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In formulating a clear and succinct answer to the question posed by this Viewpoint, the authors highlight several important considerations. They discuss how the choice of induction agent, the presence of risk factors for relapse and the definition of remission can influence the timing of the switch to maintenance therapy and/or the duration of maintenance treatment in patients with ANCA-associated vasculitis.

G protein-coupled receptors (GPCRs) are the most intensively studied class of drug targets. This article presents a pioneering analysis of all GPCR-targeted drugs and agents that are currently in clinical trials, and discusses the trends across molecule types, drug targets and therapeutic indications.

Mitochondria of circulating white blood cells (WBC) and platelets sense oxidative stress during capillary passage and react by producing reactive oxygen species (ROS). Evidence indicates that congestive heart failure (CHF) is associated with oxidative stress; however, the role of WBC and platelets as mediators in CHF has not been investigated. In this paper the authors conducted an observational study to investigate the degree of oxidation in WBC and platelets in patients with CHF and healthy volunteers. Their data shows that in CHF, the proportion of WBC and platelets that are ROS positive is raised. The raised numbers of circulating ROS-positive WBC and platelets amplify oxidative stress in CHF.

Targeted agents directed at VEGF and EGFR have become part of the standard treatment of metastatic colorectal cancer; however, only some patients benefit from such treatment. The CAIRO2 and PACCE trials have shown a detrimental effect of adding an anti-EGFR antibody to standard chemotherapy plus bevacizumab. In this Perspective, the authors discuss issues that may explain these unexpected results.

Children with Down syndrome who develop transient myeloproliferative disorder or acute megakaryoblastic leukemia harbor somatic mutations in theGATA1 gene, a phenomenon specific to this syndrome. Heald and colleagues report the first case of a stillborn fetus with Down syndrome-associated acute megakaryoblastic leukemia/transient myeloproliferative disorder and a GATA1mutation. The authors discuss the management of fetuses with suspected or confirmed diagnosis of Down syndrome and highlight the need for genetic screening and counseling based on maternal age.

Oral poly(ADP)-ribose polymerase (PARP) inhibitors have been shown to have great promise in the treatment of cancer inBRCA mutation carriers. This case provides evidence that these agents are efficacious in patients with PTEN deficiency but no BRCAmutations, opening up a new patient cohort for this treatment.

Breast cancer during pregnancy is increasingly being encountered, and establishing the safety of trastuzumab in this setting is important. The case of a 29-year-old woman diagnosed with node-positive, HER2-positive breast cancer is described. She underwent surgery followed by chemotherapy and radiotherapy and then received trastuzumab. The authors suggest that short-term trastuzumab exposure may be safe and they recommend careful monitoring of the amniotic fluid and cardiac assessment of the mother and fetus.

Subthalamic nucleus deep brain stimulation (STN DBS) is an effective treatment for Parkinson disease. Although the breadth and severity of neurobehavioral changes with STN DBS is debated, the frequency of serious adverse events is probably low. New research has identified patient characteristics that predict cognitive and emotional morbidity after STN DBS.

Patients treated with two or more courses of BCG for high-risk non-muscle-invasive bladder cancer are at increased risk of second-site primary tumours of the upper urinary tract and prostatic urethra. A new study highlights the importance of looking for urothelial cancer in extravesical disease sites.

In the shadow of societal upheaval and transformation, Eastern and South-Eastern European countries have been undergoing major reforms of their scientific and academic landscapes. Although the reforms have been slow, the success of several molecular biology institutes has highlighted what can be achieved.

Microscopic colitis—characterized by watery diarrhea, normal findings on endoscopy and characteristic findings on microscopy—is being increasingly diagnosed. An accurate pathological diagnosis of this disease is important to differentiate microscopic colitis from disease mimics. In this Review, Chetty and Govender provide an overview of the key features of microscopic colitis, describing the different subtypes, etiopathogenesis, pathology and treatment.

Sacral neuromodulation (SNM) has been investigated as a treatment for a range of refractory lower urinary tract disorders. In this Review, Kessler and Fowler discuss developments in SNM techniques and technology, assess patient outcomes, and consider potential mechanisms of action for this therapy.

The acinar cell of the exocrine pancreas produces, stores and secretes enzymes necessary for the digestion and absorption of food. Here, Logsdon and Ji describe two major stressors of the acinar cell, endoplasmic reticulum and digestive enzyme stress, which are major drivers of pancreatic pathology, as well as outlining the coping mechanisms that have evolved to compensate for these two key stressors.

Compounds that alter microtubule function can be highly active in patients with cancer. Here, the authors review the mechanisms of action of and resistance to microtubule-binding agents, then highlight novel anticancer microtubule-binding agents that have recently been approved or reached clinical trials.

A pioneering new study scrutinising the genetic aetiology of Sjögren syndrome across different ancestries and clinical subtypes shows that the striking heterogeneity of associations observed in Sjögren syndrome cannot be explained by subphenotype differences alone.

Available evidence suggests that rituximab may be safe and effective for the treatment of refractory antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis. Two studies now show that rituximab is not less effective than cyclophosphamide for treating ANCA-associated vasculitides. Should rituximab be the new standard of care for patients with ANCA-associated vasculitis?

A new study shows that serum vitamin D concentration is inversely associated with HbA_1c levels among adults in the US aged 35–74 years, in line with results from other observational studies. Should adults with diabetes mellitus or at risk of developing this disease take vitamin D to improve glycemia or reduce this risk?

A year after a devastating earthquake triggered killer avalanches and rock falls in Nepal, scientists are wiring up mountainsides to forecast hazards.

Rapid changes in Tibetan grasslands are threatening Asia's main water supply and the livelihood of nomads.

Several African nations could strike a major blow against malaria by sacrificing the efficacy of some older drugs. Can they make it work?

The development of blockers of the renin–angiotensin–aldosterone system (RAAS) has led to the identification of new RAAS components that might contribute to the effectiveness and/or adverse effects of these drugs. Here, the authors describe the roles of the prorenin receptor, type 2 angiotensin II receptors, angiotensin 1–7 and aldosterone–angiotensin II interactions and discuss the potential of modulators of these components to enhance RAAS blockade with potentially beneficial effects in patients with cardiovascular and renal diseases.

Surgery for painful shoulder conditions is usually only considered when conservative treatment fails. This article outlines the features of and indications for surgery in common painful conditions that affect the shoulder.

Cancer vaccines, which stimulate the host immune response to malignant disease, have generally failed to induce durable clinical responses in patients, partly owing to tumor-mediated suppression of the host immune system. Here, Kusmartsev and Vieweg explore ways of targeting these tumor-mediated changes to enhance the efficacy of vaccine therapy for urologic cancers.

Functional dyspepsia is thought to be a heterogeneous disorder, with a wide variety of pathophysiological mechanisms underlying the varied symptoms observed in patients. Here, Vanheel and Farré provide an overview of the pathogenesis of functional dyspepsia, adding insight on the diverse functional and structural changes in the gastrointestinal tract in this condition.

Cholangiocarcinoma is the second most common tumor of the liver worldwide. Endoscopy could have a useful role in the work-up of patients with hilar cholangiocarcinoma who are unsuitable for surgery. In this Review, the authors present an overview of the diagnostic and therapeutic role of endoscopic procedures in the management of hilar cholangiocarcinoma.

Here, Nathalie Rommel, Jan Tack and colleagues provide an overview of the extensive literature concerning globus and discuss the quality of the evidence to date. They also put forward a potential theoretical model to support management and future research in globus.

An unexplained increase in the prevalence of the congenital anomaly hypospadias led researchers to investigate the molecular events and genetic expression that underlie this disorder. This Review provides an overview of findings in mice and humans that relate to urethral development, candidate genes and steroid receptor expression, and describes the influence of environmental triggers.

Increasing evidence suggests that Alzheimer disease (AD) is not simply a CNS disorder, but involves interactions between systemic and brain-related factors. Wang and colleagues review the role of amyloid-β (Aβ) in AD, highlighting systemic abnormalities linked to Aβ metabolism and discussing how these abnormalities might influence central pathways of Aβ production and clearance.

Calcification is highly prevalent and a leading cause of death in patients with chronic kidney disease. Noninvasive imaging techniques can be used to identify patients with calcification who are at high risk of clinical events, and monitor progression and treatment-related changes in calcification burden. The authors of this Review discuss noninvasive imaging techniques that are commonly used to assess vascular and valvular calcification and evaluate their advantages and limitations.

Advances in the understanding of the molecular pathology of the two types of endometrial carcinoma have underpinned the first steps in the development and testing of targeted therapies. This Review discusses the therapeutic targets, molecular diversity of tumors, oncogene addiction and synthetic lethality in this hard-to-treat disease.

Adipose tissue transplantation is increasingly being explored as a treatment strategy for metabolic disease—to promote the beneficial metabolic effects of subcutaneous white adipose tissue and brown adipose tissue, as well as those of adipose-derived stem cells. This Review summarizes the current available data on the biology of different adipose tissue depots and conceptualizes the future of adipose tissue transplantation and ongoing research.

This Review describes the mechanisms by which the X chromosome regulates immune responses. The authors discuss how the effects of this chromosome can account for many of the immunological differences, such as altered susceptibility to infection or autoimmune disease, that occur between the sexes.

Left-handers are often excluded from neuroscience and neurogenetics studies in order to reduce variance in the data. In this Perspective, Willemset al. discuss the potential of studying this substantial but often-ignored portion of the population.

Numerous epidemiologic studies have shown a strong association between being born with a low birth weight or being born small for gestational age and the development of renal and cardiovascular disease in adult life. Here, Abitbol and Rodriguez describe how this phenomenon might relate to developmental programming of adult disease during vulnerable periods of growthin uteroand during the early postnatal period. They also discuss potential early interventions that might alter the progression of such disease.

To achieve a comprehensive mechanistic view of the cancer process do we need to assemble a physically integrated team of interdisciplinary scientists that includes mathematicians? This Perspective discusses the useful insights provided by such an interaction.

Vitamin D has an important role in regulating the innate and adaptive immune response. Patients with kidney disease are often deficient in vitamin D, which could partly explain the high morbidity and mortality associated with infection that is commonly seen in these patients. In this Review, Sterling et al. describe the pleiotropic actions of vitamin D on the immune system and how vitamin D deficiency leads to immune dysfunction.

In 1970 the Boulder Committee met to standardize the nomenclature used to describe the developing human cortex. Bystron and colleagues describe how new insights since that time have led to the need to revise this nomenclature, and provide their recommendations.