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The Kwajalein micrometeorite collection utilized high volume air samplers fitted with polycarbonate membrane filters to capture particles directly from the atmosphere at the Earth's surface. This initial study focused on identifying cosmic spherule‐like particles, conservatively categorizing them into four groups based on bulk compositional data: Group I exhibit a range of compositions designated terrestrial in origin; group II are Fe‐rich and contain only additional O, S, and/or Ni; group III are silicate spherules with Mg‐to‐Si At% ratios less than 0.4; group IV are silicate spherules with Mg‐to‐Si At% ratios greater than 0.4. Spherules in groups I, II, and III have compositions that are also consistent with particles that are produced in great numbers by natural and/or anthropogenic terrestrial activities (e.g., volcanic microspherules, fly ash from coal fired power plants, etc.) and thus are assumed terrestrial in origin. Group IV spherules exhibit compositions closest to those of cosmic spherules identified in other collections and are, therefore, designated cosmic spherule candidates. Detailed analysis of seven group IV spherules found that whilst five exhibited morphology and compositions consistent with S‐type cosmic spherules, two appear unique to this collection and could not be matched to either terrestrial or extraterrestrial spherules studied to date. [ABSTRACT FROM AUTHOR]

Objective: The Medicare Benefit Schedule (MBS) telehealth items were expanded in March 2020 during the COVID-19 pandemic. We measured the use of MBS telepsychiatry items compared to consultant physician telehealth items within the context of these item changes, to understand differences in telepsychiatry and physician telehealth utilisation. Methods: Monthly counts of face-to-face and telehealth (videoconferencing and telephone) MBS items for psychiatrists and physicians from January 2017 to December 2022 were compiled from Services Australia MBS Item Reports. Usage levels were compared before and after telehealth item expansion. Usage trends for MBS telepsychiatry and physician telehealth items were compared in time-series plots. Results: Telehealth item expansion resulted in a greater rise of telepsychiatry services from 3.8% beforehand to 43.8% of total services subsequently, compared with physician telehealth services (from 0.6% to 20.0%). More physician telehealth services were by telephone compared with telepsychiatry services. Time-series of both telehealth services displayed similar patterns until mid-2022, when physician telehealth services declined as telephone items were restricted. Telepsychiatry services consistently comprised a greater proportion of total services than physician telehealth services. Conclusions: MBS psychiatrist services showed a more substantial and persistent shift to telehealth than physician services, suggesting a greater preference and use of telepsychiatry. [ABSTRACT FROM AUTHOR]

A one-step, on-tissue chemical derivatisation method for MALDI mass spectrometry imaging was found to improve the detectability of aldehydes and ketones by charge-tagging. The developed reactive matrices, containing a UV-chromophore, ionisable moiety and hydrazide group, showed an equal or higher detection efficiency than Girard's reagent P, enabling improved imaging of brain metabolites without the need for additional co-matrices. [ABSTRACT FROM AUTHOR]

Postgraduate medical education (PGME) is an essential part of medical education and increasingly shifts into focus of educational stakeholders. Structured postgraduate medical training programs are required in the U.S. through the "American Council for Graduate Medical Education" (ACGME) guidelines with their six core competencies as common program requirements. The basis for this development was provided in Germany with the implementation of the "Standard Framework for Postgraduate Medical Training" (Musterweiterbildungsordnung) issued by the German Medical Association (Bundesärztekammer). However, implementation has been gradual and program development is often conducted in a time consuming, lengthy and top-down approach without that trainee experiences or needs are being assessed or evaluated for their impact on successful medical training. We demonstrate how application of agile working can enable rapid and efficient creation and implementation of a novel postgraduate training program. The postgraduate training program ped.tracks aims to achieve a high-quality, structured and reliable postgraduate training. Moreover, it provides the opportunity to select a priority on scientific or clinical education. The entire process from the first draft to full release of the program was completed within 8 months through agile working. Our team worked using agile working techniques, creating a trainee- customized and -centred program. We anticipate that the quantity of structured postgraduate training programs will significantly increase in Germany and Europe to improve training quality and employee satisfaction. Therefore, the use of agile methods for the creation and implementation of structured training programs represents a useful approach to support program directors rapidly and effectively in this effort. [ABSTRACT FROM AUTHOR]

Obesity is a multifactorial metabolic disorder associated with endothelial dysfunction and increased risk of cardiovascular disease. Adipose capillary adipose endothelial cells (CaECs) plays a crucial role in lipid transport and storage. Here, we investigated the mechanisms underlying CaEC-adipocyte interaction and its impact on metabolic function. Single-cell RNA sequencing (scRNAseq) revealed an enrichment of fatty acid handling machinery in CaECs from high fat diet (HFD) mice, suggesting their specialized role in lipid metabolism. Transmission electron microscopy (TEM) confirmed direct heterocellular contact between CaECs and adipocytes. To model this, we created an in vitro co-culture transwell system to model the heterocellular contact observed with TEM. Contact between ECs and adipocytes in vitro led to upregulation of fatty acid binding protein 4 in response to lipid stimulation, hinting intercellular signaling may be important between ECs and adipocytes. We mined our and others scRNAseq datasets to examine which connexins may be present in adipose capillaries and adipocytes and consistently identified connexin 43 (Cx43) in mouse and humans. Genetic deletion of endothelial Cx43 resulted in increased epididymal fat pad (eWAT) adiposity and dyslipidemia in HFD mice. Consistent with this observation, phosphorylation of Cx43 at serine 368, which closes gap junctions, was increased in HFD mice and lipid-treated ECs. Mice resistant to this post-translational modification, Cx43S368A, were placed on an HFD and were found to have reduced eWAT adiposity and improved lipid profiles. These findings suggest Cx43-mediated heterocellular communication as a possible regulatory mechanism of adipose tissue function. Graphical Abstract [ABSTRACT FROM AUTHOR]

Aim: We aimed to test the hypothesis that a high‐salt diet (HS) impairs NO signaling in kidney microvascular endothelial cells through a histone deacetylase 1 (HDAC1)‐dependent mechanism. Methods: Male Sprague Dawley rats were fed normal salt diet (NS; 0.49% NaCl) or HS (4% NaCl) for 2 weeks. NO signaling was assessed by measuring L‐NAME induced vasoconstriction of the afferent arteriole using the blood perfused juxtamedullary nephron (JMN) preparation. In this preparation, kidneys were perfused with blood from a donor rat on a matching or different diet to that of the kidney donor. Kidney endothelial cells were isolated with magnetic activated cell sorting and HDAC1 activity was measured. Results: We found HS‐induced impaired NO signaling in the afferent arteriole. This was restored by inhibition of HDAC1 with MS‐275. Consistent with these findings, HDAC1 activity was increased in kidney endothelial cells. We further found the loss of NO to be dependent upon the diet of the blood donor rather than the diet of the kidney donor and the plasma from HS‐fed rats to be sufficient to induce impaired NO signaling. This indicates the presence of a humoral factor we termed plasma‐derived endothelial dysfunction mediator (PDEM). Pretreatment with the antioxidants, PEG‐SOD and PEG‐catalase, as well as the NOS cofactor, tetrahydrobiopterin, restored NO signaling. Conclusion: We conclude that HS activates endothelial HDAC1 through PDEM leading to decreased NO signaling. This study provides novel insights into the molecular mechanisms by which a HS decreases renal microvascular endothelial NO signaling. [ABSTRACT FROM AUTHOR]

In the vasculature, nitric oxide (NO) is produced in the endothelium by endothelial nitric oxide synthase (eNOS) and is critical for the regulation of blood flow and blood pressure. Blood flow may also be regulated by the formation of nitrite-derived NO catalyzed by hemoproteins under hypoxic conditions. We sought to investigate whether nitrite administration may affect tissue perfusion and systemic hemodynamics in WT and eNOS knockout mice. We found that global eNOS KO mice show decreased tissue perfusion compared to WT mice by using laser speckle contrast imaging. To study both the acute and long-term effects of sodium nitrite (0, 0.1, 1, and 10 mg/kg) on peripheral blood flow and systemic blood pressure, a bolus of nitrite was delivered intraperitoneally every 24 h over 4 consecutive days. We found that nitrite administration resulted in a dose-dependent and acute increase in peripheral blood flow in eNOS KO mice but had no effects in WT mice. The nitrite induced changes in tissue perfusion were transient, as determined by intraindividual comparisons of tissue perfusion 24-h after injection. Accordingly, 10 mg/kg sodium nitrite acutely decreased blood pressure in eNOS KO mice but not in WT mice as determined by invasive Millar catheterization. Interestingly, we found the vasodilatory effects of nitrite to be inversely correlated to baseline tissue perfusion. These results demonstrate the nitrite acutely recovers hypoperfusion and hypertension in global eNOS KO mice and suggest the vasodilatory actions of nitrite are dependent upon tissue hypoperfusion. • ENOS KO mice to have reduced tissue perfusion. • Sodium nitrite rescues tissue hypoperfusion and hypertension in eNOS KO. • Sodium nitrite has no impact on tissue perfusion or blood pressure in WT mice. • The vasodilatory actions of nitrite correlate with baseline tissue perfusion. [ABSTRACT FROM AUTHOR]

As a result of the powerful sanctions built into the Luke S. consent decree, the State of Louisiana successfully implemented radically different assessment practices which mandated prereferral intervention, curriculum-based assessment, state-wide in-service training for assessment personnel, and direct classroom intervention on the part of assessment personnel. With these new practices in effect, long "waiting lists" for evaluation were eliminated, assessment personnel are able to more accurately and efficiently evaluate suspected handicapped children, and pupil appraisal "support services" are offered to nonhandicapped children experiencing learning or behavior problems in the classroom. [ABSTRACT FROM AUTHOR]

Objective: Telepsychiatry items in the Australian Medicare Benefits Schedule (MBS) were expanded following the COVID-19 pandemic. However, their out-of-pocket costs have not been examined. We describe and compare patient out-of-pocket payments for face-to-face and telepsychiatry (videoconferencing and telephone) MBS items for outpatient psychiatric services to understand the differential out-of-pocket cost burden for patients across these modalities. Methods: out-of-pocket cost information was obtained from the Medical Costs Finder website, which extracted data from Services Australia's Medicare claims data in 2021–2022. Cost information for corresponding face-to-face, video, and telephone MBS items for outpatient psychiatric services was compared, including (1) Median specialist fees; (2) Median out-of-pocket payments; (3) Medicare reimbursement amounts; and (4) Proportions of patients subject to out-of-pocket fees. Results: Medicare reimbursements are identical for all comparable face-to-face and telepsychiatry items. Specialist fees for comparable items varied across face-to-face to telehealth options, with resulting differences in out-of-pocket costs. For video items, higher proportions of patients were not bulk-billed, with greater out-of-pocket costs than face-to-face items. However, the opposite was true for telephone items compared with face-to-face items. Conclusions: Initial cost analyses of MBS telepsychiatry items indicate that telephone consultations incur the lowest out-of-pocket costs, followed by face-to-face and video consultations. [ABSTRACT FROM AUTHOR]

Simple Summary: Non-melanomatous cutaneous spindle cell neoplasms comprise a rare group of tumours, and in the advanced disease setting, a consensus on treatment approaches is lacking. These tumours are more common with age and have a propensity to develop in chronic ultraviolet (UV)-exposed sites. High response rates have been seen with immune-checkpoint inhibitors (ICI) in other UV-driven tumours such as cutaneous squamous cell carcinoma, yet these tumours have historically been excluded from the key clinical trials of immunotherapy. Patients with advanced non-melanomatous cutaneous spindle cell neoplasms have traditionally been offered chemotherapy for which response rates are variable and short-lived. Due to the impressive and durable response rates seen in our cohort of patients, clinicians should consider the use of ICIs in this heterogenous group of tumours. UV signatures and tumour mutational burden, if available, could serve as important biomarkers in the selection of patients for treatment with ICIs. Non-melanomatous cutaneous spindle cell neoplasms are a rare group of malignancies that present a diagnostic challenge, and for which there is a lack of consensus on how to best manage patients with advanced disease and only limited reports of immune-checkpoint inhibitor (ICI) responses. In this study, we performed a single-center retrospective review of treatment outcomes for all advanced non-melanomatous cutaneous spindle cell neoplasms treated with ICIs. Blinded histopathology reviews occurred to confirm each diagnosis. Comprehensive tumour profiling included whole exome sequencing for tumour mutational burden (TMB) and ultraviolet(UV) signatures, and immunohistochemistry for immune-cell infiltration (CD4/CD3/CD8/CD103/CD20) and immune-checkpoint expression (PD-L1/LAG3/TIGIT). Seven patients were identified. The objective response rate was 86% (6/7) with five complete responses (CR). Responses were durable with two patients in CR > 30 months after ICI commencement. All patients had high TMB and UV signatures. One patient had PD-L1 100% (combined positive score) with abundant immune-cell infiltration and LAG3 expression. In advanced non-melanomatous cutaneous spindle cell neoplasms, excellent responses to ICIs with durable disease control were observed. ICIs are worthy of further exploration in these patients. UV signatures and high TMB could be used to help select patients for treatment. [ABSTRACT FROM AUTHOR]

This paper demonstrates an optical technique to measure magnetostrictive strain in a cryogenic environment using a Fabry–Pérot resonator spaced by crystal samples. Optical measurement techniques are calibration-free and highly sensitive. This technique was used to measure the magnetostrictive strain of neodymium gallate at a temperature of 49 mK to be λ = 1.3 × 10−5 at 3 T, with a sensitivity of 3.0 × 10−8. We highlight the interesting properties of the crystal's magnetic ordering. The sensitivity of this technique was limited by the wavemeter used to measure the laser frequency, and significant improvements in the sensitivity should be possible. [ABSTRACT FROM AUTHOR]

Heme is an iron-containing prosthetic group necessary for the function of several proteins termed "hemoproteins." Erythrocytes contain most of the body's heme in the form of hemoglobin and contain high concentrations of free heme. In nonerythroid cells, where cytosolic heme concentrations are 2 to 3 orders of magnitude lower, heme plays an essential and often overlooked role in a variety of cellular processes. Indeed, hemoproteins are found in almost every subcellular compartment and are integral in cellular operations such as oxidative phosphorylation, amino acid metabolism, xenobiotic metabolism, and transcriptional regulation. Growing evidence reveals the participation of heme in dynamic processes such as circadian rhythms, NO signaling, and the modulation of enzyme activity. This dynamic view of heme biology uncovers exciting possibilities as to how hemoproteins may participate in a range of physiologic systems. Here, we discuss how heme is regulated at the level of its synthesis, availability, redox state, transport, and degradation and highlight the implications for cellular function and whole organism physiology. [ABSTRACT FROM AUTHOR]

Background: Older patients are often underrepresented in clinical trials owing to exclusionary comorbidities, which are more common with age. Chemotherapy is poorly tolerated in older comorbid advanced cutaneous squamous cell carcinoma (CSCC) patients; however, little is known on the efficacy and tolerability of immune-checkpoint inhibitors (ICIs) in this population. To our knowledge, this is the largest dedicated report on a cohort of older patients with advanced CSCC treated with immunotherapy to date. Objective: The aim was to report outcomes of ICI use in a real-world older cohort with advanced CSCC. Patients and Methods: A single-centre retrospective audit of all patients treated via an access scheme providing ICIs to patients with advanced CSCC was conducted. Participants were ≥ 70 years of age and had advanced CSCC not amenable to curative surgery or radiotherapy. Best overall response rate (ORR), 12-month overall survival (OS) and progression-free survival (PFS), and toxicity rates were assessed. Results: A total of 53 patients were analysed. The median age was 81.8 years (range 70.1–96.8); 81% were male; 34% were immunocompromised; and 34% had an Eastern Cooperative Oncology Group (ECOG) performance status score of ≥ 2. The ORR was 57%, and 12-month OS and PFS were 63% (95% confidence interval [CI] 44–78) and 41% (95% CI 25–57), respectively. Thirty-two per cent developed an immune-related adverse event (irAE), but only two patients experienced a grade 3 irAE, with no treatment-related deaths. Higher ECOG score was associated with worse OS and PFS. No significant association was identified for increasing age, sex, Charlson Comorbidity Index score, or immunocompromised status. Conclusions: ICIs have demonstrated efficacy and have an acceptable safety profile among older patients with advanced CSCC, with comparable efficacy to what has been demonstrated in current clinical trials. [ABSTRACT FROM AUTHOR]

Endothelial cells (ECs) adapt to the unique needs of their resident tissue and metabolic perturbations, such as obesity. We sought to understand how obesity affects EC metabolic phenotypes, specifically mitochondrial gene expression. We investigated the mesenteric and adipose endothelium because these vascular beds have distinct roles in lipid homeostasis. Initially, we performed bulk RNA sequencing on ECs from mouse adipose and mesenteric vasculatures after a normal chow (NC) diet or high-fat diet (HFD) and found higher mitochondrial gene expression in adipose ECs compared with mesenteric ECs in both NC and HFD mice. Next, we performed single-cell RNA sequencing and categorized ECs as arterial, capillary, venous, or lymphatic. We found mitochondrial genes to be enriched in adipose compared with mesentery under NC conditions in artery and capillary ECs. After HFD, these genes were decreased in adipose ECs, becoming like mesenteric ECs. Transcription factor analysis revealed that peroxisome proliferator-activated receptor-c (PPAR-c) had high specificity in NC adipose artery and capillary ECs. These findings were recapitulated in single-nuclei RNA-sequencing data from human visceral adipose. The sum of these findings suggests that mesenteric and adipose arterial ECs metabolize lipids differently, and the transcriptional phenotype of the vascular beds converges in obesity due to downregulation of PPAR-c in adipose artery and capillary ECs. NEW & NOTEWORTHY Using bulk and single-cell RNA sequencing on endothelial cells from adipose and mesentery, we found that an obesogenic diet induces a reduction in adipose endothelial oxidative phosphorylation gene expression, resulting in a phenotypic convergence of mesenteric and adipose endothelial cells. Furthermore, we found evidence that PPAR-c drives this phenotypic shift. Mining of human data sets segregated based on body mass index supported these findings. These data point to novel mechanisms by which obesity induces endothelial dysfunction. [ABSTRACT FROM AUTHOR]

Fenced sanctuaries that exclude feral predators are critical for threatened species conservation. However, adaptive management of these sanctuaries requires careful consideration of the potential impact herbivore populations free from predation can have on the condition of native vegetation. The Mulligans Flat Woodland Sanctuary in the Australian Capital Territory comprises Critically Endangered box-gum grassy woodland, threatened orchids, abundant macropods, and a reintroduced population of the Eastern Bettong (Bettongia gaimardi, hereafter “Ngaluda”). To understand how Ngaluda, along with other herbivores, may be potentially impacting vegetation across the sanctuary, we undertook an assessment of indicator plant species. We monitored 106 plots for 13 indicator species (10 species with tuberous roots that the burrowing Ngaluda would be preferentially targeting and three non-tuberous species). We found that most floristic indicators we investigated – including richness of indicator species and the abundance of lilies – were higher in the Goorooyarroo area of the sanctuary (where Ngaluda are absent and wallabies are rare) compared to the Mulligans Flat area of the sanctuary (where Ngaluda are present and wallabies are abundant), suggesting a negative impact of the overall herbivore assemblage of Mulligans Flat. However, within just Mulligans Flat, some indicators, including the abundance of a common orchid, were significantly lower in areas associated with high Ngaluda activity irrespective of other herbivore densities. We found no instance of Ngaluda presence or higher activity being associated with higher values for any floristic indicator we investigated. These results are consistent with known impacts of abundant herbivores and reintroduced digging marsupials in other predator-free sanctuaries in Australia. Our results highlight that Ngaluda herbivory may be outweighing any positive effect of their diggings on native vegetation and indicate the need for careful risk mitigation when deciding how critically endangered animals and vegetation communities are managed together in sanctuaries. [ABSTRACT FROM AUTHOR]

Endothelial cells (ECs) adapt to the unique needs of their resident tissue and metabolic perturbations, such as obesity. We sought to understand how obesity affects EC metabolic phenotypes, specifically mitochondrial gene expression. We investigated the mesenteric and adipose endothelium because these vascular beds have distinct roles in lipid homeostasis. Initially, we performed bulk RNA sequencing on ECs from mouse adipose and mesenteric vasculatures after a normal chow (NC) diet or high-fat diet (HFD) and found higher mitochondrial gene expression in adipose ECs compared with mesenteric ECs in both NC and HFD mice. Next, we performed single-cell RNA sequencing and categorized ECs as arterial, capillary, venous, or lymphatic. We found mitochondrial genes to be enriched in adipose compared with mesentery under NC conditions in artery and capillary ECs. After HFD, these genes were decreased in adipose ECs, becoming like mesenteric ECs. Transcription factor analysis revealed that peroxisome proliferator-activated receptor-c (PPAR-c) had high specificity in NC adipose artery and capillary ECs. These findings were recapitulated in single-nuclei RNA-sequencing data from human visceral adipose. The sum of these findings suggests that mesenteric and adipose arterial ECs metabolize lipids differently, and the transcriptional phenotype of the vascular beds converges in obesity due to downregulation of PPAR-c in adipose artery and capillary ECs. NEW & NOTEWORTHY Using bulk and single-cell RNA sequencing on endothelial cells from adipose and mesentery, we found that an obesogenic diet induces a reduction in adipose endothelial oxidative phosphorylation gene expression, resulting in a phenotypic convergence of mesenteric and adipose endothelial cells. Furthermore, we found evidence that PPAR-c drives this phenotypic shift. Mining of human data sets segregated based on body mass index supported these findings. These data point to novel mechanisms by which obesity induces endothelial dysfunction. [ABSTRACT FROM AUTHOR]

Diazomethane is a powerful reagent for numerous chemical reactions such as esterifications and the homologation of carboxylic acids. Unfortunately, the synthetic utility of diazomethane is severely limited by its toxicity and highly explosive nature. Diazald® is typically used for ex situ synthesis, however it requires cumbersome and hazardous transfer of diazomethane from a caustic aqueous phase to the reaction medium. Herein, we present a low temperature and base‐free in situ synthesis of diazomethane via a "click and release" reaction between an enamine and sulfonyl azide. Its utility is exemplified by the synthesis of diverse methyl esters in yields of up to 93%. Moreover, diazoketone synthesis from in situ generated diazomethane and acid chlorides was demonstrated for the first time. Finally, trideuteromethylation was achieved using acetone‐d6 as the deuterium source. We anticipate that this method will enable the safer use of diazomethane in organic synthesis and drug discovery programs. [ABSTRACT FROM AUTHOR]

Despite technological advancements in infectious disease rapid diagnostic tests (RDTs) and use to direct therapy at the per-patient level, RDT utilisation in antimicrobial stewardship programmes (ASPs) is variable across low-to-middle income and high-income countries. Key insights from a panel of seven infectious disease experts from Colombia, Japan, Nigeria, Thailand, the UK, and the USA, combined with evidence from a literature review, were used to assess the value of RDTs in ASPs. From this, a value framework is proposed which aims to define the benefits of RDT use in ASPs, separate from per-patient benefits. Expert insights highlight that, to realise the value of RDTs within ASPs, effective implementation is key; actionable advice for choosing an RDT is proposed. Experts advocate the inclusion of RDTs in the World Health Organization Model List of essential in vitro diagnostics and in iterative development of national action plans. [ABSTRACT FROM AUTHOR]

The visualization of small metabolites by MALDI mass spectrometry imaging in brain tissue sections is challenging due to low detection sensitivity and high background interference. We present an on-tissue chemical derivatization MALDI mass spectrometry imaging approach for the comprehensive mapping of carboxyls and aldehydes in brain tissue sections. In this approach, the AMPP (1-(4-(aminomethyl)-phenyl)-pyridin-1-ium chloride) derivatization reagent is used for the covalent charge-tagging of molecules containing carboxylic acid (in the presence of peptide coupling reagents) and aldehydes. This includes free fatty acids and the associated metabolites, fatty aldehydes, dipeptides, neurotoxic reactive aldehydes, amino acids, neurotransmitters and associated metabolites, as well as tricarboxylic acid cycle metabolites. We performed sensitive ultrahigh mass resolution MALDI-MS detection and imaging of various carboxyl- and aldehyde-containing endogenous metabolites simultaneously in rodent brain tissue sections. We verified the AMPP-derivatized metabolites by tandem MS for structural elucidation. This approach allowed us to image numerous aldehydes and carboxyls, including certain metabolites which had been undetectable in brain tissue sections. We also demonstrated the application of on-tissue derivatization to carboxyls and aldehydes in coronal brain tissue sections of a nonhuman primate Parkinson's disease model. Our methodology provides a powerful tool for the sensitive, simultaneous spatial molecular imaging of numerous aldehydes and carboxylic acids during pathological states, including neurodegeneration, in brain tissue. [ABSTRACT FROM AUTHOR]

Microresonator based dual frequency combs offer an integrated photonic solution to a wide range of technological challenges, including spectroscopy, range finding, material characterization and hyperspectral imaging. These applications require a high level of mutual coherence between combs, but achieving such stability can be demanding. Here we experimentally demonstrate that comb generation exploiting the rich structure of the nonlinear electro-optic tensor in lithium niobate can generate ultra-stable dual combs, with the two combs naturally having orthogonal polarizations. We theoretically explore the application of our technique to dual frequency comb generation from the far infrared (IR) to the ultraviolet (UV). Our combs have relative linewidths as low as ~400 μHz, and require no stabilization or post-processing methods. Dual frequency combs are a powerful tool for a range of optical measurements and technologies. The authors here generate orthogonally polarized dual combs with exceptionally high relative stability. [ABSTRACT FROM AUTHOR]

Reduced daily life physical activity (DLPA) in pulmonary arterial hypertension (PAH) contributes to a poor quality of life. Can actigraphy be used to assess changes in DLPA in patients with PAH receiving selexipag or placebo? Effect of Selexipag on Daily Life Physical Activity of Patients With Pulmonary Arterial Hypertension (TRACE) was a prospective, multicenter, randomized, placebo-controlled, double-blind, exploratory phase 4 study enrolling patients with PAH in World Health Organization functional class II/III, receiving stable endothelin receptor antagonist with/without phosphodiesterase type 5 inhibitor background therapy. Primary end points were change from baseline to Week 24 in actigraphy-assessed DLPA (recorded by using an accelerometer), including daily time spent in nonsedentary physical activity (NSPA), daily time spent in moderate to vigorous physical activity (MVPA), daily volume of activity, and daily number of steps. At baseline, patients (N = 108) were prevalent, on stable background PAH therapy, and at low risk of disease progression. Patients showed high compliance with wear of the accelerometer throughout the study. From baseline to Week 24, mean daily time spent in NSPA increased by 1.1 min and decreased by 16.7 min in the selexipag and placebo groups (treatment difference [95% CI], 17.8 [–6.0, 41.6] min); mean time spent in MVPA increased by 0.3 min and was reduced by 2.0 min in the selexipag and placebo groups (treatment difference [95% CI], 2.3 [–10.8, 15.4] min); and mean number of daily steps decreased by 0.3 and 201.9 in the selexipag and placebo groups (treatment difference [95% CI], 201.6 [–243.0, 646.2]). TRACE enrolled a prevalent population on background therapy and at low risk of disease progression. Changes in DLPA were small and highly variable, with no statistically significant differences between treatment groups. This patient-centric study was the first randomized trial in PAH to capture high-quality actigraphy data and to describe DLPA in terms of mean/median and variability, which may inform the design of future studies. ClinicalTrials.gov; No.: NCT03078907; URL: www.clinicaltrials.gov [ABSTRACT FROM AUTHOR]

Lumateperone is indicated for the treatment of schizophrenia in adults and for depressive episodes associated with bipolar I or II disorder (bipolar depression) in adults, as monotherapy and as adjunctive therapy with lithium or valproate (Calabrese et al., 2021). It is currently under evaluation for the treatment of major depressive disorder (www.ClinicalTrials.gov). Lumateperone acts by selectively modulating serotonin, dopamine, and glutamate neurotransmission in the brain. However, other mechanisms could be involved in the actions of lumateperone, and because of the connection between the immune system and psychiatric health, we hypothesized that lumateperone might improve symptoms of depression, at least in part, by normalizing pathologic inflammation. Here, we show that in male and female C57BL/6 mice subjected to an acute immune challenge, lumateperone reduced aberrantly elevated levels of key proinflammatory cytokines (e.g., IL-1β, IL-6, and TNF-α) in both brain and serum; lumateperone also reduced proinflammatory cytokines in male mice under acute behavioral stress. Further, we demonstrate that lumateperone altered key genes/pathways involved in maintaining tissue integrity and supporting blood-brain barrier function, such as claudin-5 and intercellular adhesion molecule 1. In addition, in acutely stressed male Sprague Dawley rats, lumateperone conferred anxiolytic- and antianhedonic-like properties while enhancing activity in the mammalian target of rapamycin complex 1 pathway in the PFC. Together, our preclinical findings indicate that lumateperone, in addition to its ability to modulate multiple neurotransmitter systems, could also act by reducing the impact of acute inflammatory challenges. [ABSTRACT FROM AUTHOR]

We previously reported that nonobese diabetic (NOD) congenic mice (NOD.c3c4 mice) developed an autoimmune biliary disease (ABD) with similarities to human primary biliary cholangitis (PBC), including anti-mitochondrial antibodies and organ-specific biliary lymphocytic infiltrates. We narrowed the possible contributory regions in a novel NOD.Abd3 congenic mouse to a B10 congenic region on chromosome 1 ("Abd3") and a mutated Pkhd1 gene (Pkhd1del36−67) upstream from Abd3, and we showed via backcrossing studies that the NOD genetic background was necessary for disease. Here, we show that NOD.Abd3 mice develop anti-PDC-E2 autoantibodies at high levels, and that placing the chromosome 1 interval onto a scid background eliminates disease, demonstrating the critical role of the adaptive immune system in pathogenesis. While the NOD genetic background is essential for disease, it was still unclear which of the two regions in the Abd3 locus were necessary and sufficient for disease. Here, using a classic recombinant breeding approach, we prove that the mutated Pkhd1del36−67 alone, on the NOD background, causes ABD. Further characterization of the mutant sequence demonstrated that the Pkhd1 gene is disrupted by an ETnII-beta retrotransposon inserted in intron 35 in an anti-sense orientation. Homozygous Pkhd1 mutations significantly affect viability, with the offspring skewed away from a Mendelian distribution towards NOD Pkhd1 homozygous or heterozygous genotypes. Cell-specific abnormalities, on a susceptible genetic background, can therefore induce an organ-specific autoimmunity directed to the affected cells. Future work will aim to characterize how mutant Pkhd1 can cause such an autoimmune response. [ABSTRACT FROM AUTHOR]

In the context of continental extension, transient compressional episodes (stress inversion) and phases of uplift (depth inversion) are commonly recorded with no corresponding change in plate motion. Changes in gravitational potential energy during the rifting process have been invoked as a possible source of compressional stresses, but their magnitude, timing, and relationship with depth inversions remain unclear. Using high-resolution two-dimensional numerical experiments of the full rifting process, we track the dynamic interplay between the far-field tectonic forces, loading and unloading of the surface via surface processes, and gravitational body forces. Our results show that rift basins tend to localize compressive stresses; they record transient phases of compressional stresses as high as 30 MPa and experience a profound depth inversion, 2 km in magnitude, when sediment supply ceases, providing an additional driver for the breakup unconformity, a well-documented phase of regional uplift typically associated with continental breakup. [ABSTRACT FROM AUTHOR]

• Question: Are the readability levels for COVID-19 vaccine-related fact sheets and informational materials appropriate for the general U.S. population? • Findings: This study, which analyzed fact sheets for three of the major U.S. vaccine manufacturers and other informational material, found that most of the COVID-19 vaccine-related informational materials did not meet appropriate readability levels for the U.S. population. • Meaning: Informational materials should be written at a 7th-grade reading level for the general population to fully comprehend them. More than 130 million individuals in the United States have now received at least one dose of a COVID-19 vaccine. Currently, all adults in the Unites States now have access to one of three COVID-19 vaccines. As part of the vaccination procedure, Emergency Use Authorization (EUA) fact sheets, which contain information regarding the vaccine, are provided. The purpose of this study was to analyze the ease of reading (i.e., readability) of the EUA-approved fact sheets for the vaccines currently available in the United States, the V-Safe adverse event survey script, and the Centers for Disease Control and Prevention (CDC) website information on COVID-19 vaccines designed for the general public in the United States. We acquired the Pfizer, Moderna, and Janssen EUA fact sheets, as well as the V-Safe survey script and the CDC website information regarding COVID-19 vaccines. These documents were analyzed for their complexity regarding the following readability factors: average length of paragraphs, sentences, and words; font size and style; use of passive voice; the Gunning-Fog index; the Flesch Reading Ease index; and the Flesch-Kincaid Grade Level index. Only the V-Safe adverse-event survey script met readability standards for adequate comprehension. The mean readability scores of the EUA fact sheets and the CDC website were as follows: Flesch Reading Ease score (44.35 avg); Flesch-Kincaid Grade Level (10.48 avg); and Gunning-Fog index (11.8 avg). These scores indicate that at least a 10th-grade level education would be required to understand these reading materials. The average person in the United States would have difficulty understanding the information provided in the EUA fact sheets and CDC COVID-19 vaccine website documents; however, the V-Safe survey was written at an adequate reading level. To ensure that the general public fully understands information regarding COVID-19 vaccines, greater care and effort should be given to the development of simplified information material. [ABSTRACT FROM AUTHOR]

The histone deacetylases (HDACs) are a family of enzymes that catalyse lysine deacetylation of both histone and non-histone proteins. Here, we review, summarize, and provide perspectives on the literature regarding one such HDAC, HDAC1, in endothelial biology. In the endothelium, HDAC1 mediates the effects of external and environmental stimuli by regulating major endothelial functions such as angiogenesis, inflammatory signalling, redox homeostasis, and nitric oxide signalling. Angiogenesis is most often, but not exclusively, repressed by endothelial HDAC1. The regulation of inflammatory signalling is more complex as HDAC1 promotes or suppresses inflammatory signalling depending upon the environmental stimuli. HDAC1 is protective in models of atherosclerosis where loss of HDAC1 results in increased cytokine and cell adhesion molecule (CAM) abundance. In other models, HDAC1 promotes inflammation by increasing CAMs and repressing claudin-5 expression. Consistently, from many investigations, HDAC1 decreases antioxidant enzyme expression and nitric oxide production in the endothelium. HDAC1 decreases antioxidant enzyme expression through the deacetylation of histones and transcription factors, and also regulates nitric oxide production through regulating both the expression and activity of nitric oxide synthase 3. The HDAC1-dependent regulation of endothelial function through the deacetylation of both histone and non-histone proteins ultimately impacts whole animal physiology and health. [ABSTRACT FROM AUTHOR]

Titanium doped sapphire (Ti:sapphire) is a laser gain material with broad gain bandwidth benefiting from the material stability of sapphire. These favorable characteristics of Ti:sapphire have given rise to femtosecond lasers and optical frequency combs. Shaping a single Ti:sapphire crystal into a millimeter sized high quality (Q) whispering gallery mode resonator (Q ≈ 108) reduces the lasing threshold to 14.2 mW and increases the laser slope efficiency to 34%. The observed lasing can be both multi‐mode and single‐mode. This is the first demonstration of a Ti:sapphire whispering‐gallery laser. Furthermore, a novel method of evaluating the gain in Ti:sapphire in the near infrared region is demonstrated by introducing a probe laser with a central wavelength of 795 nm. This method results in decreasing linewidth of the modes excited with the probe laser, consequently increasing their Q. These findings open avenues for the usage of whispering gallery mode resonators as cavities for the implementation of compact Ti:sapphire lasers. Moreover, Ti:sapphire whispering‐gallery laser can also be utilized as an amplifier inside its gain bandwidth by implementing a pump–probe configuration. [ABSTRACT FROM AUTHOR]

Microtubule (MT)–associated protein 7 (MAP7) is a required cofactor for kinesin-1–driven transport of intracellular cargoes. Using cryo–electron microscopy and single–molecule imaging, we investigated how MAP7 binds MTs and facilitates kinesin-1 motility. The MT-binding domain (MTBD) of MAP7 bound MTs as an extended a helix between the protofilament ridge and the site of lateral contact. Unexpectedly, the MTBD partially overlapped with the binding site of kinesin-1 and inhibited its motility. However, by tethering kinesin-1 to the MT, the projection domain of MAP7 prevented dissociation of the motor and facilitated its binding to available neighboring sites. The inhibitory effect of the MTBD dominated as MTs became saturated with MAP7. Our results reveal biphasic regulation of kinesin-1 by MAP7 in the context of their competitive binding to MTs. [ABSTRACT FROM AUTHOR]

Impacts of invasive species are often difficult to quantify, meaning that many invaders are prioritised for management without robust, contextual evidence of impact. Most impact studies for invasive plants compare heavily invaded with non-invaded sites, revealing little about abundance–impact relationships. We examined effects of increasing cover and volume of the non-native herbaceous groundcover Tradescantia fluminensis on a temperate rainforest community of southern Australia. We hypothesised that there would be critical thresholds in T. fluminensis abundance, below which the native plant community would not be significantly impacted, but above which the community's condition would degrade markedly. We modelled the abundance–impact relationship from 83 plots that varied in T. fluminensis abundance and landscape context and found the responses of almost all native plant indicators to invasion were non-linear. Native species richness, abundance and diversity exhibited negative exponential relationships with increasing T. fluminensis volume, but negative threshold relationships with increasing T. fluminensis cover. In the latter case, all metrics were relatively stable until cover reached between 20 and 30%, after which each decreased linearly, with a 50% decline occurring at 75–80% invader cover. Few growth forms (notably shrubs and climbers) exhibited such thresholds, with most exhibiting negative exponential relationships. Tradescantia fluminensis biomass increased dramatically at > 80% cover, with few native species able to persist at such high levels of invasion. Landscape context had almost no influence on native communities, or the abundance–impact relationships between T. fluminensis and the plant community metrics. Our results suggest that the diversity of native rainforest community can be maintained where T. fluminensis is present at moderate-to-low cover levels. [ABSTRACT FROM AUTHOR]

The Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) infection causes Coronavirus Disease 2019 (COVID-19), a pandemic that seriously threatens global health. SARS-CoV-2 propagates by packaging its RNA genome into membrane enclosures in host cells. The packaging of the viral genome into the nascent virion is mediated by the nucleocapsid (N) protein, but the underlying mechanism remains unclear. Here, we show that the N protein forms biomolecular condensates with viral genomic RNA both in vitro and in mammalian cells. While the N protein forms spherical assemblies with homopolymeric RNA substrates that do not form base pairing interactions, it forms asymmetric condensates with viral RNA strands. Cross-linking mass spectrometry (CLMS) identified a region that forms interactions between N proteins in condensates, and truncation of this region disrupts phase separation. We also identified small molecules that alter the formation of N protein condensates and inhibit the proliferation of SARS-CoV-2 in infected cells. These results suggest that the N protein may utilize biomolecular condensation to package the SARS-CoV-2 RNA genome into a viral particle. The packaging of the SARS-CoV-2 genome is mediated by the nucleocapsid (N) protein; this study shows that the N protein forms liquid condensates with viral genomic RNA and identifies small molecules that alter these condensates. [ABSTRACT FROM AUTHOR]

PURPOSE: Leptomeningeal disease (LMD) in epidermal growth factor receptor (EGFR)-mutant lung adenocarcinoma is associated with a poor prognosis and limited treatment options. Osimertinib is a potent third-generation EGFR tyrosine kinase inhibitor with confirmed CNS penetration. This study reports on outcomes of patients with EGFR-mutated non–small-cell lung cancer who developed LMD and were subsequently treated with osimertinib. METHODS: We identified patients treated with osimertinib 80 mg PO daily under a compassionate access scheme across nine tertiary Australian institutes between July 2017 and July 2020. Patient demographics, tumor characteristics, and treatment history were collected. Median overall survival, median progression-free survival, disease control rates (DCR), and overall response rates (ORR) were assessed. Kaplan-Meier analysis was performed and descriptive statistics were used. RESULTS: Thirty-nine patients were analyzed of which 74% were female. Exon 19 deletions (49%) and L858R point mutations (41%) were the most common EGFR mutations. Forty-nine percentage of patients were Eastern Cooperative Oncology Group 1. The median duration of osimertinib therapy was 6 months. The extracranial DCR and ORR were 60% and 54%, and the intracranial DCR and ORR were 68% and 53%, respectively. Median overall survival was 10.5 months (95% CI, 8.17 to 15.05 months). CONCLUSION: There are limited treatment options for LMD in EGFR-positive lung cancer, and osimertinib at a dose of 80 mg daily is an active therapeutic option for these patients. [ABSTRACT FROM AUTHOR]

PURPOSE: Leptomeningeal disease (LMD) in epidermal growth factor receptor (EGFR)-mutant lung adenocarcinoma is associated with a poor prognosis and limited treatment options. Osimertinib is a potent third-generation EGFR tyrosine kinase inhibitor with confirmed CNS penetration. This study reports on outcomes of patients with EGFR-mutated non–small-cell lung cancer who developed LMD and were subsequently treated with osimertinib. METHODS: We identified patients treated with osimertinib 80 mg PO daily under a compassionate access scheme across nine tertiary Australian institutes between July 2017 and July 2020. Patient demographics, tumor characteristics, and treatment history were collected. Median overall survival, median progression-free survival, disease control rates (DCR), and overall response rates (ORR) were assessed. Kaplan-Meier analysis was performed and descriptive statistics were used. RESULTS: Thirty-nine patients were analyzed of which 74% were female. Exon 19 deletions (49%) and L858R point mutations (41%) were the most common EGFR mutations. Forty-nine percentage of patients were Eastern Cooperative Oncology Group 1. The median duration of osimertinib therapy was 6 months. The extracranial DCR and ORR were 60% and 54%, and the intracranial DCR and ORR were 68% and 53%, respectively. Median overall survival was 10.5 months (95% CI, 8.17 to 15.05 months). CONCLUSION: There are limited treatment options for LMD in EGFR-positive lung cancer, and osimertinib at a dose of 80 mg daily is an active therapeutic option for these patients. [ABSTRACT FROM AUTHOR]

Hip-hop competitions are performed across the world. In the recent inclusion in the 2018 Youth Olympic Games, the assessment of hip-hop performance is undertaken by a panel of judges. The purpose of this study was to determine the reliability of different visualisation tools utilised in the assessment of the hip-hop dance movements. Ten dancers performed basic rhythmic hip-hop movements which were captured using a motion capture system and video camera. Humanoid and stick figure animations of the dancers' movements were created from the motion capture data. Ten judges then assessed 20 dance trials through observation using three different visualisation tools on a computer display, each of which provided different representations of a given hip-hop performance: (1) the actual video of the dancers; (2) an anonymous stick figure animation; (3) an anonymous humanoid animation. Judges were not informed that they were repeating an assessment of the performances across the three visualisation tools. The humanoid animation demonstrated the highest inter-class correlation coefficients among the three methods. Despite the stick figure animation demonstrating moderate to high reliability, both the humanoid animation and the video demonstrated very high reliability in the intra-class correlation coefficient. It is recommended that further research is undertaken exploring the use of humanoid animation as a formative assessment tool in the evaluation of hip-hop dance and the evolution of hip-hop into a respected artistic athletic discipline. [ABSTRACT FROM AUTHOR]

A series of multi-target directed edaravone derivatives bearing N-benzyl pyridinium moieties were designed and synthesised. Edaravone is a potent antioxidant with significant neuroprotective effects and N-benzyl pyridinium has previously exhibited positive results as part of a dual-site binding, peripheral anionic site (PAS) and catalytic anionic site (CAS), acetylcholinesterase (AChE) inhibitor. The designed edaravone-N-benzyl pyridinium hybrid compounds were docked within the AChE active site. The results indicated interactions with conserved amino acids (Trp279 in PAS and Trp84 in CAS), suggesting good dual-site inhibitory activity. Significant in vitro AChE inhibitory activities were observed for selected compounds (IC50: 1.2–4.6 µM) with limited butyrylcholinesterase inhibitory activity (IC50's >160 µM), indicating excellent selectivity towards AChE (SI: 46 – >278). The compounds also showed considerable antioxidant ability, similar to edaravone. In silico studies indicated that these compounds should cross the blood–brain barrier, making them promising lead molecules in the development of anti-Alzheimer's agents. [ABSTRACT FROM AUTHOR]

Background To explore and describe the current literature surrounding bacterial/fungal coinfection in patients with coronavirus infection. Methods MEDLINE, EMBASE, and Web of Science were searched using broad-based search criteria relating to coronavirus and bacterial coinfection. Articles presenting clinical data for patients with coronavirus infection (defined as SARS-1, MERS, SARS-CoV-2, and other coronavirus) and bacterial/fungal coinfection reported in English, Mandarin, or Italian were included. Data describing bacterial/fungal coinfections, treatments, and outcomes were extracted. Secondary analysis of studies reporting antimicrobial prescribing in SARS-CoV-2 even in absence of coinfection was performed. Results 1007 abstracts were identified. Eighteen full texts reporting bacterial/fungal coinfection were included. Most studies did not identify or report bacterial/fungal coinfection (85/140; 61%). Nine of 18 (50%) studies reported on COVID-19, 5/18 (28%) on SARS-1, 1/18 (6%) on MERS, and 3/18 (17%) on other coronaviruses. For COVID-19, 62/806 (8%) patients were reported as experiencing bacterial/fungal coinfection during hospital admission. Secondary analysis demonstrated wide use of broad-spectrum antibacterials, despite a paucity of evidence for bacterial coinfection. On secondary analysis, 1450/2010 (72%) of patients reported received antimicrobial therapy. No antimicrobial stewardship interventions were described. For non–COVID-19 cases, bacterial/fungal coinfection was reported in 89/815 (11%) of patients. Broad-spectrum antibiotic use was reported. Conclusions Despite frequent prescription of broad-spectrum empirical antimicrobials in patients with coronavirus-associated respiratory infections, there is a paucity of data to support the association with respiratory bacterial/fungal coinfection. Generation of prospective evidence to support development of antimicrobial policy and appropriate stewardship interventions specific for the COVID-19 pandemic is urgently required. [ABSTRACT FROM AUTHOR]

We describe enantioselective syntheses of strychnos and chelidonium alkaloids. In the first case, indole acetic acid esters were established as excellent partner nucleophiles for enantioselective cooperative isothiourea/Pd catalyzed α‐alkylation. This provides products containing indole‐bearing stereocenters in high yield and with excellent levels of enantioinduction in a manner that is notably independent of the N‐substituent. This led to concise syntheses of (−)‐akuammicine and (−)‐strychnine. In the second case, the poor performance of ortho‐substituted cinnamyl electrophiles in the enantioselective cooperative isothiourea/Ir catalyzed α‐alkylation was overcome by appropriate substituent choice, leading to enantioselective syntheses of (+)‐chelidonine, (+)‐norchelidonine, and (+)‐chelamine. [ABSTRACT FROM AUTHOR]

We describe enantioselective syntheses of strychnos and chelidonium alkaloids. In the first case, indole acetic acid esters were established as excellent partner nucleophiles for enantioselective cooperative isothiourea/Pd catalyzed α‐alkylation. This provides products containing indole‐bearing stereocenters in high yield and with excellent levels of enantioinduction in a manner that is notably independent of the N‐substituent. This led to concise syntheses of (−)‐akuammicine and (−)‐strychnine. In the second case, the poor performance of ortho‐substituted cinnamyl electrophiles in the enantioselective cooperative isothiourea/Ir catalyzed α‐alkylation was overcome by appropriate substituent choice, leading to enantioselective syntheses of (+)‐chelidonine, (+)‐norchelidonine, and (+)‐chelamine. [ABSTRACT FROM AUTHOR]

A validated numerical model of tidal flows and sediment transport around the Alderney South Banks was used to investigate the potential effects of large (300MW) tidal turbine arrays at different locations in Alderney territorial waters. Two methods were used, firstly looking at hydrodynamic changes only and secondly modelling sediment transport over a nonerodible bed. The baseline hydrodynamic model was validated relative to ADCP velocity data collected in the immediate vicinity of the sandbank. Realworld sand transport rates were inferred from sandwave migrations and agree favourably with sediment transport residuals calculated from model outputs. Outputs fromthe sediment model reproduced realistic morphological behaviours over the bank. Seventeen different locations were considered; most did not result in significant hydrodynamic changes over the South Banks; however, three array locations were singled out as requiring extra caution if development were to occur. The results provide a case for optimizing the array locations for twin objectives of maximizing array power and minimizing impacts on the sandbanks. This article is part of the theme issue 'New insights on tidal dynamics and tidal energy harvesting in the Alderney Race'. [ABSTRACT FROM AUTHOR]

We examined a novel database linking national donor registry identifiers to records from a US pharmaceutical claims warehouse (2007‐2015) to describe opioid and NSAID prescription patterns among LKDs during the first year postdonation, divided into three periods: 0‐14 days, 15‐182 days, and 183‐365 days. Associations of opioid and NSAID prescription fills with baseline factors were examined by logistic regression (adjusted odds ratio, LCLaORUCL). Among 23,565 donors, opioid prescriptions were highest during days 0‐14 (36.6%), but 12.6% of donors filled opioids during days 183‐365. NSAID prescriptions rose from 0.5% during days 0‐14 to 3.3% during days 183‐365. Women filled opioids more commonly than men, and black donors filled both opioids and NSAIDs more commonly than white donors. After covariate adjustment, significant correlates of opioid prescription fills during days 183‐365 included obesity (aOR,1.241.381.53), less than college education (aOR,1.191.311.43), smoking (aOR,1.331.451.58), and nephrectomy complications (aOR,1.111.291.49). NSAID prescription fills in year 1 were not associated with differences in estimated glomerular filtration rate, incidence of proteinuria or new‐onset hypertension at the first and second year postdonation. Prescription fills for opioids and NSAIDs for LKDs varied with demographic and clinic traits. Future work should examine longer‐term outcome implications to help inform safe analgesic regimen choices after donation. [ABSTRACT FROM AUTHOR]

The emergence of the Severe Acute Respiratory Syndrome coronavirus 2 (SARS-CoV-2) has required an unprecedented response to control the spread of the infection and protect the most vulnerable within society. Whilst the pandemic has focused society on the threat of emerging infections and hand hygiene, certain infection control and antimicrobial stewardship policies may have to be relaxed. It is unclear whether the unintended consequences of these changes will have a net-positive or -negative impact on rates of antimicrobial resistance. Whilst the urgent focus must be on controlling this pandemic, sustained efforts to address the longer-term global threat of antimicrobial resistance should not be overlooked. [ABSTRACT FROM AUTHOR]

With the onset of the COVID-19 pandemic, the shifting of clinical care to telemedicine visits has been hastened. Because of current limitations in resources, many elective surgeons have been forced to venture into utilizing telemedicine, in which the standards for orthopaedic examinations have not previously been fully developed. We report our experience with protocols and methods to standardize these visits to maximize the benefit and efficiency of the virtual orthopaedic examination. At the time of scheduling, patients are asked to prepare for their virtual visit and are given a checklist. In addition to confirming audiovisual capabilities prior to the visit, patients are given specific instructions on camera positioning, body positioning, setting, and attire to improve the efficiency of the visit. During the examination, digital tools can be utilized as needed. In the setting of outpatient injury evaluations, a systematic virtual examination can aid in triaging and managing common musculoskeletal conditions. With the rapid incorporation of telehealth visits, as well as the unknown future with regard to the pandemic, the utilization and capabilities of telemedicine will continue to expand. Future directions include the development of validated, modified examination techniques and new technology that will allow for improved interactive physical examinations, as we rapidly move forward into the realm of telemedicine due to unexpected necessity. [ABSTRACT FROM AUTHOR]

Pulmonary hypertension (PH) is a feature of a variety of diseases and continues to harbor high morbidity and mortality. The main consequence of PH is right-sided heart failure which causes a complex clinical syndrome affecting multiple organ systems including left heart, brain, kidneys, liver, gastrointestinal tract, skeletal muscle, as well as the endocrine, immune, and autonomic systems. Interorgan crosstalk and interdependent mechanisms include hemodynamic consequences such as reduced organ perfusion and congestion as well as maladaptive neurohormonal activation, oxidative stress, hormonal imbalance, and abnormal immune cell signaling. These mechanisms, which may occur in acute, chronic, or acute-on-chronic settings, are common and precipitate adverse functional and structural changes in multiple organs which contribute to increased morbidity and mortality. While the systemic character of PH and right-sided heart failure is often neglected or underestimated, such consequences place additional burden on patients and may represent treatable traits in addition to targeted therapy of PH and underlying causes. Here, we highlight the current state-of-the-art understanding of the systemic consequences of PH and right-sided heart failure on multiple organ systems, focusing on self-perpetuating pathophysiological mechanisms, aspects of increased susceptibility of organ damage, and their reciprocal impact on the course of the disease. [ABSTRACT FROM AUTHOR]

• A model with mutation in engineered underdominance gene drive components is proposed. • Loss-of-function mutations are likely to cause elimination of the gene drive. • The gene drive is likely to persist at high frequency for hundreds of generations. • Engineered underdominance can be reversed by release of free-suppressor constructs. • Free-suppressors can reverse engineered underdominance with extremely small releases. A range of gene drive systems have been proposed that are predicted to increase their frequency and that of associated desirable genetic material even if they confer a fitness cost on individuals carrying them. Engineered underdominance (UD) is such a system and, in one version, is based on the introduction of two independently segregating transgenic constructs each carrying a lethal gene, a suppressor for the lethal at the other locus and a desirable genetic "cargo". Under this system individuals carrying at least one copy of each construct (or no copies of either) are viable whilst those that possess just one of the transgenic constructs are non-viable. Previous theoretical work has explored various properties of these systems, concluding that they should persist indefinitely in absence of resistance or mutation. Here we study a population genetics model of UD gene drive that relaxes past assumptions by allowing for loss-of-function mutations in each introduced gene. We demonstrate that mutations are likely to cause UD systems to break down, eventually resulting in the elimination of introduced transgenes. We then go on to investigate the potential of releasing "free suppressor" carrying individuals as a new method for reversing UD gene drives and compare this to the release of wild-types; the only previously proposed reversal strategy for UD. This reveals that while free suppressor carrying individuals may represent an inexpensive reversal strategy due to extremely small release requirements, they are not able to return a fully wild-type population as rapidly as the release of wild-types. [ABSTRACT FROM AUTHOR]

This study explored men's experiences in nursing. A qualitative research design was utilized to examine (a) the stressors experienced by male nurses, (b) the strategies male nurses use to cope with these stressors, (c) the factors that motivate men to pursue a career in nursing and (d) what motivates men to remain in the profession. Six participants were conveniently and purposively selected from a range of nursing positions including cardiac, intensive care unit, theater, and general nursing to participate in semi‐structured interviews detailing their experiences. Thematic analysis of the interview data revealed that male nurses still experience gender role conflict, feelings of exclusion, and numerous other stressors working in a female‐dominated occupation. Despite these challenges, participants reported that they experienced a great sense of satisfaction in their nursing careers. Further development of educational programs aimed at challenging and breaking down the perceived social stigma regarding men entering the profession may assist in recruiting more men into nursing roles. At a broader policy level, the development of more effective strategies to prevent and manage stress may assist health care agencies to deliver more gender diverse care and retain more men in the profession. [ABSTRACT FROM AUTHOR]