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The plains vizcacha is a rodent that shows reactivation of the hypothalamic-pituitary-ovary (HPO) axis activity at mid-gestation. This process is enabled by the secretion of hypothalamic gonadotropin-releasing hormone (GnRH) at mid-gestation, followed by follicle-stimulating hormone (FSH) and luteinizing hormone (LH) secretion. However, a decrease in the pituitary GnRH receptor (GnRHR) expression is concomitantly determined. Moreover, an increment in the pituitary expression of estrogen receptor alpha (ERα) has been determined. This work aimed to study the impact of estradiol (E2) on GnRHR expression, the transcription factors early growth response protein-1 (Egr-1) and steroidogenic factor-1 (Sf-1), as well as on LH secretion. Three experimental approaches were performed: a physiological one with pregnant plains vizcachas, an in vivo approach with ovariectomized (OVX) animals treated with E2 (OVX + E2), and an ex vivo approach using pituitary glands exposed to a combination of GnRH and E2. Significant increased pituitary expression of Sf-1 and Egr-1 was determined at mid-gestation. Ovariectomy significantly increased adenohypophyseal expression levels of GnRHR, Egr-1, and Sf-1, as well as LH secretion. Then, OVX + E2 showed similar levels to SHAM. Adenohypophyses exposed to GnRH showed induced GnRHR, Egr-1, and Sf-1 expression, and LH secretion, while GnRH + E2 reverted these changes. The mid-gestation pituitary GnRHR decrease may result from the combination of increased E2 and GnRH secretion. Nevertheless, the increased expression of Egr-1 and Sf-1 at mid-gestation, together with LH release, suggests the tightly and complex regulatory system that takes place at mid-gestation, enabling a new progesterone surge that successfully carries the pregnancy to term. NEW & NOTEWORTHY: A significant increment of Sf-1 and Egr-1 at the pituitary of mid-gestating plains vizcachas was determined. Moreover, E2 reverted GnRHR, Egr-1, Sf-1, and LH increase in ovariectomized vizcachas' pituitaries and ex vivo pituitaries exposed to GnRH. The decrease of the pituitary GnRHR at mid-gestation may result from the increased E2 and GnRH levels. A tightly and complex regulatory system may take place at mid-gestation enabling a new surge of progesterone that carries pregnancy to term., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Infertility in hyperprolactinemic females is attributed to the dysregulation of GnRH release, subsequently affecting gonadotropin levels, and ultimately leading to anovulation. However, in addition to the hypothalamus, prolactin receptor (PRLR) is expressed in ovaries as well, suggesting potential local effects of PRL in cases of hyperprolactinemia. We have developed an experimental model of sulpiride (SPD)-induced hyperprolactinemia using a wild rodent, the plains vizcacha, and studied the implications of pharmacological PRL levels on folliculogenesis and steroid production. Ovaries of SPD females showed a striking number of atretic follicles along with a reduction in the collective number of viable follicles leading to a higher atretic/viable follicle ratio compared to that of control females (CTL) (P < 0.05). In terms of sensitivity to the hormonal environment, SPD ovaries substantially changed their potential responsiveness to pituitary PRL, as evidenced by the three-fold increase in PRLR expression alongside heightened expression of both gonadotropic receptors in comparison to CTL ovaries (P < 0.05). Circulating estradiol (E2) values doubled post-treatment in the SPD females, which also showed higher expressions of aromatase and 17β-hydroxysteroid dehydrogenase, along with both E2 receptors, ERα and ERβ than the CTL group (P < 0.05). Our findings strongly suggest that hyperprolactinemia-dependent dysregulation of ovarian function can be explained at least partially, by PRL direct actions facilitated by the heightened expression of PRLR in follicles and corpora lutea. Possibly these PRL actions synergize with those triggered by gonadotropic hormones ultimately leading to alteration of the steroidogenic pathway, folliculogenesis disruption and increased atresia., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Inc. All rights reserved.)

The Columbia Academy for Psychoanalytic Educators supports graduate analysts' professional development at the Columbia University Center for Psychoanalytic Training and Research. In 2018, a pilot program was launched for faculty interested in analyzing and supervising candidates, whose aim is to support and educate those interested in taking on these essential training functions. The focus is on educating the educators, which is a significant departure from the historical focus on evaluation, vetting, and faculty hierarchies. In the process of developing and piloting the program, complex and long debated issues in psychoanalytic education and development were considered that are relevant to many institutes, including training of supervisors and analysts of candidates, addressing problematic faculty hierarchies, creating safety for those presenting clinical work to colleagues, building professional peer relationships, and engagement of faculty in time consuming and nonremunerative activities. The authors report on their experience developing and evaluating this pilot program.

Background: Systemic inflammatory response syndrome (SIRS) following cardiovascular interventions is associated with adverse events during hospitalization and follow-up. Mitral transcatheter edge-to-edge repair is increasingly utilized for treatment of mitral regurgitation (MR). We investigated whether SIRS following mitral transcatheter edge-to-edge repair may occur and be associated with adverse clinical outcomes., Methods and Results: A total of 158 consecutive patients with severe MR undergoing mitral transcatheter edge-to-edge repair were studied. SIRS was defined by leukocytosis (≥12 × 10 9 /L) and fever (≥38 °C) within 48 hours after intervention. Baseline inflammation was measured by absolute neutrophil and lymphocyte counts and neutrophil-lymphocyte ratio. The primary end point of major cardiovascular events was the composite of nonfatal myocardial infarction, nonfatal stroke, and all-cause death. Recurrent MR at follow-up was also recorded. The mean patient age was 80.8±8.8 years. Forty-four (27.9%) developed SIRS. Neutrophil-lymphocyte ratio correlated with onset of leukocytosis and fever ( P =0.04). During a median follow-up of 12.5 (5.4-17.4) months, the primary end point occurred in 27 (17.1%) patients (6 myocardial infarction, 5 strokes, and 16 deaths). Patients with SIRS more often had severe MR (79.5% versus 62.7%, P =0.02) at follow-up. After adjustment for pertinent variables, SIRS (HR 2.73 [95% CI, 1.08-6.86]; P =0.03) was independently associated with major cardiovascular events., Conclusions: SIRS after mitral transcatheter edge-to-edge repair is a strong independent predictor of major cardiovascular events. Closer follow-up is warranted because patients with SIRS have more severe MR at follow-up.

CD59 is a cell-surface inhibitor of the terminal step in the complement cascade. However, in addition to its complement inhibitory function, a non-canonical role of CD59 in pancreatic beta cells has been identified. Two recently discovered intracellular alternative splice forms of CD59, IRIS-1 and IRIS-2, are involved in insulin exocytosis through interactions with SNARE-complex components. In mice, the CD59 gene has undergone duplication and to further explore the role of CD59 in insulin secretion, blood glucose homeostasis was studied in a CD59 double knockout (CD59abKO) mouse model. However, no phenotypic deviation related to insulin secretion or blood glucose homeostasis was observed for the CD59abKO mice. Instead, a CD59ba hybrid transcript formed as a consequence of the mutation induced to generate the model was identified. This hybrid transcript is expressed in pancreatic islets of the CD59abKO mice and is comprised of the remaining exons of the two CD59 genes spliced together. Similar to canonical CD59, the CD59ba hybrid was found to be glycosylated and present on the cell surface when exogenously expressed in INS-1 832/13 cells. Furthermore, INS-1 832/13 cells over-expressing the mouse CD59ba hybrid retained normal insulin secretion following siRNA-mediated knockdown of canonical CD59. Hence, although the CD59ba hybrid has lost the complement inhibitory function, the intracellular insulin secretory function remains. These results provide further information concerning the structural requirements of CD59 in its intracellular role relative to its role as a complement inhibitor. It also highlights the importance of carefully assessing plausible consequences of induced mutations in research models., (© 2024 The Author(s). The FASEB Journal published by Wiley Periodicals LLC on behalf of Federation of American Societies for Experimental Biology.)

Competing Interests: Disclosures Dr Turagam has served as a consultant for Biosense Webster and Boston Scientific. Dr Nair has served as a consultant for Boston Scientific and Johnson & Johnson. Dr Doshi has served as a consultant for Boston Scientific and Abbott Vascular. Dr Valderrabano has served as a consultant for Biosense Webster and Abbott. Dr Natale has served as a consultant for Abbott, Biosense Webster, and Boston Scientific. Dr Halperin has served as a consultant for Abbott and Bayer HealthCare. Dr Mansour has received consulting fees from Biosense Webster and Boston Scientific. Dr Reddy has served as an unpaid consultant for Boston Scientific, Biosense Webster, and Abbott. Dr Reddy has served as a consultant to Boston Scientific and Abbott; and unrelated to this manuscript, he has served as a consultant for and has equity in Ablacon, Acutus Medical, Affera-Medtronic, Anumana, Apama Medical-Boston Scientific, APN Health, Append Medical, Aquaheart, Atacor, Autonomix, Axon Therapies, Backbeat, BioSig, CardiaCare, Cardiofocus, CardioNXT/AFTx, Circa Scientific, CoRISMA, Corvia Medical, Dinova-Hangzhou DiNovA EP Technology, East End Medical, EP Frontiers, Farapulse-Boston Scientific, Field Medical, Focused Therapeutics, HRT, Intershunt, Javelin, Kardium, Laminar Medical, LuxMed, Medlumics, Neutrace, Nuvera-Biosense Webster, Oracle Health, Pulse Biosciences, Restore Medical, Sirona Medical, SoundCath; and unrelated to this work, has served as a consultant for Adagio Medical, AtriAN, Biosense-Webster, BioTel Heart, Biotronik, Cairdac, Cardionomic, CoreMap, Fire1, Gore & Associates, Impulse Dynamics, Medtronic, Novartis, Novo Nordisk, Philips; and has equity in Atraverse, DRS Vascular, Manual Surgical Sciences, Newpace, Nyra Medical, Surecor, and Vizaramed. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose.

Low-flow (LF) aortic stenosis (AS) is common among older adults and associated with worse outcomes than AS with normal stroke volume. It is unknown whether left ventricular (LV) remodeling identifies patients with LF AS at higher risk of complications. LV remodeling was evaluated in 463 patients with severe LF AS referred for transcatheter aortic valve replacement (TAVR) and classified as adaptive (normal geometry and concentric remodeling) or maladaptive (concentric and eccentric hypertrophy) using the American Society of Echocardiography gender-specific criteria. Of these, the 390 patients who underwent TAVR were followed for the end points of heart failure (HF) hospitalization and all-cause mortality. The mean patient age was 79 (74.5 to 84) years. LV remodeling was adaptive in 57.4% (62 normal geometry, 162 concentric remodeling) and maladaptive in 42.6% (127 concentric hypertrophy, 39 eccentric hypertrophy). During a median follow-up of 3 years, 45 patients (11.5%) were hospitalized for HF and 73 (18.7%) died. After adjustment for widely used echocardiographic parameters, maladaptive remodeling was independently associated with HF hospitalization and death (adjusted hazard ratio 1.75, confidence interval 1.03 to 3.00). There was no significant difference between men and women in the association of maladaptive LV remodeling with the composite outcome (p = 0.40 for men and p = 0.06 for women). In conclusion, in patients with LF AS, maladaptive LV remodeling before TAVR is independently associated with higher incidences of postprocedural HF rehospitalization and death in both men and women. Assessment of LV remodeling has prognostic value over and above LV ejection fraction and may improve risk stratification for patients with LF AS., Competing Interests: Declaration of competing interest The authors have no competing interests to declare., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Objective: To examine the relationship between gestational glucose intolerance (GGI) and neonatal hypoglycemia., Research Design and Methods: This was a secondary analysis of 8,262 mother-infant dyads, with delivery at two hospitals between 2014 and 2023. We categorized maternal glycemic status as normal glucose tolerance (NGT), GGI, or gestational diabetes mellitus (GDM). We defined NGT according to a normal glucose load test result, GGI according to an abnormal glucose load test result with zero (GGI-0) or one (GGI-1) abnormal value on the 100-g oral glucose tolerance test, and GDM according to an abnormal glucose load test result with two or more abnormal values on the glucose tolerance test. Neonatal hypoglycemia was defined according to blood glucose <45 mg/dL or ICD-9 or ICD-10 diagnosis of neonatal hypoglycemia. We used logistic regression analysis to determine associations between maternal glucose tolerance category and neonatal hypoglycemia and conducted a sensitivity analysis using Δ-adjusted multiple imputation, assuming for unscreened infants a rate of neonatal hypoglycemia as high as 33%., Results: Of infants, 12% had neonatal hypoglycemia. In adjusted models, infants born to mothers with GGI-0 had 1.28 (95% 1.12, 1.65), GGI-1 1.58 (95% CI 1.11, 2.25), and GDM 4.90 (95% CI 3.81, 6.29) times higher odds of neonatal hypoglycemia in comparison with infants born to mothers with NGT. Associations in sensitivity analyses were consistent with the primary analysis., Conclusions: GGI is associated with increased risk of neonatal hypoglycemia. Future research should include examination of these associations in a cohort with more complete neonatal blood glucose ascertainment and determination of the clinical significance of these findings on long-term child health., (© 2024 by the American Diabetes Association.)

The plains vizcacha, Lagostomus maximus, is a precocial hystricomorph rodent with a gyrencephalic brain. This work aimed to perform a time-lapse analysis of the embryonic brain cortical development in the plains vizcacha to establish a species-specific temporal window for corticogenesis and the gyrencephaly onset. Additionally, a comparative examination with evolutionarily related rodents was conducted. Embryos from 40 embryonic days (ED) until the end of pregnancy ( ∼ $\sim $ 154 ED) were evaluated. The neuroanatomical examination determined transverse sulci at 80 ED and rostral lateral and caudal intraparietal sulci around 95 ED. Histological examination of corticogenesis showed emergence of the subplate at 43 ED and expansion of the subventricular zone (SVZ) and its division into inner and outer SVZs around 54 ED. The neocortical layers formation followed an inside-to-outside spatiotemporal gradient beginning with the emergence of layers VI and V at 68 ED and establishing the final six neocortical layers around 100 ED. A progressive increment of gyrencephalization index (GI) from 1.005 ± 0.003 around 70 ED, which reflects a smooth cortex, up to 1.07 ± 0.009 at the end of gestation, reflecting a gyrencephalic neuroanatomy, was determined. Contrarily, the minimum cortical thickness (MCT) progressively decreased from 61 ED up to the end of gestation. These results show that the decrease in the cortical thickness, which enables the onset of neocortical invaginations, occurs together with the expansion and subdivision of the SVZ. The temporal comparison of corticogenesis in plains vizcacha with that in relative species reflects a prenatal long process compared with other rodents that may give an evolutionary advantage to L. maximus as a precocial species., (© 2024 Wiley Periodicals LLC.)

Allopregnanolone (ALLO) is a known neurosteroid and a progesterone metabolite synthesized in the ovary, CNS, PNS, adrenals and placenta. Its role in the neuroendocrine control of ovarian physiology has been studied, but its in situ ovarian effects are still largely unknown. The aims of this work were to characterize the effects of intrabursal ALLO administration on different ovarian parameters, and the probable mechanism of action. ALLO administration increased serum progesterone concentration and ovarian 3β-HSD2 while decreasing 20α-HSD mRNA expression. ALLO increased the number of atretic follicles and the number of positive TUNEL granulosa and theca cells, while decreasing positive PCNA immunostaining. On the other hand, there was an increase in corpora lutea diameter and PCNA immunostaining, whereas the count of TUNEL-positive luteal cells decreased. Ovarian angiogenesis and the immunohistochemical expression of GABA A receptor increased after ALLO treatment. To evaluate if the ovarian GABA A receptor was involved in these effects, we conducted a functional experiment with a specific antagonist, bicuculline. The administration of bicuculline restored the number of atretic follicles and the diameter of corpora lutea to normal values. These results show the actions of ALLO on the ovarian physiology of the female rat during the follicular phase, some of them through the GABA A receptor. Intrabursal ALLO administration alters several processes of the ovarian morpho-physiology of the female rat, related to fertility and oocyte quality., (© 2024. The Author(s).)

Oxygenated blood is required for the adequate metabolic activity of the brain. This is supplied by the circle of Willis (CoW) and the vertebrobasilar and carotid systems. The CoW ensures blood flow in case of arterial stenosis or occlusion. Different animal models have been explored for the CoW morphological and functional study. This work aims to characterize the vascular architecture of the CoW of the plains vizcacha, Lagostomus maximus (Suborder: Hystricomorpha), and to compare it with evolutionarily related species of Caviomorpha and Muroidea. The blood supply in adult plains vizcachas was studied using latex cerebrovascular casts and angiography. A caudo-rostral flow direction was determined, beginning in the spinal and vertebral arteries and converging in the basilar artery which bifurcates in the carotid-basilar communication in the caudal communicating arteries. In the first third of its course, the caudal cerebral arteries project laterally, and the middle and rostral cerebral arteries bifurcate from their rostral terminal segment, supplying the temporo-parietal and frontal cortex. The CoW architecture is mainly conserved between rodent species. Likewise, the small neurovascular variations observed could be considered phylogenetic morphological variations more than evolutionary adaptations. The absence of the rostral communicating artery that generates the rostral open architecture of the CoW in the vizcacha as in the other analyzed species, supports the need for a revision of the CoW classical function as a security system. Finally, this work supports the importance of expanding our understanding of brain anatomy among species, which may contribute to a better understanding of functional neuroanatomy., (© 2023 American Association for Anatomy.)

Background: Strokes after left atrial appendage closure (LAAC) prophylaxis are generally less severe than those after warfarin prophylaxis-thought to be secondary to more hemorrhagic strokes with warfarin. Hemorrhagic strokes are similarly infrequent with direct oral anticoagulant (DOAC) prophylaxis, so the primary subtype after either LAAC or DOAC prophylaxis is ischemic stroke (IS)., Objectives: The purpose of this study was to compare the severity of IS using the modified Rankin Scale in atrial fibrillation patients receiving prophylaxis with DOACs vs LAAC., Methods: A retrospective analysis was performed of consecutive patients undergoing LAAC at 8 centers who developed an IS (IS LAAC ) compared with contemporaneous consecutive patients who developed IS during treatment with DOACs (IS DOAC ). The primary outcome was disabling/fatal stroke (modified Rankin Scale 3-5) at discharge and 3 months later., Results: Compared with IS DOAC patients (n = 322), IS LAAC patients (n = 125) were older (age 77.2 ± 13.4 years vs 73.1 ± 11.9 years; P = 0.002), with higher HAS-BLED scores (3.0 vs 2.0; P = 0.004) and more frequent prior bleeding events (54.4% vs 23.6%; P < 0.001), but similar CHA 2 DS 2 -VASc scores (5.0 vs 5.0; P = 0.28). Strokes were less frequently disabling/fatal with IS LAAC than IS DOAC at both hospital discharge (38.3% vs 70.3%; P < 0.001) and 3 months later (33.3% vs 56.2%; P < 0.001). Differences in stroke severity persisted after propensity score matching. By multivariate regression analysis, IS LAAC was independently associated with fewer disabling/fatal strokes at discharge (OR: 0.22; 95% CI: 0.13-0.39; P < 0.001) and 3 months (OR: 0.25; 95% CI: 0.12-0.50; P < 0.001), and fewer deaths at 3 months (OR: 0.28; 95% CI: 0.12-0.64; P < 0.001)., Conclusions: Ischemic strokes in patients with atrial fibrillation are less often disabling or fatal with LAAC than DOAC prophylaxis., Competing Interests: Funding Support and Author Disclosures Dr Turagam has served as a consultant for Biosense Webster and Sanofi. Dr Nair has served as a consultant for and receives honoraria for speaking engagements from Boston Scientific, Johnson and Johnson, and Medtronic. Dr Doshi has served as a consultant to Boston Scientific, Biosense Webster, and Abbott Vascular. Dr Valderrabano has received scientific research support from and served as a consultant to Circa; has received research support from and served as a consultant to Biosense Webster; and has served as a consultant to Abbott. Dr Dukkipati has received payment for Farapulse acquisition from Boston Scientific; and has equity in Manual Surgical Sciences. Dr Natale has served as a consultant for Abbott, Baylis, Biosense Webster, Biotronik, Boston Scientific, and Medtronic. Dr Reddy has served as an unpaid consultant to Boston Scientific; unrelated to this paper, he has served as a consultant for and has equity in Ablacon, Acutus Medical, Affera-Medtronic, Apama Medical-Boston Scientific, Anumana, APN Health, Aquaheart, Atacor, Autonomix, Axon Therapies, Backbeat, BioSig, CardiaCare, CardioNXT/AFTx, Circa Scientific, CoRISMA, Corvia Medical, Dinova-Hangzhou DiNovA EP Technology, East End Medical, EPD-Philips, EP Frontiers, Epix Therapeutics-Medtronic, EpiEP, Eximo, Field Medical, Focused Therapeutics, HRT, Intershunt, Javelin, Kardium, Keystone Heart, LuxMed, Medlumics, Middlepeak, Neutrace, Nuvera-Biosense Webster, Oracle Health, Restore Medical, Sirona Medical, SoundCath, and Valcare; unrelated to this work, has served as a consultant for Abbott, AtriAN, Biosense Webster, BioTel Heart, Biotronik, Cairdac, Cardiofocus, Cardionomic, CoreMap, Fire1, Gore and Associates, Impulse Dynamics, Medtronic, Novartis, Philips, and Pulse Biosciences; and has equity in DRS Vascular, Manual Surgical Sciences, Newpace, Nyra Medical, Surecor, and Vizaramed. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose., (Copyright © 2024 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Purpose: Transgender women are disproportionately affected by HIV and are underutilizing preexposure prophylaxis (PrEP). The lower uptake of PrEP by transgender women may be, in part, owing to the perception that taking PrEP may lower the efficacy of gender-affirming hormone therapy (GAHT) or to provider concerns that GAHT may lower the efficacy of PrEP., Methods: DISCOVER was a randomized, double-blind, noninferiority trial comparing emtricitabine (FTC, F) and tenofovir alafenamide (F/TAF) versus emtricitabine and tenofovir disoproxil fumarate (F/TDF) as PrEP among transgender women and cisgender men who have sex with men (MSM). This nested substudy of the DISCOVER trial compared the exposure of the active intracellular metabolites of FTC and tenofovir (TFV), FTC triphosphate (FTC-TP) and TFV diphosphate (TFV-DP), in peripheral blood mononuclear cells (PBMC) among transgender women receiving GAHT versus MSM within the F/TAF and F/TDF groups., Results: Our results demonstrate that TFV-DP and FTC-TP levels in PBMC were comparable between transgender women on GAHT and MSM receiving F/TAF, and between transgender women on GAHT and MSM receiving F/TDF. TFV-DP concentrations remained above the EC 90 of 40 fmol/10 6 cells across all groups. No clinically significant drug-drug interactions of GAHT were observed with either F/TAF or F/TDF in this subanalysis., Conclusions: These findings are consistent with the clinical pharmacology of GAHT, FTC, TDF, and TAF reported in previous studies, and support the continued use of F/TAF and F/TDF for PrEP in transgender women., Clinicaltrials.gov registration number: NCT02842086., Competing Interests: M.D., J.Y., J.d.J., D.X., Y.S., P.W., A.K., C.C., and I.Y. are employed by Gilead Sciences and hold stock in the company. All other authors are investigators on this Gilead sponsored study., (Copyright 2024, Mary Ann Liebert, Inc., publishers.)

Visual attention allows the brain to evoke behaviors based on the most important visual features. Mouse models offer immense potential to gain a circuit-level understanding of this phenomenon, yet how mice distribute attention across features and locations is not well understood. Here, we describe a new approach to address this limitation by training mice to detect weak vertical bars in a background of dynamic noise while spatial cues manipulate their attention. By adapting a reverse-correlation method from human studies, we linked behavioral decisions to stimulus features and locations. We show that mice deployed attention to a small rostral region of the visual field. Within this region, mice attended to multiple features (orientation, spatial frequency, contrast) that indicated the presence of weak vertical bars. This attentional tuning grew with training, multiplicatively scaled behavioral sensitivity, approached that of an ideal observer, and resembled the effects of attention in humans. Taken together, we demonstrate that mice can simultaneously attend to multiple features and locations of a visual stimulus., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Aims: Gestational diabetes (GDM) is associated with the development of postpartum (PP) glucose intolerance. Plasma glycated CD59 (pGCD59) is an emerging biomarker for the detection of hyperglycaemia. The aim of this study was to assess the ability of PP pGCD59 to predict the development of PP GI as defined by the 2 h 75 g OGTT using the ADA criteria, in a cohort of women diagnosed with prior GDM in the index pregnancy using the 2 h 75 g OGTT at 24-28 weeks of gestation according to the World Health Organization (WHO) 2013 criteria., Methods: Of the 2017 pregnant women recruited prospectively 140 women with gestational diabetes had samples for pGCD59 taken PP at the time of the OGTT. The ability of pGCD59 to predict the results of the PP OGTT was assessed using nonparametric receiver operating characteristic (ROC) curves., Results: Women with PP glucose intolerance had significantly higher PP pGCD59 levels compared to women with normal glucose tolerance PP (3.8 vs. 2.7 SPU). PP pGCD59 identified women who developed glucose intolerance PP with an AUC of 0.80 (95% CI: 0.70-0.91). A PP pGCD59 cut-off value of 1.9 SPU generated a sensitivity of 100% (95% CI: 83.9-100), specificity of 16.9% (95% CI: 9.8-26.3), positive predictive value of 22.1% (95% CI: 21.0-22.6), and negative predictive value of 100% (95% CI: 87.4-100). PP fasting plasma glucose generated an AUC of 0.96 (95% CI: 0.89-0.99) for the identification of PP glucose intolerance., Conclusion: Our study found that PP pGCD9 may be a promising biomarker to identify women not requiring PP glucose intolerance screening using the traditional OGTT. While the diagnostic accuracy of pGCD59 is good, fasting plasma glucose remains a better test for the identification of PP glucose intolerance., (© 2023 The Authors. Diabetic Medicine published by John Wiley & Sons Ltd on behalf of Diabetes UK.)

Background: Interatrial block (IAB) is associated with thromboembolism and atrial arrhythmias. However, prior studies included small patient cohorts so it remains unclear whether IAB predicts adverse outcomes particularly in context of atrial fibrillation (AF)/atrial flutter (AFL)., Objectives: This study sought to determine whether IAB portends increased stroke risk in a large cohort in the presence or absence of AFAF/AFL., Methods: We performed a 5-center retrospective analysis of 4,837,989 electrocardiograms (ECGs) from 1,228,291 patients. IAB was defined as P-wave duration ≥120 ms in leads II, III, or aVF. Measurements were extracted as .XML files. After excluding patients with prior AF/AFL, 1,825,958 ECGs from 458,994 patients remained. Outcomes were analyzed using restricted mean survival time analysis and restricted mean time lost., Results: There were 86,317 patients with IAB and 355,032 patients without IAB. IAB prevalence in the cohort was 19.6% and was most common in Black (26.1%), White (20.9%), and Hispanic (18.5%) patients and least prevalent in Native Americans (9.2%). IAB was independently associated with increased stroke probability (restricted mean time lost ratio coefficient [RMTLRC]: 1.43; 95% CI: 1.35-1.51; tau = 1,895), mortality (RMTLRC: 1.14; 95% CI: 1.07-1.21; tau = 1,924), heart failure (RMTLRC: 1.94; 95% CI: 1.83-2.04; tau = 1,921), systemic thromboembolism (RMTLRC: 1.62; 95% CI: 1.53-1.71; tau = 1,897), and incident AF/AFL (RMTLRC: 1.16; 95% CI: 1.10-1.22; tau = 1,888). IAB was not associated with stroke in patients with pre-existing AF/AFL., Conclusions: IAB is independently associated with stroke in patients with no history of AF/AFL even after adjustment for incident AF/AFL and CHA 2 DS 2 -VASc score. Patients are at increased risk of stroke even when AF/AFL is not identified., Competing Interests: Funding Support and Author Disclosures This project was internally funded. Dr Reddy has served as a consultant to Kardium Inc (including Equity); is a consultant to Abbott, Ablacon, Acutus Medical, Affera-Medtronic, Apama Medical-Boston Scientific, APN Health, Aquaheart, Atacor, AtiAN, Autonomix, Axon Therapies, Backbeat, BioSig, Biosense-Webster, BioTel Heart, Biotronik, Boston Scientific, Cairdac, CardiaCare, Cardiofocus, Cardionomic, CardioNXT / AFTx, Circa Scientific, CoreMap, CoRISMA, Corvia Medical, Dinova-Hangzhou DiNovA EP Technology, East End Medical, EBR, EPD-Philips, EP Frontiers, Epix Therapeutics, EpiEP, Eximo, Farapulse-Boston Scientific, Fire1, Focused Therapeutics, Gore & Associates, HRT, Impulse Dynamics, Intershunt, Javelin, Keystone Heart, LuxMed, Medlumics, Medtronic, Middlepeak, Neutrace, Nuvera-Biosense Webster, Oracle Health, Philips, Pulse Biosciences, Restore Medical, Sirona Medical, SoundCath, and Valcare; and has equity from Ablacon, Acutus Medical, Affera-Medtronic, Apama Medical-Boston Scientific, APN Health, Aquaheart, Atacor, Autonomix, Axon Therapies, Backbeat, BioSig, CardiaCare, CardioNXT / AFTx, Circa Scientific, CoRISMA, Corvia Medical, Dinova-Hangzhou DiNovA EP Technology, East End Medical, EPD-Philips, EP Frontiers, Epix Therapeutics, EpiEP, Eximo, Farapulse-Boston Scientific, Focused Therapeutics, HRT, Intershunt, Javelin, Keystone Heart, LuxMed, Manual Surgical Sciences, Medlumics, Middlepeak, Neutrace, Newpace, Nuvera-Biosense Webster, Nyra Medical, Oracle Health, Restore Medical, Sirona Medical, SoundCath, Surecor, Valcare, and Vizaramed. Dr Fuster serves as the Editor-in-Chief of JACC. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose., (Copyright © 2023 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

In mammals, gestation is considered a physiological hyperprolactinemia status. Prolactin (PRL) is one of the modulators of gonadotropin-releasing hormone (GnRH) neurons function. The South American plains vizcacha (Lagostomus maximus) is a unique model to study the regulation of hypothalamic GnRH neurons by direct and indirect steroid-dependent pathways. The aim was to characterize the hypothalamic expression of endocrine markers in vizcacha during gestation as well as their response to experimental induced hyperprolactinemia. The possible involvement of PRL regulatory pathways on GnRH in the context of hypothalamic and pituitary reactivation in mid-gestating vizcachas was discussed. Using two in vivo approaches, we determined changes in the hypothalamic expression and distribution of prolactin receptor (PRLR), tyrosine hydroxylase (TH), and dopamine type 2 receptor. A significant increment in the number of tuberoinfundibular dopaminergic (TIDA) neurons was determined in the arcuate nucleus from early to term pregnancy. On the other hand, at preoptic area, the number of both TH+PRLR+ and GnRH+PRLR+ double-labeled neurons significantly decreased at mid-pregnancy probably allowing the recovery of GnRH expression indicating that both types of neurons may represent the key points of PRL indirect and direct pathways modulating GnRH. Moreover, in a model of induced hyperprolactinemic vizcachas, the inhibitory effect of PRL on GnRH at both expression and delivery levels were confirmed. These results suggest the concomitant participation of both PRL regulatory pathways on GnRH modulation and pinpoint the key role of PRL on GnRH expression enabling the recovery of the hypothalamic activity during the gestation in this species., (© 2023 Wiley Periodicals LLC.)

Background Venous thromboembolism (VTE) often occurs after hospitalization in medically ill patients, but the population benefit-risk of extended thromboprophylaxis remains uncertain. Methods and Results The MARINER (Medically Ill Patient Assessment of Rivaroxaban Versus Placebo in Reducing Post-Discharge Venous Thrombo-Embolism Risk) study (NCT02111564) was a randomized double-blind trial that compared thromboprophylaxis with rivaroxaban 10 mg daily versus placebo for 45 days after hospital discharge in medically ill patients with a creatinine clearance ≥50 mL/min. The benefit-risk balance in this population was quantified by calculating the between-treatment rate differences in efficacy and safety end points per 10 000 patients treated. Clinical characteristics of the study population were consistent with a hospitalized medical population at risk for VTE. Treating 10 000 patients with rivaroxaban resulted in 32.5 fewer symptomatic VTE and VTE-related deaths but was associated with 8 additional major bleeding events. The treatment benefit was driven by the prevention of nonfatal symptomatic VTE (26 fewer events). There was no between-treatment difference in the composite of critical site or fatal bleeding. Conclusions Extending thromboprophylaxis with rivaroxaban for 45 days after hospitalization provides a positive benefit-risk balance in medically ill patients at risk for VTE who are not at high risk for bleeding. Registration URL: https://clinicaltrials.gov/; Unique identifier: NCT02111564.

Aims: The aim of this retrospective study was to evaluate the rate of conversion to surgical release after a steroid injection in patients with a trigger finger, and to analyze which patient- and trigger finger-related factors affect the outcome of an injection., Methods: The medical records of 500 patients (754 fingers) treated for one or more trigger fingers with a steroid injection or with surgical release, between 1 January 2016 and 1 April 2020 with a follow-up of 12 months, were analyzed. Conversion to surgical release was recorded as an unsuccessful treatment after an injection. The effect of patient- and trigger finger-related characteristics on the outcome of an injection was assessed using stepwise manual backward multivariate logistic regression analysis., Results: Treatment with an injection was unsuccessful in 230 fingers (37.9%). Female sex (odds ratio (OR) 1.87 (95% confidence interval (CI) 1.21 to 2.88)), Quinnell stage IV (OR 16.01 (95% CI 1.66 to 154.0)), heavy physical work (OR 1.60 (95% CI 0.96 to 2.67)), a third steroid injection (OR 2.02 (95% CI 1.06 to 3.88)), and having carpal tunnel syndrome (OR 1.59 (95% CI 0.98 to 2.59)) were associated with a higher risk of conversion to surgical release. In contrast, an older age (OR 0.98 (95% CI 0.96 to 0.99)), smoking (OR 0.39 (95% CI 0.24 to 0.64)), and polypharmacy (OR 0.39, CI 0.12 to 1.12) were associated with a lower risk of conversion. The regression model predicted 15.6% of the variance found for the outcome of the injection treatment (R 2 > 0.25)., Conclusion: Factors associated with a worse outcome following a steroid injection were identified and should be considered when choosing the treatment of a trigger finger. In women with a trigger finger, the choice of treatment should take into account whether there are also one or more patient- or trigger-related factors that increase the risk of conversion to surgery.Cite this article: Bone Joint J  2022;104-B(10):1142-1147.

Aims: To evaluate the ability of first trimester plasma glycated CD59 (pGCD59) to predict gestational diabetes mellitus (GDM) at 24-28 weeks of gestation., Methods: Prospectively, in 378 pregnant women, GDM was diagnosed using the one step 2 h 75 g oral glucose tolerance test adjudicated by the World Health Organisation (WHO) 2013 criteria. The ability of pGCD59 to predict GDM was assessed using receiver operating characteristic (ROC) curves adjusted for maternal age, body mass index (BMI), maternal ethnicity, parity, previous GDM, family history of diabetes mellitus and week of gestation at time of pGCD59 sampling., Results: pGCD59 generated an adjusted area under the curve (AUC) of (a) 0.63 (95 %CI:0.56-0.70, p < 0.001) for predicting GDM, and (b) 0.71 (95 %CI:0.62-0.79, p < 0.001 for GDM diagnosed with a fasting plasma glucose (FPG) ≥ 5.1 mmol/L. Sensitivity analysis of BMI subgroups showed that pGCD59 generated the highest AUC in the 35 kg/m 2  ≤ BMI < 40 kg/m 2 (AUC:0.85, 95 %CI:0.70-0.98) and BMI ≥ 40 kg/m 2 (AUC:0.88, 95 %CI:0.63-0.99) categories., Conclusions: Early in pregnancy, pGCD59 may be a good predictor of GDM in women with a high BMI and a fair predictor of GDM diagnosed by an elevated FPG independent of BMI., Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: JAH has a financial interest in Mellitus LLC. Mellitus has licensed intellectual property for the technology used in this research and in developing diagnostic tools for diabetes. The interests of J.A.H. are reviewed and are managed by Brigham and Women's Hospital and Partners HealthCare in accordance with their conflict-of-interest policies. Reagents and laboratory analysis for pGCD59 were provided by Prof Jose Halperin., (Copyright © 2022 The Authors. Published by Elsevier B.V. All rights reserved.)

Reactivation of the hypothalamic-pituitary-ovarian (HPO) axis triggered by the decline in serum progesterone in mid-gestation is an uncommon trait that distinguishes the vizcacha from most mammals. Accessory corpora lutea (aCL) developed upon this event have been proposed as guarantors of the restoration of the progesterone levels necessary to mantain gestation. Therefore, the steroidogenic input of primary CL (pCL) vs aCL was evaluated before and after HPO axis-reactivation (BP and AP respectively) and in term pregnancy (TP). Nonpregnant-ovulated females (NP) were considered as the pCL-starting point group. In BP, the ovaries mainly showed pCL, whose LH receptor (LHR), StAR, 3β-HSD, 20α-HSD, and VEGF immunoexpressions were similar or lower than those of NP. In AP, luteal reactivity increased significantly compared to the previous stages, and the pool of aCL developed in this stage represented 20% of the ovarian structures, equaling the percentage of pCL. Both pCL and aCL luteal cells shared similar histological features consistent with secretory activity. Although pCL and aCL showed equivalent labeling intensity for the luteotropic markers, pCL were significantly larger than aCL. Towards TP, both showed structural disorganization and loss of secretory characteristics. No significant DNA fragmentation was detected in luteal cells throughout gestation. Our findings indicate that the LH surge derived from HPO axis-reactivation targets the pCL and boost luteal steroidogenesis and thus progesterone production. Because there are many LHR-expressing antral follicles in BP, they also respond to the LH stimuli and luteinize without extruding the oocyte. These aCL certainly contribute but it is the steroidogenic restart of the pCL that is the main force that restores progesterone levels, ensuring that gestation is carried to term. Most importantly, the results of this work propose luteal steroidogenesis reboot as a key event in the modulation of vizcacha pregnancy and depict yet another distinctive aspect of its reproductive endocrinology., Competing Interests: The authors have declared that no competing interests exist.

Introduction: The significant maternal and neonatal outcomes of gestational diabetes mellitus (GDM) make it a major public health concern. Mothers with GDM are at greater risk of pregnancy complications and their offspring are at higher risk of diabetes and obesity. Currently, GDM is diagnosed with glucose load methods which are time-consuming and inconvenient to administer more than once during pregnancy; for this reason, there is a recognised need for a more accurate and simpler test for GDM. Previous studies indicate that plasma-glycated CD59 (pGCD59) is a novel biomarker for GDM. We present here the protocol of a prospective cohort study designed to (1) determine the accuracy of pGCD59 as an early, first trimester predictor of GDM and gestational impaired glucose tolerance and (2) assess the associations between pGCD59 levels and adverse maternal and neonatal outcomes., Methods and Analysis: We will obtain discarded plasma samples from pregnant women at two time points: first prenatal visit (usually <14 weeks gestation) and gestational weeks 24-28. A study-specific medical record abstraction tool will be used to obtain relevant maternal and neonatal clinical data from the EPIC clinical database. The prevalence of GDM will be determined using standard of care glucose load test results. We will determine the sensitivity and specificity of pGCD59 to predict the diagnosis of GDM and gestational impaired glucose tolerance, as well as the associations between levels of pGCD59 and the prevalence of maternal and neonatal outcomes., Ethics and Dissemination: This study has been approved by the Mass General Brigham Institutional Review Board (protocol 2011P002254). The results of this study will be presented at international meetings and disseminated in peer-reviewed journals., Competing Interests: Competing interests: JH is a founder and has financial interest in Mellitus LLC. Mellitus had licensed related IP and has interests in developing diagnostic tools for diabetes. JH’s interests were reviewed and are managed by Brigham and Women’s Hospital and Brigham Health in accordance with their conflict of interest policies. All other authors declare no competing financial interests in relation to the work described., (© Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Sarcoidosis is a systemic inflammatory disease of unknown etiology with a myriad of clinical presentations depending on the organ systems involved. Neurosarcoidosis is an uncommon entity which is characterized by non-caseating granuloma infiltration of the central nervous system. Dysphagia in sarcoidosis is even more uncommon, and can involve one or more pathophysiological mechanisms: central nervous system involvement (cranial nerves associated with swallowing), lower motor neuron involvement (invasion of the enteric nervous plexus), direct muscle infiltration (invasion of the skeletal muscle portion of the esophagus and posterior pharynx), or mechanical obstruction (extrinsic compression by mediastinal lymph nodes). We report a case of a middle-aged woman presenting with severe dysphagia due to neurosarcoidosis which markedly improved after starting corticosteroids. The purpose of this case report is to highlight an atypical presentation of this disease., Competing Interests: There are no conflicts of interest that need declaration for this case report., (© 2022 The Authors.)

The incidence of left ventricular (LV) thrombus following acute myocardial infarction has markedly declined in recent decades caused by advancements in reperfusion and antithrombotic therapies. Despite this, embolic events remain the most feared complication of LV thrombus necessitating systemic anticoagulation. Mechanistically, LV thrombus development depends on Virchow's triad (ie, endothelial injury from myocardial infarction, blood stasis from LV dysfunction, and hypercoagulability triggered by inflammation, with each of these elements representing potential therapeutic targets). Diagnostic modalities include transthoracic echocardiography with or without ultrasound-enhancing agents and cardiac magnetic resonance. Most LV thrombi develop within the first 2 weeks post-acute myocardial infarction, and the role of surveillance imaging appears limited. Vitamin K antagonists remain the mainstay of therapy because the efficacy of direct oral anticoagulants is less well established. Only meager data support the routine use of prophylactic anticoagulation, even in high-risk patients., Competing Interests: Funding Support and Author Disclosures Dr Giustino has received honoraria from Bristol Myers Squibb. Dr Halperin has performed consulting activities with Bayer HealthCare, Boehringer Ingelheim, and Ortho-McNeil-Janssen; and has served on the Steering Committee of the CATALYST trial, sponsored by Abbott. Dr Sharma has received consulting fees or honoraria from Abbott, Boston Scientific, Abiomed, and Cardiovascular Systems, Inc. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose., (Copyright © 2022. Published by Elsevier Inc.)

Kisspeptin (KISS), a key hormone involved in the regulation of the hypothalamic-pituitary-ovarian (HPO) axis, has been localized in the anteroventral periventricular (AVPV) nucleus and the neighboring rostral periventricular nucleus (PeVN), and in the arcuate (ARC) nucleus of the mammalian hypothalamus. In the ARC, the KISS neurons that co-express neurokinin B (NKB) and dynorphin A (Dyn) are named KNDy cells. The South American plains vizcacha is a rodent with peculiar reproductive traits. Around mid-pregnancy, vizcacha shows the reactivation of its HPO axis with the pulsatile release of gonadotropin-releasing hormone (GnRH) and luteinizing hormone (LH), an essential event for the success of gestation. Considering the role of KISS system in GnRH modulation, the aim of this work was to study their neuroanatomical distribution in adult vizcachas. AVPV showed sexual dimorphism with a significant smaller area in males (t-Test, p < 0.05), and KISS immunoreactivity was detected in somas and varicosities homogenously distributed in the AVPV with a concordant sex-related expression pattern. NKB and Dyn expression was also observed in cytoplasm of neurons scattered in the AVPV. Three subpopulations of neurons were detected in the AVPV: neurons expressing Dyn and NKB (DyNK cells), neurons expressing KISS and NKB (KiNK cells), and single NKB expressing neurons. Strikingly, KISS and Dyn were always expressed in different cells. In addition, in the ARC nucleus, KNDy cells were detected. On the other hand, KISS and GnRH expression was detected in different subpopulations of neurons, GnRH cells showed KISS receptor (KISSR or GPR-54) expression, and KISS immunoreactive afferent contacts were detected making close appositions onto somas and dendrites of GnRH cells. These results show similarities and differences between the KISS system in the hypothalamus of the vizcacha and other mammals, and constitute crucial observations about KISS and GnRH relation. Considering the peculiarity of HPO axis regulation in this species, the present work provides a neuroanatomical framework for the further elucidation of molecular mechanisms underlying GnRH expression and secretion., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Objective: To update the 2011 American Academy of Neurology (AAN) guideline on the treatment of painful diabetic neuropathy (PDN) with a focus on topical and oral medications and medical class effects., Methods: The authors systematically searched the literature from January 2008 to April 2020 using a structured review process to classify the evidence and develop practice recommendations using the AAN 2017 Clinical Practice Guideline Process Manual., Results: Gabapentinoids (standardized mean difference [SMD] 0.44; 95% confidence interval [CI], 0.21-0.67), serotonin-norepinephrine reuptake inhibitors (SNRIs) (SMD 0.47; 95% CI, 0.34-0.60), sodium channel blockers (SMD 0.56; 95% CI, 0.25-0.87), and SNRI/opioid dual mechanism agents (SMD 0.62; 95% CI, 0.38-0.86) all have comparable effect sizes just above or just below our cutoff for a medium effect size (SMD 0.5). Tricyclic antidepressants (TCAs) (SMD 0.95; 95% CI, 0.15-1.8) have a large effect size, but this result is tempered by a low confidence in the estimate., Recommendations Summary: Clinicians should assess patients with diabetes for PDN (Level B) and those with PDN for concurrent mood and sleep disorders (Level B). In patients with PDN, clinicians should offer TCAs, SNRIs, gabapentinoids, and/or sodium channel blockers to reduce pain (Level B) and consider factors other than efficacy (Level B). Clinicians should offer patients a trial of medication from a different effective class when they do not achieve meaningful improvement or experience significant adverse effects with the initial therapeutic class (Level B) and not use opioids for the treatment of PDN (Level B)., (© 2021 American Academy of Neurology.)

Melatonin, the key messenger of photoperiodic information, is synthesized in the pineal gland by arylalkylamine N-acetyltransferase enzyme (AANAT). It binds to specific receptors MT 1 and MT 2 located in the hypothalamus and pituitary gland. Melatonin can modulate the reproductive axis affecting the secretion of gonadotropin-releasing hormone (GnRH) and luteinizing hormone (LH). The South American plains vizcacha, Lagostomus maximus, shows natural poliovulation of up to 800 oocytes per estrous cycle, a 154-day long pregnancy, and reactivation of the reproductive axis at mid-gestation with pre-ovulatory follicular recruitment, presence of active corpora lutea, and variations of the endocrine status. Here we analyzed the involvement of melatonin in the modulation of the hypothalamic and pituitary gland physiology of vizcacha thorough several approaches, including histological localization of melatoninergic system components, assessment of melatoninergic components expression throughout the reproductive cycle, and evaluation of the effect of melatonin on hypothalamic and pituitary activities during the follicular and luteal phases of the estrous cycle. AANAT and melatonin receptors were localized in the pineal gland and preoptic area of the hypothalamus. Increase in pineal AANAT and serum melatonin expression was observed as pregnancy progressed, with the lowest hypothalamic MT 1 and MT 2 levels at mid-pregnancy. Pulsatility assays demonstrated that melatonin induces GnRH and LH secretion at luteal phase. The melatoninergic system effects on hypothalamic and pituitary gland hormones secretion during pregnancy pinpoint to melatonin as a potential key factor underlying the reactivation of the reproductive axis activity at mid-gestation., (© 2021. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Innovative delivery strategies are needed to facilitate access to HIV pre-exposure prophylaxis (PrEP). The objective of this study was to evaluate a navigator-facilitated PrEP referral process from a sexual health center (SHC) to a co-located PrEP clinic as an alternative delivery model. Electronic health record (EHR) data were used to calculate the number of clients seen at the SHC in 2019. Charts were manually reviewed to determine whether a PrEP clinic referral was made and document type of referral method: face-to-face appointment scheduling with the navigator ( warm handoff ), EHR messaging to navigator to schedule the appointment at a later time ( EHR message ), or provision of navigator's contact information to the client ( card only ). In 2019, 2481 unique potentially PrEP-eligible clients were seen at the SHC; 220 (9%) received a PrEP referral. Of referred clients, median age was 30 years (interquartile range, 24-34), 182 (83%) were male, 89 (40%) were non-Hispanic Black, and 24 (11%) were Latinx. In total, 94/220 (43%) referred clients attended an initial PrEP visit with a provider, and the proportion attending by referral method was 81%, 36%, and 27% for warm handoff, EHR message, and card only, respectively ( p  < 0.0001). Despite co-location of these two clinics, there were significant drop-offs along the PrEP care continuum for this referral system. Warm handoff was the most effective referral method, but further efforts are needed to understand barriers to referral. Implementation of same-day PrEP services at SHCs is one potential solution to engaging additional clients.

Endoparasites of the Sarcocystidae family share the ability to form tissue cysts in their intermediate hosts, ultimately leading to pathogenesis in the definitive hosts that include various mammals, reptiles and birds. In our research on the endocrinology of the female vizcachas ( Lagostomus maximus ), we have found abnormal cystic structures in the ovaries of some individuals. So far, no cases of infection by tissue cyst-forming parasites have been reported in this species. To evaluate whether this autochthonous wild rodent is an intermediate host of an undescribed endoparasite, histological sections from various organs were examined. Pinhead-sized tissue cysts were found in the ovaries, mammary glands, uterus, pituitary, brain, adrenals and spleen, of both pregnant and non-pregnant females. The presence of cysts in the adult brain and embryonic tissue is indicative of the ability of the parasite to cross both the blood-brain and placental barriers. The infected brains exhibited a lower cyst density than that seen in other organs. Regardless of their location in superficial or deep tissue, the cysts were surrounded by a layer of connective tissue. Histologically, the cyst wall consisted of an outer layer of fibroblasts and collagen fibers, and an inner, granular-looking layer composed of host nucleated cells surrounding thousands of spindle-shaped bradyzoites. Outside the cysts, the host cellular structures showed normal appearance. The remarkable morphological similarities between the cysts studied here with those reported in naturally infected rabbits from an area neighboring the one inhabited by the vizcachas point to Besnoitia sp. as a plausible candidate. More studies will be necessary to confirm the identity of the parasite. Nevertheless, this is the first report of L. maximus as an intermediate host for a tissue cyst-forming coccidia., Competing Interests: The authors of this publication have nothing to disclose., (© 2021 The Authors. Published by Elsevier Ltd on behalf of Australian Society for Parasitology.)

Federally qualified health centers (FQHCs) are on the front lines of the COVID-19 pandemic. Their mission of providing essential medical care to underserved populations is now even more vital. CrescentCare, an FQHC in New Orleans, evaluated and tested 3366 patients between March 16 and July 2, with an overall rate of 12% SARS-CoV-2 positivity. The clinic's experience demonstrates how to effectively and rapidly integrate COVID-19 programing, while preserving essential health services. Strategies include developing a walk-in COVID-19 testing site, ensuring appropriate clinical evaluation, providing accurate public health information, and advocating for job safety on behalf of our patients.

The Covid-19 pandemic and the social distancing required to combat it have set in motion an experiment in psychoanalytic education of unprecedented scope. Following an abrupt shift from in-person study to remote classes, supervision, clinical work, and training analyses, the Columbia University Center for Psychoanalytic Training and Research polled its psychotherapy and psychoanalysis trainees to assess their initial experience of remote training. Most candidates found the technical aspects of online learning easy and were satisfied with remote training overall. Across all programs, most trainees considered class length and reading load about right and felt their class participation was unaffected, though they found it harder to concentrate. Most found it no harder to start a training case, felt the shift to remote supervision had no negative effect, and were satisfied with seeing their training analyst remotely. Most trainees preferred in-person classes, clinical work, and training analyses to those offered remotely, yet in light of the health risks they said they were less likely to continue training in fall 2020 if in-person work resumed. Trainees suggested several modifications of teaching techniques to improve their participation and concentration in class. These findings' implications for the debate regarding remote training in psychoanalysis are explored.

Federally qualified health centers are on the frontlines of the coronavirus disease 2019 (COVID-19) pandemic in the United States. It is essential to develop the workflows necessary to evaluate patients, perform appropriate diagnostics, make clinical recommendations, and provide public health messaging. This brief report presents findings from our COVID-19 response and compares the characteristics between the 345 patients screened between March 16 and April 10, 2020. One hundred seventeen patients tested positive for COVID-19, an overall rate of 33.9%; and Black race, increased heart rate, elevated temperature, and the use of antipyretic agents were associated with positive results., (© 2020 Mayo Foundation for Medical Education and Research. Published by Elsevier Inc.)

Aims: This study aimed to describe baseline characteristics of patients with atrial fibrillation (AF) at risk of stroke with and without history of heart failure (HF) and report 2-year outcomes in the dabigatran-treated subset of a prospective, global, observational study (GLORIA-AF)., Methods and Results: Newly diagnosed patients with AF and CHA 2 DS 2 -VASc score ≥ 1 were consecutively enrolled. Baseline characteristics were assessed by the presence or absence of HF diagnosis at enrolment. Incidence rates for outcomes in dabigatran-treated patients were estimated with and without standardization by stroke (excluding HF component) and bleeding risk scores. A total of 15 308 eligible patients were enrolled, including 15 154 with known HF status; of these, 3679 (24.0%) had been diagnosed with HF, 11 475 (75.0%) had not. Among 4873 dabigatran-treated patients, 1169 (24.0%) had HF, and 3658 (75.1%) did not; the risk of stroke was high (CHA 2 DS 2 -VASc score ≥ 2) for 94.3% of patients with HF and 85.8% without, while 6.0% and 7.0%, respectively, had a high bleeding risk (HAS-BLED ≥ 3). Incidence rates of all-cause death in dabigatran-treated patients with and without HF, standardized for CHA 2 DS 2 -VASc and HAS-BLED scores, were 4.76 vs. 1.80 per 100 patient years (py), with roughly comparable rates of stroke (0.82 vs. 0.60 per 100 py) and major bleeding (1.20 vs. 0.92 per 100 py)., Conclusions: Patients with AF and history of HF may have greater disease burden at AF diagnosis and increased mortality rates vs. patients without HF. Stroke and major bleeding rates were roughly comparable between groups confirming the long-term safety and effectiveness of dabigatran in patients with HF., (© 2020 The Authors. ESC Heart Failure published by John Wiley & Sons Ltd on behalf of the European Society of Cardiology.)

In addition to key mammotrophic hormones such as the pituitary prolactin (PRL) and the ovarian steroids progesterone and estradiol, there are local factors that modulate the tissue dynamics of the mammary glands during pregnancy and lactation. By immunohistochemistry and RT-PCR, we found local transcription and translation of gonadotropin-releasing hormone (GNRH), GNRH receptor (GNRHR), PRL and PRL receptor (PRLR) in mammary glands of adult vizcachas during pregnancy and lactation. Both GNRH and GNRHR showed a lag between protein expression and gene transcription throughout the gestational period: while the highest transcription levels of these genes were recorded at early-pregnancy, the epithelial immunoexpressions of both showed their maximum during lactation. RIA results corroborated the presence of GNRH in mammary glands at all the analyzed stages and confirmed the maximum amount of this peptide in the lactating group. Significant amounts of GNRH were detected in milk samples as well. Conversely, PRL and PRLR shared similar protein and gene expression profiles, all exhibiting maximum values during lactation. GNRH peptide content in mammary glands of females with sulpiride-induced hyperprolactinemia (HP) was significantly lower than that of control females (CT). Although PRL mRNA levels remained unchanged, there was a marked increase in theα-lactalbumin (LALBA) transcription in mammary glands of HP- vs CT-females. These results suggest that after targeting mammary glands, PRL stimulates the expression of milk protein genes, but also, tempers the local expression of GNRH. Mammary gland-explantssupplemented with a GNRH analogue (GN-explants) had no differences in terms of PRLR orLALBA transcription levels compared to CT-explants, so the mammary PRLR signaling would not appear to be modulated by GNRH. Yet, mRNA expression levels of both GNRH and the GNRHR-downstream factor, EGR1, were significantly higher in GN-explants compared to that of CT which would point to a GNRH-positive feedback mechanism. In summary, the local coupled expression of GNRH, GNRHR and EGR1 in the mammary gland throughout pregnancy of vizcachas, the PRL-dependent mammary GNRH secretion as well as the GNRH positive feedback on its own transcription suggest an autocrine-paracrine regulatory mechanism and propose an active role for GNRH in mammary gland tissue remodeling., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Background: The prevalence of Gestational Diabetes (GDM) is rising and with it the number of mothers and children at risk of adverse outcomes. As treatment has been shown to reduce adverse events, it is imperative that we identify all at-risk pregnant women. In Ireland, the national standard of care is selective screening with a 2-hour 75 g oral glucose tolerance test (OGTT). Aiming for universal screening is of utmost importance but this is difficult given the length, the unfeasibility and impracticability of the OGTT. We aim to assess if the novel biomarker glycated CD59 (gCD59) is a suitable contender for the OGTT in identifying women with GDM., Methods: In this prospective cohort study, the study participants will be consecutive pregnant women at Galway University Hospital, Galway, Ireland. Samples for the plasma gCD59 biomarker will be taken together with routine bloods at the first antenatal visit, at weeks 24-28 at the time of routine 75 g OGTT, in trimester 3- and 12-weeks post-partum for women with GDM while having their routine post-partum 75 g OGTT. The constructed database will contain baseline information on each study participant, baseline laboratory data, follow-up laboratory data and pregnancy related outcomes. We aim to recruit a total of 2,000 participants over the project period and with a national GDM prevalence of 12-13%, we will have 240-260 subjects who meet OGTT criteria for GDM. Following regional prevalence, we expect to have 34-37 women who will develop either diabetes or pre-diabetes in the early post-partum period. The sensitivity and specificity of plasma gCD59 to predict the results of the OGTT will be assessed using nonparametric estimates of the receiver operating characteristic (ROC) curves and respective area under the ROC curve (AUROC)., Discussion: A body of clinical and experimental evidence supports a link between the complement system, complement regulatory proteins, and the pathogenesis of diabetes complications. Building on this research, our study plans to look at the plasma gCD59 capacity to classify pregnant women with normal or abnormal glucose tolerance but also to assess if plasma gCD59 can be used as an early predictor for GDM, for adverse pregnancy outcomes and/or post-partum glucose intolerance.

Purpose: The objective of this study was to analyse the expression and cellular localization of FOXO3, pFOXO3 and PTEN throughout human ovary development both before and after birth., Methods: Foetal, pubertal and adult paraffin-embedded ovarian samples were analysed by immunohistochemistry for cellular localization of FOXO3, pFOXO3 and PTEN proteins. Protein and mRNA expression were analysed by western blot and real time PCR, respectively, from fresh biopsies., Results: PTEN was not detected by immunohistochemistry in germ cells and follicles of foetal, pubertal and adult ovaries. Occasional PTEN immunoreactive granulosa cells were found in atretic antral follicles in the adult ovary. Western blot analysis showed low levels of PTEN protein. Nuclear FOXO3-expressing primordial follicles represented a variable proportion of the ovarian reserve. The presence of FOXO3-expressing primordial follicles was very low in foetal ovary; although always represented in a low proportion, prevalence increased during pubertal and adult life., Conclusion: Our results seem to indicate that two subpopulations of primordial follicles, i.e. nuclear FOXO3-expressing and no FOXO3-expressing primordial follicles are found in the postnatal human ovary. This scenario suggests that FOXO3 could be acting as in the mouse model, preventing primordial follicle activation. However, the strategy would not be an "all or nothing" system as in mouse ovary but rather a selected subpopulation of primordial follicles preserved to ensure long-term fertility.

The South American plains vizcacha, Lagostomus maximus, is the only mammal described so far that shows expression of estrogen receptors (ERs) and progesterone receptors (PRs) in gonadotropin-releasing hormone (GnRH) neurons. This animal therefore constitutes an exceptional model for the study of the effect of steroid hormones on the modulation of the hypothalamic-pituitary-ovarian (HPO) axis. By using both in vivo and ex vivo approaches, we have found that pharmacological doses of progesterone (P4) and estradiol (E2) produced an inhibition in the expression of hypothalamic GnRH, while physiological doses produced a differential effect on the pulsatile release frequency or genomic expression of GnRH. Our ex vivo experiment indicates that a short-term effect of E2 modulates the frequency of GnRH release pattern that would be associated with membrane ERs. On the other hand, our in vivo approach suggests that a long-term effect of E2, acting through the classical nuclear ERs-PRs pathway, would produce the modification of GnRH mRNA expression during the GnRH pre-ovulatory surge. Particularly, P4 induced a rise in GnRH mRNA expression and protein release with a decrease in its release frequency. These results suggest different levels of action of steroid hormones on GnRH modulation. We conclude that the fine action of E2 and P4 constitute the key factor to enable the hypothalamic activity during the pregnancy of this mammal., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Research over several decades has identified significant problems with the progression model-the traditional approach to assessment and advancement of psychoanalytic candidates-including candidates' anxiety and uncertainty about the methods and fairness of their assessment, avoidance of conflictual issues with patients in order to keep cases, and reluctance to share their challenges with supervisors and advisors. In light of these findings, the Columbia Center for Psychoanalytic Training and Research restructured its psychoanalytic training programs. The progression committee, the progression advisor role, candidate application to advance through the program, and routine committee discussion of candidates were eliminated and replaced by confidential mentorship and a clear and predictable system of trainee advancement. Analytic competency-a requirement for graduation-is now determined solely from detailed written feedback regarding the candidate's achievement of the Center's learning objectives. The number of months of supervised analysis required for graduation has been reduced, as has the required length of the candidate's longest case; in addition, three-times-weekly analyses are now accepted for credit. These changes are meant to increase the transparency, objectivity, and predictability of the training experience and reduce the pressure on clinical decision making and communication between trainees and faculty. An extensive evaluation of the impact of these innovations is currently under way.

Heme-regulated inhibitor (HRI), a eukaryotic translation initiation factor 2 alpha (eIF2α) kinase, is critically important for coupling protein synthesis to heme availability in reticulocytes and adaptation to various environmental stressors in all cells. HRI modifies the severity of several hemoglobin misfolding disorders including β-thalassemia. Small molecule activators of HRI are essential for studying normal- and patho-biology of this kinase as well as for the treatment of various human disorders for which activation of HRI or phosphorylation of eIF2α may be beneficial. We previously reported development of 1-((1,4-trans)-4-aryloxycyclohexyl)-3-arylureas (cHAUs) as specific HRI activators and demonstrated their potential as molecular probes for studying HRI biology and as lead compounds for treatment of various human disorders. To develop more druglike cHAUs for in vivo studies and drug development and to expand the chemical space, we undertook bioassay guided structure-activity relationship studies replacing cyclohexyl ring with various 4-6-membered rings and explored further substitutions on the N-phenyl ring. We tested all analogs in the surrogate eIF2α phosphorylation and cell proliferation assays, and a subset of analogs in secondary mechanistic assays that included endogenous eIF2α phosphorylation and expression of C/EBP homologous protein (CHOP), a downstream effector. Finally, we determined specificity of these compounds for HRI by testing their anti-proliferative activity in cells transfected with siRNA targeting HRI or mock. These compounds have significantly improved cLogPs with no loss of potencies, making them excellent candidates for lead optimization for development of investigational new drugs that potently and specifically activate HRI., (Copyright © 2019. Published by Elsevier Masson SAS.)

Depending on the presence or absence of sulci and convolutions, the brains of mammals are classified as gyrencephalic or lissencephalic. We analyzed the encephalic anatomy of the hystricomorph rodent Lagostomus maximus in comparison with other evolutionarily related species. The encephalization quotient (EQ), gyrencephaly index (GI), and minimum cortical thickness (MCT) were calculated for the plains vizcacha as well as for other myomorph and hystricomorph rodents. The vizcacha showed a gyrencephalic brain with a sagittal longitudinal fissure that divides both hemispheres, and 3 pairs of sulci with bilateral symmetry; that is, lateral-rostral, intraparietal, and transverse sulci. The EQ had one of the lowest values among Hystricomorpha, while GI was one of the highest. Besides, the MCT was close to the mean value for the suborder. The comparison of EQ, GI, and MCT values between hystricomorph and myomorph species allowed the detection of significant variations. Both EQ and GI showed a significant increase in Hystricomorpha compared to Myomorpha, whereas a Pearson's analysis between EQ and GI depicted an inverse correlation pattern for Hystricomorpha. Furthermore, the ratio between MCT and GI also showed a negative correlation for Hystricomorpha and Myomorpha. Our phylogenetic analyses showed that Hystricomorpha and Myomorpha do not differ in their allometric patterning between the brain and body mass, GI and brain mass, and MCT and GI. In conclusion, gyrencephalic neuroanatomy in the vizcacha could have developed from the balance between the brain size, the presence of invaginations, and the cortical thickness, which resulted in a mixed encephalization strategy for the species. Gyrencephaly in the vizcacha, as well as in other Hystricomorpha, advocates in favor of the proposal that in the more recently evolved Myomorpha lissencephaly would have arisen from a phenotype reversal process., (© 2021 S. Karger AG, Basel.)

The striatum is an essential component of the basal ganglia that regulatessensory processing, motor, cognition, and behavior. Depending on the species, the striatum shows a unique structure called caudate-putamen as in mice, or its separation into two regions called caudate and lenticular nuclei, the latter formed by putamen and globus pallidus areas, as in primates. These structures have two compartments, striosome and matrix. We investigated the structural organization, GABAergic and tyrosine hydroxylase (TH) expression in the striatum and globus pallidus of the South American plains vizcacha, Lagostomus maximus. Its striatum showed regionalization arising from the presence of an internal capsule, and a similar organization to a striosome-matrix compartmentalization. GABAergic neurons in the matrix of caudate exhibited parvalbumin, calretinin, calbindin, GAD65, and NADPH-d-immunoreactivity. These were also expressed in cells of the putamen with the exception of calretinin showing neurofibers localization. Globus pallidus showed parvalbumin- and GAD65-immunoreactive cells, and calretinin- and calbindin-immunoreactive neuropil, plus GABA-A-immunoreactive neurofibers. NADPH-d-, GAD65- and GABA-A-immunoreactive neurons were larger than parvalbumin-, calretinin-, and calbindin-immunoreactive cells, whereas calbindin-immunoreactive cells were the most abundant. In addition, TH-immunoreactive neuropil was observed in the matrix of the striatum. A significant larger TH-immunoreactive area and neuron number was found in females compared to males. The presence of an internal capsule suggests an adaptive advantage concerning motor and cognitive abilities favoring reaction time in response to predators. In an anatomy-evolutive perspective, the striatum of vizcacha seems to be closer to that of humans than to that of laboratory traditional models such as mouse.

Objective: The aim of this study was to validate the use of region of interest (ROI) measurements in MRI to objectively assess for enhancement in suspected solid renal masses and to determine a minimum threshold value for true enhancement., Methods: Contrast-enhanced renal MRI studies performed between January 2015 and December 2017 for patients with a known renal mass who had subsequent biopsy, or partial/radical nephrectomy were included. Two body imaging fellows independently measured the mean ROI values of renal masses, normal renal parenchyma, the ipsilateral psoas muscle and external air on the pre- and post-contrast sequences. The absolute and percentage changes in the mean ROI values were calculated. The readers were blinded to the pathology results., Results: 104 patients were included in this study (mean age of 65 years; 58 males and 46 females). 74 patients (71%) had a diagnosis of renal cell carcinoma (RCC). Pathology showed clear-cell RCC in 55%, papillary RCC in 22%, and other RCC subtypes in 23%. There were 30 non-RCC renal lesions (29%), including oncocytoma, renal papillary adenoma, and renal metastasis.The minimum percentage change in ROI values in the pre- versus post-contrast images for all pathology-proven RCCs was 23% (range: 23-437%, mean: 143%); this represents relative enhancement and was referred to as the Signal Intensity Index (SII). The percentage change for normal renal parenchyma ranged from 32-317%. The maximum percentage change in ROI values for pathology proven renal cysts was 13% (range: -5-13%, mean: 3.5%). There was excellent inter observer agreement between the two readers [Intra-class correlation coefficient (r) 0.81]., Conclusion: The percentage change in ROI values (SII) can be a helpful tool in the objective assessment of true enhancement of renal masses and can supplement subtraction images. The minimum threshold for enhancement in our study was 23%., Advances in Knowledge: Enhancement of a renal lesion can be determined using the objective tool of ROI measurements in the pre- and post-contrast MR images with a percentage change of 20% or above indicating enhancement. This is an additional objective tool, which in conjunction with the subtraction images may improve detection and appropriate diagnosis of renal lesions. It could also be helpful in cases where the subtraction images are degraded by motion artefact.

Rapid-start, immediate antiretroviral therapy (ART) initiation is a novel intervention that leads to earlier viral suppression. Longer-term data is essential before supporting this strategy more widely. CrescentCare, a federally qualified health center in New Orleans, followed 195 patients who received same-day ART; here we present a continuum of care for immediate ART intervention.

The South American plains vizcacha, Lagostomus maximus, is a caviomorph rodent native from Argentina, Bolivia and Paraguay. It shows peculiar reproductive features like pre-ovulatory follicle recruitment during pregnancy with an ovulatory process at around mid-gestation. We have described the activation of the hypothalamic - pituitary - ovarian (HPO) axis during pregnancy. A progressive decrease of progesterone (P4) at mid-pregnancy elicits the delivery of gonadotropin-releasing hormone (GnRH) with the consequent secretion of follicle stimulating hormone (FSH) and estradiol (E 2 ) followed by luteinizing hormone (LH) release resulting in follicular luteinization and the P4 concentration recover. Pituitary gland is the central regulator of the HPO axis being E 2 a key hormone involved in the regulation of its activity. In this work we analyzed the action of E 2 on the pituitary response to the GnRH wave as well as its involvement on LH secretion at mid-gestation in L. maximus. The expression of GnRHR at the pituitary pars distalis showed a significant decrease at mid-pregnancy compared to early- and term-gestating females. ERα showed a significant increment from mid-gestation whereas ERβ did not show variations throughout pregnancy; whereas the LH expression in the pituitary pars distalis showed a significant increase at mid-gestation, concordantly with serum LH, which was followed by a decrease at term-gestation with similar values than at early-pregnancy. The number of cells with co-localization of ERα and GnRHR showed a decline at mid-pregnancy related to early- and term-gestation, whereas the cells with co-localization of ERα and LH increased at mid- and term-pregnancy. On the other hand, ex vivo measuring of LH pulsatility showed a significant increment in the total mass of LH delivered at mid-pregnancy followed by a decrease at term-gestation. The stimulation of ERα with the PPT specific agonist induced a significant increment in the total mass of LH released, whereas no changes were determined when ERβ was stimulated with its specific agonist MPP. These results suggest that LH pulsatility rise at mid-pregnancy would be enabled by the increase of E 2 acting through ERα., (Copyright © 2018 Elsevier Inc. All rights reserved.)

The PIONEER AF-PCI trial demonstrated that in atrial fibrillation patients who underwent intracoronary stenting, either rivaroxaban 15 mg daily plus P2Y 12 inhibitor monotherapy (Group 1) or 2.5 mg rivaroxaban twice daily plus dual antiplatelet therapy (DAPT) (Group 2) was associated with fewer recurrent hospitalizations, primarily for bleeding and cardiovascular events, compared with standard-of-care vitamin K antagonist and DAPT (Group 3). Associated costs are unknown. This study estimates costs associated with rivaroxaban strategies compared with vitamin K antagonist and DAPT. Medication costs were estimated using wholesale acquisition costs, medication discontinuation rates, and costs of monitoring. Using a large US healthcare claims database, the mean adjusted increase in 1-year cost of care for individuals with atrial fibrillation and percutaneous coronary intervention (PCI) rehospitalized for bleeding, cardiovascular, and other events was compared with those not rehospitalized. Using adjudicated rehospitalization rates from PIONEER AF-PCI, cost differences were estimated. Rates of rehospitalization for bleeding were 6.5%, 5.4%, 10.5%, and 20.3%, 20.3%, 28.4% for cardiovascular events in Groups 1, 2, and 3. Medication and monitoring costs were $3,942, $4,115, and $1,703. One-year costs for all recurrent hospitalization costs and/or patient for the groups were $24,535, $20,205, and $29,756. One-year cost increase associated with bleeding rehospitalizations and/or patient was $4,160, $3,212, and $6,876 and was $13,264, $11,545, and $17,220 for cardiovascular rehospitalizations and/or patient. Overall estimated cost per patient was $28,476, $24,320, and $31,458. Compared with warfarin, both rivaroxaban treatment strategies had higher medication costs, but these were more than accounted for by fewer hospitalizations., (Copyright © 2018. Published by Elsevier Inc.)

Aims: Catheter ablation for atrial fibrillation (AF) is associated with a transitory increase in the risk of both thromboembolic and bleeding events. Evidence on the use of nonvitamin K antagonist oral anticoagulants (NOACs) in patients undergoing AF ablation mostly comes from small observational studies, underpowered to detect differences in clinical outcomes between NOACs and vitamin K antagonists (VKAs) treated patients. This updated meta-analysis aimed to determine the safety and efficacy of periprocedural anticoagulation with NOACs compared with VKAs in AF patients undergoing catheter ablation., Methods: We searched MEDLINE, Cochrane library, and web sources for randomized and observational studies comparing periprocedural treatment with NOACs and VKAs in patients undergoing AF ablation. The primary safety endpoint was major bleeding events, and the primary efficacy endpoint was thromboembolic events (a composite of systemic thromboembolism, transient ischemic attack, and stroke)., Results: A total of 29 studies with 12 644 patients were included in the meta-analysis. Overall, patients on NOACs had a significantly lower risk of major bleeding compared to VKAs either in observational studies (Peto OR 0.68; 95% CI: 0.48-0.95; P = 0.022; I 2  = 20%) or in RCTs (Peto OR 0.30; 95% CI: 0.14-0.62; P = 0.001; I 2  = 28%). Uninterrupted NOACs reduced the risk of major bleeding when compared to uninterrupted VKAs (Peto OR 0.66; 95% CI: 0.45-0.96; P = 0.028; I 2  = 1%), similarly, interrupted NOACs lowered the risk of major bleeding compared to interrupted VKAs (Peto OR 0.29; 95% CI: 0.13-0.66; P = 0.003; I 2  = 0%; P interaction  = 0.076). The rate of thromboembolic complications was very low and did not significantly differ between the study groups either in observational studies (Peto OR 0.91; 95% CI: 0.49-1.67; P = 0.755; I 2  = 0%) or in RCTs (Peto OR 0.14; 95% CI: 0.01-1.30; P = 0.083; I 2  = 0%)., Conclusions: Use of NOACs compared to VKAs significantly reduced the risk of bleeding in patients with AF ablation. Similarly, the risk of bleeding was lower with uninterrupted NOACs than with uninterrupted VKAs, and with interrupted NOACs than with interrupted VKAs. The rate of thromboembolic complications was extremely low in both study groups without any differences., (© 2018 John Wiley & Sons Ltd.)

Prolactin (PRL) is essential for the maintenance of the corpora lutea and the production of progesterone (P4) during gestation of mice and rats, which makes it a key factor for their successful reproduction. Unlike these rodents and the vast majority of mammals, female vizcachas ( Lagostomus maximus ) have a peculiar reproductive biology characterized by an ovulatory event during pregnancy that generates secondary corpora lutea with a consequent increment of the circulating P4. We found that, although the expression of pituitary PRL increased steadily during pregnancy, its ovarian receptor (PRLR) reached its maximum in midpregnancy and drastically decreased at term pregnancy. The luteinizing hormone receptor (LHR) exhibited a similar profile than PRLR. Maximum P4 and LH blood levels were recorded at midpregnancy as well. Remarkably, the P4-sinthesizing enzyme 3 β -HSD accompanied the expression pattern of PRLR/LHR throughout gestation. Instead, the luteolytic enzyme 20 α -HSD showed low expression at early and midpregnancy, but reached its maximum at the end of gestation, when PRLR/LHR/3 ß -HSD expressions and circulating P4 were minimal. In conclusion, both the PRLR and LHR expressions in the ovary would define the success of gestation in vizcachas by modulating the levels of 20 α -HSD and 3 ß -HSD, which ultimately determine the level of serum P4 throughout gestation.