Humans

Efficacy and Safety of Seltorexant in Insomnia Disorder: A Randomized Clinical Trial

Author/s: 
Sofie Mesens, Andrew D Krystal, Rama Melkote, Haiyan Xu, Gahan Pandina, Jay B Saoud, Remy Luthringer, Adam Savitz, Wayne C Drevets

Importance: Existing pharmacological treatments for insomnia have significant limitations.

Objective: To assess the effective dose range, safety, and tolerability of the novel selective orexin-2 receptor antagonist seltorexant in insomnia disorder.

Design, setting, and participants: This randomized, double-blind, active- and placebo-controlled, dose-finding, polysomnography study was conducted from November 2017 to April 2019 at 55 sites in 6 countries and analyzed in August 2019. The timeline for submission of this data for publication was impacted by internal strategic decision-making. Adults (aged 18-64 years) and older adults (aged 65-85 years) with insomnia (Insomnia Severity Index score ≥15) and no psychiatric comorbidity were included.

Interventions: Participants were randomized 1:1:1:1:1 to receive nightly oral-seltorexant (5 mg, 10 mg, or 20 mg), placebo, or zolpidem (5-10 mg) for 14 days.

Main outcomes and measures: Primary and key secondary outcomes included the dose-response relationship of night 1 latency to persistent sleep (LPS) and wake after sleep onset over the first 6 hours (WASO-6). Other secondary outcomes included night 13 LPS and WASO-6. Due to asymmetrical distributions of LPS and WASO-6 at baseline, log transformation was applied and results were expressed as back-transformed least-squares mean (LSM) ratios for comparisons between groups.

Results: Overall, 364 participants (mean [SD] age, 57.8 [12.4] years; 246 [67.6%] female) received seltorexant, 5 mg (n = 71), 10 mg (n = 74), or 20 mg (n = 71); placebo (n = 75); or zolpidem (n = 73). The night 1 dose-response relationship for LPS was significant (with trend test t statistics ≥3.99 and adjusted P values <.001 for all 4 prespecified models), with greater improvements in seltorexant, 10 mg and 20 mg, vs placebo (10 mg: LSM ratio, 0.64; 90% CI, 0.51-0.81; 20 mg: LSM ratio, 0.51; 90% CI, 0.41-0.64) and in seltorexant, 20 mg, vs zolpidem (LSM ratio, 0.71; 90% CI, 0.57-0.88). The night 1 dose-response relationship for WASO-6 was also significant, with trend test t statistics ≥3.99 and adjusted P values <.001 for all 4 prespecified models (seltorexant, 10 mg: LSM ratio, 0.68; 90% CI, 0.55-0.85; seltorexant, 20 mg: LSM ratio, 0.60; 90% CI, 0.48-0.74). Night 1 LPS and WASO-6 improvements were maintained on night 13 for seltorexant, 10 mg and 20 mg, but diminished for zolpidem. On night 13, compared with zolpidem, seltorexant, 10 mg and 20 mg, improved LPS by 30% and 28%, respectively, and seltorexant, 20 mg, improved WASO-6 by 31%. Treatment-emergent adverse events (TEAEs) were lower across the combined seltorexant doses (73/216 [33.8%]) relative to placebo (37/75 [49.3%]) and zolpidem (31/73 [42.5%]). Two participants experienced serious TEAEs during the double-blind phase (1 in the seltorexant, 20 mg, group and 1 in the zolpidem group). Three participants in the seltorexant, 5 mg, and 1 in the seltorexant, 20 mg, group experienced asymptomatic electrocardiogram-related TEAEs leading to discontinuation.

Conclusions and relevance: Among participants with insomnia in this study, seltorexant, 10 mg and 20 mg, improved sleep initiation and maintenance throughout 14 days of treatment. Seltorexant was generally well tolerated.

Trial registration: ClinicalTrials.gov Identifier: NCT03375203.

Hemorrhoidal Disease: A Review

Author/s: 
Jean H Ashburn

Importance Hemorrhoidal disease, pathology of the tissue lining of the anal canal, affects approximately 10 million individuals in the US. Hemorrhoidal disease may impair quality of life due to bleeding, pain, anal irritation, and tissue prolapse.

Observations Hemorrhoids are classified as internal, external, or mixed (concurrent internal and external hemorrhoidal disease). Internal hemorrhoids originate above the dentate line, the boundary between the upper and lower anal canal, and may cause rectal bleeding, discomfort, and tissue prolapse from the anal canal. Internal hemorrhoid prolapse is classified as grade I (into anal canal), grade II (beyond the anus with spontaneous reduction), grade III (requiring manual reduction), and grade IV (irreducible). External hemorrhoids, arising below the dentate line, cause rectal pain when engorged or thrombosed. Initial treatment of all hemorrhoidal disease involves increasing intake of dietary fiber and water and avoiding straining during defecation. Phlebotonics (eg, flavonoids [thought to improve venous tone]) reduce bleeding, rectal pain, and swelling, although symptom recurrence reaches 80% within 3 to 6 months after treatment cessation. If dietary modification and phlebotonics are ineffective, grade I to grade III internal hemorrhoidal disease can be treated with office-based interventions. Rubber band ligation—placing a band around the base of hemorrhoid tissue during anoscopy to restrict blood flow—resolves symptoms in 89% of patients, but repeated banding is needed in up to 20%. Sclerotherapy, which induces fibrosis with a sclerosant injection, is efficacious in the short term (weeks to months) among 70% to 85% of patients, but long-term remission occurs in only one-third of patients. Infrared coagulation uses heat to coagulate hemorrhoidal tissue, yielding 70% to 80% success in reducing bleeding and prolapse. Excisional hemorrhoidectomy, for disease unresponsive to office-based therapy or for mixed hemorrhoidal disease, achieves low recurrence (2%-10%), although with longer recovery (9-14 days). External hemorrhoidal disease rarely requires surgery unless acutely thrombosed. Outpatient clot evacuation within 72 hours of onset of a thrombosed external hemorrhoid is associated with decreased pain and reduced risk of repeat thrombosis. Patients presenting more than 72 hours after external hemorrhoid acute thrombosis should receive medical treatment (eg, stool softeners, oral and topical analgesics such as 5% lidocaine).

Conclusions and Relevance Hemorrhoidal disease affects 10 million people in the US. First-line treatment is increased fiber intake, avoidance of straining during defecation, and phlebotonics. In-office rubber band ligation for grade I to III internal hemorrhoid disease is first-line procedural treatment for persistent symptoms despite conservative therapies. Excisional hemorrhoidectomy is recommended for grade III to IV prolapse, thrombosis, or mixed hemorrhoidal disease that does not improve with less invasive approaches.

The 2024 National Academies of Sciences, Engineering, and Medicine Long COVID Definition: What Clinicians Need to Know

Author/s: 
Lily Chu, Karyn Bishof, Abigail A Dumes, E Wesley Ely, Paule V Joseph, Andrea B Troxel

Millions of Americans affected by Long COVID (LC) report difficulty accessing care and support. One barrier is obtaining a diagnosis. In response, US federal agencies commissioned a National Academies of Sciences, Engineering, and Medicine (NASEM) committee to re-examine the existing federal definitions for LC. The Committee concluded that LC is "an infection-associated chronic condition (IACC) occurring after SARS-CoV-2 infection that is present for at least 3 months as a continuous, relapsing and remitting, or progressive disease state that can present as singular or multiple symptoms and/or diagnosable conditions." The full report was released in June 2024. We briefly highlight features and aspects of the definition that may help clinicians identify those who remain undiagnosed and improve care for all LC patients.

Managing Adverse Effects of Incretin-Based Medications for Obesity

Author/s: 
Robert F Kushner, Jaime P Almandoz, Domenica M Rubino

This JAMA Insights explores optimal strategies for managing the adverse effects associated with incretin-based medications for obesity, including semaglutide and tirzepatide.

What Is Prostate Cancer?

Author/s: 
Rebecca Voelker, MSJ

Prostate cancer is a common malignancy in older men. Prostate cancer typically affects older men (average age at diagnosis is 67 years) and is more common among Black men than White men.1 More than half of prostate cancer risk is due to genetic factors. Prostate cancer is the second most common cause of cancer in men worldwide, with about 1.5 million cases diagnosed in 2021. In the US, 3.4 million men were living with prostate cancer in 2021.

Addictive Screen Use Trajectories and Suicidal Behaviors, Suicidal Ideation, and Mental Health in US Youths

Author/s: 
Yunyu Xiao, PhD, Yuan Meng, PhD, Timothy T. Brown, PhD

Importance: Increasing child and adolescent use of social media, video games, and mobile phones has raised concerns about potential links to youth mental health problems. Prior research has largely focused on total screen time rather than longitudinal addictive use trajectories.

Objectives: To identify trajectories of addictive use of social media, mobile phones, and video games and to examine their associations with suicidal behaviors and ideation and mental health outcomes among youths.

Design, setting, and participants: Cohort study analyzing data from baseline through year 4 follow-up in the Adolescent Brain Cognitive Development Study (2016-2022), with population-based samples from 21 US sites.

Exposures: Addictive use of social media, mobile phones, and video games using validated child-reported measures from year 2, year 3, and year 4 follow-up surveys.

Main outcomes and measures: Suicidal behaviors and ideation assessed using child- and parent-reported information via the Kiddie Schedule for Affective Disorders and Schizophrenia. Internalizing and externalizing symptoms were assessed using the parent-reported Child Behavior Checklist.

Results: The analytic sample (n = 4285) had a mean age of 10.0 (SD, 0.6) years; 47.9% were female; and 9.9% were Black, 19.4% Hispanic, and 58.7% White. Latent class linear mixed models identified 3 addictive use trajectories for social media and mobile phones and 2 for video games. Nearly one-third of participants had an increasing addictive use trajectory for social media or mobile phones beginning at age 11 years. In adjusted models, increasing addictive use trajectories were associated with higher risks of suicide-related outcomes than low addictive use trajectories (eg, increasing addictive use of social media had a risk ratio of 2.14 [95% CI, 1.61-2.85] for suicidal behaviors). High addictive use trajectories for all screen types were associated with suicide-related outcomes (eg, high-peaking addictive use of social media had a risk ratio of 2.39 [95% CI, 1.66-3.43] for suicidal behaviors). The high video game addictive use trajectory showed the largest relative difference in internalizing symptoms (T score difference, 2.03 [95% CI, 1.45-2.61]), and the increasing social media addictive use trajectory for externalizing symptoms (T score difference, 1.05 [95% CI, 0.54-1.56]), compared with low addictive use trajectories. Total screen time at baseline was not associated with outcomes.

Conclusions and relevance: High or increasing trajectories of addictive use of social media, mobile phones, or video games were common in early adolescents. Both high and increasing addictive screen use trajectories were associated with suicidal behaviors and ideation and worse mental health.

Ovarian Cancer: A Review

Author/s: 
Giuseppe Caruso, MD, S. John Weroha, MD, PhD, William Cliby, MD

Importance: Ovarian cancer is the eighth most common cause of cancer and cancer death in women worldwide. In 2022, ovarian cancer was diagnosed in approximately 324 398 individuals, and 206 839 died of ovarian cancer worldwide. In 2025, it is estimated that 20 890 US women will be diagnosed with ovarian cancer and 12 730 patients will die of ovarian cancer.

Observations: Approximately 90% of ovarian cancers are epithelial malignancies, of which 70% to 80% are high-grade serous ovarian cancers. Less common epithelial subtypes include endometrioid, clear cell, low-grade serous, mucinous, and carcinosarcoma. The median age at diagnosis of ovarian cancer is 63 years. Risk factors include older age, family history of breast or ovarian cancer, endometriosis, and nulliparity. Hereditary factors are associated with 25% of cases, predominantly linked to BRCA1/2 gene variants. At diagnosis, approximately 95% of patients experience nonspecific symptoms, such as abdominal pain, bloating, and urinary urgency and frequency, and about 80% have advanced-stage disease (stage III-IV), including extrapelvic disease, ascites, and abdominal masses. Diagnostic and staging evaluation includes pelvic ultrasound; computed tomography of the chest, abdomen, and pelvis; and serum tumor markers such as carbohydrate antigen 125, carbohydrate antigen 19-9, and carcinoembryonic antigen. First-line treatment for early-stage ovarian cancer, defined as limited to the ovary or fallopian tube (stage I) or confined to the pelvis (stage II), is surgery (hysterectomy, bilateral salpingo-oophorectomy, omentectomy, and lymphadenectomy), followed by adjuvant chemotherapy (carboplatin and paclitaxel). With treatment, early-stage ovarian cancer has a 5-year overall survival of 70% to 95%. Advanced-stage ovarian cancer may be treated with primary cytoreductive surgery (removal of all visible cancer in the abdominal cavity) and adjuvant chemotherapy (carboplatin and paclitaxel) or with neoadjuvant chemotherapy followed by cytoreductive surgery and adjuvant chemotherapy. Most patients with advanced-stage ovarian cancer receive maintenance therapy with bevacizumab (a monoclonal antibody that blocks angiogenesis) and/or poly–adenosine diphosphate ribose polymerase (PARP) inhibitors. With treatment, the 5-year overall survival rate for advanced-stage ovarian cancer is 10% to 40%. However, individuals with BRCA-related gene variants have a 5-year overall survival rate of approximately 70% with PARP inhibitor treatment. Despite an initial remission rate of 80%, approximately 75% of patients with advanced-stage disease have ovarian cancer relapse within 2 years.

Conclusions and Relevance: Approximately 21 000 women are diagnosed with ovarian cancer annually in the US, and approximately 80% have advanced-stage ovarian cancer at diagnosis. First-line treatment of early-stage ovarian cancer is surgery and adjuvant platinum-based chemotherapy. Treatment of advanced-stage ovarian cancer includes cytoreductive surgery, platinum-based chemotherapy, and targeted maintenance therapies such as bevacizumab and/or PARP inhibitors.

Canadian guideline for the clinical management of high-risk drinking and alcohol use disorder

Author/s: 
Evan Wood, Jessica Bright, Katrina Hsu, Nirupa Goel, Josey W G Ross

Background: In Canada, low awareness of evidence-based interventions for the clinical management of alcohol use disorder exists among health care providers and people who could benefit from care. To address this gap, the Canadian Research Initiative in Substance Misuse convened a national committee to develop a guideline for the clinical management of high-risk drinking and alcohol use disorder.

Methods: Development of this guideline followed the ADAPTE process, building upon the 2019 British Columbia provincial guideline for alcohol use disorder. A national guideline committee (consisting of 36 members with diverse expertise, including academics, clinicians, people with lived and living experiences of alcohol use, and people who self-identified as Indigenous or Métis) selected priority topics, reviewed evidence and reached consensus on the recommendations. We used the Appraisal of Guidelines for Research and Evaluation Instrument (AGREE II) and the Guidelines International Network’s Principles for Disclosure of Interests and Management of Conflicts to ensure the guideline met international standards for transparency, high quality and methodological rigour. We rated the final recommendations using the Grading of Recommendations, Assessment, Development and Evaluation (GRADE) tool; the recommendations underwent external review by 13 national and international experts and stakeholders.

Recommendations: The guideline includes 15 recommendations that cover screening, diagnosis, withdrawal management and ongoing treatment, including psychosocial treatment interventions, pharmacotherapies and community-based programs. The guideline committee identified a need to emphasize both underused interventions that may be beneficial and common prescribing and other practice patterns that are not evidence based and that may potentially worsen alcohol use outcomes.

Interpretation: The guideline is intended to be a resource for physicians, policymakers and other clinical and nonclinical personnel, as well as individuals, families and communities affected by alcohol use. The recommendations seek to provide a framework for addressing a large burden of unmet treatment and care needs for alcohol use disorder within Canada in an evidence-based manner.

Hidradenitis suppurativa

Author/s: 
Robert Sabat, Afsaneh Alavi, Kerstin Wolk, Ximena Wortsman, Barry McGrath, Amit Garg, Jacek C Szepietowski

Hidradenitis suppurativa is a chronic inflammatory disease characterised by painful, deep-seated nodules, abscesses, and draining tunnels in the skin of axillary, inguinal, genitoanal, or inframammary areas. In recent years, the body of knowledge in hidradenitis suppurativa has advanced greatly. This disorder typically starts in the second or third decade of life. The average worldwide prevalence is 1% but varies geographically. Hidradenitis suppurativa has a profound negative effect on patients' quality of life and on the gross value added to society. Comorbidities (eg, metabolic syndrome, inflammatory arthritis, and inflammatory bowel disease) frequently accompany skin alterations, because of systemic inflammation. Pathogenesis of hidradenitis suppurativa is complex and includes innate immune mechanisms (eg, macrophages, neutrophils, IL-1β, tumour necrosis factor [TNF], and granulocyte colony-stimulating factor), T-cell mechanisms (eg, IL-17 and IFN-γ), and B-cell mechanisms (eg, associated with dermal tertiary lymphatic structures and autoantibodies). Chronic inflammation leads to irreversible skin damage with tunnel formation and morbid scarring. Current treatment includes drug therapy (for the initial, purely inflammatory phase), combined drug and surgical therapy (for the destructive phase), or surgery alone (for the burnout phase). The first systemic therapies approved for hidradenitis suppurativa targeting TNF (adalimumab) and IL-17 (secukinumab and bimekizumab) have expanded drug therapy options for moderate-to-severe disease, which were previously mainly restricted to oral antibiotics. Moreover, there is a robust pipeline of immunomodulatory drugs in various stages of development for hidradenitis suppurativa. Aims of management should include early intervention to prevent irreversible skin damage, adequate control of symptoms including pain, and mitigation of extra-cutaneous comorbidities, all requiring early diagnosis and an interdisciplinary, holistic and personalised approach.

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