miR-486-5p protects against rat ischemic kidney injury and prevents the transition to chronic kidney disease and vascular dysfunction.

AIM:  Acute kidney injury (AKI) increases the risk for progressive chronic kidney disease (CKD). MicroRNA (miR)-486-5p protects against kidney ischemia reperfusion (IR) injury in mice, although its longterm effects on the vasculature and development of CKD are unknown. We studied whether miR-486-5p would prevent the AKI to CKD transition in rat, and affect vascular function. Methods: Adult male rats were subjected to bilateral kidney IR followed by i.v. injection of liposomal-packaged miR-486-5p (0.5 mg/kg). Kidney function and histologic injury were assessed after 24 h and 10 weeks. Kidney endothelial protein levels were measured by immunoblot and immunofluorescence, and mesenteric artery reactivity was determined by wire myography. Results: In rats with IR, miR-486-5p blocked kidney endothelial cell increases in intercellular adhesion molecule-1 (ICAM-1), reduced neutrophil infiltration and histologic injury, and normalized plasma creatinine (p<0.001). However, miR-486-5p attenuated IR-induced kidney endothelial nitric oxide synthase (eNOS) expression (p<0.05). At 10 weeks, kidneys from rats with IR alone had decreased peritubular capillary density and increased interstitial collagen deposition (p<0.0001), and mesenteric arteries showed impaired endothelium-dependent vasorelaxation (p<0.001). These changes were inhibited by miR-486-5p. Delayed miR-486-5p administration (96 h, 3 weeks after IR) had no impact on kidney fibrosis, capillary density, or endothelial function. Conclusion: In rats, administration of miR-486-5p early after kidney IR prevents injury, and protects against CKD development and systemic endothelial dysfunction. These protective effects are associated with inhibition of endothelial ICAM-1 and occur despite reduction in eNOS. miR-486-5p holds promise for the prevention of ischemic AKI and its complications.

Determination of sensed and paced atrial-ventricular delay in cardiac resynchronization therapy.

BACKGROUND: Optimization of atrial-ventricular delay (AVD) during atrial sensing (SAVD) and pacing (PAVD) provides the most effective cardiac resynchronization therapy (CRT). We demonstrate a novel electrocardiographic methodology for quantifying electrical synchrony and optimizing SAVD/PAVD. METHODS: We studied 40 CRT patients with LV activation delay. Atrial-sensed to RV-sensed (As-RVs) and atrial-paced to RV-sensed (Ap-RVs) intervals were measured from intracardiac electrograms (IEGM). LV-only pacing was performed over a range of SAVD/PAVD settings. Electrical dyssynchrony (cardiac resynchronization index; CRI) was measured at each setting using a multilead ECG system placed over the anterior and posterior torso. Biventricular pacing, which included multiple interventricular delays, was also conducted in a subset of 10 patients. RESULTS: When paced LV-only, peak CRI was similar (93 ± 5% vs. 92 ± 5%) during atrial sensing or pacing but optimal PAVD was 61 ± 31 ms greater than optimal SAVD. The difference between As-RVs and Ap-RVs intervals on IEGMs (62 ± 31 ms) was nearly identical. The slope of the correlation line (0.98) and the correlation coefficient r (0.99) comparing the 2 methods of assessing SAVD-PAVD offset were nearly 1 and the y-intercept (0.63 ms) was near 0. During simultaneous biventricular (BiV) pacing at short AVD, SAVD and PAVD programming did not affect CRI, but CRI was significantly (p < .05) lower during atrial sensing at long AVD. CONCLUSIONS: A novel methodology for measuring electrical dyssynchrony was used to determine electrically optimal SAVD/PAVD during LV-only pacing. When BiV pacing, shorter AVDs produce better electrical synchrony.

Using a targeted metabolomics approach to explore differences in ARDS associated with COVID-19 compared to ARDS caused by H1N1 influenza and bacterial pneumonia.

RATIONALE: Acute respiratory distress syndrome (ARDS) is a life-threatening critical care syndrome commonly associated with infections such as COVID-19, influenza, and bacterial pneumonia. Ongoing research aims to improve our understanding of ARDS, including its molecular mechanisms, individualized treatment options, and potential interventions to reduce inflammation and promote lung repair. OBJECTIVE: To map and compare metabolic phenotypes of different infectious causes of ARDS to better understand the metabolic pathways involved in the underlying pathogenesis. METHODS: We analyzed metabolic phenotypes of 3 ARDS cohorts caused by COVID-19, H1N1 influenza, and bacterial pneumonia compared to non-ARDS COVID-19-infected patients and ICU-ventilated controls. Targeted metabolomics was performed on plasma samples from a total of 150 patients using quantitative LC-MS/MS and DI-MS/MS analytical platforms. RESULTS: Distinct metabolic phenotypes were detected between different infectious causes of ARDS. There were metabolomics differences between ARDSs associated with COVID-19 and H1N1, which include metabolic pathways involving taurine and hypotaurine, pyruvate, TCA cycle metabolites, lysine, and glycerophospholipids. ARDSs associated with bacterial pneumonia and COVID-19 differed in the metabolism of D-glutamine and D-glutamate, arginine, proline, histidine, and pyruvate. The metabolic profile of COVID-19 ARDS (C19/A) patients admitted to the ICU differed from COVID-19 pneumonia (C19/P) patients who were not admitted to the ICU in metabolisms of phenylalanine, tryptophan, lysine, and tyrosine. Metabolomics analysis revealed significant differences between C19/A, H1N1/A, and PNA/A vs ICU-ventilated controls, reflecting potentially different disease mechanisms. CONCLUSION: Different metabolic phenotypes characterize ARDS associated with different viral and bacterial infections.

Implementation of a 1-Day Living Kidney Donor Evaluation Program: A Qualitative Analysis of Donor Candidate and Stakeholder Perspectives.

Introduction: A lengthy donor evaluation process hinders living donor kidney transplantation (LDKT). At The Ottawa Hospital, 1-day evaluation process was recently developed, with a goal to accelerate the determination of donor suitability. The major objective of this study was to solicit feedback from donor candidates and key stakeholders who participated in the 1-day living kidney donor evaluation process, to determine the program's acceptability and factors influencing its implementation elsewhere. Methods: Semi-structured interviews were conducted with donor candidates who participated in the 1-day living kidney donor evaluation process, and with stakeholders who are instrumental to the implementation strategy. Interviews were conducted via videoconference or by telephone from May 2022 to December 2022. Directed content analysis was conducted using 2 unique frameworks for stakeholder and donor candidate interviews. Results: Our study included 13 stakeholders and 18 donor candidates, of whom 16 (89%) were women and 7 (39%) proceeded to kidney donation. Eighteen (100%) perceived the process to be both time-effective and cost-effective, due to reduced travel and missed work time. Thirteen (72%) felt that the 1-day evaluation may accelerate determination of donor suitability. Sequential virtual sessions with a nurse and social worker in advance of the evaluation day were seen as providing critical education and support. Among stakeholders, 11 (85%) emphasized donor candidate care and faster candidacy determinations. Conclusion: The 1-day evaluation process was preferred by most donor candidates, and was perceived as time-effective and cost-effective by most interviewees. An expedited, 1-day evaluation may accelerate determination of donor suitability and improve LDKT rates.

Tourniquet Use in the Prehospital Setting.

PURPOSE: Tourniquets are a mainstay of life-saving hemorrhage control. The US military has documented the safety and effectiveness of tourniquet use in combat settings. In civilian settings, events such as the Boston Marathon bombing and mass shootings show that tourniquets are necessary and life-saving entities that must be used correctly and whenever indicated. Much less research has been done on tourniquet use in civilian settings compared to military settings. The purpose of this study is to describe the prehospital use of tourniquets in a regional EMS system served by a single trauma center. METHODS: All documented cases of prehospital tourniquet use from 2015 to 2020 were identified via a search of EMS, emergency department, and inpatient records, and reviewed by the lead investigator. The primary outcomes were duration of tourniquet placement, success of hemorrhage control, and complications; secondary outcomes included time of day (by EMS arrival time), transport interval, extremity involved, who placed/removed the tourniquet, and mechanism of injury. RESULTS: Of 182 patients with 185 tourniquets applied, duration of application was available for 52, with a median (IQR) of 43 (56) minutes. Hemorrhage control was achieved in all but two cases (96%). Three cases (5.8%) required more than one tourniquet. Complications included five cases of temporary paresthesia, one case of ecchymosis, two cases of fasciotomy, and two cases of compression nerve injury. The serious complication rate was 7.7% (4/52). Time of day was daytime (08:01-16:00) = 15 (31.9%), evening (16:01-00:00) = 27 (57.4%), and night (00:01- 08:00) = 5 (10.6%). The median transport interval was 22 (IQR 5] minutes. The limbs most often injured were the left and right upper extremities (15 each). EMS clinicians and police officers were most often the tourniquet placers. Common mechanisms of injury included gunshot wounds, motorcycle accidents, and glass injuries. CONCLUSION: Tourniquets used in the prehospital setting have a high rate of hemorrhage control and a low rate of complications.

Specimen collection is essential for modern science.

Natural history museums are vital repositories of specimens, samples and data that inform about the natural world; this Formal Comment revisits a Perspective that advocated for the adoption of compassionate collection practices, querying whether it will ever be possible to completely do away with whole animal specimen collection.

Effects of Two Soluble ACE2-Fc Variants on Blood Pressure and Albuminuria in Hypertensive Mice: Research Letter.

Background: Angiotensin-converting enzyme 2 (ACE2) hydrolyzes angiotensin (Ang) II to Ang-(1-7), promoting vasodilatation, and inhibiting oxidative stress and inflammation. Plasma membrane ACE2 is the receptor for all known SARS-CoV-2 (severe acute respiratory syndrome coronavirus 2) viral variants. In COVID-19 infection, soluble ACE2 variants may act as decoys to bind and neutralize the coronavirus, reducing its tissue infectivity. Furthermore, soluble ACE2 variants have been proposed as potential therapeutics for kidney disease and hypertensive disorders. Objective: Soluble ACE2 variants conjugated to human Fc domains and selected for high-potency viral SARS-CoV-2 neutralization were prepared and evaluated for ACE2 activity in vitro. Lead candidates were then tested for systemic ACE2 activity, stability, and effects on blood pressure and albuminuria in mice with Ang II-induced hypertension. Methods: ACE2 activity of 10 soluble ACE2 variants was first assessed in cell-free conditions using a fluorogenic substrate, or by Ang II hydrolysis to Ang-(1-7). Hypertension was induced in male or female mice by implantation of osmotic minipumps containing Ang II. Two lead ACE2 variants were injected intravenously (i.v.) into hypertensive mice, followed by measurements of blood pressure (tail-cuff plethysmography), albuminuria, and tissue ACE2 activity and protein (immunoblots). Results: Soluble ACE2-Fc variants demonstrated significant ACE2 enzymatic activity, with kinetics comparable with human recombinant ACE2. In hypertensive mice, single dose i.v. injection of ACE2-Fc variant K (10 mg/kg) significantly decreased systolic blood pressure at 24 hours, with partial lowering sustained to 48 hours, and tendency to reduce albuminuria at 72 hours. By contrast, ACE2-Fc variant I had no effect on blood pressure or albuminuria in hypertensive mice; ACE2-Fc variant K was detected by immunoblotting in plasma, kidney, heart, lung, liver, and spleen lysates 72 hours after injection, associated with significantly increased ACE2 activity in all tissues except kidney and spleen. Angiotensin-converting enzyme 2-Fc variant I had no effect on plasma ACE2 activity. Conclusions: Soluble ACE2-Fc variant K reduces blood pressure and tends to lower albuminuria in hypertensive mice. Furthermore, soluble ACE2-Fc variant K has prolonged tissue retention, associated with increased tissue ACE2 activity. The results support further studies directed at the therapeutic potential of soluble ACE2-Fc variant K for cardiovascular and kidney protection.

Contexte: L'enzyme de conversion de l'angiotensine 2 (ACE2) hydrolyse l'angiotensine (Ang) II en angiotensine (Ang)-(1-7), ce qui favorise la vasodilatation et inhibe le stress oxydatif et l'inflammation. L'ACE2 de la membrane plasmique est le récepteur de tous les variants connus du SARS-COV-2. Dans les cas d'infection à la COVID-19, les variants solubles de l'ACE2 peuvent agir comme leurres pour lier et neutraliser le coronavirus, et réduire ainsi son infectiosité dans les tissus. Des variants solubles de l'ACE2 ont également été proposés comme agents thérapeutiques potentiels pour l'insuffisance rénale et les troubles liés à l'hypertension. Objectif: Des variants solubles de l'ACE2 conjugués au domaine Fc humain ont été sélectionnés pour leur fort potentiel neutralisant du virus SARS-COV-2, puis préparés et évalués pour la mesure de l'activité de l'ACE2 in vitro. Les meilleurs candidats ont ensuite été testés chez des souris souffrant d'hypertension induite par l'Ang II afin de mesurer l'activité d'ACE2, ainsi que leur stabilité et leurs effets sur la pression artérielle et l'albuminurie. Méthodologie: L'activité de 10 variants solubles de l'ACE2 a d'abord été évaluée en conditions acellulaires à l'aide d'un substrat fluorogène, ou par hydrolyse de l'Ang II en Ang-(1-7). L'hypertension a été induite chez des souris mâles ou femelles par l'implantation de minipompes osmotiques contenant de l'Ang II. Deux des meilleurs variants de l'ACE2 ont été injectés par voie intraveineuse (i.v.) à des souris hypertendues, puis des mesures de la pression artérielle (pléthysmographie par manchon caudal), de l'albuminurie, de l'activité de l'ACE2 dans les tissus et des protéines (immunobuvardage) ont été effectuées. Résultats: Les variants solubles ACE2-Fc ont montré une activité enzymatique significative, avec une cinétique comparable à celle de l'ACE2 recombinante humaine. Chez les souris hypertendues, l'injection i.v. d'une dose unique (10 mg/kg) du variant K ACE2-Fc a abaissé significativement la pression artérielle systolique après 24 heures­une réduction partielle s'étant prolongée jusqu'à 48 heures­et a montré une tendance à réduire l'albuminurie après 72 heures. En revanche, le variant I ACE2-Fc n'a eu aucun effet sur la pression artérielle ou l'albuminurie des souris hypertendues. Après 72 heures, le variant K ACE2-Fc a été détecté par immunobuvardage dans le plasma, ainsi que dans des lysats de reins, de cœur, de poumon, de foie et de rate, ce qui a été associé à une augmentation significative de l'activité de l'ACE2 dans tous les tissus sauf dans les reins et la rate. Le variant I ACE2-Fc n'a montré aucun effet sur l'activité de l'ACE2 dans le plasma. Conclusion: Le variant soluble K ACE2-Fc abaisse la pression artérielle et tend à diminuer l'albuminurie chez les souris hypertendues. Il présente en outre une rétention tissulaire prolongée, laquelle est associée à une plus grande activité de l'ACE2 dans les tissus. Ces résultats appuient d'autres études portant sur le potentiel thérapeutique du variant soluble K ACE2-Fc dans la protection cardiovasculaire et rénale.

Outcomes and characteristics of patients hospitalized for COVID-19 in British Columbia, Ontario and Quebec during the Omicron wave.

BACKGROUND: Omicron is the current predominant variant of concern of SARS-CoV-2. We hypothesized that vaccination alters outcomes of patients hospitalized with COVID-19 during the Omicron wave and that these patients have different characteristics and outcomes than in previous waves. METHODS: This is a substudy of the Host Response Mediators in Coronavirus (COVID-19) Infection (ARBs CORONA I) trial, which included adults admitted to hospital with acute COVID-19 up to July 2022 from 9 hospitals in British Columbia, Ontario and Quebec. We excluded emergency department visits without hospital admission, readmissions and admissions for another reason. Using adjusted regression analysis, we compared mortality and organ dysfunction between vaccinated (≥ 2 doses) and unvaccinated patients during the Omicron wave, as well as between all patients in the Omicron and first 3 waves of the COVID-19 pandemic. RESULTS: During the Omicron wave, 28-day mortality was significantly lower in vaccinated (n = 19/237) than unvaccinated hospitalized patients (n = 12/127) (adjusted odds ratio [OR] 0.36, 95% confidence interval [CI] 0.15-0.89); vaccinated patients had lower risk of admission to the intensive care unit, invasive ventilation and acute respiratory distress syndrome and shorter hospital length of stay. Patients hospitalized during the Omicron wave had more comorbidities than in previous waves, and lower 28-day mortality than in waves 1 and 2 (adjusted OR 0.38, 95% CI 0.24-0.59; and 0.42, 95% CI 0.26-0.65) but not wave 3 (adjusted OR 0.81, 95% CI 0.43-1.51) and had less organ dysfunction than in the first 2 waves. INTERPRETATION: Patients who were at least double vaccinated had lower mortality than unvaccinated patients hospitalized during the Omicron wave. Patients hospitalized during the Omicron wave had more chronic disease and lower mortality than in the first 2 waves, but not wave 3. Changes in vaccination, treatments and predominant SARS-CoV-2 variant may have decreased mortality in patients hospitalized during the Omicron wave.

Comparative Analysis of Hypertensive Tubulopathy in Animal Models of Hypertension and Its Relevance to Human Pathology.

Assessment of hypertensive tubulopathy for more than fifty animal models of hypertension in experimental pathology employs criteria that do not correspond to lesional descriptors for tubular lesions in clinical pathology. We provide a critical appraisal of experimental hypertension with the same approach used to estimate hypertensive renal tubulopathy in humans. Four models with different pathogenesis of hypertension were analyzed-chronic angiotensin (Ang) II-infused and renin-overexpressing (TTRhRen) mice, spontaneously hypertensive (SHR), and Goldblatt two-kidney one-clip (2K1C) rats. Mouse models, SHR, and the nonclipped kidney in 2K1C rats had no regular signs of hypertensive tubulopathy. Histopathology in animals was mild and limited to variations in the volume density of tubular lumen and epithelium, interstitial space, and interstitial collagen. Affected kidneys in animals demonstrated lesion values that are significantly different compared with healthy controls but correspond to mild damage if compared with hypertensive humans. The most substantial human-like hypertensive tubulopathy was detected in the clipped kidney of 2K1C rats. For the first time, our study demonstrated the regular presence of chronic progressive nephropathy (CPN) in relatively young mice and rats with induced hypertension. Because CPN may confound the assessment of rodent models of hypertension, proliferative markers should be used to verify nonhypertensive tubulopathy.

Storytelling for impact: the creation of a storytelling program for patient partners in research.

Storytelling is a powerful means to evoke empathy and understanding among people. When patient partners, which include patients, family members, caregivers and organ donors, share their stories with health professionals, this can prompt listeners to reflect on their practice and consider new ways of driving change in the healthcare system. However, a growing number of patient partners are asked to 'share their story' within health care and research settings without adequate support to do so. This may ultimately widen, rather than close, the gap between healthcare practitioners and people affected by chronic disease in this new era of patient and public involvement in research. To better support patient partners with storytelling in the context of a patient-oriented research network, Canadians Seeking Solutions and Innovations to Overcome Chronic Kidney Disease (Can-SOLVE CKD) Network adapted an existing in-person storytelling workshop for patient educators within a hospital setting. The result is a 6-week virtual program called Storytelling for Impact, which guides patients, family members, caregivers and organ donors in developing impactful stories and sharing them at health care and research events, e.g., conferences. The online series of synchronous workshops is co-facilitated by story coaches, who are program alumni and Can-SOLVE CKD staff with trained storytelling experience. Each story follows a structure that includes a call to action, which aims to positively impact the priority-setting and delivery of care and research in Canada. The program has been a transformational process for many who have completed it, and numerous other health organizations have expressed interest in sharing this tool with their own patient partners. As result, we have also created an asynchronous online program that can be used by other interested parties outside our network. Patient partners who share their stories can be powerful mediators for inspiring changes in the health care and research landscape, with adequate structured support. We describe two novel programs to support patient partners in impactful storytelling, which are applicable across all health research disciplines. Additional resources are required for sustainability and scale up of training, by having alumni train future storytellers.

Storytelling is a powerful means to evoke empathy and understanding among people. When patient partners share their stories with health professionals, this can prompt listeners to reflect on their practice and consider new ways of improving the healthcare system. However, as a growing number of patient partners are asked to 'share their story' within health care and research settings, there is often not enough tools and resources to support them in preparing their stories in a way that will be impactful for the audience members. Our kidney research network sought to create a novel in-person storytelling program to address this gap within our health research context. The result is a 6-week program called Storytelling for Impact, which guides patient partners­which includes patients, family members, caregivers and organ donors­in developing impactful stories and sharing them in a formal setting. The program is led by story coaches, who are patient partners and staff with trained storytelling experience. Participants are encouraged to include a call to action in their story, which aims to outline clear ways in which health professionals can facilitate positive change in health research or care. Many participants have described the program as transformational, and numerous other health organizations have expressed interest in sharing this tool with their own patient partners. As a result, we have also created a second online program that can be used by other interested parties outside our network. This paper highlights the adaptation process, content, participant feedback and next steps for the program.

Sampling affects population genetic inference: A case study of the Allen's (Selasphorus sasin) and rufous hummingbird (Selasphorus rufus).

Gene flow can affect evolutionary inference when species are undersampled. Here, we evaluate the effects of gene flow and geographic sampling on demographic inference of 2 hummingbirds that hybridize, Allen's hummingbird (Selasphorus sasin) and rufous hummingbird (Selasphorus rufus). Using whole-genome data and extensive geographic sampling, we find widespread connectivity, with introgression far beyond the Allen's × rufous hybrid zone, although the Z chromosome resists introgression beyond the hybrid zone. We test alternative hypotheses of speciation history of Allen's, rufous, and Calliope (S. calliope) hummingbird and find that rufous hummingbird is the sister taxon to Allen's hummingbird, and Calliope hummingbird is the outgroup. A model treating the 2 subspecies of Allen's hummingbird as a single panmictic population fit observed genetic data better than models treating the subspecies as distinct populations, in contrast to morphological and behavioral differences and analyses of spatial population structure. With additional sampling, our study builds upon recent studies that came to conflicting conclusions regarding the evolutionary histories of these 2 species. Our results stress the importance of thorough geographic sampling when assessing demographic history in the presence of gene flow.

Granulosa cell-derived miR-379-5p regulates macrophage polarization in polycystic ovarian syndrome.

Polycystic ovarian syndrome (PCOS) is associated with hyperandrogenemia and ovarian antral follicle growth arrest. We have previously demonstrated that androgen-induced exosomal release of miR-379-5p (miR379) from preantral follicle granulosa cells increases the proliferation of target cells via phosphoinositide-dependent kinase 1 (PDK1) upregulation. Androgen also increases inflammatory M1 macrophage abundance, but reduces anti-inflammatory M2 polarization in rat antral and preovulatory follicles. However, the role of small extracellular vesicles (sEVs; also known as exosomes) secretion in determining the cellular content and function of miRNAs in exosome-receiving cells is largely unknown. Our objectives were to determine: 1) the regulatory role of granulosa cells (GC)-derived exosomal miR379 on macrophage polarization and ovarian inflammation; 2) whether miR379-induced M1 polarization regulates GC proliferation; and 3) if this regulated process is follicular stage-specific. Compared with non-PCOS subjects, PCOS subjects had a higher M1/M2 ratio, supporting the concept that PCOS is an inflammatory condition. Ovarian overexpression of miR379 increased the number of M1 macrophages and the M1/M2 ratio in preantral follicles specifically. Transfection of macrophages with a miR379 mimic reduced the cellular content of PDK1 and induced M0→M1 polarization; whereas its inhibitor polarized M0→M2. Conditioned media from macrophages transfected with miR379 mimic and follicular fluid from PCOS subjects had higher galectin-3 content, a pro-inflammatory cytokine which specifically suppresses human antral follicle GC proliferation. These results indicate that miR379 inhibits M2 macrophage polarization, a condition which suppresses GC proliferation in a follicle stage-dependent manner, as exhibited in PCOS.

Androgen-induced exosomal miR-379-5p release determines granulosa cell fate: cellular mechanism involved in polycystic ovaries.

Polycystic ovarian syndrome (PCOS) is a complex multi-factorial syndrome associated with androgen excess and anovulatory infertility. In the current study, we investigated the role of dihydrotestosterone-induced exosomal miR-379-5p release in determining the destiny of the developing follicles. Our hypothesis was that androgen regulates granulosa cell miR-379-5p content by facilitating its exosomal release in a follicular-stage dependent manner, a process which determines granulosa cell fate. Compared to human non-PCOS subjects, individuals with PCOS exhibit higher follicular fluid free testosterone levels, lower exosomal miR-379-5p content and granulosa cell proliferation. Androgenized rats exhibited lower granulosa cell miR-379-5p but higher phosphoinositide-dependent kinase-1 (PDK1; a miR-379-5p target) content and proliferation. Androgen reduced granulosa cell miR-379-5p content by increasing its exosomal release in preantral follicles, but not in antral follicles in vitro. Studies with an exosomal release inhibitor confirmed that androgen-induced exosomal miR-379-5p release decreased granulosa cell miR-379-5p content and proliferation. Ovarian overexpression of miR-379-5p suppressed granulosa cell proliferation, and basal and androgen-induced preantral follicle growth in vivo. These findings suggest that increased exosomal miR-379-5p release in granulosa cells is a proliferative response to androgenic stimulation specific for the preantral stage of follicle development and that dysregulation of this response at the antral stage is associated with follicular growth arrest, as observed in human PCOS.

Protecting the kidney in sepsis: resident macrophages to the rescue.

Kidney resident macrophages exert pro-inflammatory or reparative effects in experimental acute kidney injury, but their role in sepsis is unclear. In a mouse model of sepsis, Privratsky et al. show that kidney resident F4/80hi macrophages protect against kidney injury by expressing interleukin-1 receptor antagonist, which blocks interleukin-6 production selectively from endothelial cells. Discovery of this novel autocrine loop enhances opportunities for targeted therapies to diminish kidney injury during sepsis.

The island biogeography of human population size.

For decades, biogeographers have sought a better understanding of how organisms are distributed among islands. However, the island biogeography of humans remains largely unknown. Here, we investigate how human population size varies among 486 islands at two spatial scales. At a global scale, we tested whether population size increases with island area and declines with island elevation and nearest mainland, as is common in non-human species, or whether humans escape such biogeographic constraints. At a regional scale, we tested whether population sizes vary among islands within archipelagos according to the positioning of different cultural source pools. Results illustrate that on a global scale, human populations increased in size with island area, similar to non-human species, yet they did not decline in size with elevation and distance to nearest mainland. At a regional scale, human population size often varied among islands within archipelagos relative to the location of different cultural source pools. Despite broad-scale similarities in the geographical distribution of human and non-human species among islands, results from this study indicate that the island biogeography of humans may also be influenced by archipelago-specific social, political and historical circumstances.

Widespread convergent morphological evolution within the largest family of songbirds.

Although convergence is a common evolutionary phenomenon, few studies have quantified its prevalence across a large, densely sampled clade. Large-scale phylogenies and the advent of novel computational methods facilitate more robust identification of convergent events and their statistical significance. The tanagers (Aves: Thraupidae), the largest family of songbirds, offer an excellent opportunity to study the extent of phenotypic convergence in response to similar ecological pressures on a continental scale. To investigate convergence in the group, we used the largest phylogenetic and multivariate morphological dataset to date for the clade. First, we used phylogenetic comparative analyses to show a correlation between diet and aspects of bill shape. We then investigated our dataset for the presence and magnitude of convergent events and assessed significance through simulations and modeling analyses. Overall, we found that around half (45.3%) of species and clades we tested have converged in morphological space more than would be expected by chance alone. Our study shows that across Thraupidae, various bill shapes have evolved convergently to fill multiple distinct sections of ecological niche space, reflecting a signal of ecological opportunity and structural constraints.

EMS Non-Transport of Low-Risk COVID-19 Patients.

Objectives: COVID-19 infections in the community have the potential to overwhelm both prehospital and in-hospital resources. Transport of well-appearing patients, in the absence of available emergency department treatment capacity, increases strain on the hospital and EMS system. In May of 2020, the Connecticut Office of EMS issued a voluntary, EMS-initiated, non-transport protocol for selected low-risk patients with symptoms consistent with COVID-19. We evaluated the implementation of this non-transport protocol in a mixed urban/suburban EMS system.Methods: We conducted a retrospective review of contemporaneously recorded quality improvement documentation for uses of the Connecticut COVID-19 non-transport protocol by EMS clinicians within our EMS system during two implementations: from 12/14/2020 to 5/1/21, and again from 1/3/22 to 2/18/22, which coincided with large COVID-19 case surges in our region.Results: The vast majority of patients treated under the non-transport protocol were not reevaluated by EMS or in our emergency departments in the subsequent 24 hours. There was reasonable adherence to the protocol, with 83% of cases appropriate for the non-transport protocol. The most common reasons for protocol violations were age outside of protocol scope (pediatric patients), failure of documentation, or vital signs outside of the established protocol parameters. We did not find an increased 24-hour ED visit rate in patients who were inappropriately triaged to the protocol. Of patients who had ED visits within 24 hours, only two were admitted, none to higher levels of care.Conclusion: Within this small study, EMS clinicians in our system were able to safely and accurately apply a non-transport protocol for patients presenting with symptoms consistent with COVID-19. This is consistent with previous literature suggesting that EMS-initiated non-transport is a viable strategy to reduce the burden on health systems.

An Evaluation of Prehospital Adenosine Use.

BACKGROUND: Adenosine has been safely used by paramedics for the treatment of stable supraventricular tachycardia since the mid-1990s. However, there continues to be variability in paramedics' ability to identify appropriate indications for adenosine administration. As the first of a planned series of studies aimed at improving the accuracy of SVT diagnosis and successful administration of adenosine by paramedics, this study details the current usage patterns of adenosine by paramedics. METHODS: This cross-sectional retrospective study investigated adenosine use within a large northeast EMS region from January 1, 2019, through September 30, 2021. Excluding pediatric and duplicate case reports, we created a dataset containing patient age, sex, and vital signs before, during, and after adenosine administration; intravenous line location; and coded medical history from paramedic narrative documentation, including a history of atrial fibrillation, suspected arrhythmia diagnosis, and effect of adenosine. In cases with available prehospital electrocardiograms (EKGs) for review, two physicians independently coded the arrhythmia diagnosis and outcome of adenosine administration. Statistical analysis included interrater reliability with Cohen's kappa statistic. RESULTS: One hundred eighty-three cases were included for final analysis, 84 did not have a documented EKG for review. Categorization of presenting rhythms in these cases occurred by a physician reviewing EMS narrative and documentation. Forty of these 84 cases (48%) were adjudicated as SVT likely, 32 (38%) as SVT unlikely and 12 (14%) as uncategorized due to lack of supporting documentation. Of the 99 cases with EKGs available to review, there was substantial agreement of arrhythmia diagnosis interpretation between physician reviewers (Cohen's kappa 0.77-1.0); 54 cases were adjudicated as SVT by two physician reviewers. Other identified cardiac rhythms included atrial fibrillation (16), sinus tachycardia (11), and ventricular tachycardia (2). Adenosine cardioversion occurred in 47 of the 99 cases with EKGs available for physician review (47.5%). Adenosine cardioversion was also deemed to occur in 87% (47/54) of cases when the EKG rhythm was physician adjudicated SVT. CONCLUSIONS: This study supports the use of adenosine as a prehospital treatment for SVT while highlighting the need for continued efforts to improve paramedics' identification and management of tachyarrhythmias.

Kidney function, cardiovascular outcomes and survival of living kidney donors with hypertension: a systematic review protocol.

INTRODUCTION: Hypertension has been considered a contraindication for living kidney donation in the past. Since transplantation from living kidney donors remains the best modality for kidney failure, there is now an increased acceptance of living kidney donors with hypertension. However, the safety of this practice for the cardiovascular and kidney health of the donor is unclear. We will conduct a systematic review to summarise and synthesise the existing literature on this topic. METHODS AND ANALYSIS: A systematic review of prospective randomised and non-randomised and retrospective studies will be conducted. MEDLINE, EMBASE, Cochrane CENTRAL and EBM reviews published from January 1946 to December 2021 will be reviewed. Primary outcome will be the difference in the survival, major adverse cardiovascular events, estimated glomerular filtration rate of 45 mL/min or less and development of end-stage kidney failure, between living kidney donors with and without hypertension. Study screening, selection, and data extraction will be performed by two independent reviewers. Studies must fulfil all eligibility criteria for inclusion into the systematic review and meta-analysis. The Risk of Bias in Non-Randomised studies tool will be used to assess bias. ETHICS AND DISSEMINATION: No ethical approval is required for this systematic review. The results of this review will be disseminated in a peer-reviewed, open-access journal to ensure access to all stakeholders in kidney transplantation and to inform clinical guidelines on the evaluation and follow-up care of living kidney donor candidates. PROSPERO REGISTRATION NUMBER: CRD42022300119.