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Orexin receptors (nomenclature as agreed by the NC-IUPHAR Subcommittee on Orexin receptors [43]) are activated by the endogenous polypeptides orexin-A and orexin-B (also known as hypocretin-1 and -2; 33 and 28 aa) derived from a common precursor, preproorexin or orexin precursor, by proteolytic cleavage and some typical peptide modifications [117]. Orexin signaling has been associated with regulation of sleep and wakefulness, reward and addiction, appetite and feeding, pain gating, stress response, anxiety and depression. Currently the orexin receptor ligands in clinical use are the dual orexin receptor antagonists suvorexant and lemborexant and daridorexant, which are used as hypnotics, and several dual and OX2-selective antagonists are under development. Multiple orexin agonists are in development for the treatment of narcolepsy and other sleep disorders. Orexin receptor 3D structures have been solved [146, 144, 55, 126, 47, 109, 7, 145].

The hypocretins (Hcrts), also known as orexins, are two neuropeptides produced exclusively in the lateral hypothalamus. They act on two specific receptors that are widely distributed across the brain and involved in a myriad of neurophysiological functions that include sleep, arousal, feeding, reward, fear, anxiety and cognition. Hcrt cell loss in humans leads to narcolepsy with cataplexy (narcolepsy type 1), a disorder characterized by intrusions of sleep into wakefulness, demonstrating that the Hcrt system is nonredundant and essential for sleep/wake stability. The causal link between Hcrts and arousal/wakefulness stabilisation has led to the development of a new class of drugs, Hcrt receptor antagonists to treat insomnia, based on the assumption that blocking orexin-induced arousal will facilitate sleep. This has been clinically validated: currently, two Hcrt receptor antagonists are approved to treat insomnia (suvorexant and lemborexant), with a New Drug Application recently submitted to the US Food and Drug Administration for a third drug (daridorexant). Other therapeutic applications under investigation include reduction of cravings in substance-use disorders and prevention of neurodegenerative disorders such as Alzheimer's disease, given the apparent bidirectional relationship between poor sleep and worsening of the disease. Circuit neuroscience findings suggest that the Hcrt system is a hub that integrates diverse inputs modulating arousal (e.g., circadian rhythms, metabolic status, positive and negative emotions) and conveys this information to multiple output regions. This neuronal architecture explains the wealth of physiological functions associated with Hcrts and highlights the potential of the Hcrt system as a therapeutic target for a number of disorders. We discuss present and future possible applications of drugs targeting the Hcrt system for the treatment of circuit-related neuropsychiatric and neurodegenerative conditions.

Objective: We compared prenatal care utilization, preterm birth, and low birth weight neonates among women 35 years and older compared to women 20-34 years old in Mexico, 2008-2019. Methods: We used birth certificate data and conducted a historical cohort study of all singleton live births in Mexico from 2008-2019. Study outcomes were inadequate prenatal care (timing of initiation of care and number of visits), preterm birth, and low birth weight. We compared outcomes among women 35-39, 40-44, and 45-49 with births to women 20-34. We used logistic regression to account for individual and contextual confounders. Results: We included a total of N=19,526,922 births; 11.9% (n=2,325,725) were to women 35 and older. Compared to women aged 20 to 34, the oldest (45-49 years old) were more likely to reside in poorer communities, have less education, and be uninsured. The odds of inadequate prenatal care (aOR 1.12 95% CI 1.09-1.15 p

Obstetric fistula is a devastating childbirth injury. Despite successful closure of the fistula, 16% to 55% of women suffer from persistent urinary incontinence after surgery.This study assessed the type and severity of persistent incontinence after successful fistula closure and its impact on the quality of life of Ugandan women post-fistula treatment.This cross-sectional study enrolled women with a history of obstetric fistula repair who continued to have persistent urinary incontinence (cases, N=36) and women without incontinence (controls, N=52) after successful fistula closure. Data were collected in central and eastern Uganda between 2017 and 2019. All the participants completed a semistructured questionnaire. Cases underwent a clinical evaluation and a 2-hour pad test and completed a series of incontinence questionnaires, including two novel tools designed to assess the severity of incontinence in low-literacy populations.Cases were more likely to have acquired a fistula during their first delivery (63% vs 37%, P=.02), were younger when they developed a fistula (20.3±5.8 vs 24.8±7.5 years old, P=.003), and were more likely to have had2 fistula surgeries (67% vs 2%, P≤.001). Cases reported a much higher rate of planned home birth for their index pregnancy compared to controls (44% vs 11%), though only 14% of cases and 12% of controls actually delivered at home. Cases reported higher rates of pain with intercourse (36% vs 18%, P=.05), but recent sexual activity status (intercourse within the previous six months) was not significantly different between the groups (47% vs 62%, P=.18). Among cases, 67% reported stress incontinence, 47% reported urgency incontinence, and 47% reported mixed incontinence. The cough stress test was successfully done with 92% of the cases, and of these, almost all (97%) had a positive cough stress test. More than half (53%) rated their incontinence as "very severe," which was consistent with objective findings. The 24-hour voiding diary indicated both high urinary frequency (average 14) and very frequent leakage episodes (average 20). Two-hour pad-tests indicated that 86% of cases had4 g change in pad weight within 2 hours. Women with more severe incontinence reported a more negative impact on their quality of life. The mean score of the International Consultation on Incontinence Questionnaire-Quality of Life was 62.77±12.76 (range, 28-76, median=67), with a higher score indicating a greater impact on the quality of life. There was also a high mental health burden, with both cases and controls reporting high rates of suicidal ideation at any point since developing fistula (36% vs 31%, P=.67).Women with obstetric fistulas continue to suffer from severe persistent urinary incontinence even after successful fistula closure. Both stress and urgency incontinence are highly prevalent in this population. Worsening severity of incontinence is associated with a greater negative impact on the quality of life.

Hypocretin neuron hyperexcitability underlies disrupted sleep quality associated with age

Child maltreatment is an important clinical condition. The emergency department (ED) is frequently the site of initial evaluation when a child is the victim of an acute inflicted injury. Abused children may present to the ED for vague complaints that could be attributed to a more benign illness such as a viral infection, but have evidence of abusive injuries. This evidence is sometimes overt but often subtle. Recognition of these injuries may save the child’s life, spare them from years of psychological and physical suffering, and prevent long-term morbidity such as intellectual disability and need for chronic medical care. In this way, emergency providers are at the front line of child abuse detection. This chapter details important diagnostic tools for evaluation of potential child maltreatment.

This is the first reported case of lymphoproliferative disease presenting with adrenal insufficiency after liver transplantation. A 38-year-old white man was admitted 8 months after transplantation for cryptogenic cirrhosis with fever (38-39 degrees C), chills, cough, and dyspnea. His blood pressure was 100/70 mm Hg, there was pallor of the conjunctiva, and a lymph node was palpable in the left groin. Laboratory analyses revealed the following values: serum sodium concentration (112 mmol/L), potassium (5.4 mmol/L), hemoglobin (7.8 g/L), white blood cell count (7.7 x 10(9)/L), glucose 3.9 (mmol/L), and mildly elevated liver functions. Abdominal ultrasound showed multiple hypoechoic solid-appearing lesions throughout the liver and spleen. Results of a biopsy specimen of the groin node confirmed polymorphic B-cell lymphoma. A negative Epstein- Barr virus screen before transplant became positive. The patient's fever increased to 40 degrees C. He subsequently developed sepsis and later, multiple organ failure. Autopsy confirmed extensive abdominal disease. The adrenal glands had been completely replaced by the tumor. Primary Epstein-Barr virus infection is associated with posttransplant lymphoproliferative disease. Replacement of the adrenal glands with a tumor produces a clinical picture of adrenal insufficiency.

The clinical and pathological findings of idiopathic ductopenia were studied in a 30-year-old woman who initially manifested jaundice and pruritus. Serum biochemical tests of liver function indicated severe and progressive cholestasis. Viral hepatitis markers and circulating autoantibodies were absent. The patient had a normal cholangiogram and lacked evidence of inflammatory bowel disease. Histological examination of a liver specimen showed severe cholestasis and absence of interlobular bile ducts. Severe jaundice and intractable pruritus developed in the patient and served as the indications for liver transplantation 4 months after initial examination. Transplantation resulted in prompt and complete resolution of the jaundice and pruritus. Two types of idiopathic adulthood ductopenia associated with different prognoses are recognized. Patients with type 1 idiopathic adulthood ductopenia are asymptomatic or manifest symptoms of cholestatic liver disease. They tend to have less destruction of the intrahepatic bile ducts on liver biopsy specimens. Their clinical course ranges from spontaneous improvement to progression to biliary cirrhosis. In contrast, patients with type 2 idiopathic adulthood ductopenia generally manifest initial symptoms of decompensated biliary cirrhosis, have extensive destruction of the intrahepatic bile ducts on liver biopsy, and frequently require orthotopic liver transplantation.

Infective endocarditis and its complications are life-threatening and require prompt recognition and treatment. We report a patient who developed a sinus tract connecting a mitral valve vegetation to a subepicardial abscess