Activation of uranyl peroxides by ionizing radiation prior to uranyl carbonate formation.

The solid form of the uranyl peroxide cage (UPC) cluster LiU28 (Li28[(UO2)28(O2)42]) was irradiated by 5 MeV He2+ ions to achieve doses up to 42 MGy. An intermediate compound formed that reacts with atmospheric CO2 to form uranyl carbonates. The role of water in the UPC to uranyl carbonate transformation was studied by flowing either dry or hydrated Ar over samples during He2+ irradiation, and by storing samples in dry and humid environments before and after irradiation. Raman, infrared, and X-ray photoelectron spectroscopies and electrospray ionization mass spectrometry were used to characterize solid Li-U28 salts before and after He2+ irradiation. The highest yield of uranyl carbonates occurred when hydrated Ar gas was flowed across the sample during He2+ irradiation. Electron paramagnetic resonance spectroscopy provided evidence of hydroxyl and superoxide radicals in both unirradiated and γ-irradiated Li-U28.

Resistance Management for Cancer: Lessons from Farmers.

One of the main reasons we have not been able to cure cancers is that treatments select for drug-resistant cells. Pest managers face similar challenges with pesticides selecting for pesticide-resistant insects, resulting in similar mechanisms of resistance. Pest managers have developed ten principles that could be translated to controlling cancers: (1) prevent onset, (2) monitor continuously, (3) identify thresholds below which there will be no intervention, (4) change interventions in response to burden, (5) preferentially select non-chemical control methods, (6) use target-specific drugs, (7) use the lowest effective dose, (8) reduce cross-resistance, (9) evaluate success based on long-term management, and (10) forecast growth and response. These principles are general to all cancers and cancer drugs and so could be employed broadly to improve oncology. Here, we review the parallel difficulties in controlling drug resistance in pests and cancer cells. We show how the principles of resistance management in pests might be applied to cancer. Integrated pest management inspired the development of adaptive therapy in oncology to increase progression-free survival and quality of life in patients with cancers where cures are unlikely. These pest management principles have the potential to inform clinical trial design.

Benefit of Whole-Pelvis Radiation for Patients With Muscle-Invasive Bladder Cancer: An Inverse Probability Treatment Weighted Analysis.

PURPOSE: The value of pelvic lymph node irradiation is debated for patients with muscle-invasive bladder cancer (MIBC) undergoing curative-intent radiation therapy (RT). We sought to compare the oncological outcomes between bladder-only (BO)-RT and whole-pelvis (WP)-RT using a large Canadian multicenter collaborative database. PATIENTS AND METHODS: The study cohort consisted of 809 patients with MIBC (cT2-4aN0-2M0) who underwent curative RT at academic centers across Canada. Patients were divided into two groups on the basis of the RT volume: WP-RT versus BO-RT. Inverse probability of treatment weighting (IPTW) and absolute standardized differences (ASDs) were used to balance covariates across treatment groups. Regression models were used to assess the effect of the RT volume on the rates of complete response (CR), cancer-specific survival (CSS), and overall survival (OS). RESULTS: After exclusion criteria, 599 patients were included, of whom 369 (61.6%) underwent WP-RT. Patients receiving WP-RT were younger (ASD, 0.41) and more likely to have an Eastern Cooperative Oncology Group performance status of 0-1 (ASD, 0.21), clinical node-positive disease (ASD, 0.40), and lymphovascular invasion (ASD, 0.25). In addition, WP-RT patients were more commonly treated with neoadjuvant chemotherapy (ASD, 0.29) and concurrent chemotherapy (ASD, 0.44). In the IPTW cohort, BO-RT and WP-RT groups were well balanced (all pretreatment parameters with an ASD <0.10). In multivariable analysis, WP-RT was not associated with CR rates post-RT (odds ratio, 1.14 [95 CI, 0.76 to 1.72]; P = .526) but was associated with both CSS (hazard ratio [HR], 0.66 [95% CI, 0.47 to 0.93]; P = .016) and OS (HR, 0.68 [95% CI, 0.54 to 0.87]; P = .002), independent of other prognostic factors. CONCLUSION: Our study demonstrated that WP radiation was associated with better survival compared with bladder radiation alone after adjusted analysis. Additional randomized controlled trials are needed to confirm our findings.

Do health care quality improvement policies work for all? Distributional effects by baseline quality in South Africa.

Health care quality improvement (QI) initiatives are being implemented by a number of low- and middle-income countries. However, there is concern that these policies may not reduce, or may even worsen, inequities in access to high-quality care. Few studies have examined the distributional impact of QI programmes. We study the Ideal Clinic Realization and Maintenance program implemented in health facilities in South Africa, assessing whether the effects of the program are sensitive to previous quality performance. Implementing difference-in-difference-in-difference and changes-in-changes approaches we estimate the effect of the program on quality across the distribution of past facility quality performance. We find that the largest gains are realized by facilities with higher baseline quality, meaning this policy may have led to a worsening of pre-existing inequity in health care quality. Our study highlights that the full consequences of QI programmes cannot be gauged solely from examination of the mean impact.

Vitamin A Metabolism and Resistance of Hepatic Metastases to Immunotherapy.

The liver is an immune tolerant organ, allowing for organ transplantation with less immune suppression compared to other organs. It also provides fertile soil for tumor metastases, which tend to be more resistant to checkpoint blockade immunotherapy than metastases in other organs. This resistance may result from the sum of incremental evolutionary adaptions in various cell types to prevent overaction to antigens absorbed from the gut into the portal circulation or it might involve a central mechanism. Here we propose that metabolism of vitamin A, which is highly concentrated in the liver, is a root source of tolerance and resistance of hepatic metastases to checkpoint blockade. Suppression of retinoic acid synthesis from vitamin A with disulfiram may mitigate tolerance and produce enhanced immunotherapy treatment results for patients with liver metastases.

Plasma adenosine deaminase-1 and -2 activities are lower at birth in Papua New Guinea than in The Gambia but converge over the first weeks of life.

Introduction: Dynamic cellular and molecular adaptations in early life significantly impact health and disease. Upon birth, newborns are immediately challenged by their environment, placing urgent demands on the infant immune system. Adenosine deaminases (ADAs) are enzymatic immune modulators present in two isoforms - ADA-1 and ADA-2. Infants exhibit low ADA activity, resulting in high plasma adenosine concentrations and a consequent anti-inflammatory/anti-Th1 bias. While longitudinal studies of plasma ADA have been conducted in infants in The Gambia (GAM), little is known regarding ADA trajectories in other parts of the world. Methods: Herein, we characterized plasma ADA activity in an infant cohort in Papua New Guinea (PNG; n=83) and compared to ontogeny of ADA activity in a larger cohort in GAM (n=646). Heparinized peripheral blood samples were collected at day of life (DOL) 0, DOL7, DOL30, and DOL128. Plasma ADA-1, ADA-2, and total ADA activities were measured by chromogenic assay. Results: Compared to GAM infants, PNG infants had significantly lower ADA-1 (0.9-fold), ADA-2 (0.42-fold), and total ADA (0.84-fold) activities at birth which converged by DOL30. Discussion: Overall, discovery of a distinct baseline and a consistent pattern of increasing plasma ADA activity in early life in two genetically and geographically distinct populations validates and extends previous findings on the robustness of early life immune ontogeny.

Multidimensional Rietveld refinement of high-pressure neutron diffraction data of PbNCN.

High-pressure neutron powder diffraction data from PbNCN were collected on the high-pressure diffraction beamline SNAP located at the Spallation Neutron Source (SNS) of Oak Ridge National Laboratory (Tennessee, USA). The diffraction data were analyzed using the novel method of multidimensional (two dimensions for now, potentially more in the future) Rietveld refinement and, for comparison, employing the conventional Rietveld method. To achieve two-dimensional analysis, a detailed description of the SNAP instrument characteristics was created, serving as an instrument parameter file, and then yielding both cell and spatial parameters as refined under pressure for the first time for solid-state cyanamides/carbodi-imides. The bulk modulus B 0 = 25.1 (15) GPa and its derivative B'0 = 11.1 (8) were extracted for PbNCN following the Vinet equation of state. Surprisingly, an internal transition was observed beyond 2.0 (2) GPa, resulting from switching the bond multiplicities (and bending direction) of the NCN2- complex anion. The results were corroborated using electronic structure calculation from first principles, highlighting both local structural and chemical bonding details.

Significance of honeybee pollination in increasing seed yield of Trifolium alexandrinum (Fabales: Fabaceae) and its impact on economic sustainability of smallholder farmers.

A major limitation to producing high seed yields in berseem clover (Trifolium alexandrinum L.) is failure to set seed, predominantly due to lack of pollination. Despite the importance of berseem clover as a leading forage legume, the contribution of pollinators to seed set is scarce. In Pakistan, the honeybee population is declining mainly because of the extensive use of neonicotinoid pesticides and habitat fragmentation. This, combined with the region's harsh environment and the use of inferior, locally bred genotypes, has resulted in low seed yields. Insufficient seed availability leads to limited forage supply, resulting in poor livestock nutrition, which subsequently impacts livestock health and productivity, and reduces farmers' income. The present study estimated the seed production of 3 berseem clover genotypes resulting from honeybees [Apis mellifera L. (Hymenoptera: Apidae)] pollination in 2 growing seasons (2012-2014) in the central Punjab region of Pakistan. Experiments had 2 pollination treatments (open pollination and honeybee inclusion) and 3 seed genotypes, viz. farmer own-saved, market, and the improved variety cultivars. For both growing seasons, honeybee pollination resulted in significant increases in seed yields ranging from 35% to 67%, regardless of seed genotype. With the exception of the number of seed heads/m2, all seed yield parameters also increased significantly in response to honeybee inclusion. The combination of improved variety and honeybee inclusion resulted in the production of a maximum number of seeds per head (45.3), 1,000-seed weight (3.7 g), and estimated seed yield (375.5 kg/ha). In addition, the increase in estimated net income of seed ranged from PKR 82,485 Rs/ha (US$844/ha) to PKR 168,975 Rs/ha (US$1728/ha) with the use of honeybees as an insect pollinator across all the seed genotypes. Honeybee pollination has broader implications for mixed farming systems by playing a key role in preserving biodiversity and promoting sustainable agriculture. It also enhances the quality and quantity of berseem crops by increasing the production of high-quality seeds and forage leading to improved livestock productivity and family food security which strengthens the economic resilience of rural communities.

Management of Patients with Advanced Prostate Cancer. Report from the 2024 Advanced Prostate Cancer Consensus Conference (APCCC).

BACKGROUND AND OBJECTIVE: Innovations have improved outcomes in advanced prostate cancer (PC). Nonetheless, we continue to lack high-level evidence on a variety of topics that greatly impact daily practice. The 2024 Advanced Prostate Cancer Consensus Conference (APCCC) surveyed experts on key questions in clinical management in order to supplement evidence-based guidelines. Here we present voting results for questions from APCCC 2024. METHODS: Before the conference, a panel of 120 international PC experts used a modified Delphi process to develop 183 multiple-choice consensus questions on eight different topics. Before the conference, these questions were administered via a web-based survey to the voting panel members ("panellists"). KEY FINDINGS AND LIMITATIONS: Consensus was a priori defined as ≥75% agreement, with strong consensus defined as ≥90% agreement. The voting results show varying degrees of consensus, as discussed in this article and detailed in the Supplementary material. These findings do not include a formal literature review or meta-analysis. CONCLUSIONS AND CLINICAL IMPLICATIONS: The voting results can help physicians and patients navigate controversial areas of clinical management for which high-level evidence is scant or conflicting. The findings can also help funders and policymakers in prioritising areas for future research. Diagnostic and treatment decisions should always be individualised on the basis of patient and cancer characteristics, and should incorporate current and emerging clinical evidence, guidelines, and logistic and economic factors. Enrolment in clinical trials is always strongly encouraged. Importantly, APCCC 2024 once again identified important gaps (areas of nonconsensus) that merit evaluation in specifically designed trials.

Unemployment and Personal Income Loss After Traumatic Brain Injury.

Importance: Employment and personal income loss after traumatic brain injury is a major source of postinjury stress and a barrier to societal reintegration. The magnitude of labor market ramifications following traumatic brain injury remains largely unknown. Objectives: To quantify the 3-year postinjury labor market consequences following traumatic brain injury in Canada. To also estimate the incurred national labor market cost over the study period. Design, Setting, and Participants: This retrospective quasi-experimental, pan-Canadian observational cohort study used linked administrative health and federal taxation data obtained between 2007 and 2017. Mixed-effects difference-in-difference regressions were constructed to estimate the annualized magnitude of the personal income and employment loss during each of the 3 years following injury, respectively, relative to preinjury baseline. Participants included tax-filing adult (19 to 61 years old) traumatic brain injury survivors. Exposure: Traumatic brain injury. Main Outcome Measures: Coprimary outcomes were personal income loss and the proportion of newly unemployed individuals per annum. Secondary objectives were to quantify income and employment loss within mild, moderate, and severe traumatic brain injury subgroups. Results: A total of 18 050 patients with traumatic brain injury between 2007 and 2017 were identified (mean age, 38.0 [SD, 12.4] years; 13 360 male [74.0%]), each of whom was followed up with for 3 consecutive fiscal years. Mean income was CAD $42 600 (US $31 083) in the fiscal year prior to injury and 82% were employed at time of injury. The adjusted mean loss of personal income was CAD $7635 (US $5650) in the first year after injury (Y+1) and CAD $5000 (US $3700) in the third year after injury (Y+3) relative to uninjured controls. In each of the 3 postinjury years, 7.8% individuals were newly unemployed compared with the preinjury baseline. The adjusted average personal income loss for mild, moderate, and severe traumatic brain injury subgroups were CAD $3354 (US $2482), CAD $6750 (US $4995), and CAD $17 375 (US $12 859), respectively, at Y+3; the proportion of unemployed individuals increased by 5.8%, 9.2%, and 20% across the same groups at Y+3 after injury relative to preinjury baseline. The estimated total reduction in personal income aggregated over the 3 postinjury years for the affected participants was CAD $588 million (US $435 million). Conclusions and Relevance: This work represents national cohort data quantifying the labor market implications of traumatic brain injury. These results may be used to inform economic evaluations and social service resource allocation.

Integration of auditory and visual cues in spatial navigation under normal and impaired viewing conditions.

Auditory landmarks can contribute to spatial updating during navigation with vision. Whereas large inter-individual differences have been identified in how navigators combine auditory and visual landmarks, it is still unclear under what circumstances audition is used. Further, whether or not individuals optimally combine auditory cues with visual cues to decrease the amount of perceptual uncertainty, or variability, has not been well-documented. Here, we test audiovisual integration during spatial updating in a virtual navigation task. In Experiment 1, 24 individuals with normal sensory acuity completed a triangular homing task with either visual landmarks, auditory landmarks, or both. In addition, participants experienced a fourth condition with a covert spatial conflict where auditory landmarks were rotated relative to visual landmarks. Participants generally relied more on visual landmarks than auditory landmarks and were no more accurate with multisensory cues than with vision alone. In Experiment 2, a new group of 24 individuals completed the same task, but with simulated low vision in the form of a blur filter to increase visual uncertainty. Again, participants relied more on visual landmarks than auditory ones and no multisensory benefit occurred. Participants navigating with blur did not rely more on their hearing compared with the group that navigated with normal vision. These results support previous research showing that one sensory modality at a time may be sufficient for spatial updating, even under impaired viewing conditions. Future research could investigate task- and participant-specific factors that lead to different strategies of multisensory cue combination with auditory and visual cues.

Direct-bonded diamond membranes for heterogeneous quantum and electronic technologies.

Diamond has superlative material properties for a broad range of quantum and electronic technologies. However, heteroepitaxial growth of single crystal diamond remains limited, impeding integration and evolution of diamond-based technologies. Here, we directly bond single-crystal diamond membranes to a wide variety of materials including silicon, fused silica, sapphire, thermal oxide, and lithium niobate. Our bonding process combines customized membrane synthesis, transfer, and dry surface functionalization, allowing for minimal contamination while providing pathways for near unity yield and scalability. We generate bonded crystalline membranes with thickness as low as 10 nm, sub-nm interfacial regions, and nanometer-scale thickness variability over 200 by 200 µm2 areas. We measure spin coherence times T2 for nitrogen vacancy centers in 150 nm-thick bonded membranes of up to 623 ± 21 µs, suitable for advanced quantum applications. We demonstrate multiple methods for integrating high quality factor nanophotonic cavities with the diamond heterostructures, highlighting the platform versatility in quantum photonic applications. Furthermore, we show that our ultra-thin diamond membranes are compatible with total internal reflection fluorescence (TIRF) microscopy, which enables interfacing coherent diamond quantum sensors with living cells while rejecting unwanted background luminescence. The processes demonstrated herein provide a full toolkit to synthesize heterogeneous diamond-based hybrid systems for quantum and electronic technologies.

Research Note: Comparison of Enterococcus cecorum genomes from broiler chickens with enterococcal spondylitis in Australian farms and strains from other countries.

Chickens in Australia have recently been identified with symptoms and morphological findings including spondylitis attributed to pathogenic Enterococcus cecorum. Notably, there is limited information on clinical E. cecorum strains in Australia. The cpsO gene, located downstream of the capsular polysaccharide (cps) locus, was recently reported to successfully differentiate between pathogenic and commensal E. cecorum strains, as this gene is highly conserved in the pathogenic strains. In this study, pathogenic E. cecorum, with a conserved cpsO gene, was detected on 1 of the 2 farms studied in Australia. E. cecorum strains isolated from clinical sites of the diseased birds from the second farm did not have the cpsO gene and were distant from the isolates of the first farm. A cpsO PCR of the caecal content of the birds on this farm was positive, while cpsO PCR of washed culture plates where the tissue extracts were spread onto and incubated for bacterial growth was negative. This suggests that pathogenic E. cecorum with the cpsO gene, as detected in Farm 1 and reported in other countries, was present in the second farm but could not grow on the selective agar plates during the initial step of E. cecorum isolation. Nevertheless, E. cecorum isolated from the clinical sites on the second farm might represent the pathogenic strain, but further animal studies are required to validate this possibility. Phylogenetic analysis showed that the pathogenic strains in Australia were most closely related to the clinical strains in North America.

Characteristics of walk-in clinic physicians and patients in Ontario: Cross-sectional study.

OBJECTIVE: To describe family physicians who primarily practise in a walk-in clinic setting and compare them with family physicians who provide longitudinal care. DESIGN: A cross-sectional study that linked results from a 2019 physician survey to provincial administrative health care data in Ontario. The characteristics, practice patterns, and patients of physicians primarily working in a walk-in clinic setting were compared with those of family physicians providing longitudinal care. SETTING: Ontario. PARTICIPANTS: Physicians who primarily worked in a walk-in clinic setting in 2019, as indicated by an annual physician survey. MAIN OUTCOME MEASURES: Physician demographic and practice characteristics, as well as their patients' demographic and health care utilization characteristics, were reported according to whether the physician was a walk-in clinic physician or a family physician who provided longitudinal care. RESULTS: Compared with the 9137 family physicians providing longitudinal care, the 597 physicians who self-identified as practising primarily in walk-in clinics were more frequently male (67% vs 49%) and more likely to speak a language other than English or French (43% vs 32%). Walk-in clinic physicians tended to have more encounters with patients who were younger (mean 37 vs 47 years), who had lower levels of prior health care utilization (15% vs 19% in highest band), who resided in large urban areas (87% vs 77%), and who lived in highly ethnically diverse neighbourhoods (45% vs 35%). Walk-in clinic physicians tended to have more encounters with unattached patients (33% vs 17%) and with patients attached to another physician outside their group (54% vs 18%). CONCLUSION: Physicians who primarily work in walk-in clinics saw many patients from historically underserved groups and many patients who were attached to another family physician.

Genotype by environment interaction across water regimes in relation to cropping season response of quinoa (Chenopodium quinoa).

Genotype × environment (GxE) interaction effects are one of the major challenges in identifying cultivars with stable performance across agri-environments. In this study we analysed GE interactions to identify quinoa (Chenopodium quinoa) cultivars with high and stable yields under different soil moisture regimes, representing control conditions, waterlogging and drought. Waterlogging and drought treatments were artificially induced using normoxia, a combination of hypoxia-normoxia, and 10% PEG (Polyethylene glycol) under hydroponic growth conditions, respectively. Both waterlogging and drought conditions significantly reduced the plant height (PH), number of leaves (NoL) and number of branches (NoB), stem diameter (SD), leaf area (LA) and dry weight (DW) of quinoa genotypes. The genotype, water regime, and genotype by water regime effects all significantly affected the measured quinoa traits. Based on the additive main effects and multiplicative interaction (AMMI) model for DW, the genotypes G18, Puno, Q4, 2-Want, Puno, Real1 x Ruy937 and Titicaca were found to exhibit tolerance and were stable across water regimes. A second-stage evaluation was conducted to test genotype × environment interaction effects in crop production field trials, selecting two contrasting seasons based on soil moisture conditions involving a diverse set of genotypes (58 varieties in total). Our results demonstrate significant variations in both growth and yield among the quinoa genotypes across the cropping seasons. The GGE analysis for grain yield indicate that field conditions matched to G × E under hydroponic experimental conditions and the cultivars G18, Q1, Q4, NL-3, G28, 42-Test, Atlas and 59-ALC were classified within a range of high productivity. Our findings provide a basis for understanding the mechanisms of wide adaptation, while identifying germplasm that enhances the water stress tolerance of quinoa cultivars at early growth stages.

Ictal and interictal epileptic networks of 34 patients with Hypothalamic Hamartoma on scalp electroencephalography.

OBJECTIVE: To investigate ictal and interictal cortical involvement in epilepsy associated with hypothalamic hamartoma. We conducted a retrospective study of 34 patients with epilepsy and hypothalamic hamartoma, using data from long-term video-EEG-monitoring. METHODS: We analyzed onset and propagation of ictal and interictal scalp EEG and visualized the resulting networks of cortical involvement. According to clinical and EEG criteria we grouped patients in: (1) focal disease, (2) focal advanced disease, (3) extended disease. We compared networks between these groups and different seizure types. Eight patients underwent several video-EEGs, and we analyzed all to investigate epilepsy progression. RESULTS: Epileptic activity mainly involved frontal and temporal cortex regions. Involvement of frontal regions was more common in advanced stages of the disease, and strong fronto-temporal connections were observed in the ictal networks of patients in intermediate stages (25.0% (left) and 35.7% (right) of seizures with EEG correlate). Occurrence and timing of EEG-correlate significantly depended on the seizure type (Chi-2-test, p<<0.001). In patients with several EEGs, seizure activity increased by +0.67 seizures/day/month (mean). There were significant differences between patients with normal and impaired cognitive function, with the latter showing pronounced ictal involvement of fronto-temporal cortex areas (p<0.001). CONCLUSION: Overall, in epilepsy due to hypothalamic hamartoma, cortical involvement focuses on frontal and temporal regions and varies systematically with the stage of the disease, different seizure types and presence of impaired cognitive function. We propose that these data may help improve our general understanding of epileptogenesis and potentially provide insights for the surgical therapy of hypothalamic hamartomas.

Strategies for the biocontrol Pseudomonas infections pre-fruit harvest.

The efficiency of global crop production is under threat from microbial pathogens which is likely to be worsened by climate change. Major contributors to plant disease are Pseudomonas syringae (P. syringae) pathovars which affect a variety of important crops. This opinion piece focuses on P. syringae pathovars actinidiae and syringae, which affect kiwifruit and stone fruits, respectively. We discuss some of the current control strategies for these pathogens and highlight recent research developments in combined biocontrol agents such as bacteriophages and combinations of bacteriophages with known anti-microbials such as antibiotics and bacteriocins.

Potentiation of cortico-spinal output via targeted electrical stimulation of the motor thalamus.

Cerebral white matter lesions prevent cortico-spinal descending inputs from effectively activating spinal motoneurons, leading to loss of motor control. However, in most cases, the damage to cortico-spinal axons is incomplete offering a potential target for therapies aimed at improving volitional muscle activation. Here we hypothesize that, by engaging direct excitatory connections to cortico-spinal motoneurons, stimulation of the motor thalamus could facilitate activation of surviving cortico-spinal fibers thereby immediately potentiating motor output. To test this hypothesis, we identify optimal thalamic targets and stimulation parameters that enhance upper-limb motor-evoked potentials and grip forces in anesthetized monkeys. This potentiation persists after white matter lesions. We replicate these results in humans during intra-operative testing. We then design a stimulation protocol that immediately improves strength and force control in a patient with a chronic white matter lesion. Our results show that electrical stimulation targeting surviving neural pathways can improve motor control after white matter lesions.

Activation of PIEZO1 Attenuates Kidney Cystogenesis In Vitro and Ex Vivo.

BACKGROUND: The disruption of calcium signaling associated with polycystin deficiency is a key factor in abnormal epithelial growth in Autosomal Dominant Polycystic Kidney Disease (ADPKD). Calcium homeostasis can be influenced by mechanotransduction. The mechanosensitive cation channel PIEZO1 has been implicated in sensing intrarenal pressure and regulating urinary osmoregulation, but its role in kidney cystogenesis is unclear. METHODS: We hypothesized that altered mechanotransduction contributes to cystogenesis in ADPKD, and that activation of mechanosensitive cation channels could be a therapeutic strategy. RESULTS: We demonstrate that Yoda1, a PIEZO1 activator, increases intracellular calcium and reduces forskolin-induced cAMP levels in mouse inner medullary collecting duct (mIMCD3) cells. Notably, knockout of polycystin-2 attenuated the efficacy of Yoda1 in reducing cAMP levels in mIMCD3 cells. Yoda1 also reduced forskolin-induced mIMCD3 cyst surface area in vitro and cystic index in mouse metanephros ex vivo in a dose-dependent manner. However, collecting duct-specific Piezo1 knockout neither induced cystogenesis in wild-type mice nor altered cystogenesis in the Pkd1RC/RC mouse model. CONCLUSIONS: These findings support the potential role of PIEZO1 agonists in mitigating cystogenesis by increasing intracellular calcium and reducing cAMP levels, but the unaltered in vivo cystic phenotype following Piezo1 knockout in the collecting duct suggests possible redundancy in mechanotransductive pathways.

Does Concomitant Use of Methotrexate with JAK Inhibition Confer Benefit for Cardiovascular Outcomes? A Commentary.

This commentary explores the potential cardiovascular (CV) benefits of combining methotrexate (MTX) and Janus kinase inhibitors (JAKis) in the treatment of rheumatoid arthritis (RA). While European guidelines recommend MTX as first-line treatment, concerns about the CV risks associated with JAKis have emerged. This article reviews the existing literature to assess the role of concomitant MTX in reducing CV risk when used with JAKis. Clinical trials confirm the efficacy of JAKis in combination with MTX in terms of treatment outcomes in RA. However, the number of major adverse cardiovascular events (MACEs) reported is too low to draw conclusions on adverse CV outcomes. Indirect evidence does, however, suggest potential protective effects of MTX on CV outcomes, as several mechanisms may contribute to MTX's cardioprotective effects, including reduced inflammation, adenosine monophosphate-activated protein kinase (AMPK) activation, increased cholesterol efflux, and adenosine accumulation. These mechanisms and the available data may support the case for CV benefits of concomitant MTX when JAKis are used in the treatment of patients with RA, although further research is needed. In particular, the lipid paradox associated with RA highlights the complex relationship between RA treatments (MTX, JAKis, tumor necrosis factor (TNF) inhibitors, and interleukin (IL)-6 receptor inhibitors), inflammation, different lipid profiles, and CV risk. In the absence of contraindications and when MTX is tolerated, this commentary suggests the concomitant use of MTX and JAKis as a preferred option for optimizing CV protection in patients with RA.