than the IAA-PIN1. These results suggest that PA could act as an auxin-mimics bioherbicide. The exogenous application of PA would be responsible for the alterations observed both at structural and ultrastructural levels, which would be caused by the alteration on the transport of auxins into the plant, inducing root inhibition and ultimately total stop of root growth.

Nerve-associated macrophages control adipose homeostasis across lifespan and restrain age-related inflammation.

Age-related inflammation or inflammaging is a key mechanism that increases disease burden and may control lifespan. How adipose tissue macrophages (ATMs) control inflammaging is not well understood in part because the molecular identities of niche-specific ATMs are incompletely known. Using intravascular labeling to exclude circulating myeloid cells and subsequent single-cell sequencing with orthogonal validation, we define the diversity and alterations in niche resident ATMs through lifespan. Aging led to depletion of vessel-associated macrophages (VAMs), expansion of lipid-associated macrophages (LAMs), and emergence of a unique subset of CD38+ age-associated macrophages (AAMs) in visceral white adipose tissue (VAT). Interestingly, CD169+CD11c- ATMs are enriched in a subpopulation of nerve-associated macrophages (NAMs) that declines with age. Depletion of CD169+ NAMs in aged mice increases inflammaging and impairs lipolysis suggesting that they are necessary for preventing catecholamine resistance in VAT. These findings reveal specialized ATMs control adipose homeostasis and link inflammation to tissue dysfunction during aging.

Evolutive Study of Dietary Aspects and Intestinal Microbiota of Pediatric Cohort with Cow's Milk Protein Allergy.

BACKGROUND: One of the most common food allergies in the pediatric population is allergy to cow's milk protein (CMPA). Treatment consists of avoiding cow's milk proteins in lactating mothers and/or using therapeutic formulas based on hydrolysates or vegetable formulas. In infants with CMPA at diagnosis, a different gut microbial profile has been found compared to healthy children, with a reduction in beneficial bacteria. The aim of this study was to evaluate changes in the gut microbiota profile and its metabolites, dietary patterns and anthropometric variables in a pediatric cohort with CMPA after six months on a restrictive diet compared to healthy controls. METHODS: In total, 21 patients diagnosed with CMPA and a control group of 24 healthy infants participated in this study. The fecal microbiota of all participants were investigated by metataxonomic analysis of 16S rDNA amplicons, and fecal short-chain fatty acids were measured by gas chromatography. Epidemiological assessment and dietary questionnaires were carried out for both groups. RESULTS: Regarding growth, no significant differences were found, but differences in dietary intake of some macro- and micronutrients were observed. Patients who were breastfed at six months had higher bifidobacteria and lipid intakes than patients fed with hydrolyzed formulas. CONCLUSIONS: Although the growth of CMPA infants fed with therapeutic formula is similar to breastfed CMPA infants, there are differences in microbiota composition and macronutrient intake that underline the importance of continued breastfeeding in CMPA cases.

Chemical profiling of organic contaminants in rural surface waters combining target and non-target LC-HRMS/MS analysis.

The pollution of natural waters by contaminants of emerging concern (CECs) is one of the pressing problems due to their global distribution and potential negative effects on the environment and human health. In rural areas with lower population density and limited industrial development, less contamination is expected. However, the lack of wastewater treatment plants (WWTPs) or their poor removal efficiency can lead to significant input of pollutants. In this context, 11 streams of rural areas in the Guadalquivir River basin, southeast of Spain, were studied over two years to obtain an overview of the origin and distribution of contaminants. A target method using solid-phase extraction and liquid chromatography coupled to high resolution mass spectrometry (LC-HRMS) was developed for the analysis of 316 compounds in surface waters. A total of 78 target analytes were detected, comprising pesticides, pharmaceuticals, personal care products (PCPs), transformation products (TPs), and industrial chemicals. The flame retardant tributyl phosphate (16-3572 ng L-1) was detected in all samples, followed by caffeine (30-8090 ng L-1) and the analgesic tramadol (3-1493 ng L-1). The target approach was combined with a non-target analysis (NTA) strategy to obtain an overall perspective of the chemical profile of unexpected or unknown compounds in the samples. Up to 79 contaminants were tentatively identified, and 12 of them were finally confirmed with standards. Most of the contaminants determined by NTA were pharmaceuticals and their TPs. The results indicated that most of CECs have an urban origin despite traditional agriculture is the main economic activity in this region. Moreover, the absence of WWTPs in small towns is significant, as contamination levels at these sites were comparable to or higher than those in larger populations with sewage treatments.

Physiological properties of auditory neurons responding to omission deviants in the anesthetized rat.

The detection of novel, low probability events in the environment is critical for survival. To perform this vital task, our brain is continuously building and updating a model of the outside world; an extensively studied phenomenon commonly referred to as predictive coding. Predictive coding posits that the brain is continuously extracting regularities from the environment to generate predictions. These predictions are then used to supress neuronal responses to redundant information, filtering those inputs, which then automatically enhances the remaining, unexpected inputs. We have recently described the ability of auditory neurons to generate predictions about expected sensory inputs by detecting their absence in an oddball paradigm using omitted tones as deviants. Here, we studied the responses of individual neurons to omitted tones by presenting individual sequences of repetitive pure tones, using both random and periodic omissions, presented at both fast and slow rates in the inferior colliculus and auditory cortex neurons of anesthetized rats. Our goal was to determine whether feature-specific dependence of these predictions exists. Results showed that omitted tones could be detected at both high (8 Hz) and slow repetition rates (2 Hz), with detection being more robust at the non-lemniscal auditory pathway.

Early Adjuvant Chemotherapy Improves Survival in Muscle Invasive Bladder Cancer: A Systematic Review and Meta-analysis.

OBJECTIVE: To evaluate whether earlier administration of adjuvant chemotherapy (AC) can significantly augment survival rates in muscle-invasive bladder cancer. METHODS: We systematically searched PubMed, Cochrane Central, Scopus, and Web of Science library databases for original articles that looked at timing to AC after radical cystectomy. Heterogeneity was assessed using Higgins I2%, with values over 50% considered heterogeneous and analyzed with a random effects model; otherwise, a fixed effects model was used. Studies were stratified based on the cutoff time used for administering AC. Two primary cutoffs were employed: 45 days and 90 days. Immediate AC was defined as chemotherapy administered before the predefined cutoff, while delayed AC was defined as chemotherapy administered after this cutoff. Comparisons were made between immediate versus delayed. RESULTS: A total of 5 studies were included. Overall survival (OS) was reported in all of the studies. The meta-analysis showed that immediate AC significantly improved OS, with a hazard ratio (HR) of 1.20 [1.06, 1.36], P=.004. When stratifying by the timing of therapy, starting chemotherapy within 45 days resulted in a greater improvement in survival (HR 1.27 [1.02, 1.59], P=.03) compared to starting within 90 days (HR 1.17 [1.00, 1.36], P=.04). CONCLUSION: The findings of this systematic review and meta-analysis emphasize that the timing of AC post-radical cystectomy significantly influences survival outcomes in patients with MIBC. The benefits of early AC initiation underscore its potential in mitigating disease progression and improving long-term survival rates.

APPLICATIONS OF MULTIMODAL GENERATIVE ARTIFICIAL INTELLIGENCE IN A REAL-WORLD RETINA CLINIC SETTING.

PURPOSE: This study evaluates a large language model, Generative Pre-trained Transformer 4 with vision, for diagnosing vitreoretinal diseases in real-world ophthalmology settings. METHODS: A retrospective cross-sectional study at Bascom Palmer Eye Clinic, analyzing patient data from January 2010 to March 2023, assesses Generative Pre-trained Transformer 4 with vision's performance on retinal image analysis and International Classification of Diseases 10th revision coding across 2 patient groups: simpler cases (Group A) and complex cases (Group B) requiring more in-depth analysis. Diagnostic accuracy was assessed through open-ended questions and multiple-choice questions independently verified by three retina specialists. RESULTS: In 256 eyes from 143 patients, Generative Pre-trained Transformer 4-V demonstrated a 13.7% accuracy for open-ended questions and 31.3% for multiple-choice questions, with International Classification of Diseases 10th revision code accuracies at 5.5% and 31.3%, respectively. Accurately diagnosed posterior vitreous detachment, nonexudative age-related macular degeneration, and retinal detachment. International Classification of Diseases 10th revision coding was most accurate for nonexudative age-related macular degeneration, central retinal vein occlusion, and macular hole in OEQs, and for posterior vitreous detachment, nonexudative age-related macular degeneration, and retinal detachment in multiple-choice questions. No significant difference in diagnostic or coding accuracy was found in Groups A and B. CONCLUSION: Generative Pre-trained Transformer 4 with vision has potential in clinical care and record keeping, particularly with standardized questions. Its effectiveness in open-ended scenarios is limited, indicating a significant limitation in providing complex medical advice.

Comparison of Results from Two Commercially Available In-House Tissue-Based Comprehensive Genomic Profiling Solutions: Research Use Only AVENIO Tumor Tissue Comprehensive Genomic Profiling Kit and TruSight Oncology 500 Assay.

Increased adoption of personalized medicine has brought comprehensive genomic profiling (CGP) to the forefront. However, differences in assay, bioinformatics, and reporting systems and lack of understanding of their complex interplay are a challenge for implementation and achieving uniformity in CGP testing. Two commercially available, tissue-based, in-house CGP assays were compared, in combination with a tertiary analysis solution in a research use only (RUO) context: the AVENIO Tumor Tissue CGP RUO Kit paired with navify Mutation Profiler (RUO) software and the TruSight Oncology 500 RUO assay paired with PierianDx Clinical Genomics Workspace software. Agreements and differences between the assays were assessed for short variants, copy number alterations, rearrangements, tumor mutational burden, and microsatellite instability, including variant categorization and clinical trial-matching (CTM) recommendations. Results showed good overall agreement for short variant, known gene fusion, and microsatellite instability detection. Important differences were obtained in tumor mutational burden scoring, copy number alteration detection, and CTM. Differences in variant and biomarker detection could be explained by bioinformatic approaches to variant calling, filtering, tiering, and normalization; differences in CTM, by underlying reported variants and conceptual differences in system parameters. Thus, distinctions between different approaches may lead to inconsistent results. Complexities in calling, filtering, and interpreting variants illustrate key considerations for implementation of any high-quality CGP in the laboratory and bringing uniformity to genomic insight results.