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Abstract Cyclosporin A (CsA), an immunosuppressive drug used in transplant recipients, inhibits graft rejection by binding to cyclophilins and competitively inhibiting calcineurin. While concerns about respiratory infections in immunosuppressed patients exist, contradictory data emerged during the COVID‐19 pandemic, prompting investigations into CsA's impact on viral infections. This study explores CsA's antiviral effects on SARS‐CoV‐2 Omicron BA.1, Delta variants, and human parainfluenza virus 3 (HPIV3) using an ex vivo model of human airway epithelium (HAE). CsA exhibited a dose‐dependent antiviral effect against the SARS‐CoV‐2 Delta variant, reducing viral load over 10 days. However, no significant impact was observed against SARS‐CoV‐2 Omicron or HPIV3, indicating a virus‐specific effect. At high concentrations, CsA was associated with an increase of IL‐8 and a decrease of IFNλ expression in infected and noninfected HAE. This study highlights the complexity of CsA's antiviral mechanisms, more likely involving intricate inflammatory pathways and interactions with specific viral proteins. The research provides novel insights into CsA's effects on respiratory viruses, emphasizing the need for understanding drug–virus interactions in optimizing therapeutic approaches for transplant recipients and advancing knowledge on immunosuppressive treatments' implications on respiratory viral infections. Limitations include the model's inability to assess T lymphocyte activation, suggesting the necessity for further comprehensive studies to decipher the intricate dynamics of immunosuppressive treatments on respiratory viral infections.

Key Clinical Message Polypoid endometriosis is a rare manifestation of endometriosis, which may mimic pelvic cancer. This subtype commonly encountered in post‐menopausal women may be wrongly mistaken for a neoplasm on clinical, radiological, perioperative or pathologic assessments leading to inadequate treatment.

Abstract Conservation of the Atlantic salmon Salmo salar requires to monitor the spatial distribution and abundance of juveniles at a local scale in tributaries. However, tributaries are rarely accounted for in monitoring programs despite their importance for juvenile life stages. This is mainly because inventories of young salmon populations in tributaries can be technically challenging with traditional methods, as the number of tributaries in a watershed can be important and their access limited compared to the main stem. In this study, we tested the use of environmental DNA (eDNA) to quantify the abundance of juvenile Atlantic salmon in tributaries. We successfully detected eDNA of juvenile Atlantic salmon in 19 tributaries of three main rivers of the Gaspé Peninsula (Québec, Canada) using quantitative real‐time PCR analyses. By comparing the eDNA approach with electrofishing surveys conducted in parallel to water sampling, we found that eDNA concentrations positively correlated with juvenile abundance, total biomass, and body surface area. The use of the allometrically scaled mass (ASM) instead of abundance improved the correlation. Furthermore, we demonstrated that the levels of eDNA molecules detected for juvenile Atlantic salmon were also correlated with water temperature and canopy cover measured in each tributary. Finally, we tested if eDNA concentrations measured in a tributary could be used as a reliable indicator of juvenile abundance or biomass in that tributary. We found that our models slightly better predicted juvenile biomass than juvenile abundance. The use of ASM did not improve model prediction, suggesting that further refinement would be required in the future. Our method will facilitate the implementation of conservation practices appropriate to the ecology of juvenile Atlantic salmon in tributaries.

The androgen receptor (AR) is an established orchestrator of cell metabolism in prostate cancer (PCa), notably by inducing an oxidative mitochondrial program. Intriguingly, AR regulates cytoplasmic isocitrate dehydrogenase 1 (IDH1), but not its mitochondrial counterparts IDH2 and IDH3. Here, we aimed to understand the functional role of IDH1 in PCa. Mouse models, in vitro human PCa cell lines, and human patient‐derived organoids (PDOs) were used to study the expression and activity of IDH enzymes in the normal prostate and PCa. Genetic and pharmacological inhibition of IDH1 was then combined with extracellular flux analyses and gas chromatography–mass spectrometry for metabolomic analyses and cancer cell proliferation in vitro and in vivo. In PCa cells, more than 90% of the total IDH activity is mediated through IDH1 rather than its mitochondrial counterparts. This profile seems to originate from the specialized prostate metabolic program, as observed using mouse prostate and PDOs. Pharmacological and genetic inhibition of IDH1 impaired mitochondrial respiration, suggesting that this cytoplasmic enzyme contributes to the mitochondrial tricarboxylic acid cycle (TCA) in PCa. Mass spectrometry‐based metabolomics confirmed this hypothesis, showing that inhibition of IDH1 impairs carbon flux into the TCA cycle. Consequently, inhibition of IDH1 decreased PCa cell proliferation in vitro and in vivo. These results demonstrate that PCa cells have a hybrid cytoplasmic–mitochondrial TCA cycle that depends on IDH1. This metabolic enzyme represents a metabolic vulnerability of PCa cells and a potential new therapeutic target.

Abstract Objective Clinical practice guidelines (CPGs) are evidence‐based tools well‐suited to translate the latest research evidence into recommendations for routine clinical care. Given the rapid expansion of psychosocial oncology research, they represent a key opportunity for informing the treatment decisions of overburdened clinicians, standardizing service delivery, and improving patient‐reported outcomes. Yet, there is little consensus on how clinicians can most effectively access these tools and little to no information on the current availability and scope of CPGs for the range of psychosocial symptoms and concerns experienced by patients with cancer. Method Our environmental scan consisted of an academic and gray literature designed to identify currently available CPGs addressing a range of cancer‐related psychosocial symptoms. Results Findings revealed a total of 23 existing psychosocial oncology CPGs that met full eligibility criteria. The gray literature search was found to be more effective at identifying CPGs (n = 22) compared to the academic search (n = 9). Conclusion Several concerns arose from the systematic search. The limited publication of CPGs in peer‐reviewed journals may make clinicians and stakeholders more hesitant to implement CPGs due to uncertainties about the methodological rigor of the development process. Further, many existing CPGs are outdated or failed to be updated according to guideline recommendations, meaning that the recommendations may fall short of their purpose to translate up‐to‐date research findings. Future directions Future research should seek to systematically assess the quality of existing psychosocial oncology CPGs and shed light on the current state of implementation and adherence in clinical practice in order to better inform guideline developers on the current needs of the psychosocial oncology community.

Abstract Aims In Envigado, Colombia, the Secretariat of Health has implemented, since 2011, an interprofessional program involving nurses to support and train relatives to improve the quality of life of people with a loss of autonomy and their family caregivers. The objectives of this study are to assess the outcomes of this program and to explore the contextual elements and mechanisms that can explain these outcomes. Design This article presents the research protocol for a realist evaluation that will be carried out to gather the perspectives of various local stakeholders involved. Methods Four outcomes on family caregivers will be measured quantitatively using self‐administered questionnaires and numerical scales. Contextual elements and mechanisms will then be explored qualitatively through focus groups and individual interviews. An iterative analysis will enable the refinement of a program theory. Results The results will inform a program theory that underlies the outcomes of the family caregiver support and training program. Patient or Public Contribution Community stakeholders, family caregivers, people with a loss of autonomy and their relatives will be involved in data collection and/or in the validation of the program theory.

Abstract Evapotranspiration (ET) surface barriers store infiltrated precipitation during the recharge period and release the stored water to the atmosphere via ET. The primary purpose of a surface barrier is to reduce or eliminate drainage to the underlying waste zone. The objective of this study is to analyze the spatial and temporal dynamics of soil moisture within an ET surface barrier based on observed and simulated data. This study characterizes the water movement processes using contour plots of soil moisture content and flux rate in the depth‐time domain. Zero‐flux planes (ZFPs) divide the depth‐time domain into stored water, ET, and drainage zones. Some flow dynamics (e.g., flow rate and direction) that were not observed in the field were elaborated with simulation results to identify the depth of the recharge front of infiltrated water, the release front of stored water, and the bottom of the ET zone. The ET‐drainage divide marks the bottom of the ET zone and the top of the drainage zone. The results showed that the temporal analysis of soil moisture storage could indicate the degree of usage of the storage capacity of a surface barrier. The spatial‐temporal analyses of soil moisture content and flux rate can characterize the durations of the recharge/release processes and the depth of the stored water. Quantification of these processes and related zones provides beneficial understanding of the state and dynamics of soil moisture for a range of weather and vegetation conditions and is useful in optimizing the design of an ET surface barrier.

Abstract We conducted a single‐center, open‐label, dose escalation, and expansion phase I trial of the antiangiogenic multikinase inhibitor regorafenib in patients with advanced myeloid neoplasms. We enrolled 16 patients with relapsed/refractory acute myeloid leukemia (AML), myeloproliferative neoplasms (MPN), chronic myelomonocytic leukemia (CMML), or myelodysplastic syndrome (MDS). A 3 + 3 dose escalation design was used with two planned dose levels (120 or 160 mg daily) and one de‐escalation level (80 mg daily). An additional 10 patients were treated on an expansion cohort. The recommended phase two dose of regorafenib was 160 mg daily, with no dose‐limiting toxicities. The best overall disease response by International Working Group criteria included one partial and stable disease in 11 patients. Tissue studies indicated no change in Ras/mitogen‐activated protein kinase (MAPK) pathway activation in responders. Pharmacodynamic changes in plasma VEGF, PlGF, and sVEGFR2 were detected during treatment. Baseline proinflammatory and angiogenic cytokine levels were not associated with clinical response. Single‐agent regorafenib demonstrated an acceptable safety profile in relapsed/refractory myeloid malignancy patients. Most patients achieved stable disease, with modest improvements in cell counts in some MDS patients. Biomarker studies were consistent with on‐target effects of regorafenib on angiogenesis. Future studies should investigate the role of regorafenib in combination therapy approaches.

Abstract Primary care physicians and endocrinologists should be aware that neck masses with concerning features like, in this case, a delay in evaluation and treatment may dramatically shorten a patient's life.

Abstract Background Hypertrophic cardiomyopathy (HCM) is characterized by left ventricular hypertrophy (LVH) in the absence of predisposing cardiovascular conditions. Pathogenic variants in at least 16 cardiac sarcomeric genes have been implicated in HCM, most of which act in a dominant‐negative fashion. However loss‐of‐function (haploinsufficiency) is the most common disease mechanism for pathogenic variants in MYBPC3, suggesting that MYBPC3 complete deletion may play a role in HCM pathogenesis. Here, we investigate MYBPC3 complete deletion as a disease mechanism in HCM by analyzing two unrelated patients with confirmed diagnosis of HCM that tested negative by Sanger sequencing analysis. Methods MYBPC3 complete deletion was investigated by Multiplex ligation‐dependent probe amplification (MLPA) and microarray analyses. The mechanism of deletion was investigated by interrogating the SINEBase database. Results Patient‐1 was diagnosed with nonobstructive HCM in his mid‐40s while undergoing assessment for palpitations, and patient‐2 with obstructive HCM in his late‐20s while undergoing systolic heart murmur assessment for an unrelated illness. MLPA testing revealed a heterozygous deletion of all MYBPC3 exons in both patients. Subsequent microarray testing confirmed these deletions which extended beyond the 5′ and 3′ ends of MYBPC3. Genomic assessment suggested that these deletions resulted from Alu/Alu‐homologous recombination. Conclusion Our results demonstrate that haploinsufficiency resulting from MYBPC3 complete deletion, potentially mediated by Alu recombination, is an important disease mechanism in cardiomyopathy and emphasizes the importance of copy number variation analysis in patients clinically suspected of HCM.

Abstract Along with insulin, β‐cells co‐secrete the neurotransmitter ATP which acts as a positive autocrine signal via P2Y1 receptors to activate phospholipase C and increase the production of diacylglycerol (DAG). However, the downstream signaling that couples P2Y1 activation to insulin secretion remains to be fully elucidated. Since DAG activates protein kinase D1 (PKD1) to potentiate glucose‐stimulated insulin release, we hypothesized that autocrine ATP signaling activates downstream PKD1 to regulate insulin secretion. Indeed, we find that the P2Y1 receptor agonists, MRS2365 and ATP induce, PKD1 phosphorylation at serine 916 in mouse islets. Similarly, direct depolarization of islets by KCl caused PKD1 activation, which is reduced upon P2Y1 antagonism. Potentiation of insulin secretion by P2Y1 activation was lost from PKD1−/− mouse islets, and knockdown of PKD1 reduced the ability of P2Y1 activation to facilitate exocytosis in single mouse β‐cells. Finally, qPCR analysis confirmed PKD1 transcript (PRKD1) expression in human islets, and insulin secretion assays showed that inhibition of either P2Y1 or PKD1 signaling impaired glucose‐stimulated insulin secretion. Human islets showed donor‐to‐donor variation in their responses to both P2Y1 and PKD1 inhibition, however, and we find that the P2Y1‐PKD1 pathway contributes a substantially greater proportion of insulin secretion from islets of overweight and obese donors. Thus, PKD1 promotes increased insulin secretion, likely mediating an autocrine ATP effect via P2Y1 receptor activation which may be more important in islets of donors who are overweight or obese.

Abstract Understanding intra‐specific variation in climate sensitivity could improve the prediction of tree responses to climate change. We attempted to identify the degree of genetic control of tree phenology and growth of trembling aspen (Populus tremuloides Mchx.) in a natural stand of this species in northwestern Quebec. We mapped and genotyped 556 aspen trees growing within the plot, using seven nuclear microsatellite loci for clone identification. We selected 13 clones (n of trees per clone >5, in total 350 trees) and evaluated the explanatory power of clone identity in (a) variability of spring leaf phenology and (b) short‐ and long‐term growth responses. The clone's identity explained 43% of the variability in spring leaf phenology, between 18% and 20% of variability in response to monthly climate variables significantly affecting growth, between 8% and 26% of growth response to insect outbreaks, and 12% in the long‐term growth rates. Strong clonal control of aspen phenology and moderate control of growth responses to monthly weather do not result in an equally large impact on long‐term growth rates. The result suggests an important role of environmental extremes and within community interactions as factors averaging aspen growth performance at the stand level.

Abstract Expression of Kv1.2 within Kv1.x potassium channel complexes is critical in maintaining appropriate neuronal excitability and determining the threshold for action potential firing. This is attributed to the interaction of Kv1.2 with a hitherto unidentified protein that confers bimodal channel activation gating, allowing neurons to adapt to repetitive trains of stimulation and protecting against hyperexcitability. One potential protein candidate is the sigma‐1 receptor (Sig‐1R), which regulates other members of the Kv1.x channel family; however, the biophysical nature of the interaction between Sig‐1R and Kv1.2 has not been elucidated. We hypothesized that Sig‐1R may regulate Kv1.2 and may further act as the unidentified modulator of Kv1.2 activation. In transiently transfected HEK293 cells, we found that ligand activation of the Sig‐1R modulates Kv1.2 current amplitude. More importantly, Sig‐1R interacts with Kv1.2 in baseline conditions to influence bimodal activation gating. These effects are abolished in the presence of the auxiliary subunit Kvβ2 and when the Sig‐1R mutation underlying ALS16 (Sig‐1R‐E102Q), is expressed. These data suggest that Kvβ2 occludes the interaction of Sig‐1R with Kv1.2, and that E102 may be a residue critical for Sig‐1R modulation of Kv1.2. The results of this investigation describe an important new role for Sig‐1R in the regulation of neuronal excitability and introduce a novel mechanism of pathophysiology in Sig‐1R dysfunction.