Psoriasis is a chronic inflammatory disease characterised by sharply demarcated erythematous and scaly skin lesions accompanied by systemic manifestations. Classified by WHO as one of the most serious non-infectious diseases, psoriasis affects 2-3% of the global population. Mechanistically, psoriatic lesions result from hyperproliferation and disturbed differentiation of epidermal keratinocytes that are provoked by immune mediators of the IL-23 and IL-17 pathway. Translational immunology has had impressive success in understanding and controlling psoriasis. Psoriasis is the first disease to have been successfully treated with therapeutics that directly block the action of the cytokines of this pathway; in fact, therapeutics that specifically target IL-23, IL-17, and IL-17RA are approved for clinical use and show excellent efficacy. Furthermore, inhibitors of IL-23 and IL-17 intracellular signalling, such as TYK2 or RORγt, are in clinical development. Although therapies that target the IL-23 and IL-17 pathway also improve psoriatic arthritis symptoms, their effects on long-term disease modification and psoriasis-associated comorbidities still need to be explored.

Armed conflict disproportionately affects the morbidity, mortality, and wellbeing of women, newborns, children, and adolescents. Our study presents insights from a collection of ten country case studies aiming to assess the provision of sexual, reproductive, maternal, newborn, child, and adolescent health and nutrition interventions in ten conflict-affected settings in Afghanistan, Colombia, Democratic Republic of the Congo, Mali, Nigeria, Pakistan, Somalia, South Sudan, Syria, and Yemen. We found that despite large variations in contexts and decision making processes, antenatal care, basic emergency obstetric and newborn care, comprehensive emergency obstetric and newborn care, immunisation, treatment of common childhood illnesses, infant and young child feeding, and malnutrition treatment and screening were prioritised in these ten conflict settings. Many lifesaving women's and children's health (WCH) services, including the majority of reproductive, newborn, and adolescent health services, are not reported as being delivered in the ten conflict settings, and interventions to address stillbirths are absent. International donors remain the primary drivers of influencing the what, where, and how of implementing WCH interventions. Interpretation of WCH outcomes in conflict settings are particularly context-dependent given the myriad of complex factors that constitute conflict and their interactions. Moreover, the comprehensiveness and quality of data remain limited in conflict settings. The dynamic nature of modern conflict and the expanding role of non-state armed groups in large geographic areas pose new challenges to delivering WCH services. However, the humanitarian system is creative and pluralistic and has developed some novel solutions to bring lifesaving WCH services closer to populations using new modes of delivery. These solutions, when rigorously evaluated, can represent concrete response to current implementation challenges to modern armed conflicts.

The nature of armed conflict throughout the world is intensely dynamic. Consequently, the protection of non-combatants and the provision of humanitarian services must continually adapt to this changing conflict environment. Complex political affiliations, the systematic use of explosive weapons and sexual violence, and the use of new communication technology, including social media, have created new challenges for humanitarian actors in negotiating access to affected populations and security for their own personnel. The nature of combatants has also evolved as armed, non-state actors might have varying motivations, use different forms of violence, and engage in a variety of criminal activities to generate requisite funds. New health threats, such as the COVID-19 pandemic, and new capabilities, such as modern trauma care, have also created new challenges and opportunities for humanitarian health provision. In response, humanitarian policies and practices must develop negotiation and safety capabilities, informed by political and security realities on the ground, and guidance from affected communities. More fundamentally, humanitarian policies will need to confront a changing geopolitical environment, in which traditional humanitarian norms and protections might encounter wavering support in the years to come.

Existing global guidance for addressing women's and children's health and nutrition in humanitarian crises is not sufficiently contextualised for conflict settings specifically, reflecting the still-limited evidence that is available from such settings. As a preliminary step towards filling this guidance gap, we propose a conflict-specific framework that aims to guide decision makers focused on the health and nutrition of women and children affected by conflict to prioritise interventions that would address the major causes of mortality and morbidity among women and children in their particular settings and that could also be feasibly delivered in those settings. Assessing local needs, identifying relevant interventions from among those already recommended for humanitarian settings or universally, and assessing the contextual feasibility of delivery for each candidate intervention are key steps in the framework. We illustratively apply the proposed decision making framework to show what a framework-guided selection of priority interventions might look like in three hypothetical conflict contexts that differ in terms of levels of insecurity and patterns of population displacement. In doing so, we aim to catalyse further iteration and eventual field-testing of such a decision making framework by local, national, and international organisations and agencies involved in the humanitarian health response for women and children affected by conflict.

Women and children bear substantial morbidity and mortality as a result of armed conflicts. This Series paper focuses on the direct (due to violence) and indirect health effects of armed conflict on women and children (including adolescents) worldwide. We estimate that nearly 36 million children and 16 million women were displaced in 2017, on the basis of international databases of refugees and internally displaced populations. From geospatial analyses we estimate that the number of non-displaced women and children living dangerously close to armed conflict (within 50 km) increased from 185 million women and 250 million children in 2000, to 265 million women and 368 million children in 2017. Women's and children's mortality risk from non-violent causes increases substantially in response to nearby conflict, with more intense and more chronic conflicts leading to greater mortality increases. More than 10 million deaths in children younger than 5 years can be attributed to conflict between 1995 and 2015 globally. Women of reproductive ages living near high intensity conflicts have three times higher mortality than do women in peaceful settings. Current research provides fragmentary evidence about how armed conflict indirectly affects the survival chances of women and children through malnutrition, physical injuries, infectious diseases, poor mental health, and poor sexual and reproductive health, but major systematic evidence is sparse, hampering the design and implementation of essential interventions for mitigating the harms of armed conflicts.

Classical Hodgkin lymphoma is one of the more frequent lymphomas and is generally considered a highly curable disease with standard first-line chemotherapy and radiotherapy in some cases. Despite these outstanding results, major problems remain unresolved. First, there are still patients who will not be cured with front-line regimens and, second, many patients who are cured of classical Hodgkin lymphoma continue to die prematurely due to the late toxic effects of their therapy. Because the median age of patients with classical Hodgkin lymphoma is in the mid-30s, the disease's impact on the number of years lost from productive life is remarkable. In recent years, the gold standard of chemotherapy (often combined with radiotherapy) has changed, with the approval of immunotherapy mostly in relapse settings.

Adrenal insufficiency can arise from a primary adrenal disorder, secondary to adrenocorticotropic hormone deficiency, or by suppression of adrenocorticotropic hormone by exogenous glucocorticoid or opioid medications. Hallmark clinical features are unintentional weight loss, anorexia, postural hypotension, profound fatigue, muscle and abdominal pain, and hyponatraemia. Additionally, patients with primary adrenal insufficiency usually develop skin hyperpigmentation and crave salt. Diagnosis of adrenal insufficiency is usually delayed because the initial presentation is often non-specific; physician awareness must be improved to avoid adrenal crisis. Despite state-of-the-art steroid replacement therapy, reduced quality of life and work capacity, and increased mortality is reported in patients with primary or secondary adrenal insufficiency. Active and repeated patient education on managing adrenal insufficiency, including advice on how to increase medication during intercurrent illness, medical or dental procedures, and profound stress, is required to prevent adrenal crisis, which occurs in about 50% of patients with adrenal insufficiency after diagnosis. It is good practice for physicians to provide patients with a steroid card, parenteral hydrocortisone, and training for parenteral hydrocortisone administration, in case of vomiting or severe illness. New modes of glucocorticoid delivery could improve the quality of life in some patients with adrenal insufficiency, and further advances in oral and parenteral therapy will probably emerge in the next few years.

Congenital haemophilia A (factor VIII deficiency) and B (factor IX deficiency) are X-linked bleeding disorders. Replacement therapy has been the cornerstone of the management of haemophilia, aiming to reduce the mortality and morbidity of chronic crippling arthropathy. Frequent intravenous injections are burdensome and costly for patients, consequently with poor adherence and restricted access to therapy for many patients worldwide. Bioengineered clotting factors with enhanced pharmacokinetic profiles can reduce the burden of treatment. However, replacement therapy is associated with a risk for inhibitor development that adversely affects bleeding prevention and outcomes. Novel molecules that are subcutaneously delivered provide effective prophylaxis in the presence or absence of inhibitors, either substituting for the procoagulant function of clotting factors (eg, emicizumab) or targeting the natural inhibitors of coagulation (ie, antithrombin, tissue factor pathway inhibitor, or activated protein C). The ultimate goal of haemophilia treatment would be a phenotypical cure achievable with gene therapy, currently under late phase clinical investigation.

Acute flaccid myelitis (AFM) is a disabling, polio-like illness mainly affecting children. Outbreaks of AFM have occurred across multiple global regions since 2012, and the disease appears to be caused by non-polio enterovirus infection, posing a major public health challenge. The clinical presentation of flaccid and often profound muscle weakness (which can invoke respiratory failure and other critical complications) can mimic several other acute neurological illnesses. There is no single sensitive and specific test for AFM, and the diagnosis relies on identification of several important clinical, neuroimaging, and cerebrospinal fluid characteristics. Following the acute phase of AFM, patients typically have substantial residual disability and unique long-term rehabilitation needs. In this Review we describe the epidemiology, clinical features, course, and outcomes of AFM to help to guide diagnosis, management, and rehabilitation. Future research directions include further studies evaluating host and pathogen factors, including investigations into genetic, viral, and immunological features of affected patients, host-virus interactions, and investigations of targeted therapeutic approaches to improve the long-term outcomes in this population.

It is estimated that infertility affects 8-12% of couples globally, with a male factor being a primary or contributing cause in approximately 50% of couples. Causes of male subfertility vary highly, but can be related to congenital, acquired, or idiopathic factors that impair spermatogenesis. Many health conditions can affect male fertility, which underscores the need for a thorough evaluation of patients to identify treatable or reversible lifestyle factors or medical conditions. Although semen analysis remains the cornerstone for evaluating male infertility, advanced diagnostic tests to investigate sperm quality and function have been developed to improve diagnosis and management. The use of assisted reproductive techniques has also substantially improved the ability of couples with infertility to have biological children. This Seminar aims to provide a comprehensive overview of the assessment and management of men with infertility, along with current controversies and future endeavours.

Acute retinal vascular occlusions are common causes of visual impairment. Although both retinal artery occlusions and retinal vein occlusions are associated with increased age and cardiovascular risk factors, their pathophysiology, systemic implications, and management differ substantially. Acute management of retinal artery occlusions involves a multidisciplinary approach including neurologists with stroke expertise, whereas treatment of retinal vein occlusions is provided by ophthalmologists. Optimisation of systemic risk factors by patients' primary care providers is an important component of the management of these two disorders.

Primary biliary cholangitis is an autoimmune liver disease that predominantly affects women. It is characterised by a chronic and destructive, small bile duct, granulomatous lymphocytic cholangitis, with typical seroreactivity for antimitochondrial antibodies. Patients have variable risks of progressive ductopenia, cholestasis, and biliary fibrosis. Considerations for the cause of this disease emphasise an interaction of chronic immune damage with biliary epithelial cell responses and encompass complex, poorly understood genetic risks and environmental triggers. Licensed disease-modifying treatment focuses on amelioration of cholestasis, with weight-dosed oral ursodeoxycholic acid. For patients who do not respond sufficiently, or patients with ursodeoxycholic acid intolerance, conditionally licensed add-on therapy is with the FXR (NR1H4) agonist, obeticholic acid. Off-label therapy is recognised as an alternative, notably with the pan-PPAR agonist bezafibrate; clinical trial agents are also under development. Baseline characteristics, such as young age, male sex, and advanced disease, and serum markers of liver injury, particularly bilirubin and ALP, are used to stratify risk and assess treatment responsiveness. Parallel attention to the burden of patient symptoms is paramount, including pruritus and fatigue.

Several tumour types are responsive to immunotherapy, as shown by regulatory approvals for immune checkpoint inhibitors. However, many patients either do not respond or do not have durable clinical benefit. Thus, there is great interest in developing predictors of response to immunotherapy and rational combination therapies that can enhance efficacy by overcoming primary and acquired resistance. In this Review, we provide an assessment of immunotherapy response biomarkers that can identify patients who will benefit from monotherapy rather than from combinations. We review the rationale for combination therapy and different strategies, including combinations with chemotherapy, targeted therapy, radiation therapy, intratumoural therapies, other immunomodulators, and adaptive cell therapy, including chimeric antigen T-cell receptors and other novel T-cell receptor-based therapies. There are many combination partners in development; therefore, a programmatic approach is needed to develop a framework for biomarker-driven combination therapy selection.

Iron deficiency is one of the leading contributors to the global burden of disease, and particularly affects children, premenopausal women, and people in low-income and middle-income countries. Anaemia is one of many consequences of iron deficiency, and clinical and functional impairments can occur in the absence of anaemia. Iron deprivation from erythroblasts and other tissues occurs when total body stores of iron are low or when inflammation causes withholding of iron from the plasma, particularly through the action of hepcidin, the main regulator of systemic iron homoeostasis. Oral iron therapy is the first line of treatment in most cases. Hepcidin upregulation by oral iron supplementation limits the absorption efficiency of high-dose oral iron supplementation, and of oral iron during inflammation. Modern parenteral iron formulations have substantially altered iron treatment and enable rapid, safe total-dose iron replacement. An underlying cause should be sought in all patients presenting with iron deficiency: screening for coeliac disease should be considered routinely, and endoscopic investigation to exclude bleeding gastrointestinal lesions is warranted in men and postmenopausal women presenting with iron deficiency anaemia. Iron supplementation programmes in low-income countries comprise part of the solution to meeting WHO Global Nutrition Targets.

Bipolar disorders are a complex group of severe and chronic disorders that includes bipolar I disorder, defined by the presence of a syndromal, manic episode, and bipolar II disorder, defined by the presence of a syndromal, hypomanic episode and a major depressive episode. Bipolar disorders substantially reduce psychosocial functioning and are associated with a loss of approximately 10-20 potential years of life. The mortality gap between populations with bipolar disorders and the general population is principally a result of excess deaths from cardiovascular disease and suicide. Bipolar disorder has a high heritability (approximately 70%). Bipolar disorders share genetic risk alleles with other mental and medical disorders. Bipolar I has a closer genetic association with schizophrenia relative to bipolar II, which has a closer genetic association with major depressive disorder. Although the pathogenesis of bipolar disorders is unknown, implicated processes include disturbances in neuronal-glial plasticity, monoaminergic signalling, inflammatory homoeostasis, cellular metabolic pathways, and mitochondrial function. The high prevalence of childhood maltreatment in people with bipolar disorders and the association between childhood maltreatment and a more complex presentation of bipolar disorder (eg, one including suicidality) highlight the role of adverse environmental exposures on the presentation of bipolar disorders. Although mania defines bipolar I disorder, depressive episodes and symptoms dominate the longitudinal course of, and disproportionately account for morbidity and mortality in, bipolar disorders. Lithium is the gold standard mood-stabilising agent for the treatment of people with bipolar disorders, and has antimanic, antidepressant, and anti-suicide effects. Although antipsychotics are effective in treating mania, few antipsychotics have proven to be effective in bipolar depression. Divalproex and carbamazepine are effective in the treatment of acute mania and lamotrigine is effective at treating and preventing bipolar depression. Antidepressants are widely prescribed for bipolar disorders despite a paucity of compelling evidence for their short-term or long-term efficacy. Moreover, antidepressant prescription in bipolar disorder is associated, in many cases, with mood destabilisation, especially during maintenance treatment. Unfortunately, effective pharmacological treatments for bipolar disorders are not universally available, particularly in low-income and middle-income countries. Targeting medical and psychiatric comorbidity, integrating adjunctive psychosocial treatments, and involving caregivers have been shown to improve health outcomes for people with bipolar disorders. The aim of this Seminar, which is intended mainly for primary care physicians, is to provide an overview of diagnostic, pathogenetic, and treatment considerations in bipolar disorders. Towards the foregoing aim, we review and synthesise evidence on the epidemiology, mechanisms, screening, and treatment of bipolar disorders.

For the Chinese, French, German, and Spanish translations of the abstract see Supplementary Materials section.

The COVID-19 pandemic has placed enormous strain on countries around the world, exposing long-standing gaps in public health and exacerbating chronic inequities. Although research and analyses have attempted to draw important lessons on how to strengthen pandemic preparedness and response, few have examined the effect that fragmented governance for health has had on effectively mitigating the crisis. By assessing the ability of health systems to manage COVID-19 from the perspective of two key approaches to global health policy-global health security and universal health coverage-important lessons can be drawn for how to align varied priorities and objectives in strengthening health systems. This Health Policy paper compares three types of health systems (ie, with stronger investments in global health security, stronger investments in universal health coverage, and integrated investments in global health security and universal health coverage) in their response to the ongoing COVID-19 pandemic and synthesises four essential recommendations (ie, integration, financing, resilience, and equity) to reimagine governance, policies, and investments for better health towards a more sustainable future.

Currently licenced direct oral anticoagulants selectively target thrombin (eg, dabigatran) or coagulation factor Xa (eg, apixaban, betrixaban, edoxaban, and rivaroxaban). Designed to be given in fixed doses without routine monitoring, direct oral anticoagulants have a lower propensity for food and drug interactions than do vitamin K antagonists, and in randomised controlled trials involving around 250 000 patients, they were at least as effective for prevention and treatment of thrombosis and were associated with a lower risk of life-threatening bleeding. The absolute benefits of direct oral anticoagulants over vitamin K antagonists are modest; however, guidelines recommend them in preference to vitamin K antagonists for most indications because of their ease of use and superior safety. The greatest benefits of direct oral anticoagulants are likely to be in patients who were previously deemed unsuitable for vitamin K antagonist therapy. The emergence of generic preparations is expected to further increase the uptake of direct oral anticoagulants, particularly in countries where they are currently not widely used because of cost. Direct oral anticoagulants are contraindicated in patients with mechanical heart valves and should be used with caution or avoided in patients with advanced kidney or liver disease. In this Therapeutics paper, we review the pharmacology of direct oral anticoagulants, summarise the evidence that led to their approval and incorporation into treatment guidelines, and explore key unresolved issues. We also briefly discuss future perspectives for the development of oral anticoagulants.

The clinical benefit of LDL cholesterol lowering treatment in older patients remains debated. We aimed to summarise the evidence of LDL cholesterol lowering therapies in older patients.