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A report from the Australian Acute Care Genomics programme shows that the integration of rapid whole-genome sequencing and multi-omic analyses informs diagnoses and treatment decisions in a prospective cohort of 290 critically ill infants and children.

In a new study including 200 families who experienced perinatal death, adding genomic analyses to standard autopsies improved the identification of underlying pathogenic causes and informed genetic counseling.

Transcriptome sequencing is a powerful tool for functional analysis of different types of RNA molecules in a wide range of applications. Here the authors use targeted resequencing of cDNA with single-molecule molecular inversion probes as a cost-effective, high-throughput tool for mRNA quantification.

Follicle-stimulating hormone (FSH) administration is effective in patients with hypogonadotropic hypogonadism, which suggests it might be useful in patients with oligozoospermia and normal FSH levels. Although, many studies have evaluated the efficacy of FSH in these patients, in this Perspectives article, the authors argue that FSH can be effective in idiopathic oligozoospermic men if patients are carefully selected.

Systemic infection with the fungal pathogenC. albicans is characterized by high mortality, and the precise antifungal defence mechanisms in humans are poorly defined. Using a systems approach, Smeekens et al. describe a previously unknown role for type I interferons in human anti-Candidadefence.

Heart failure is a major global health problem with unmet therapeutic requirements despite the development of neurohormonal modulators for systolic heart failure. In this Review, the authors discuss the evidence resulting from clinical trials of novel pharmacological agents targeting contractility, neurohormonal signalling, vasodilatation, renal preservation, inflammation, and myocardial protection.

Joris Veltman, Han Brunner and colleagues report results of a family based exome sequencing study of ten individuals with unexplained mental retardation. They identified and validated de novo mutations in nine genes, six of which are likely to be pathogenic based on functional criteria, suggesting an important role for de novo point mutations in the etiology of unexplained mental retardation.

Joris Veltman and colleagues apply exome sequencing to identify heterozygous de novo mutations in SETBP1 as the cause of Schinzel-Giedion syndrome, a rare sporadic disorder characterized by severe intellectual disability and multiple congenital malformations.

Patients with coronary artery disease, who do not respond to optimal medical therapy, are candidates for revascularization. In this Review, Javaid Iqbal and colleagues discuss the evidence for CABG surgery versus percutaneous coronary intervention as the optimal revascularization method in patients with complex coronary artery disease. The choice of technique is dependent on the patient's overall medical state, and the authors highlight the most appropriate surgery in specific patient groups.

In this Perspective, Owolabi et al. propose strategies to improve brain health and address the growing global burden of neurological disorders. They present a new framework — the neurological quadrangle — which aims to provide equitable and effective surveillance, prevention, acute care and rehabilitation of neurological disorders globally.

Implantation of a synthetic mid-urethral sling (SMUS) is the most widely used anti-incontinence surgery performed in women. Despite this widespread use, a dearth of knowledge of the safety, risks and potential complications of SMUS currently exists. Here, Jerry Blaivas and co-authors draw upon the available evidence to provide an in-depth review of the risks of SMUS-associated complications.

High levels of seminal oxidative stress lead to sperm DNA damage and male factor infertility. In this review, the authors describe the mechanisms of oxidative-stress-induced male factor infertility, and how lifestyle-related interventions might reduce levels of seminal oxidative stress, ameliorate infertility and potentially improve the health of the children of men with high levels of seminal oxidative stress.

Traumatic brain injury (TBI) can occur as a single severe cranial impact or as repetitive concussions, and commonly affects professional athletes in contact sports and soldiers exposed to explosions. DeKosky and colleagues describe the distinct pathological changes accompanying each type of TBI, and characteristics of the resultant neuropathology, which frequently involves amyloid-β and tau aggregates. Potential biomarkers of TBI-induced damage are also outlined.

A new publication finds that varicocele repair might improve semen quality enough to enable couples who are awaiting in vitro fertilization or intrauterine insemination to attempt natural conception or less-invasive assisted reproductive techniques. The approach is interesting because it seeks to establish varicocele treatment as one step in a multimodal path to parenthood.

The time course of events after acute coronary syndromes (ACS) might influence the timing and duration of therapeutic interventions. In this paper the authors study the timing of death, reinfarction, stroke, and major bleeding within 6 months of ACS in 46,829 patients enrolled in the Global Registry of Acute Coronary Events (GRACE). Their data shows that the timing of events after ACS was affected by ST category and influenced by GRACE risk score within each electrocardiographic category of ACS. They recommend that risk stratification should, therefore, include multiple risk factors rather than ST shift alone.

Sports-related concussion is increasingly recognized as a potential danger to paediatric populations, but its short-term and long-term consequences remain poorly understood. This Expert Consensus Document is the result of a 1-day meeting convened by Safe Kids Worldwide, the Alzheimer's Drug Discovery Foundation, and the Andrews Institute for Orthopaedics and Sports Medicine, with the aim of highlighting knowledge gaps and areas of critically needed research in youth sports-related concussion.

In many countries, patient outcomes with peritoneal dialysis are comparable or superior to those with haemodialysis. Here, the authors discuss the changing epidemiology of peritoneal dialysis worldwide, including the remaining country-specific challenges that must be overcome to improve utilization of this cost-effective therapy.

Allogeneic haematopoietic stem-cell transplantation (HSCT) is frequently applied as part of treatment in patients with acute myeloid leukaemia in their first or subsequent remission. In this Review, the authors propose risk assessment as a dynamic process during treatment, incorporating both disease-related and transplant-related factors for the decision to proceed either to allogeneic HSCT or to apply a nontransplant strategy.

MEN1 is a syndrome with a complex nature and specific international clinical practice guidelines outlining standards of care have been developed. Genetic testing is recommended for patients with MEN1 and their families; however, the ethical, social, psychological and financial implications of such tests should be taken into account.

Nanotechnology offers great promise for the detection, prevention and treatment of cancer. Current limitations of this technology include the heterogeneous distribution of nanoparticles to tumors, caused in part by the physiological barriers presented by the abnormal tumor vasculature and interstitial matrix. This Review discusses these barriers and summarizes strategies that have been developed to overcome them. It additionally examines design considerations for the optimization of delivery of nanoparticles to tumors.

The primary objective of invasive treatment strategies for multivessel coronary artery disease is complete anatomical revascularization. As objective evidence of ischemia can be provided by a functional assessment based on fractional flow reserve, the focus of contemporary treatment could shift from anatomical to functional revascularization. In this Perspectives article, the authors summarize the data that supports contemporary functional revascularization and its applicability to real-world practice.

The pathophysiology of heart failure is complex, but mitochondrial dysfunction is an emerging therapeutic target to improve cardiac function. In this Consensus Statement, insights into the mechanisms of mitochondrial dysfunction in heart failure are presented, along with an overview of emerging treatments with the potential to improve the function of the failing heart by targeting mitochondria.

Timely and accurate identification and determination of the antimicrobial susceptibility of uropathogens is central to the management of UTIs and antimicrobial stewardship. In this Review, Davenport and colleagues discuss emerging technologies including biosensors, microfluidics, and other integrated platforms that could improve UTI diagnosis and treatment choice.

Vascular disrupting agents (VDAs) are designed to disrupt the already established abnormal vasculature, and induce rapid shutdown of tumor blood supply causing subsequent tumor death from hypoxia and nutrient deprivation. The authors discuss the strategies to improve drug delivery, and suggest that further clinical trials need to evaluate novel treatment strategies that combine VDAs with radiotherapy, cytotoxic drugs, anti-angiogenic agents, and other novel targeted therapies. Close attention to the cardiovascular side effect profile of these agents is also imperative during their clinical development.

Unlike prokaryotes, which do not leave a fossil trail, the patterns of change over evolutionary time of eukaryotic phytoplankton can be derived from microfossils. Here, Paul Falkowski and Matthew Oliver use the fossil record, resource competition theory and the physical principles of ocean dynamics to propose how climate might have affected phytoplankton populations in the past, and make predictions for the future.

In conditions of prolonged stress valvular cells can contribute to valve disease progression. In this Review, Wang and colleagues describe how the biophysical and biochemical properties of the extracellular matrix can regulate valve cell function in the context of calcific valvular diseases. The authors also describe how new cell culture approaches can be employed to better understand the pathophysiology of valve diseases.

Brain metastases remain a serious obstacle in the successful treatment of patients with solid tumors. This Review discusses what is known about the biology of brain metastases, what preclinical models are available to study the disease, and which novel therapeutic strategies are being studied in patients.

Blockade of the pro-inflammatory cytokine interleukin-1 (IL-1) is emerging as an effective approach for the treatment of an increasing number of diseases. Here, Dinarello and colleagues discuss the pathogenic roles of IL-1, present therapeutic strategies aimed at modulating the activity of this cytokine and review clinical trial data for multiple indications.

Mounting evidence indicates that cognitive and emotional processes are important determinates of how individuals with rheumatic disorders experience pain. Depression and catastrophizing, in particular, shape pain responses and pain outcomes through several distinct pathways, and could represent targets for improving and individualizing therapy.

Endometriosis predominantly affects the reproductive organs but can also affect the urinary tract. The optimal therapeutic approach depends on the extent, depth, and location of these lesions. In this Review, the authors discuss the pathogenesis and optimal management of patients with urogenital endometriosis, describing the diagnostic challenges faced and surgical techniques used when managing patients with this disorder.

Considerable progress has been made in understanding the mechanisms that control cell division in plants. However, little is known about how the cell cycle responds to environmental and developmental stimuli and how the cell cycle is turned on and off.

Neuroinflammation during critical phases of brain development can increase the risk of neurological and neuropsychiatric disorders, even in adulthood. In this Review, Hagberg et al. review the mechanisms through which inflammation can exacerbate perinatal brain injury, and outline how understanding the interplay between inflammation and brain injury can aid the identification of new strategies to alleviate neurological and neuropsychiatric morbidity.