Hypertrophic cardiomyopathy, one of the most common genetic cardiovascular conditions, will be encountered by nearly every health-care provider regardless of specialty. In 2020, new hypertrophic cardiomyopathy management guidelines were published, updating and evolving preceding versions. This Seminar provides a concise review and practical guide to the updated recommendations for patients with hypertrophic cardiomyopathy.

Obesity is now recognised as a disease that is associated with serious morbidity and increased mortality. One of its main metabolic complications is type 2 diabetes, as the two conditions share key pathophysiological mechanisms. Weight loss is known to reverse the underlying metabolic abnormalities of type 2 diabetes and, as such, improve glucose control; loss of 15% or more of bodyweight can have a disease-modifying effect in people with type 2 diabetes, an outcome that is not attainable by any other glucose-lowering intervention. Furthermore, weight loss in this population exerts benefits that extend beyond glycaemic control to improve risk factors for cardiometabolic disease and quality of life. We review the evidence supporting the role of weight loss in the management of type 2 diabetes and propose that many patients with type 2 diabetes would benefit from having a primary weight-centric approach to diabetes treatment. We discuss the logistical challenges to implementing a new weight-centric primary treatment goal in people with type 2 diabetes.

Head and neck cancer is the seventh most common type of cancer worldwide and comprise of a diverse group of tumours affecting the upper aerodigestive tract. Although many different histologies exist, the most common is squamous cell carcinoma. Predominant risk factors include tobacco use, alcohol abuse, and oncogenic viruses, including human papillomavirus and Epstein-Barr virus. Head and neck malignancies remain challenging to treat, requiring a multidisciplinary approach, with surgery, radiotherapy, and systemic therapy serving as key components of the treatment of locally advanced disease. Although many treatment principles overlap, treatment is generally site-specific and histology-specific. This Seminar outlines the current understanding of head and neck cancer and focuses on treatment principles, while also discussing future directions to improve the outcomes of patients with these malignancies.

The rapid spread of COVID-19 renewed the focus on how health systems across the globe are financed, especially during public health emergencies. Development assistance is an important source of health financing in many low-income countries, yet little is known about how much of this funding was disbursed for COVID-19. We aimed to put development assistance for health for COVID-19 in the context of broader trends in global health financing, and to estimate total health spending from 1995 to 2050 and development assistance for COVID-19 in 2020.

Cirrhosis is widely prevalent worldwide and can be a consequence of different causes, such as obesity, non-alcoholic fatty liver disease, high alcohol consumption, hepatitis B or C infection, autoimmune diseases, cholestatic diseases, and iron or copper overload. Cirrhosis develops after a long period of inflammation that results in replacement of the healthy liver parenchyma with fibrotic tissue and regenerative nodules, leading to portal hypertension. The disease evolves from an asymptomatic phase (compensated cirrhosis) to a symptomatic phase (decompensated cirrhosis), the complications of which often result in hospitalisation, impaired quality of life, and high mortality. Progressive portal hypertension, systemic inflammation, and liver failure drive disease outcomes. The management of liver cirrhosis is centred on the treatment of the causes and complications, and liver transplantation can be required in some cases. In this Seminar, we discuss the disease burden, pathophysiology, and recommendations for the diagnosis and management of cirrhosis and its complications. Future challenges include better screening for early fibrosis or cirrhosis, early identification and reversal of causative factors, and prevention of complications.

Immune checkpoint inhibitors target the dysfunctional immune system, to induce cancer-cell killing by CD8-positive T cells. Immune checkpoint inhibitors, specifically anti-CTLA4 and anti-PD-1 antibodies, have revolutionised the management of many cancers, particularly advanced melanoma, for which tumour regression and long-term durable cancer control is possible in nearly 50% of patients, compared with less than 10% historically. Despite the absence of adequately powered trial data, combined anti-CTLA4 and anti-PD-1 checkpoint inhibition has the highest 5-year overall survival rate of all therapies in advanced melanoma, and has high activity in melanoma brain metastases. A phase 3 study has shown the addition of an anti-LAG3 antibody to nivolumab improves progression-free survival, but its effect on overall survival and how this combination compares to combined anti-CTLA4 and anti-PD-1 checkpoint inhibition is unknown. At present, there are no highly sensitive and specific biomarkers of response to immune checkpoint inhibitors, and clinical factors, such as volume and sites of disease, serum lactate dehydrogenase, and BRAF mutation status, are used to select initial therapy for patients with advanced melanoma. Immune checkpoint inhibitors can induce autoimmune toxicities by virtue of their mechanism of action. These toxicities, termed immune-related adverse events, occur most frequently with combined anti-CTLA4 and anti-PD-1 checkpoint inhibition; can have a variety of presentations; can affect any organ system (most often the skin, colon, endocrine system, and liver); and appear to mimic classic autoimmune diseases. Immune-related adverse events require prompt recognition and management, which may be different from the autoimmune disease it mimics. Immune checkpoint inhibitors appear to be safe for use in patients with HIV, viral hepatitis, and patients with mild-to-moderate pre-existing autoimmune diseases. Patients with organ transplants can respond to immune checkpoint inhibitors but have a high chance of transplant loss. PD-1 inhibitors are now an established standard of care as adjuvant therapy in high-risk resected stage III or IV melanoma. Neoadjuvant checkpoint inhibition for resectable stage III melanoma, which is currently limited to clinical trials, is emerging as a highly effective therapy.

Fibrotic interstitial lung disease (ILD) represents a large group of pulmonary disorders that are often progressive and associated with high morbidity and early mortality. Important advancements in the past 10 years have enabled a better understanding, characterisation, and treatment of these diseases. This Series paper summarises the current approach to treatment of fibrotic ILDs, both pharmacological and non-pharmacological, including recent discoveries and practice-changing clinical trials. We further outline controversies and challenges, with discussion of evolving concepts and future research directions.

The interstitial pneumonias comprise a diverse group of diseases that are typically defined by their cause (either idiopathic or non-idiopathic) and their distinct histopathological features, for which radiology, in the form of high-resolution CT, is often used as a surrogate. One trend, fuelled by the failure of conventional therapies in a subset of patients and the broad-spectrum use of antifibrotic therapies, has been the focus on the progressive fibrosing phenotype of interstitial lung disease. The histological pattern, known as usual interstitial pneumonia, is the archetype of progressive fibrosis. However, it is clear that progressive fibrosis is not exclusive to this histological entity. Techniques including immunohistochemistry and single-cell RNA sequencing are providing pathogenetic insights and, if integrated with traditional histopathology, are likely to have an effect on the pathological classification of interstitial lung disease. This review, which focuses on the histopathology of interstitial lung disease and its relationship with progressive fibrosis, asks the question: is it all about usual interstitial pneumonia?

The COVID-19 pandemic has heightened interest in how physician mental health can be protected and optimised, but uncertainty and misinformation remain about some key issues. In this Review, we discuss the current literature, which shows that despite what might be inferred during training, physicians are not immune to mental illness, with between a quarter and a third reporting increased symptoms of mental ill health. Physicians, particularly female physicians, are at an increased risk of suicide. An emerging consensus exists that some aspects of physician training, working conditions, and organisational support are unacceptable. Changes in medical training and health systems, and the additional strain of working through a pandemic, might have amplified these problems. A new evidence-informed framework for how individual and organisational interventions can be used in an integrated manner in medical schools, in health-care settings, and by professional colleagues is proposed. New initiatives are required at each of these levels, with an urgent need for organisational-level interventions, to better protect the mental health and wellbeing of physicians.

Community-acquired pneumonia is not usually considered a high-priority problem by the public, although it is responsible for substantial mortality, with a third of patients dying within 1 year after being discharged from hospital for pneumoniae. Although up to 18% of patients with community-acquired pneumonia who were hospitalised (admitted to hospital and treated there) have at least one risk factor for immunosuppression worldwide, strong evidence on community-acquired pneumonia management in this population is scarce. Several features of clinical management for community-acquired pneumonia should be addressed to reduce mortality, morbidity, and complications related to community-acquired pneumonia in patients who are immunocompetent and patients who are immunocompromised. These features include rapid diagnosis, microbiological investigation, prevention and management of complications (eg, respiratory failure, sepsis, and multiorgan failure), empirical antibiotic therapy in accordance with patient's risk factors and local microbiological epidemiology, individualised antibiotic therapy according to microbiological data, appropriate outcomes for therapeutic switch from parenteral to oral antibiotics, discharge planning, and long-term follow-up. This Seminar offers an updated view on community-acquired pneumonia in adults, with suggestions for clinical and translational research.

Since Singapore became an independent nation in 1965, the development of its health-care system has been underpinned by an emphasis on personal responsibility for health, and active government intervention to ensure access and affordability through targeted subsidies and to reduce unnecessary costs. Singapore is achieving good health outcomes, with a total health expenditure of 4·47% of gross domestic product in 2016. However, the health-care system is contending with increased stress, as reflected in so-called pain points that have led to public concern, including shortages in acute hospital beds and intermediate and long-term care (ILTC) services, and high out-of-pocket payments. The main drivers of these challenges are the rising prevalence of non-communicable diseases and rapid population ageing, limitations in the delivery and organisation of primary care and ILTC, and financial incentives that might inadvertently impede care integration. To address these challenges, Singapore's Ministry of Health implemented a comprehensive set of reforms in 2012 under its Healthcare 2020 Masterplan. These reforms substantially increased the capacity of public hospital beds and ILTC services in the community, expanded subsidies for primary care and long-term care, and introduced a series of financing health-care reforms to strengthen financial protection and coverage. However, it became clear that these measures alone would not address the underlying drivers of system stress in the long term. Instead, the system requires, and is making, much more fundamental changes to its approach. In 2016, the Ministry of Health encapsulated the required shifts in terms of the so-called Three Beyonds-namely, beyond health care to health, beyond hospital to community, and beyond quality to value.

Mortality remains unacceptably high in patients with heart failure and reduced left ventricular ejection fraction (LVEF) despite advances in therapeutics. We hypothesised that a novel artificial intelligence approach could better assess multiple and higher-dimension interactions of comorbidities, and define clusters of β-blocker efficacy in patients with sinus rhythm and atrial fibrillation.

Cardiopulmonary resuscitation prioritises treatment for cardiac arrests from a primary cardiac cause, which make up the majority of treated cardiac arrests. Early chest compressions and, when indicated, a defibrillation shock from a bystander give the best chance of survival with a good neurological status. Cardiac arrest can also be caused by special circumstances, such as asphyxia, trauma, pulmonary embolism, accidental hypothermia, anaphylaxis, or COVID-19, and during pregnancy or perioperatively. Cardiac arrests in these circumstances represent an increasing proportion of all treated cardiac arrests, often have a preventable cause, and require additional interventions to correct a reversible cause during resuscitation. The evidence for treating these conditions is mostly of low or very low certainty and further studies are needed. Irrespective of the cause, treatments for cardiac arrest are time sensitive and most effective when given early-every minute counts.

As more people are surviving cardiac arrest, focus needs to shift towards improving neurological outcomes and quality of life in survivors. Brain injury after resuscitation, a common sequela following cardiac arrest, ranges in severity from mild impairment to devastating brain injury and brainstem death. Effective strategies to minimise brain injury after resuscitation include early intervention with cardiopulmonary resuscitation and defibrillation, restoration of normal physiology, and targeted temperature management. It is important to identify people who might have a poor outcome, to enable informed choices about continuation or withdrawal of life-sustaining treatments. Multimodal prediction guidelines seek to avoid premature withdrawal in those who might survive with a good neurological outcome, or prolonging treatment that might result in survival with severe disability. Approximately one in three admitted to intensive care will survive, many of whom will need intensive, tailored rehabilitation after discharge to have the best outcomes.

An enhanced understanding of the importance of Janus kinase (JAK) and signal transducer and activator of transcription (STAT) signalling in multiple disease states has led to an increasing applicability of therapeutic intervention with JAK inhibitors. These agents have revolutionised treatments for a heterogeneous group of disorders, such as myeloproliferative neoplasms, rheumatoid arthritis, inflammatory bowel disease, and multiple immune-driven dermatological diseases, exemplifying rapid bench-to-bedside translation. In this Therapeutics paper, we summarise the currently available data concerning the successes and safety of an array of JAK inhibitors and hypothesise on how these fields could develop.

Tyrosine-kinase inhibitors have changed the natural history of chronic myeloid leukaemia in such a way that patients with adequate access to these agents, who are properly managed, and who respond well to this treatment can expect a near-normal life expectancy. Achieving this goal requires an adequate understanding of the patient's treatment goals, careful monitoring for the achievement of optimal response hallmarks, implementation of proper interventions according to the attainment of such endpoints, adequate recognition and management of adverse events, and acknowledgment of the relevance of comorbidities. Treatment with tyrosine-kinase inhibitors, once considered lifelong, has become terminable for at least some patients, and promising new agents are emerging for those whose disease does not respond to any of the multiple therapeutic options currently available. If these advances reach all patients with chronic myeloid leukaemia, cure might eventually become a reality in most instances.

Heat extremes (ie, heatwaves) already have a serious impact on human health, with ageing, poverty, and chronic illnesses as aggravating factors. As the global community seeks to contend with even hotter weather in the future as a consequence of global climate change, there is a pressing need to better understand the most effective prevention and response measures that can be implemented, particularly in low-resource settings. In this Series paper, we describe how a future reliance on air conditioning is unsustainable and further marginalises the communities most vulnerable to the heat. We then show that a more holistic understanding of the thermal environment at the landscape and urban, building, and individual scales supports the identification of numerous sustainable opportunities to keep people cooler. We summarise the benefits (eg, effectiveness) and limitations of each identified cooling strategy, and recommend optimal interventions for settings such as aged care homes, slums, workplaces, mass gatherings, refugee camps, and playing sport. The integration of this information into well communicated heat action plans with robust surveillance and monitoring is essential for reducing the adverse health consequences of current and future extreme heat.

Hot ambient conditions and associated heat stress can increase mortality and morbidity, as well as increase adverse pregnancy outcomes and negatively affect mental health. High heat stress can also reduce physical work capacity and motor-cognitive performances, with consequences for productivity, and increase the risk of occupational health problems. Almost half of the global population and more than 1 billion workers are exposed to high heat episodes and about a third of all exposed workers have negative health effects. However, excess deaths and many heat-related health risks are preventable, with appropriate heat action plans involving behavioural strategies and biophysical solutions. Extreme heat events are becoming permanent features of summer seasons worldwide, causing many excess deaths. Heat-related morbidity and mortality are projected to increase further as climate change progresses, with greater risk associated with higher degrees of global warming. Particularly in tropical regions, increased warming might mean that physiological limits related to heat tolerance (survival) will be reached regularly and more often in coming decades. Climate change is interacting with other trends, such as population growth and ageing, urbanisation, and socioeconomic development, that can either exacerbate or ameliorate heat-related hazards. Urban temperatures are further enhanced by anthropogenic heat from vehicular transport and heat waste from buildings. Although there is some evidence of adaptation to increasing temperatures in high-income countries, projections of a hotter future suggest that without investment in research and risk management actions, heat-related morbidity and mortality are likely to increase.

The management of prostate cancer continues to evolve rapidly, with substantial advances being made in understanding the genomic landscape and biology underpinning both primary and metastatic prostate cancer. Similarly, the emergence of more sensitive imaging methods has improved diagnostic and staging accuracy and refined surveillance strategies. These advances have introduced personalised therapeutics to clinical practice, with treatments targeting genomic alterations in DNA repair pathways now clinically validated. An important shift in the therapeutic framework for metastatic disease has taken place, with metastatic-directed therapies being evaluated for oligometastatic disease, aggressive management of the primary lesion shown to benefit patients with low-volume metastatic disease, and with several novel androgen pathway inhibitors significantly improving survival when used as a first-line therapy for metastatic disease. Research into the molecular characterisation of localised, recurrent, and progressive disease will undoubtedly have an impact on clinical management. Similarly, emerging research into novel therapeutics, such as targeted radioisotopes and immunotherapy, holds much promise for improving the lives of patients with prostate cancer.