The complement system is recognised as a protector against blood-borne pathogens and a controller of immune system and tissue homoeostasis. However, dysregulated complement activity is associated with unwanted or non-resolving immune responses and inflammation, which induce or exacerbate the pathogenesis of a broad range of inflammatory and autoimmune diseases. Although the merit of targeting complement clinically has long been acknowledged, the overall complement drug approval rate has been modest. However, the success of the humanised anti-C5 antibody eculizumab in effectively treating paroxysmal nocturnal haemoglobinuria and atypical haemolytic syndrome has revitalised efforts to target complement therapeutically. Increased understanding of complement biology has led to the identification of novel targets for drug development that, in combination with advances in drug discovery and development technologies, has resulted in a surge of interest in bringing new complement therapeutics into clinical use. The rising number of approved drugs still almost exclusively target rare diseases, but the substantial pipeline of up-and-coming treatment options will possibly provide opportunities to also expand the clinical targeting of complement to common diseases.

The Lancet Countdown is an international research collaboration that independently monitors the evolving impacts of climate change on health, and the emerging health opportunities of climate action. In its eighth iteration, this 2023 report draws on the expertise of 114 scientists and health practitioners from 52 research institutions and UN agencies worldwide to provide its most comprehensive assessment yet. In 2022, the Lancet Countdown warned that people’s health is at the mercy of fossil fuels and stressed the transformative opportunity of jointly tackling the concurrent climate change, energy, cost-of-living, and health crises for human health and wellbeing. This year’s report finds few signs of such progress. At the current 10-year mean heating of 1·14°C above pre-industrial levels, climate change is increasingly impacting the health and survival of people worldwide, and projections show these risks could worsen steeply with further inaction. However, with health matters gaining prominence in climate change negotiations, this report highlights new opportunities to deliver health-promoting climate change action and a safe and thriving future for all.

Deferred (also known as delayed) cord clamping can improve survival of infants born preterm (before 37 weeks of gestation), but the optimal duration of deferral remains unclear. We conducted a systematic review and individual participant data network meta-analysis with the aim of comparing the effectiveness of umbilical cord clamping strategies with different timings of clamping or with cord milking for preterm infants.

Umbilical cord clamping strategies at preterm birth have the potential to affect important health outcomes. The aim of this study was to compare the effectiveness of deferred cord clamping, umbilical cord milking, and immediate cord clamping in reducing neonatal mortality and morbidity at preterm birth.

Global campaigns to control HIV, tuberculosis, malaria, and vaccine-preventable illnesses showed that large-scale impact can be achieved by using additional international financing to support selected, evidence-based, high-impact investment areas and to catalyse domestic resource mobilisation. Building on this paradigm, we make the case for targeting additional international funding for selected high-impact investments in primary health care. We have identified and costed a set of concrete, evidence-based investments that donors could support, which would be expected to have major impacts at an affordable cost. These investments are in: (1) individuals and communities empowered to engage in health decision making, (2) a new model of people-centred primary care, and (3) next generation community health workers. These three areas would be supported by strengthening two cross-cutting elements of national systems. The first is the digital tools and data that support facility, district, and national managers to improve processes, quality of care, and accountability across primary health care. The second is the educational, training, and supervisory systems needed to improve the quality of care. We estimate that with an additional international investment of between US$1·87 billion in a low-investment scenario and $3·85 billion in a high-investment scenario annually over the next 3 years, the international community could support the scale-up of this evidence-based package of investments in the 59 low-income and middle-income countries that are eligible for external financing from the World Bank Group's International Development Association.

Multiple sclerosis remains one of the most common causes of neurological disability in the young adult population (aged 18-40 years). Novel pathophysiological findings underline the importance of the interaction between genetics and environment. Improvements in diagnostic criteria, harmonised guidelines for MRI, and globalised treatment recommendations have led to more accurate diagnosis and an earlier start of effective immunomodulatory treatment than previously. Understanding and capturing the long prodromal multiple sclerosis period would further improve diagnostic abilities and thus treatment initiation, eventually improving long-term disease outcomes. The large portfolio of currently available medications paved the way for personalised therapeutic strategies that will balance safety and effectiveness. Incorporation of cognitive interventions, lifestyle recommendations, and management of non-neurological comorbidities could further improve quality of life and outcomes. Future challenges include the development of medications that successfully target the neurodegenerative aspect of the disease and creation of sensitive imaging and fluid biomarkers that can effectively predict and monitor disease changes.

Radiotherapy has become much better targeted since the 1980s, improving both safety and efficacy. In breast cancer, radiotherapy to regional lymph nodes aims to reduce risks of recurrence and death. Its effects have been studied in randomised trials, some before the 1980s and some after. We aimed to assess the effects of regional node radiotherapy in these two eras.

Malaria is resurging in many African and South American countries, exacerbated by COVID-19-related health service disruption. In 2021, there were an estimated 247 million malaria cases and 619 000 deaths in 84 endemic countries. Plasmodium falciparum strains partly resistant to artemisinins are entrenched in the Greater Mekong region and have emerged in Africa, while Anopheles mosquito vectors continue to evolve physiological and behavioural resistance to insecticides. Elimination of Plasmodium vivax malaria is hindered by impractical and potentially toxic antirelapse regimens. Parasitological diagnosis and treatment with oral or parenteral artemisinin-based therapy is the mainstay of patient management. Timely blood transfusion, renal replacement therapy, and restrictive fluid therapy can improve survival in severe malaria. Rigorous use of intermittent preventive treatment in pregnancy and infancy and seasonal chemoprevention, potentially combined with pre-erythrocytic vaccines endorsed by WHO in 2021 and 2023, can substantially reduce malaria morbidity. Improved surveillance, better access to effective treatment, more labour-efficient vector control, continued drug development, targeted mass drug administration, and sustained political commitment are required to achieve targets for malaria reduction by the end of this decade.

Numerous randomised clinical trials and real-world studies have supported the safety of paclitaxel-coated devices for the treatment of femoropopliteal occlusive disease. However, a 2018 summary-level meta-analysis suggested an increased mortality risk for paclitaxel-coated devices compared with uncoated control devices. This study presents an updated analysis of deaths using the most complete and current data available from pivotal trials of paclitaxel-coated versus control devices.

In their recent guidelines, the European Society of Hypertension upgraded β blockers, putting them on equal footing with thiazide diuretics, renin-angiotensin system blockers (eg, angiotensin-converting enzyme inhibitors and angiotensin receptor blockers), and calcium channel blockers. The reason offered for upgrading β blockers was the observation that they are often used for many other clinical conditions commonly encountered with hypertension. This upgrade would allow for the treatment of two conditions with a single drug (a so-called twofer). In most current national and international hypertension guidelines, β blockers are only considered to be an alternative when there are specific indications. Compared with the other first-line antihypertensive drug classes, β blockers are significantly less effective in preventing stroke and cardiovascular mortality. To relegate β blockers to an inferiority status as previous guidelines have done was based on the evidence in aggregate, and still stands. No new evidence supports the switch of β blockers back to first-line therapy. We are concerned that this move might lead to widespread harm because of inferior stroke protection.

The future of work is rapidly changing, with higher flexibility of the labour market and increasing informal employment in many countries worldwide. There is also an increased pressure to extend working careers until older age. We introduce the concept of working life expectancy as a useful metric, capturing the expected numer of years in paid employment across the working age individuals, in particular among different groups. We describe factors that determine working life expectancy. Macro-level factors focus on the socioeconomic and political context that influences labour force participation, primarily policies and legislation in specific countries. At the meso level, employment contracts and working conditions are important. The micro level shows that individual characteristics, such as education, gender, and age, influence working careers. There are three important groups with a disadvantaged position in the labour market-workers with chronic diseases, workers with impairing disabilities, and workers aged 50 years or more. Within each of these disadvantaged groups, macro-level, meso-level, and micro-level factors that influence entering and exiting paid employment are discussed. To assure that paid employment is available for everyone of working age and that work contributes to better health, specific challenges need to be addressed at the macro, meso, and micro levels. To reach inclusive labour force participation, national policies, company practices, and workplace improvements need to be aligned to ensure safe and healthy workplaces that contribute to the health and wellbeing of workers and their communities.

Mental health problems and disorders are common among working people and are costly for the affected individuals, employers, and whole of society. This discussion paper provides an overview of the current state of knowledge on the relationship between work and mental health to inform research, policy, and practice. We synthesise available evidence, examining both the role of working conditions in the development of mental disorders, and what can be done to protect and promote mental health in the workplace. We show that exposure to some working conditions is associated with an increased risk of the onset of depressive disorders, the most studied mental disorders. The causality of the association, however, is still debated. Causal inference should be supported by more research with stronger linkage to theory, better exposure assessment, better understanding of biopsychosocial mechanisms, use of innovative analytical methods, a life-course perspective, and better understanding of the role of context, including the role of societal structures in the development of mental disorders. There is growing evidence for the effectiveness of interventions to protect and promote mental health and wellbeing in the workplace; however, there is a disproportionate focus on interventions directed towards individual workers and illnesses, compared with interventions for improving working conditions and enhancing mental health. Moreover, research on work and mental health is mainly done in high-income countries, and often does not address workers in lower socioeconomic positions. Flexible and innovative approaches tailored to local conditions are needed in implementation research on workplace mental health to complement experimental studies. Improvements in translating workplace mental health research to policy and practice, such as through workplace-oriented concrete guidance for interventions, and by national policies and programmes focusing on the people most in need, could capitalise on the growing interest in workplace mental health, possibly yielding important mental health gains in working populations.

This paper, the first in a three-part Series on work and health, provides a narrative review of research into work as a social determinant of health over the past 25 years, the key emerging challenges in this field, and the implications of these challenges for future research. By use of a conceptual framework for work as a social determinant of health, we identified six emerging challenges: (1) the influence of technology on the nature of work in high-income countries, culminating in the sudden shift to telework during the COVID-19 pandemic; (2) the intersectionality of work with gender, sexual orientation, age, race, ethnicity, migrant status, and socioeconomic status as codeterminants of health disparities; (3) the arrival in many Organisation for Economic Co-operation and Development countries of large migrant labour workforces, who are often subject to adverse working conditions and social exclusion; (4) the development of precarious employment as a feature of many national labour markets; (5) the phenomenon of working long and irregular hours with potential health consequences; and (6) the looming threat of climate change's effects on work. We conclude that profound changes in the nature and availability of work over the past few decades have led to widespread new psychosocial and physical exposures that are associated with adverse health outcomes and contribute to increasing disparities in health. These new exposures at work will require novel and creative methods of data collection for monitoring of their potential health impacts to protect the workforce, and for new research into better means of occupational health promotion and protection. There is also an urgent need for a better integration of occupational health within public health, medicine, the life sciences, and the social sciences, with the work environment explicitly conceptualised as a major social determinant of health.

Every year, an estimated 21 million girls aged 15-19 years become pregnant in low-income and middle-income countries (LMICs). Policy responses have focused on reducing the adolescent birth rate whereas efforts to support pregnant adolescents have developed more slowly. We did a systematic review of interventions addressing any health-related outcome for pregnant adolescents and their newborn babies in LMICs and mapped its results to a framework describing high-quality health systems for pregnant adolescents. Although we identified some promising interventions, such as micronutrient supplementation, conditional cash transfers, and well facilitated group care, most studies were at high risk of bias and there were substantial gaps in evidence. These included major gaps in delivery, abortion, and postnatal care, and mental health, violence, and substance misuse-related outcomes. We recommend that the fields of adolescent, maternal, and sexual and reproductive health collaborate to develop more adolescent-inclusive maternal health care and research, and specific interventions for pregnant adolescents. We outline steps to develop high-quality, evidence-based care for the millions of pregnant adolescents and their newborns who currently do not receive this.

Polymyalgia rheumatica is an inflammatory disease producing pain and stiffness, mainly in the shoulders and pelvic girdle, in people older than 50 years. Elevation of acute phase reactants is common due to the inflammatory nature of the disease. Since there are no specific diagnostic tests, diagnosis requires the exclusion of other diseases with similar presentations. Imaging has helped to identify the pathological substrate of polymyalgia rheumatica and it is increasingly used to support clinical diagnosis or to detect coexistent giant cell arteritis. Although polymyalgia rheumatica does not clearly impair survival or organ function, it can have a detrimental effect on quality of life. Glucocorticoids at 12·5-25·0 mg prednisone per day are effective in inducing remission in most individuals but, when tapered, relapses occur in 40-60% of those affected and side-effects are common. Assessment of disease activity can be difficult because pain related to common comorbidities such as osteoarthritis and tendinopathies, can return when glucocorticoids are reduced, and acute phase reactants are increased less during flares in individuals undergoing treatment or might increase for other reasons. The role of imaging in assessing disease activity is not yet completely defined. In the search for more efficient and safer therapies, tocilizumab and sarilumab have shown efficacy in randomised controlled trials and additional targeted therapies are emerging. However, judicious risk-benefit balance is essential in applying therapeutic innovations to people with polymyalgia rheumatica.

The Lancet celebrates its 200th anniversary in 2023. In this survey of the journal's history, we explore how it has contributed to shaping medicine both in the UK and internationally, and how it has demonstrated a commitment to "The best science for better lives". For two centuries, the journal has published pioneering articles on key developments in medical science and the organisation of health care. We explore the campaigning and advocacy work of the journal through several indicative areas where science and policy meet, balancing national and global themes over the 19th and 20th centuries. Themes include the raising of professional standards; environmental health in urbanising Britain; the transformation of surgery; the emergence of tropical medicine; the science and politics of vaccination; the advance towards universal health coverage; and the transition from international to global health. In the imperial era, both the journal's research reports and editorial stance were sometimes inflected with colonial attitudes, although it consistently presented medicine as an international endeavour. The Lancet's blend of science and advocacy demonstrates a track record of campaigning for medicine in the cause of social betterment.

Despite the tremendous progress in the clinical management of autoimmune diseases, many patients do not respond to the currently used treatments. Autoreactive B cells play a key role in the pathogenesis of autoimmune diseases, such as systemic lupus erythematosus, rheumatoid arthritis, and multiple sclerosis. B-cell-depleting monoclonal antibodies, such as rituximab, have poor therapeutic efficacy in autoimmune diseases, mainly due to the persistence of autoreactive B cells in lymphatic organs and inflamed tissues. The adoptive transfer of T cells engineered to target tumour cells via chimeric antigen receptors (CARs) has emerged as an effective treatment modality in B-cell malignancies. In the last 2 years treatment with autologous CAR T cells directed against the CD19 antigen has been introduced in therapy of autoimmune disease. CD19 CAR T cells induced a rapid and sustained depletion of circulating B cells, as well as in a complete clinical and serological remission of refractory systemic lupus erythematosus and dermatomyositis. In this paper, we discuss the evolving strategies for targeting autoreactive B cells via CAR T cells, which might be used for targeted therapy in autoimmune diseases.