Medicine general internal:

IMPORTANCE: Endometriosis is a chronic, estrogen-dependent, inflammatory disease defined by endometrial-like tissue (lesions) outside the uterine lining. It affects up to 10% of women worldwide, and 9 million women in the US, during reproductive years.

IMPORTANCE: Whether α2-adrenergic receptor agonist-based sedation, compared with propofol-based sedation, reduces time to extubation in patients receiving mechanical ventilation in the intensive care unit (ICU) is uncertain.

IMPORTANCE: Colorectal cancer screening is widely recommended but underused. Blood-based screening offers the potential for higher adherence compared with endoscopy or stool-based testing but must first be clinically validated in a screening population.

IMPORTANCE: In prior monotherapy studies of patients with hypertension, single subcutaneous doses of zilebesiran, an investigational RNA interference therapeutic, reduced serum angiotensinogen levels and systolic blood pressure (SBP) at 3 and 6 months.

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OBJECTIVE: To explore the increasing incidence of gastrointestinal (GI) cancers and related risk factors in younger patients.

OBJECTIVE: To investigate the causal association between insomnia and chronic kidney disease (CKD) and to explore the underlying protein pathways.

Groin hernias are among the most common indications for surgery worldwide, affecting both men and women, with a significantly higher prevalence in men. These hernias occur when intra-abdominal contents protrude through a weakened area in the groin region, most commonly as inguinal or femoral hernias. The pathogenesis of groin hernias is a complex interplay of genetic predisposition, connective tissue abnormalities and mechanical strain. While watchful waiting is an option for some asymptomatic patients, surgical repair remains the definitive treatment, with both open and minimally invasive techniques available. Tension-free mesh repair has significantly reduced the overall recurrence rates and is now the standard approach in adults in most clinics. However, tissue-based repairs are still preferred in select populations such as children, teenagers and those in resource-limited settings. Advances in laparoscopic and robotic-assisted techniques offer benefits such as reduced postoperative pain and faster recovery. Despite surgical advancements, complications, such as chronic postoperative pain and recurrence, continue to pose challenges. Future research aims to refine surgical techniques, look at mesh-related complications, develop bioengineered meshes and explore the genetic basis of hernia formation.

Early-onset type 2 diabetes (defined as type 2 diabetes diagnosed in people aged <40 years) is increasingly prevalent with substantial health and socioeconomic implications. Unlike late-onset type 2 diabetes, early-onset type 2 diabetes is a high-risk and aggressive phenotype, with accelerated pancreatic β-cell decline and greater insulin resistance due to the rising rate of obesity. People with early-onset type 2 diabetes have higher rates of macrovascular and microvascular complications with increased health-care use and premature mortality (due to cardiovascular and non-cardiovascular complications) than do people with late-onset type 2 diabetes. Emerging evidence also suggests that people with early-onset type 2 diabetes face an increased risk of complications in reproductive health (eg, during periconception and postpartum periods), metabolic-associated steatotic liver disease, mental health (eg, diabetes distress, depression, anxiety, and psychotic disorders), and some cancers, creating additional challenges in managing multiple long-term conditions. In this Series paper, we highlight the consequences of early-onset type 2 diabetes and the key driver for these risks-long duration of exposure to hyperglycaemia, with its effects amplified by younger age at type 2 diabetes diagnosis and interactions with other cardiometabolic risk factors. Recognising these adverse risks associated with early-onset type 2 diabetes is crucial for guiding the development and implementation of a more focused and integrated life-course approach to mitigate its long-term effect on individuals, communities, and health-care systems globally. However, substantial research gaps remain that must be addressed, particularly in diverse populations.

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Knowledge about Gaucher disease (GD), considered a model for rare diseases, has considerably increased since its discovery. The pathophysiology of this lysosomal disorder is better known, and specific therapies that can control many aspects of the disease have been developed, particularly for the most common form, Type 1 GD. Yet, in part because of the rarity of GD, but also because of a lack of awareness by physicians, diagnostic delay too often leads to a belated management of patients having accumulated comorbidities. Gaucher cells, the most visible consequence of glucocerebrosidase deficiency, have been known for many years. However, the pathophysiological mechanisms underlying some major lesions, such as bone disease, predisposition to Parkinson's disease in Type 1 GD, or neurological involvement in Type 2 and Type 3 GD, remain poorly understood. Diagnostic, therapeutic, and follow-up issues associated with these symptoms remain critical to optimize the care of these patients. In this review, clinical characteristics, pathophysiology, diagnosis, treatment, and prognosis of GD are successively considered, highlighting for each of them the remaining challenges. Continued efforts to better understand pathophysiological mechanisms, use of the most modern methods such as artificial intelligence, international collaboration, and development of new therapeutic strategies seem essential for the future of this rare disease.

OBJECTIVE: To assess differences in cancer prevalence across the urban-rural continuum, which may help identify target areas for cancer treatment and prevention efforts.

IMPORTANCE: Osteoporosis is characterized by low bone mass, increased bone fragility, and increased susceptibility to fracture, which is associated with substantial morbidity, mortality, and economic costs. Worldwide, 1 in 3 women and 1 in 5 men older than 50 years of age experience osteoporotic fractures in their lifetime.

OBJECTIVE: To investigate the most prevalent diagnosed conditions contributing to health care visitations in a defined US population by age and racial group, educational level, and socioeconomic deprivation.

Early-onset type 2 diabetes (defined as type 2 diabetes diagnosed in people aged <40 years) is an increasingly prevalent condition with a more aggressive disease trajectory than late-onset type 2 diabetes. It is associated with accelerated microvascular and macrovascular complications, reduced life expectancy, and adverse pregnancy outcomes. Despite its rising incidence, global management strategies have mostly been extrapolated from studies in older adults with limited evidence specific to younger populations. In this Series paper, we aim to highlight the unique challenges in the management of early-onset type 2 diabetes and why current models of care are inadequate. We emphasise that early-onset type 2 diabetes necessitates proactive and combination treatment strategies to address weight, faster β-cell decline, worse insulin resistance, and rapidly progressing hyperglycaemia compared with late-onset type 2 diabetes. However, there is minimal evidence on how best to address these factors and clinical inertia risks contributing to glycaemic burden. Cardiovascular risk assessment tools underestimate long-term risk, contributing to low use of statin and antihypertensive therapy. Reproductive health remains a key concern, yet preconception and pregnancy care are inadequate, with low adherence to recommended interventions. Health-care systems are not optimised to address the distinct needs of young adults, and gaps in transitional care (from paediatric to adult services) contribute to disengagement and adverse outcomes. Addressing these challenges requires tailored management strategies that consider the unique metabolic and psychosocial factors in this population. In this Series paper, we summarise the evidence base for the management of early-onset type 2 diabetes, key evidence gaps, and discuss the multisectoral and transdisciplinary elements needed to achieve population-level prevention to reverse these concerning trends.

Digital health interventions (DHIs) show promise for the treatment of mental health disorders. However, existing meta-analytical research is methodologically heterogeneous, with studies including a mix of clinical, non-clinical, and transdiagnostic populations, hindering a comprehensive understanding of DHI effectiveness. Thus, we conducted an umbrella review of meta-analyses of randomised controlled trials investigating the effectiveness of DHIs for specific mental health disorders and evaluating the quality of evidence. We searched three public electronic databases from inception to February, 2024 and included 16 studies. DHIs were effective compared with active interventions for schizophrenia spectrum disorders, major depressive disorder, social anxiety disorder, and panic disorder. Notable treatment effects compared with a waiting list were also observed for specific phobias, generalised anxiety disorder, obsessive-compulsive disorder, post-traumatic stress disorder, and bulimia nervosa. Certainty of evidence was rated as very low or low in most cases, except for generalised anxiety disorder-related outcomes, which showed a moderate rating. To integrate DHIs into clinical practice, further high-quality studies with clearly defined target populations and robust comparators are needed.

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The incidence of early-onset type 2 diabetes is increasing, with a growing number of cases now occurring in children, adolescents, and young adults. This transition is primarily driven by the rising prevalence of obesity in younger populations, especially in high-income countries. However, the relationship between obesity and early-onset type 2 diabetes varies across ethnic groups, with some populations exhibiting a higher risk at lower BMI thresholds, possibly due to differences in insulin resistance and β-cell function. Socioeconomic factors further shape disease patterns, with early-onset type 2 diabetes disproportionately affecting lower-income populations in high-income settings, whereas in low-income and middle-income countries, economic development and urbanisation have contributed to increasing incidence among more affluent groups. The consequences of this transition to early-onset type 2 diabetes are severe, with accelerated disease progression, heightened risks of microvascular and macrovascular complications, and considerable societal and health-care burdens compared with later-onset disease. Given the continuing rise in childhood and adolescent obesity, the incidence of early-onset type 2 diabetes is expected to increase further, placing mounting pressure on health-care systems worldwide. In the first of three papers in this Series, we examine global trends in the incidence and prevalence of early-onset type 2 diabetes, identify key drivers of this transition to diagnosis at younger ages, and review the evidence for risk factors both at population and individual level.