WHO recently announced a process to review and potentially update the procedures for selecting essential medicines. This announcement presents an opportunity to reflect on the evolution of the WHO Model Lists of Essential Medicines (EML), including the composition of the stakeholders that shape priorities. We contextualised our findings within the broader history of the WHO EML to support future reforms to improve access to essential medicines. The current system allows individuals to propose a medicine for the WHO EML. This makes the EML reactive to applicant priorities. Almost all medicines (687/700; 98·1%) proposed to the WHO EML between 2003 and 2023 came from applicants in high-income countries. Most applications (210/700; 30·0%) were submitted by universities and research institutions, followed by non-governmental organisations (159/700; 22·7%), the UN system (158/700; 22·6%), professional associations (98/700; 14·0%), and the pharmaceutical industry (75/700; 10·7%). Between 1977 and 2023, over half of the Expert Committee members were from low-income and middle-income countries, with an increasing proportion in recent EML updates. Mainly, UN agencies acted as observers between 1977 and 2023. One central question emerges when evaluating whether applicants' geographical distribution translates to the WHO EML's intended purpose: for whom is the EML intended? Over the years, the geographical applicability has blurred. Defining a strategic vision for the WHO EML, including articulating a target audience and structured selection process, would strengthen decision-making processes by providing additional clarity, including to those implementing the guidance, mostly in low-income and middle-income countries.

Hypothyroidism, the deficiency of thyroid hormone, is a common condition worldwide. It affects almost all body systems and has a wide variety of clinical presentations from being asymptomatic to, in rare cases, life threatening. The classic symptoms of hypothyroidism include fatigue, lethargy, weight gain, and cold intolerance; however, these symptoms are non-specific and the diagnosis is typically made on biochemical grounds through serum thyroid function tests. The most common cause of hypothyroidism is chronic autoimmune thyroiditis (Hashimoto's thyroiditis), although other causes, including drugs (such as amiodarone, lithium, and immune checkpoint inhibitors), radioactive-iodine treatment, and thyroid surgery, are frequent. Historically, severe iodine deficiency was the most common cause. Reference ranges for thyroid function tests are based on fixed percentiles of the population distribution, but there is increasing awareness of the need for more individualised reference intervals based on key factors such as age, sex, and special circumstances such as pregnancy. Levothyroxine monotherapy is the standard treatment for hypothyroidism; it is safe and inexpensive, restores thyroid function tests to within the reference range, and improves symptoms in the majority of patients. However, 10% of patients have persistent symptoms of ill health despite normalisation of thyroid function tests biochemically and a substantial proportion of patients on levothyroxine have thyroid-stimulating hormone concentrations outside the reference range. Ongoing symptoms despite levothyroxine treatment has led to some patients using liothyronine or desiccated thyroid extract. Taken together, these factors have led to intense debate around the treatment thresholds and treatment strategies for hypothyroidism. In this Seminar, we review the epidemiology, genetic determinants, causes, and presentation of hypothyroidism; highlight key considerations and controversies in its diagnosis and management; and provide future directions for research.

Phenylketonuria is an inherited condition characterised by neurotoxic accumulation of phenylalanine (Phe). APHENITY assessed the efficacy and safety of orally administered synthetic sepiapterin in children and adults with phenylketonuria.