Varicella zoster virus (VZV) is an exclusively human alphaherpesvirus that infects >90% of the global population. Primary infection typically causes varicella (chickenpox), after which VZV establishes lifelong latency in ganglionic neurons along the entire neuroaxis. Virus reactivation, typically triggered by age-associated immune dysfunction or immune suppressive conditions, produces herpes zoster (shingles) that can be complicated by post-herpetic neuralgia. In limited instances, VZV reactivation (and rarely primary infection) also produces multisystem disease including vasculopathy, cranial neuropathies, myelopathy and cardiovascular or gastrointestinal complications; these complications can occur without, or temporally dissociated from, rash. Diagnosis of varicella or herpes zoster relies on clinical presentation of a disseminated or dermatomal-distribution rash, respectively; diagnosis of VZV infection (owing to replicating virus) is more challenging when cases are atypical and/or occur without rash. Prevention strategies include administration of live attenuated varicella vaccine and recombinant zoster vaccine. VZV infection is treated with antiviral drugs including oral valacyclovir (drug of choice), famciclovir, acyclovir or amenamevir; for severe or disseminated disease, intravenous acyclovir or foscarnet (when other drugs fail) are used. Critical challenges remain in recognizing and diagnosing atypical presentations, developing novel therapeutics, establishing the causal role of VZV in vascular and neurodegenerative disease, and achieving broader vaccine implementation worldwide.
Cancer pain is a persistent and multifaceted global health problem that profoundly impairs quality of life, function and prognosis. Cancer pain occurs across all cancer types and stages, including in long-term survivors, with prevalence and severity influenced by tumour location, treatment modality, metastatic burden, sex, age and comorbidities. Mechanistically, cancer pain is not a single entity but arises from diverse processes including peripheral nociception, central sensitization and maladaptive neuroplasticity. Growing evidence highlights a key contribution of non-neuronal cells, such as immune cells, Schwann cells and central glia, in regulating cancer-related nociceptive signalling. Sex differences and effects of sex hormones further modulate pain perception, susceptibility to treatment-related toxicities and response to analgesic therapies. Comprehensive assessment integrates quantitative sensory testing with psychosocial screening to capture biological and psychosocial determinants of pain. Effective management requires individualized, multimodal strategies combining non-opioid and opioid analgesics, adjuvant agents and emerging targeted therapies with non-pharmacological approaches such as interventional and neuromodulatory procedures, psychological therapies and palliative care. Improving patient-reported outcomes remains central, particularly in cancer survivors with chronic pain. Precision medicine approaches, including mechanistic phenotyping and biomarker-driven and pharmacogenomic strategies, hold promise for tailoring cancer pain management to individual clinical, psychosocial and molecular profiles, ultimately enhancing treatment efficacy and long-term outcomes.
Cancer pain is a persistent and multifaceted global health problem that profoundly impairs quality of life, function and prognosis. Cancer pain occurs across all cancer types and stages, including in long-term survivors, with prevalence and severity influenced by tumour location, treatment modality, metastatic burden, sex, age and comorbidities. Mechanistically, cancer pain is not a single entity but arises from diverse processes including peripheral nociception, central sensitization and maladaptive neuroplasticity. Growing evidence highlights a key contribution of non-neuronal cells, such as immune cells, Schwann cells and central glia, in regulating cancer-related nociceptive signalling. Sex differences and effects of sex hormones further modulate pain perception, susceptibility to treatment-related toxicities and response to analgesic therapies. Comprehensive assessment integrates quantitative sensory testing with psychosocial screening to capture biological and psychosocial determinants of pain. Effective management requires individualized, multimodal strategies combining non-opioid and opioid analgesics, adjuvant agents and emerging targeted therapies with non-pharmacological approaches such as interventional and neuromodulatory procedures, psychological therapies and palliative care. Improving patient-reported outcomes remains central, particularly in cancer survivors with chronic pain. Precision medicine approaches, including mechanistic phenotyping and biomarker-driven and pharmacogenomic strategies, hold promise for tailoring cancer pain management to individual clinical, psychosocial and molecular profiles, ultimately enhancing treatment efficacy and long-term outcomes. In this Primer, Nassini and colleagues review the epidemiology, pathophysiology, diagnosis and management of cancer pain, a devastating sequela of cancer and/or its treatment that profoundly impairs quality of life, function and prognosis.
Methicillin-resistant Staphylococcus aureus (MRSA) is a leading cause of antimicrobial-resistant infection worldwide. The spectrum of diseases caused by MRSA range from uncomplicated skin and soft-tissue infections to life-threatening invasive infections such as bacteraemia, pneumonia, osteomyelitis and endocarditis. MRSA commonly colonizes the skin and mucosal surfaces as an asymptomatic commensal but can transition to an invasive pathogen when host barriers are disrupted or immune defences are compromised. The shift from commensal to pathogen is facilitated by a broad repertoire of virulence factors that promote adhesion, immune evasion, tissue invasion and persistence within host tissues. Despite the development of several new antibiotics with activity against MRSA, clinical outcomes during invasive infections are poor, with many patients experiencing persistent or recurrent infection. Strategies to prevent MRSA infection include infection control measures, screening and targeted decolonization approaches; however, the effectiveness of these interventions varies and often depends on local MRSA prevalence and epidemiological context. Understanding the epidemiology, pathogenesis and clinical management of MRSA remains essential to guide effective prevention and treatment strategies.
Influenza A and B viruses are considerable public health threats. Annual seasonal epidemics are driven by antigenic drift and cause an estimated 3-5 million severe cases and 290,000-650,000 deaths annually. The clinical presentation of seasonal influenza is typically an abrupt, uncomplicated acute respiratory illness with full recovery; however, it can lead to severe, life-threatening complications in individuals at high risk. Antigenic shift caused by reassortment of a seasonal influenza A virus with avian and/or swine influenza A viruses has led to unpredictable pandemics. The successful cross-species transmission of influenza A viruses requires key viral adaptations, including changes in receptor specificity and compatibility with host factors such as ANP32A. Host defence involves a layered innate response, which is antagonized by proteins, such as non-structural protein 1, and a robust adaptive immunity comprising cytotoxic CD8+ T cells targeting conserved internal proteins and B cells producing neutralizing antibodies. Diagnosis primarily depends on highly sensitive PCR-based methods and multiplexed rapid antigen tests. Prevention involves annually updated seasonal vaccines (including inactivated, live attenuated and protein-based vaccines), while treatment relies on early use of neuraminidase and polymerase acidic protein inhibitors. Research priorities include the development of improved vaccines and a better understanding of influenza virus transmission from animals to humans.
Eosinophilic gastrointestinal diseases (EGID) are characterized by abnormal and prominent eosinophilic inflammation of the gastrointestinal mucosa, associated with symptoms related to the segment involved, in the absence of secondary causes of eosinophilia. EGID may affect different parts of the gastrointestinal tract, causing eosinophilic oesophagitis (EoE), eosinophilic gastritis, eosinophilic enteritis and eosinophilic colitis either individually or in combination. Secondary causes of eosinophilic infiltration of the gastrointestinal tract include parasitic infections, the use of certain medications, vasculitis, allergic syndromes, haematological conditions and other inflammatory diseases. The incidence of EGID is increasing globally. EoE is the most reported form, with a prevalence of ~1 in 700 individuals. Several pathogenetic mechanisms are being investigated, in particular, the crosstalk between aeroallergens and mucosal inflammatory cell activation, which leads to a T helper 2 cell inflammatory response and disruption of epithelial barrier integrity. EGID is frequently associated with other T helper 2 cell-driven disorders, such as atopic dermatitis, allergic rhinitis and asthma. EGID is diagnosed through histological assessment, with biopsy samples of affected areas typically showing increased eosinophils, after excluding secondary causes of eosinophilia. For EoE, new treatments, including biologic therapies, are now available, whereas therapeutic options for non-EoE EGID remain limited. Patients' quality of life may be impaired owing to social and functional limitations from symptoms, such as dysphagia and food impaction in EoE, or diarrhoea and abdominal pain in eosinophilic colitis.
Accidental hypothermia is an unintentional drop in core body temperature below 35 °C. It can occur at any time of year and in any climate, and can affect all age groups. The epidemiology of accidental hypothermia reflects the interaction between biological susceptibility, social conditions and exposure to environmental factors. As core temperature falls and thermoregulation mechanisms become insufficient, the metabolism slows, consciousness deteriorates and the hypothermic myocardium becomes increasingly prone to arrhythmias and cardiac arrest. The prognosis is variable, and treatment outcomes are dependent on multiple factors, with cardiac arrest being the decisive determinant, carrying an in-hospital mortality rate of up to 50%. Diagnosis relies on accurate core temperature measurement whenever possible, together with clinical staging when measurement is unavailable. The management of accidental hypothermia should follow the hypothermic chain of survival: prevent further cooling, handle the patient gently, provide airway, breathing and circulatory support, choose the correct destination hospital, and rewarm the patient using passive, active external, active internal or extracorporeal techniques according to severity. Extracorporeal life support is crucial for patients with hypothermic cardiac arrest. Most survivors of hypothermic cardiac arrest have excellent neurological outcomes. Effective prevention and education, together with well-organized regional pathways of care and personalized strategies to prevent cardiac arrest, are needed to improve outcomes.
Accidental hypothermia is an unintentional drop in core body temperature below 35 °C. It can occur at any time of year and in any climate, and can affect all age groups. The epidemiology of accidental hypothermia reflects the interaction between biological susceptibility, social conditions and exposure to environmental factors. As core temperature falls and thermoregulation mechanisms become insufficient, the metabolism slows, consciousness deteriorates and the hypothermic myocardium becomes increasingly prone to arrhythmias and cardiac arrest. The prognosis is variable, and treatment outcomes are dependent on multiple factors, with cardiac arrest being the decisive determinant, carrying an in-hospital mortality rate of up to 50%. Diagnosis relies on accurate core temperature measurement whenever possible, together with clinical staging when measurement is unavailable. The management of accidental hypothermia should follow the hypothermic chain of survival: prevent further cooling, handle the patient gently, provide airway, breathing and circulatory support, choose the correct destination hospital, and rewarm the patient using passive, active external, active internal or extracorporeal techniques according to severity. Extracorporeal life support is crucial for patients with hypothermic cardiac arrest. Most survivors of hypothermic cardiac arrest have excellent neurological outcomes. Effective prevention and education, together with well-organized regional pathways of care and personalized strategies to prevent cardiac arrest, are needed to improve outcomes. Accidental hypothermia, in particular its moderate and severe forms, is a medical emergency owing to the associated risks of arrhythmias, organ dysfunction and cardiac arrest. In this Primer, Darocha et al. describe the epidemiology and mechanisms of this condition, and discuss its diagnosis, management and effects on quality of life, and future research directions.
Primary aldosteronism (PA) results from excessive aldosterone production by one or both adrenal glands and is an important cause of hypertension, leading to increased cardiovascular and renal morbidities. PA is primarily caused by a spectrum of somatic or germline mutations in aldosterone-driver genes and superimposed aberrant adrenal expression of various G-protein-coupled receptors and their ligands, leading to dysregulated aldosterone production. PA remains underdiagnosed, and simplified testing by measuring renin and aldosterone is recommended in all people with hypertension to maximize the diagnosis of PA. Some individuals with PA may also have co-secretion of cortisol, which contributes to cardiometabolic morbidities. Adrenal vein sampling, emerging functional imaging and novel biomarkers can identify whether a unilateral source of PA can be treated with surgical adrenalectomy. However, the majority of patients with PA have bilateral disease, warranting medical therapy with dietary sodium restriction and mineralocorticoid receptor antagonists, and aldosterone synthase inhibitors in the near future. Medical therapy objectives are to normalize blood pressure and serum potassium; a rise in renin can serve as a biomarker of adequate therapy and reduced risk for adverse cardio-renal outcomes. Patients with PA should be monitored longitudinally for disease progression or recurrence, to manage potential adverse effects of treatment, and to optimize therapy of cardiovascular and other co-morbidities.
Osteomyelitis, defined as inflammation of bone, is a highly morbid disease that is most commonly caused by bacterial infection. Infectious osteomyelitis occurs across a spectrum of ages and affects previously healthy individuals as well as individuals with medical comorbidities. Establishment of osteomyelitis typically occurs following one of three general pathological mechanisms, including haematogenous seeding of healthy or injured bone, extension of a contiguous soft tissue infection, or direct inoculation of microorganisms into the bone following trauma. A wide spectrum of microbial pathogens can cause osteomyelitis in these settings. The most common aetiologies share common pathogenic traits such as the propensity to form biofilms, the elaboration of immunoevasive toxins and virulence factors, and the ability to adhere to and invade bone tissue. Challenges in diagnosing, prognosing and treating osteomyelitis remain owing to limitations of conventional cultures, absence of faithful biomarkers, inability to delineate acute versus chronic infection, and therapeutic recalcitrance. Despite prolonged antimicrobial therapy, many individuals with osteomyelitis fail treatment and go on to develop highly morbid complications. Improvements in the management of osteomyelitis will require an ongoing commitment to multidisciplinary clinical care, basic and translational research to uncover pathophysiological mechanisms of disease, and sustained investments in new approaches for the diagnosis, treatment and mitigation of complications.
Primary aldosteronism (PA) results from excessive aldosterone production by one or both adrenal glands and is an important cause of hypertension, leading to increased cardiovascular and renal morbidities. PA is primarily caused by a spectrum of somatic or germline mutations in aldosterone-driver genes and superimposed aberrant adrenal expression of various G-protein-coupled receptors and their ligands, leading to dysregulated aldosterone production. PA remains underdiagnosed, and simplified testing by measuring renin and aldosterone is recommended in all people with hypertension to maximize the diagnosis of PA. Some individuals with PA may also have co-secretion of cortisol, which contributes to cardiometabolic morbidities. Adrenal vein sampling, emerging functional imaging and novel biomarkers can identify whether a unilateral source of PA can be treated with surgical adrenalectomy. However, the majority of patients with PA have bilateral disease, warranting medical therapy with dietary sodium restriction and mineralocorticoid receptor antagonists, and aldosterone synthase inhibitors in the near future. Medical therapy objectives are to normalize blood pressure and serum potassium; a rise in renin can serve as a biomarker of adequate therapy and reduced risk for adverse cardio-renal outcomes. Patients with PA should be monitored longitudinally for disease progression or recurrence, to manage potential adverse effects of treatment, and to optimize therapy of cardiovascular and other co-morbidities. In this Primer, Vaidya and colleagues review the epidemiology, pathophysiology, diagnosis, management and quality of life of patients with primary aldosteronism, an important cause of hypertension resulting from excessive aldosterone production by one or both adrenal glands.
