The genetic etiologies of bilateral renal agenesis.

OBJECTIVE: The goal of this study was to review and analyze the medical literature for cases of prenatal and/or postnatally diagnosed bilateral renal agenesis (BRA) and create a comprehensive summary of the genetic etiologies known to be associated with this condition. METHODS: A literature search was conducted as a scoping review employing Online Mendeliain Inheritance in Man, PubMed, and Cochrane to identify cases of BRA with known underlying genetic (chromosomal vs. single gene) etiologies and those described in syndromes without any known genetic etiology. The cases were further categorized as isolated versus non-isolated, describing additional findings reported prenatally, postnatally, and postmortem. Inheritance pattern was also documented when appropriate in addition to the reported timing of diagnosis and sex. RESULTS: We identified six cytogenetic abnormalities and 21 genes responsible for 20 single gene disorders associated with BRA. Five genes have been reported to associate with BRA without other renal anomalies; sixteen others associate with both BRA as well as unilateral renal agenesis. Six clinically recognized syndromes/associations were identified with an unknown underlying genetic etiology. Genetic etiologies of BRA are often phenotypically expressed as other urogenital anomalies as well as complex multi-system syndromes. CONCLUSION: Multiple genetic etiologies of BRA have been described, including cytogenetic abnormalities and monogenic syndromes. The current era of the utilization of exome and genome-wide sequencing is likely to significantly expand our understanding of the underlying genetic architecture of BRA.

Role of inflammation in benign gynecologic disorders: from pathogenesis to novel therapies†.

Emerging evidence supports the notion that inflammation fosters the development of common benign gynecologic disorders, including uterine leiomyoma, endometriosis, and adenomyosis. Numerous cytokines, chemokines, and growth and transcription factors have indisputable roles in the establishment and maintenance of benign gynecologic disorders by initiating complex cascades that promote proliferation, angiogenesis, and lesion progression. The interaction between inflammation and benign gynecologic disorders is orchestrated by a plethora of factors, including sex steroids, genetics, epigenetics, extracellular matrix, stem cells, cardiometabolic risk factors, diet, vitamin D, and the immune system. The role of inflammation in these disorders is not limited to local pathobiology but also extends to involve clinical sequelae that range from those confined to the reproductive tract, such as infertility and gynecologic malignancies, to systemic complications such as cardiovascular disease. Enhanced understanding of the intricate mechanisms of this association will introduce us to unvisited pathophysiological perspectives and guide future diagnostic and therapeutic implications aimed at reducing the burden of these disorders. Utilization of inflammatory markers, microRNA, and molecular imaging as diagnostic adjuncts may be valuable, noninvasive techniques for prompt detection of benign gynecologic disorders. Further, use of novel as well as previously established therapeutics, such as immunomodulators, hormonal treatments, cardiometabolic medications, and cyclooxygenase-2 and NF-κB inhibitors, can target inflammatory pathways involved in their pathogenesis. In this comprehensive review, we aim to dissect the existing literature on the role of inflammation in benign gynecologic disorders, including the proposed underlying mechanisms and complex interactions, its contribution to clinical sequelae, and the clinical implications this role entails.

Vascular biology of uterine fibroids: connecting fibroids and vascular disorders.

Fibroids are benign tumors caused by the proliferation of myometrial smooth muscle cells in the uterus that can lead to symptoms such as abdominal pain, constipation, urinary retention, and infertility. While traditionally thought of as a disease process intrinsic to the uterus, accumulating evidence suggests that fibroid growth may be linked with the systemic vasculature system, although cell-intrinsic factors are certainly of principal importance in their inception. Fibroids are associated with essential hypertension and preeclampsia, as well as atherosclerosis, for reasons that are becoming increasingly elucidated. Factors such as the renin-angiotensin-aldosterone system, estrogen, and endothelial dysfunction all likely play a role in fibroid pathogenesis. In this review, we lay out a framework for reconceptualizing fibroids as a systemic vascular disorder, and discuss how pharmaceutical agents and other interventions targeting the vasculature may aid in the novel treatment of fibroids.

Which patients on a gynecologic oncology service will require perioperative transfusion? A single-center retrospective cohort study.

The purpose of this study was to determine which patient- or surgery-related factors are predictive of need for perioperative transfusion to avoid obtaining unnecessary pre-operative type and screens (T&S). We conducted an observational retrospective cohort study of 1200 women ≥ 18 years old undergoing gynecologic surgery for benign, possibly benign, or malignant indications on a gynecologic oncology service at a university medical center from 2009-2016. A logistic regression model was used to examine patient-related and surgery-related variables predictive of outcome of transfusion. Independent variables included patient demographics, comorbidities, and surgical indication surgical route, and surgical type. Dependent variable was transfusion outcome (T&S only, conversion to type and cross (T&C), or transfusion). Eight hundred ninety-nine (74.9%) women underwent pre-operative T&S, of which 118 (9.8%) were converted to T&C, and 80 (6.7%) received a transfusion of blood or blood products. Cancer indication, major surgery, and preoperative hematocrit less than 36% were significantly associated with need for transfusion (P = 0.002, P < 0.0001, P < 0.0001, respectively). Patients with a benign indication undergoing minor procedures and with normal preoperative hematocrit are least likely to require transfusion.

Does the adoption of an emergency general surgery service model influence volume of cholecystectomies at a tertiary care center.

INTRODUCTION: The purpose of this study was to evaluate the rate of cholecystectomy before and after adoption of an emergency general surgery (EGS) model at our institution. METHODS: A longitudinal, observational study was conducted prior to and following introduction of an EGS model at our institution. Using the New York SPARCS Administrative Database, all adult patients presenting to the emergency department with gallbladder-related emergencies were identified. The rates of laparoscopic and open cholecystectomies performed 3 years prior and 3 years following the adoption of the EGS model were examined. A multivariable logistic regression model was used to compare the incidence of cholecystectomy at initial ED visit at our institution pre- and post-EGS introduction as well as to those in the rest of the state as an external control group, while adjusting for potentially confounding factors. RESULTS: There were 176,159 total ED visits of patients with gallbladder emergencies (154,743 excluding repeat presenters) in the studied period in NY State. Of these, 63,912 patients (41.3%) had a concurrent cholecystectomy in NY State. The rate of cholecystectomy at these institutions remained relatively steady from 38.8% from 2010 to 2013 and 38.6% from 2013 to 2016. At our institution, there were 2039 gallbladder emergencies, and of those 755 underwent cholecystectomy. At our institution, there was an increase from 28.21% 3 years prior to the adoption of the EGS model to 40.2% in the following 3 years (RR = 1.06, 95% CI 1.0164-1.1078, p = 0.0069). CONCLUSION: The initiation of the EGS model at a tertiary center was associated with a significant increase in the number of concurrent cholecystectomies from 28.21 to 40.2% over a 6-year period. This change was accompanied by an increase in the number of patient comorbidities and a lower insurance status.

Relationship between body temperature and heart rate in adults and children: A local and national study.

BACKGROUND: A patient's vital signs are all inextricably interrelated, and together provide critical information regarding hemodynamic and physiological status. Yet, the precise relationship between body temperature (T) and heart rate (HR) in adults remains a fundamental gap in our knowledge. METHODS: We performed a retrospective secondary analysis of (1) electronic medical records from a large academic center (annual ED census of 110,000) and (2) the National Hospital Ambulatory Medical Care Survey (NHAMCS), a large CDC-sponsored weighted sample of U.S. EDs and our own large tertiary care ED, extracting demographic and clinical data including vital signs. RESULTS: We included 8715 local ED visits and approximately 123.3 million estimated national adult ED visits. Mean T was 36.9 °C, and 5.2% of patients had a T over 38 °C. Mean (SD) HR was 93.3 bpm, 28% had a HR over 100 bpm. Males had significantly lower HR than females (coefficient -1.6, 95%CI -2.4 to -0.8), while age was negatively associated with HR (coefficient -0.08, 95%CI -0.10 to -0.06). For national data, an increase of 1 °C in T corresponded to an increase in HR of 7.2 bpm (95%CI 6.2 to 8.3). After adjusting for age and gender, a 1 °C increase in T corresponded to a mean (95%CI) 10.4 (9.5-11.4) and 6.9 (5.9-7.8) increase in HR locally and nationally, respectively. CONCLUSIONS: Among adult ED patients nationally, for every increase in T of 1 °C, the HR increases by approximately 7 bpm.

Assisted reproductive technologies (ART) and placental abnormalities.

Objectives Assisted reproductive technologies (ART) may be associated with placental abnormalities including placenta previa, umbilical cord abnormalities, and placental abruption. Our study evaluates the relationship between ART and placental abnormalities compared with spontaneously conceived controls. Methods An IRB-approved cohort study was conducted including women who delivered between January 2013 and December 2018. We excluded delivery prior to 23 weeks and known fetal anomalies. Patients were matched with controls (2:1) for parity, age, and mode of delivery. Controls were women who had spontaneously conceived and delivered immediately preceding and following the index delivery. The primary outcome was placental abnormalities found on both antenatal ultrasound and pathology in ART gestations compared with spontaneously conceived gestations. Results There were 120 ART pregnancies and 240 matched control pregnancies identified. The groups were similar for parity, BMI, comorbidities, number of multiples, mode of delivery, and female newborns. The ART group had a higher maternal age (37.1±5 y vs. 30.0±5 y; p<0.001), greater preterm birth (29 vs. 6%; p<0.001), and lower BW (2,928±803 g vs. 3,273±586 g; p<0.001). The ART group had a higher incidence of placenta previa on ultrasound (4.0 vs. 0.4%, p=0.01), adherent placentas at delivery (3 vs. 0% p=0.014), placental abruption (2 vs. 0%; p=0.04), as well as an increased rate of velamentous cord insertion (12 vs. 3%, p<0.001) and marginal cord insertion (28 vs. 15%, p=0.002). ART demonstrated a two-fold likelihood of abnormal placental pathology. Conclusions ART is associated with increased rate of placental abnormalities, including abnormal umbilical cord insertion and increased rates of adherent placentation. This information may be beneficial in planning and surveillance in patients with ART pregnancies.

The Impact of Sleep Duration on Performance Among Competitive Athletes: A Systematic Literature Review.

The athletic advantage of sleep, although commonly touted by coaches, trainers, and sports physicians, is still unclear and likely varies by sport, athletic performance metric, and length of sufficient or insufficient sleep. Although recent literature reviews have highlighted circadian and nutritional factors that influence different aspects of athletic performance, a systematic summary of the effects of sleep duration and sleep quality on performance among competitive athletes is lacking. Here we systematically review the relationship between sleep duration and sleep quality and objective athletic performance among competitive athletes across 19 studies representing 12 sports. Taken holistically, we find that the sports requiring speed, tactical strategy, and technical skill are most sensitive to sleep duration manipulations. Furthermore, longer-term sleep manipulations are more likely than acute sleep manipulations (whether deprivation or extension) to affect athletic performance. Thus, the importance of sleep for competitive athletes to achieve high performance is dependent on the demands of the sport as well as the length of sleep interventions. In light of the limited number of studies investigating sleep quality and performance, the potential relevance of subjective sleep quality remains an interesting question for future work.

Reading the Child Within: How Bibliotherapy Can Help the Victim of Child Sexual Abuse.

Bibliotherapy, the use of storytelling as part of the healing process, has been successfully incorporated into clinical practice for a variety of indications including psychological trauma. This therapeutic modality, which incorporates mindful meditation, non-threatening use of metaphor, and autonomic regulation, can help children and adults alike, who are willing to engage in a story. Yet, bibliotherapy has not been widely adapted as a routine part of the therapeutic toolbox in the context of sufferers of childhood sexual abuse. Here, we review current practices regarding the adjunctive use of bibliotherapy for victims of child sexual abuse, touch upon the theoretical basis of bibliotherapy, and lay out a number of readily-useable strategies for implementing bibliotherapy in one's practice.

Repositioning of Somatic Golgi Apparatus Is Essential for the Dendritic Establishment of Adult-Born Hippocampal Neurons.

New dentate granule cells (DGCs) are continuously generated, and integrate into the preexisting hippocampal network in the adult brain. How an adult-born neuron with initially simple spindle-like morphology develops into a DGC, consisting of a single apical dendrite with further branches, remains largely unknown. Here, using retroviruses to birth date and manipulate newborn neurons, we examined initial dendritic formation and possible underlying mechanisms. We found that GFP-expressing newborn cells began to establish a DGC-like morphology at ∼7 d after birth, with a primary dendrite pointing to the molecular layer, but at this stage, with several neurites in the neurogenic zone. Interestingly, the Golgi apparatus, an essential organelle for neurite growth and maintenance, was dynamically repositioning in the soma of newborn cells during this initial integration stage. Two weeks after birth, by which time most neurites in the neurogenic zone were eliminated, a compact Golgi apparatus was positioned exclusively at the base of the primary dendrite. We analyzed the presence of Golgi-associated genes using single-cell transcriptomes of newborn DGCs, and among Golgi-related genes, found the presence of STK25 and STRAD, regulators of embryonic neuronal development. When we knocked down either of these two proteins, we found Golgi mislocalization and extensive aberrant dendrite formation. Furthermore, overexpression of a mutated form of STRAD, underlying the disorder polyhydramnios, megalencephaly, and symptomatic epilepsy, characterized by abnormal brain development and intractable epilepsy, caused similar defects in Golgi localization and dendrite formation in adult-born neurons. Together, our findings reveal a role for Golgi repositioning in regulating the initial integration of adult-born DGCs.SIGNIFICANCE STATEMENT Since the discovery of the continuous generation of new neurons in the adult hippocampus, extensive effort was directed toward understanding the functional contribution of these newborn neurons to the existing hippocampal circuit and associated behaviors, while the molecular mechanisms controlling their early morphological integration are less well understood. Dentate granule cells (DGCs) have a single, complex, apical dendrite. The events leading adult-born DGCs' to transition from simple spindle-like morphology to mature dendrite morphology are largely unknown. We studied establishment of newborn DGCs dendritic pattern and found it was mediated by a signaling pathway regulating precise localization of the Golgi apparatus. Furthermore, this Golgi-associated mechanism for dendrite establishment might be impaired in a human genetic epilepsy syndrome, polyhydramnios, megalencephaly, and symptomatic epilepsy.

Active Dentate Granule Cells Encode Experience to Promote the Addition of Adult-Born Hippocampal Neurons.

The continuous addition of new dentate granule cells (DGCs), which is regulated exquisitely by brain activity, renders the hippocampus plastic. However, how neural circuits encode experiences to affect the addition of adult-born neurons remains unknown. Here, we used endoscopic Ca2+ imaging to track the real-time activity of individual DGCs in freely behaving mice. For the first time, we found that active DGCs responded to a novel experience by increasing their Ca2+ event frequency preferentially. This elevated activity, which we found to be associated with object exploration, returned to baseline by 1 h in the same environment, but could be dishabituated via introduction to a novel environment. To transition seamlessly between environments, we next established a freely controllable virtual reality system for unrestrained mice. We again observed increased firing of active neurons in a virtual enriched environment. Interestingly, multiple novel virtual experiences increased the number of newborn neurons accumulatively compared with a single experience. Finally, optogenetic silencing of existing DGCs during novel environmental exploration perturbed experience-induced neuronal addition. Our study shows that the adult brain conveys novel, enriched experiences to increase the addition of adult-born hippocampal neurons by increasing the firing of active DGCs.SIGNIFICANCE STATEMENT Adult brains are constantly reshaping themselves from synapses to circuits as we encounter novel experiences from moment to moment. Importantly, this reshaping includes the addition of newborn hippocampal neurons. However, it remains largely unknown how our circuits encode experience-induced brain activity to govern the addition of new hippocampal neurons. By coupling in vivo Ca2+ imaging of dentate granule neurons with a novel, unrestrained virtual reality system for rodents, we discovered that a new experience increased firing of active dentate granule neurons rapidly and robustly. Exploration in multiple novel virtual environments, compared with a single environment, promoted dentate activation and enhanced the addition of new hippocampal neurons accumulatively. Finally, silencing this activation optogenetically during novel experiences perturbed experience-induced neuronal addition.

Obesity diminishes synaptic markers, alters microglial morphology, and impairs cognitive function.

Obesity is a major public health problem affecting overall physical and emotional well-being. Despite compelling data suggesting an association between obesity and cognitive dysfunction, this phenomenon has received relatively little attention. Neuroimaging studies in obese humans report reduced size of brain regions involved in cognition, but few studies have investigated the cellular processes underlying cognitive decline in obesity or the influence of obesity on cognition in the absence of obesity-related illnesses. Here, a rat model of diet-induced obesity was used to explore changes in brain regions important for cognition. Obese rats showed deficits on cognitive tasks requiring the prefrontal and perirhinal cortex. Cognitive deficits were accompanied by decreased dendritic spine density and synaptic marker expression in both brain regions. Microglial morphology was also changed in the prefrontal cortex. Detrimental changes in the prefrontal cortex and perirhinal cortex occurred before metabolic syndrome or diabetes, suggesting that these brain regions may be particularly vulnerable to early stage obesity.

Betrayal of the Body: Group Approaches to Hypo-Sexuality for Adult Female Sufferers of Childhood Sexual Abuse.

Hypo-sexuality, self-reported hypoactive sexual desire and/or sexual aversion, is a common symptom experienced by women who were victims of childhood sexual abuse. This symptom may be distressing to the patient herself, and may place strain on her romantic relationships in adulthood. Unfortunately, this problem often remains undiscussed between patient and provider, in part due to the provider's lack of comfort or knowledge regarding how best to address this issue. In this article, we explore several strategies that providers may employ in a group setting in order to help women realize their sexuality while minimizing untoward side effects such as feelings of guilt or shame, or flashbacks. We highlight the merits of each technique, and provide insights from clinical experience to guide practitioners to help their patients facing this difficult issue.

Laparoscopic Management of a 12-Week Pregnancy Loss in a Rudimentary Uterine Horn.

Unicornuate uterus with rudimentary horn is a rare structural uterine anomaly resulting from incomplete Mullerian duct development and/or fusion. Pregnancy in rudimentary horn is an uncommon presentation of a Mullerian anomaly and may lead to substantial morbidity and mortality due to high risk of uterine rupture with intraabdominal hemorrhage. Medical and/or surgical management may be undertaken; however, currently, no treatment guidelines exist. We describe the management of a 12-week rudimentary horn pregnancy in a 25-year-old multiparous patient with a prior spontaneous preterm breech vaginal delivery and one spontaneous early term cephalic vaginal delivery in whom this congenital uterine condition was previously unknown. The rudimentary horn, nonviable pregnancy, and contiguous ipsilateral fallopian tube were excised laparoscopically without complication. Given the infrequency of rudimentary horn pregnancies and the high risk for obstetric complications, a high index of suspicion should be maintained. We emphasize that a history of preterm birth or malpresentation should raise suspicion for maternal Mullerian anomaly, and that a minimally invasive approach can be feasible for treatment of a rudimentary horn pregnancy.

A Case Report of Spontaneous Vaginal Delivery Under General Anesthesia in a Patient With a Large Cerebral Aneurysm.

Cerebral aneurysms are rarely encountered in pregnancy. Their antepartum and intrapartum management remain clinically challenging, primarily due to concern regarding potential rupture. We present a case of a patient in preterm labor at risk for imminent delivery with a 10mm cerebral aneurysm. She was recommended for cesarean section (CS), yet delivered via spontaneous vaginal delivery in the operating room after induction of general anesthesia for the intended CS. Her aneurysm and neurologic function remained intact postpartum. Cerebral aneurysms <5mm are unlikely to undergo significant growth during pregnancy. The presence of a cerebral aneurysm is not automatically a contraindication to the Valsalva maneuver. The recommendation for which patients with unruptured cerebral aneurysms should deliver by CS, operative vaginal delivery, or unassisted vaginal delivery (i.e., which patients should avoid Valsalva maneuver intrapartum), is complex and requires multidisciplinary discussion.

Modeling of vertical transmission and pathogenesis of cytomegalovirus in pregnancy: Opportunities and challenges.

In addition to facilitating nutrient, oxygen, and waste transfer between developing fetus and mother, the placenta provides important immune barrier function against infection. Elucidation of the complexity of placental barrier function at the maternal-fetal interface has been greatly aided through experimental model organism systems. In this review, we focus on models of vertical transmission of cytomegalovirus (CMV), a ubiquitous double-stranded DNA viruses whose vertical transmission during pregnancy can lead to devastating neurological and obstetric sequelae. We review the current evidence related to guinea pig and murine models of congenital CMV infection, discuss the possible translatability of a non-human primate model, and conclude with recently developed technology using human placental organoids.

Obesity Contributes to Transformation of Myometrial Stem-Cell Niche to Leiomyoma via Inducing Oxidative Stress, DNA Damage, Proliferation, and Extracellular Matrix Deposition.

Leiomyomas (fibroids) are monoclonal tumors in which myometrial stem cells (MSCs) turn tumorigenic after mutation, abnormal methylation, or aberrant signaling. Several factors contribute to metabolic dysfunction in obesity, including abnormal cellular proliferation, oxidative stress, and DNA damage. The present study aims to determine how adipocytes and adipocyte-secreted factors affect changes in MSCs in a manner that promotes the growth of uterine leiomyomas. Myometrial stem cells were isolated from the uteri of patients by fluorescence-activated cell sorting (FACS) using CD44/Stro1 antibodies. Enzyme-linked immunosorbent assay (ELISA), Western blot, and immunocytochemistry assays were performed on human adipocytes (SW872) co-cultured with MSCs and treated with leptin or adiponectin to examine the effects of proliferation, extracellular matrix (ECM) deposition, oxidative damage, and DNA damage. Co-culture with SW872 increased MSC proliferation compared to MSC culture alone, according to 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) results. The expressions of PCNA and COL1A increased significantly with SW872 co-culture. In addition, the expression of these markers was increased after leptin treatment and decreased after adiponectin treatment in MSCs. The Wnt/ß-catenin and TGF-ß/SMAD signaling pathways promote proliferation and ECM deposition in uterine leiomyomas. The expression of Wnt4, ß-catenin, TGFß3, and pSMAD2/3 of MSCs was increased when co-cultured with adipocytes. We found that the co-culture of MSCs with adipocytes resulted in increased NOX4 expression, reactive oxygen species production, and γ-H2AX expression. Leptin acts by binding to its receptor (LEP-R), leading to signal transduction, resulting in the transcription of genes involved in cellular proliferation, angiogenesis, and glycolysis. In MSCs, co-culture with adipocytes increased the expression of LEP-R, pSTAT3/STAT3, and pERK1/2/ERK/12. Based on the above results, we suggest that obesity may mediate MSC initiation of tumorigenesis, resulting in leiomyomas.