Reconstructing 120 years of climate change impacts on Joshua tree flowering.

Quantifying how global change impacts wild populations remains challenging, especially for species poorly represented by systematic datasets. Here, we infer climate change effects on masting by Joshua trees (Yucca brevifolia and Y. jaegeriana), keystone perennials of the Mojave Desert, from 15 years of crowdsourced observations. We annotated phenophase in 10,212 geo-referenced images of Joshua trees on the iNaturalist crowdsourcing platform, and used them to train machine learning models predicting flowering from annual weather records. Hindcasting to 1900 with a trained model successfully recovers flowering events in independent historical records and reveals a slightly rising frequency of conditions supporting flowering since the early 20th Century. This reflects increased variation in annual precipitation, which drives masting events in wet years-but also increasing temperatures and drought stress, which may have net negative impacts on recruitment. Our findings reaffirm the value of crowdsourcing for understanding climate change impacts on biodiversity.

Superior functional outcome following reverse shoulder arthroplasty compared to hemiarthroplasty for displaced three and four-part fractures in patients 65 and older: Results from a prospective multicentre randomised controlled trial - The Shoulder Hemiarthroplasty or Reverse Polarity Arthoplasty (SHeRPA) trial.

BACKGROUND: Acute unreconstructible 3- or 4-part proximal humerus fractures can be treated with hemiarthroplasty or reverse polarity shoulder arthroplasty. Randomized trials using implants from multiple different companies or uncemented implants have found superior results with reverse polarity arthroplasty. AIMS: This study aims to determine whether cemented reverse polarity arthroplasty produces a superior outcome compared to cemented hemiarthroplasty using one implant system in patients aged 65 years and over at 12 months follow-up as measured with the Constant score. METHODS: A prospective patient and assessor blinded multicenter randomized controlled trial was conducted of shoulder hemiarthroplasty or reverse polarity arthroplasty in patients aged 65 years and older with acute 3- and 4-part proximal humerus fracture not amenable to osteosynthesis. The primary outcome was the Constant score at 12 months with total follow-up to 24 months. Block randomization by site was undertaken using random number generation and sealed envelopes. Power analysis indicated that 17 patients were required in each arm to achieve 80% power with an alpha-value of 5%. Secondary outcome measures were the difference in the mean Constant Score, Quick Disabilities of the Arm Shoulder and Hand Questionnaire (QuickDASH), Oxford Shoulder Score (OSS), American Shoulder and Elbow Surgeons (ASES) Score and EQ5D-5L up to two years; differences in complication rate at one and two years; differences in revision and implant failure at one and two years. RESULTS: 18 patients were randomized to hemiarthroplasty and 18 to reverse polarity arthroplasty across 4 sites. The primary outcome as measured by the Constant score at 12 months was better in the reverse polarity shoulder arthroplasty (RSA) group (Mean 51.1, s.d. 14.9) compared to the hemiarthroplasty (HA) group (mean 35.0, s.d. 13.5) (p=0.004). No significant difference was reported at 24 months but this may be due to high rates of attrition (22%). The mean EQ-5D-5L patient rated health status score was significantly higher in the RSA group compared to the HA group at 12 months. One hemiarthroplasty was revised due to implant uncoupling and one reverse polarity shoulder replacement was revised due to instability. No other complications were recorded. DISCUSSION: Treatment of unreconstructible 3- or 4-part proximal humerus fractures with reverse polarity shoulder arthroplasty results in a superior outcome compared to shoulder hemiarthroplasty at 12 months measured with the Constant score with no increased risk of failure up to 24 months in patients age 65 years and over. High attrition rates are observed in this older population due to cognitive decline and death from other causes.

Selective Btk inhibition by PRN1008/PRN473 blocks human CLEC-2 & PRN473 reduces venous thrombosis formation in mice.

Platelet CLEC-2 is a hemITAM-containing receptor which has a critical role in venous thrombosis, but minimal involvement in haemostasis. CLEC-2 can be blocked by Btk inhibitors. Treatment with ibrutinib is associated with increased bleeding due to off-target inhibition of Src family kinases (SFKs). Patients with X-linked agammaglobulinemia (XLA) who lack Btk however do not bleed, suggesting selective Btk inhibition is a viable antithrombotic strategy. We assessed the effects of selective Btk inhibitors PRN1008 (rilzabrutinib) and PRN473 on platelet signalling and function mediated by CLEC-2 and GPVI. We used healthy donor and XLA platelets to determine off-target inhibitor effects. Inferior vena cava (IVC) stenosis and Salmonella infection mouse models were used to assess antithrombotic effects of PRN473 in vivo. PRN1008 and PRN473 potently inhibited CLEC-2-mediated platelet activation to rhodocytin. No off-target inhibition of SFKs was seen. PRN1008 treatment of Btk-deficient platelets resulted in minor additional inhibition of aggregation and tyrosine phosphorylation, likely reflecting inhibition of Tec. No effect on GPCR-mediated platelet function was observed. PRN473 significantly reduced the number of thrombi in podoplanin positive vessels following Salmonella infection and the presence of IVC thrombosis following vein stenosis. The potent inhibition of human platelet CLEC-2, and reduced thrombosis in in vivo models, together with the lack of off-target SFK inhibition and absence of bleeding reported in rilzabrutinib treated immune thrombocytopenia patients, suggest Btk inhibition as a promising antithrombotic strategy.

A morphometric comparison of the ductus reuniens in humans and guinea pigs, with a note on its evolutionary importance.

The mammalian inner ear contains the sensory organs responsible for balance (semicircular canals, utricle, and saccule) and hearing (cochlea). While these organs are functionally distinct, there exists a critical structural connection between the two: the ductus reuniens (DR). Despite its functional importance, comparative descriptions of DR morphology are limited, hindering our understanding of the evolutionary diversification of hearing and balance systems among mammals. Using virtual 3D models derived from micro-CT, we examine the morphology of the DR and its relationship to the bony labyrinth in humans compared to that in a commonly used animal model, the guinea pig. Anatomical reconstructions and univariate measurements were carried out in the software 3D Slicer. Data indicate similarities in DR morphology between humans and guinea pigs in terms of overall shape. However, there are considerable differences in relative DR length and width between humans and guinea pigs. Humans possess a relatively shorter and narrower DR but with wider openings to the saccule and cochlear duct. This results in a relatively more constricted DR lumen in humans which may differentially limit fluid transfer between the saccule and cochlea. Our results reveal previously hidden morphological diversity in the communication between the hearing and balance systems of the mammalian inner ear which may indicate alternative strategies for isolating the Organ of Corti from the peripheral vestibular system throughout mammalian evolution.

Educational and professional experiences of men in nursing: An interpretive description study to guide change and foster inclusive environments for men in nursing.

BACKGROUND: Nursing shortages are occurring due to decreased student enrollment, nurse burnout, staffing deficits, nurse retirements, and increasingly low numbers of nursing faculty. Men are an untapped resource that can offset these crises. However, men's presence in nursing remains underwhelming. Changes aimed at improving diversity and inclusivity related to men's presence is needed in the nursing workforce. PURPOSE: Explore men's experiences in modern nursing environments to identify barriers to men's presence in nursing faculty and clinical workforce roles. METHOD: This study used interpretive description design. Data were collected through individual and group interviews. Interviews were video recorded. Interview questions were semi-structured and open ended. Data were analyzed using thematic analysis. RESULTS: Two themes were identified and reflected men's experiences in nursing: educational and professional change. Subthemes for educational change included increasing numbers of men in student and faculty roles; instructional change; admission, retention, and advising. Subthemes for professional change included inclusive hiring practices; healthy working environments; and leadership outcomes. CONCLUSION: Findings constitute calls for action. Change implementation should address barriers to diversity and inclusivity related to men's presence in nursing. Recommendations and strategies presented can guide change implementation. Change implementation is expected to strengthen the nursing profession.

Zirconium Hydride Catalysis Initiated by Tetrabutylammonium Fluoride.

In our drug discovery campaigns to target the oncogenic drivers of cancers, the demand for a chemoselective, stereoselective and economical synthesis of chiral benzylamines drove the development of a catalytic zirconium hydride reduction. This methodology uses the inexpensive, bench stable zirconocene dichloride, and a novel tetrabutylammonium fluoride activation tactic to catalytically generate a metal hydride under ambient conditions. The diastereo- and chemoselectivity of this reaction was tested with the preparation of key intermediates from our discovery programs and in the scope of sulfinyl ketimines and carbonyls relevant to medicinal chemistry and natural product synthesis. A preliminary mechanistic investigation conducted into the role of tetrabutylammonium fluoride indicates that formation of a zirconocene fluoride occurs to initiate catalysis. The implications of this convenient activation approach may provide expanded roles for zirconium hydrides in catalytic transformations.

Complex Scalp Reconstruction with Super Thin DIEP Free Flap.

Scalp reconstruction provides a unique challenge to the reconstructive surgeon, especially in terms of matching skin color and contour. We present a case of a 67-year-old man with a chronic scalp wound requiring soft tissue coverage after major debridement and coverage of a skull defect. We chose to use a super thin deep inferior epigastric perforator (DIEP) flap to provide good skin coverage along with good contour to the scalp. The use of a super thin DIEP flap, dissected above the superficial fascial plane, is a newer technique in the realm of free tissue transfers that has shown improved outcomes in wound contour. Although the DIEP flap has been popularized for breast reconstruction, the authors believe that it has the ability to provide good soft tissue and skin coverage to other areas of the body, including in head and neck reconstruction.

The SOS1 Inhibitor MRTX0902 Blocks KRAS Activation and Demonstrates Antitumor Activity in Cancers Dependent on KRAS Nucleotide Loading.

KRAS is the most frequently mutated oncogene in human cancer and facilitates uncontrolled growth through hyperactivation of the receptor tyrosine kinase (RTK)/mitogen-activated protein kinase (MAPK) pathway. The Son of Sevenless homolog 1 (SOS1) protein functions as a guanine nucleotide exchange factor (GEF) for the RAS subfamily of small GTPases and represents a druggable target in the pathway. Using a structure-based drug discovery approach, MRTX0902 was identified as a selective and potent SOS1 inhibitor that disrupts the KRAS:SOS1 protein-protein interaction to prevent SOS1-mediated nucleotide exchange on KRAS and translates into an anti-proliferative effect in cancer cell lines with genetic alterations of the KRAS-MAPK pathway. MRTX0902 augmented the antitumor activity of the KRAS G12C inhibitor adagrasib when dosed in combination in eight out of 12 KRAS G12C-mutant human non-small cell lung cancer and colorectal cancer xenograft models. Pharmacogenomic profiling in preclinical models identified cell cycle genes and the SOS2 homolog as genetic co-dependencies and implicated tumor suppressor genes (NF1 and PTEN) in resistance following combination treatment. Lastly, combined vertical inhibition of RTK/MAPK pathway signaling by MRTX0902 with inhibitors of EGFR or RAF/MEK led to greater downregulation of pathway signaling and improved antitumor responses in KRAS-MAPK pathway-mutant models. These studies demonstrate the potential clinical application of dual inhibition of SOS1 and KRAS G12C and additional SOS1 combination strategies that will aide in the understanding of SOS1 and RTK/MAPK biology in targeted cancer therapy.

Multidisciplinary approach to patients with lymphatic conduction disorders.

Patients with lymphatic disorders are remarkably complex and require a wide variety of medical and surgical services. Establishing a multidisciplinary program improves the efficiency of the patients' hospital experience minimizing the compartmentalization of their care. Offering a clear intake process guarantees that patients will be seen promptly by all the required teams. Additionally, having regular multidisciplinary meetings allows all participating teams to learn from each other and gain experience in the care of a population that is extraordinarily heterogeneous. Additionally, establishing a solid program allows for long-term data collection, research and education.

State-of-the-art imaging for children with central lymphatic disorders.

Lymphatic imaging plays a crucial role in novel lymphatic interventions, offering valuable insights into central lymphatic drainage. Lymphatic system abnormalities may appear in various pediatric disorders, and accurate imaging is crucial for effective diagnosis and tailored therapeutic interventions. Traditional imaging modalities have offered valuable insights, but the demand for non-invasive, high-resolution techniques has fueled the development of innovative lymphatic imaging methods. In this review, we explore the state of the art in lymphatic imaging specifically within the context of pediatric surgery.

Lymphatic interventions in congenital heart disease.

Congenital heart disease affects 1/100 live births and is one of the most common congenital abnormalities. The relationship between congenital heart disease and lymphatic abnormalities and/or dysfunction is well documented and can be grossly divided into syndromic and non-syndromic etiologies. In patients with genetic syndromes (as examples listed above), there are known primary abnormal lymphatic development leading to a large pleiotropic manifestation of lymphatic dysfunction. Non-syndromic patients, or those without clear genetic etiologies for their lymphatic dysfunction, are often thought to be secondary to physiologic abnormalities as sequelae of congenital heart disease and palliative surgeries. Patients with congenital heart disease and lymphatic dysfunction have a wide variety of clinical manifestations for which there were not many therapeutic interventions available. The development of new imaging techniques allows us to understand better the pathophysiology of these problems and to develop different percutaneous interventions aiming to restore normal lymphatic function.

Percutaneous procedures for central lymphatic conduction disorders.

Percutaneous endovascular techniques established in interventional cardiology and radiology are well-suited for managing lymphatic conduction disorders. In this article, we provide a synopsis of technical aspects of these procedures, including access of the thoracic duct, selective lymphatic embolization, and management of thoracic duct obstruction. In aggregate, these techniques have developed into an integral component of multidisciplinary management of these complex diseases.

FIELD TECHNIQUES FOR VASECTOMY IN BLACK HOWLER MONKEYS (ALOUATTA PIGRA).

Three adult black howler monkeys (Alouatta pigra) were vasectomized for the purpose of population control. Two different surgical approaches (inguinal and pelvic) were used to vasectomize the animals under general anesthesia. One monkey was vasectomized with a pelvic approach, and the other two monkeys were vasectomized with an inguinal approach. The inguinal approach was minimally invasive and proved to be an effective field procedure, utilizing minimal surgical equipment with a mean operative time of 35 min. The inguinal approach allowed for better visualization of the spermatic cord, which prompted easier ligation and transection of the ductus deferens. Identification of the ductus deferens was successfully performed intraoperatively using a tuberculin syringe to aseptically aspirate cord contents, as histopathology was not available. All howler monkeys fully recovered without complication. The social hierarchy of the troop and mating behavior has not been affected. There have been no new pregnancies reported in the troop since the vasectomies were performed. The inguinal approach is preferred as it is minimally invasive and can be performed confidently in a field setting.

A secreted proteomic footprint for stem cell pluripotency.

With a view to developing a much-needed non-invasive method for monitoring the healthy pluripotent state of human stem cells in culture, we undertook proteomic analysis of the waste medium from cultured embryonic (Man-13) and induced (Rebl.PAT) human pluripotent stem cells (hPSCs). Cells were grown in E8 medium to maintain pluripotency, and then transferred to FGF2 and TGFß deficient E6 media for 48 hours to replicate an early, undirected dissolution of pluripotency. We identified a distinct proteomic footprint associated with early loss of pluripotency in both hPSC lines, and a strong correlation with changes in the transcriptome. We demonstrate that multiplexing of four E8- against four E6- enriched secretome biomarkers provides a robust, diagnostic metric for the pluripotent state. These biomarkers were further confirmed by Western blotting which demonstrated consistent correlation with the pluripotent state across cell lines, and in response to a recovery assay.

Defect-Free, Few-Atomic-Layer Thin ZnO Nanosheets with Superior Excitonic Properties for Optoelectronic Devices.

Two-dimensional (2D) wide bandgap materials are gaining significant interest for next-generation optoelectronic devices. However, fabricating electronic-grade 2D nanosheets from non-van der Waals (n-vdW) oxide semiconductors poses a great challenge due to their stronger interlayer coupling compared with vdW crystals. This strong coupling typically introduces defects during exfoliation, impairing the optoelectronic properties. Herein, we report the liquid-phase exfoliation of few-atomic-layer thin, defect-free, free-standing ZnO nanosheets. These micron-sized, ultrathin ZnO structures exhibit three different orientations aligned along both the polar c-plane as well as the nonpolar a- and m-planes. The superior crystalline quality of the ZnO nanosheets is validated through comprehensive characterization techniques. This result is supported by density functional theory (DFT) calculations, which reveals that the formation of oxygen vacancies is energetically less favorable in 2D ZnO and that the c-plane loses its polarity upon exfoliation. Unlike bulk ZnO, which is typically dominated by defect-induced emission, the exfoliated nanosheets exhibit a strong, ambient-stable excitonic UV emission. We further demonstrate the utility of solution processing of ZnO nanosheets by their hybrid integration with organic components to produce stable light emitting diodes (LEDs) for display applications.

Development of a Novel Web-Based Tool to Enhance Clinical Skills in Medical Education.

Unlabelled: A significant component of Canadian medical education is the development of clinical skills. The medical educational curriculum assesses these skills through an objective structured clinical examination (OSCE). This OSCE assesses skills imperative to good clinical practice, such as patient communication, clinical decision-making, and medical knowledge. Despite the widespread implementation of this examination across all academic settings, few preparatory resources exist that cater specifically to Canadian medical students. MonkeyJacket is a novel, open-access, web-based application, built with the goal of providing medical students with an accessible and representative tool for clinical skill development for the OSCE and clinical settings. This viewpoint paper presents the development of the MonkeyJacket application and its potential to assist medical students in preparation for clinical examinations and practical settings. Limited resources exist that are web-based; accessible in terms of cost; specific to the Medical Council of Canada (MCC); and, most importantly, scalable in nature. The goal of this research study was to thoroughly describe the potential utility of the application, particularly its capacity to provide practice and scalable formative feedback to medical students. MonkeyJacket was developed to provide Canadian medical students with the opportunity to practice their clinical examination skills and receive peer feedback by using a centralized platform. The OSCE cases included in the application were developed by using the MCC guidelines to ensure their applicability to a Canadian setting. There are currently 75 cases covering 5 specialties, including cardiology, respirology, gastroenterology, neurology, and psychiatry. The MonkeyJacket application is a web-based platform that allows medical students to practice clinical decision-making skills in real time with their peers through a synchronous platform. Through this application, students can practice patient interviewing, clinical reasoning, developing differential diagnoses, and formulating a management plan, and they can receive both qualitative feedback and quantitative feedback. Each clinical case is associated with an assessment checklist that is accessible to students after practice sessions are complete; the checklist promotes personal improvement through peer feedback. This tool provides students with relevant case stems, follow-up questions that probe for differential diagnoses and management plans, assessment checklists, and the ability to review the trend in their performance. The MonkeyJacket application provides medical students with a valuable tool that promotes clinical skill development for OSCEs and clinical settings. MonkeyJacket introduces a way for medical learners to receive feedback regarding patient interviewing and clinical reasoning skills that is both formative and scalable in nature, in addition to promoting interinstitutional learning. The widespread use of this application can increase the practice of and feedback on clinical skills among medical learners. This will not only benefit the learner; more importantly, it can provide downstream benefits for the most valuable stakeholder in medicine-the patient.

SafeVRwards: Designing a complementary virtual reality module to the Safewards framework intended to relax and manage conflict in mental health wards.

BACKGROUND: Aggression and negative activation in mental health inpatient units pose significant challenges for both patients and staff with severe physical and psychological ramifications. The Safewards model is an evidence-based conflict-containment framework including 10 strategies, such as 'Calm Down Methods'. As virtual reality (VR) scenarios have successfully enhanced anxiolytic and deactivating effects of therapeutic interventions, they are increasingly considered a means to enhance current models, like Safewards. OBJECTIVES: The present participatory design investigates the feasibility and user experience of integrating VR therapy as an add-on strategy to the Safewards model, gathering preliminary data and qualitative feedback from bedside staff in an adult inpatient mental health unit. METHODS: An exploratory within-subjects design combining qualitative observations, self-report questionnaires and semistructured interviews is employed with four nurse champions from the mental health unit at Michael Garron Hospital (Toronto, Canada). RESULTS: A chronological overview of the design process, adaptations and description of the user experience is reported. CONCLUSION: 'SafeVRwards' introduces VR as a promising conflic-containment strategy complementary to the Safewards model, which can be optimised for deployment through user-oriented refinements and enhanced customisation capacity driven by clinical staff input.

Preliminary report of a thoracic duct-to-pulmonary vein lymphovenous anastomosis in swine: A novel technique and potential treatment for lymphatic failure.

OBJECTIVE: The thoracic duct is the largest lymphatic vessel in the body, and carries fluid and nutrients absorbed in abdominal organs to the central venous circulation. Thoracic duct obstruction can cause significant failure of the lymphatic circulation (i.e., protein-losing enteropathy, plastic bronchitis, etc.). Surgical anastomosis between the thoracic duct and central venous circulation has been used to treat thoracic duct obstruction but cannot provide lymphatic decompression in patients with superior vena cava obstruction or chronically elevated central venous pressures (e.g., right heart failure, single ventricle physiology, etc.). Therefore, this preclinical feasibility study sought to develop a novel and optimal surgical technique for creating a thoracic duct-to-pulmonary vein lymphovenous anastomosis (LVA) in swine that could remain patent and preserve unidirectional lymphatic fluid flow into the systemic venous circulation to provide therapeutic decompression of the lymphatic circulation even at high central venous pressures. METHODS: A thoracic duct-to-pulmonary vein LVA was attempted in 10 piglets (median age 80 [IQR 80-83] days; weight 22.5 [IQR 21.4-26.8] kg). After a right thoracotomy, the thoracic duct was mobilized, transected, and anastomosed to the right inferior pulmonary vein. Animals were systemically anticoagulated on post-operative day 1. Lymphangiography was used to evaluate LVA patency up to post-operative day 7. RESULTS: A thoracic duct-to-pulmonary vein LVA was successfully completed in 8/10 (80.0%) piglets, of which 6/8 (75.0%) survived to the intended study endpoint without any complication (median 6 [IQR 4-7] days). Initially, 2/10 (20.0%) LVAs were aborted intraoperatively, and 2/10 (20.0%) animals were euthanized early due to post-operative complications. However, using an optimized surgical technique, the success rate for creating a thoracic duct-to-pulmonary vein LVA in six animals was 100%, all of which survived to their intended study endpoint without any complications (median 6 [IQR 4-7] days). LVAs remained patent for up to seven days. CONCLUSION: A thoracic duct-to-pulmonary vein LVA can be completed safely and remain patent for at least one week with systemic anticoagulation, which provides an important proof-of-concept that this novel intervention could effectively offload the lymphatic circulation in patients with lymphatic failure and elevated central venous pressures.

Adults with paternal UPD14 causing Kagami-Ogata syndrome: Case report and review of the literature.

Kagami-Ogata syndrome (KOS) is a clinically recognizable syndrome in the neonatal period. It is characterized by specific skeletal anomalies and facial dysmorphisms. It is typically caused by paternal uniparental disomy of chromosome 14, while epimutations and microdeletions are less commonly reported causes. In the pediatric setting, KOS is a well delineated syndrome. However, there is a dearth of literature describing the natural history of the condition in adults. Herein, we describe a 35-year-old man, the first adult with KOS reported due to paternal uniparental disomy 14, and review reports of KOS in other affected adults. This highlights the variability in neurocognitive phenotypes, the presence of connective tissue abnormalities, and the uncertainties around long-term cancer risk.

Pharmacokinetics of oral clonazepam in growing commercial pigs (Sus scrofa domestica).

Clonazepam causes sedation and psychomotor impairment in people. Due to similarities between people and swine in response to benzodiazepines, clonazepam may represent a viable option to produce mild-to-moderate tranquillization in pigs. The objective of this study was to determine the pharmacokinetic profile of a single oral dose (0.5 mg/kg) of clonazepam in eight healthy, growing commercial cross pigs. Serial plasma samples were collected at baseline and up to 96 h after administration. Plasma concentrations were quantified using reverse-phase high-performance liquid chromatography, and compartment models were fit to time-concentration data. A one-compartment first-order model best fits the data. Maximum plasma concentration was 99.5 ng/mL, and time to maximum concentration was 3.4 h. Elimination half-life was 7.3 h, mean residence time 7.4 h, and apparent volume of distribution 5.7 L/kg. Achieved plasma concentrations exceeded those associated with psychomotor impairment in people although pharmacodynamic effects have not been investigated in pigs. A simulated oral regimen consisting of 0.35 mg/kg administered every 8 h to pigs would achieve plasma concentrations above 32 ng/mL which are shown to produce psychomotor impairment in people. Further studies to test the clinical efficacy of these dosages in commercial and miniature pigs are warranted.