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Despite their adverse impacts, definitions and measurements of heat waves are ambiguous and inconsistent, generally being endemic to only the group affected, or the respective study reporting the analysis. The present study addresses this issue by employing a set of three heat wave definitions, derived from surveying heat-related indices in the climate science literature. The definitions include three or more consecutive days above one of the following: the 90th percentile for maximum temperature, the 90th percentile for minimum temperature, and positive extreme heat factor (EHF) conditions. Additionally, each index is studied using a multiaspect framework measuring heat wave number, duration, participating days, and the peak and mean magnitudes. Observed climatologies and trends computed by Sen’s Kendall slope estimator are presented for the Australian continent for two time periods (1951–2008 and 1971–2008). Trends in all aspects and definitions are smaller in magnitude but more significant for 1951–2008 than for 1971–2008. Considerable similarities exist in trends of the yearly number of days participating in a heat wave and yearly heat wave frequency, suggesting that the number of available heat wave days drives the number of events. Larger trends in the hottest part of a heat wave suggest that heat wave intensity is increasing faster than the mean magnitude. Although the direct results of this study cannot be inferred for other regions, the methodology has been designed as such that it is widely applicable. Furthermore, it includes a range of definitions that may be useful for a wide range of systems impacted by heat waves.

When Anna's romance-novelist father sends her to an elite American boarding school in Paris for her senior year of high school, she reluctantly goes, and meets an amazing boy who becomes her best friend, in spite of the fact that they both want something more.

Recently, the Vaccines to Vaccinate (v2V) initiative was reconfigured into the Partnership for Dengue Control (PDC), a multi-sponsored and independent initiative. This redirection is consistent with the growing consensus among the dengue-prevention community that no single intervention will be sufficient to control dengue disease. The PDC's expectation is that when an effective dengue virus (DENV) vaccine is commercially available, the public health community will continue to rely on vector control because the two strategies complement and enhance one another. Although the concept of integrated intervention for dengue prevention is gaining increasingly broader acceptance, to date, no consensus has been reached regarding the details of how and what combination of approaches can be most effectively implemented to manage disease. To fill that gap, the PDC proposed a three step process: (1) a critical assessment of current vector control tools and those under development, (2) outlining a research agenda for determining, in a definitive way, what existing tools work best, and (3) determining how to combine the best vector control options, which have systematically been defined in this process, with DENV vaccines. To address the first step, the PDC convened a meeting of international experts during November 2013 in Washington, DC, to critically assess existing vector control interventions and tools under development. This report summarizes those deliberations.

Two Burmese boys, one a Karenni refugee and the other the son of an imprisoned Burmese doctor, meet in the jungle and in order to survive they must learn to trust each other.

Heatwaves have increased in intensity, frequency and duration, with these trends projected to worsen under enhanced global warming. Understanding regional heatwave trends has critical implications for the biophysical and human systems they impact. Until now a comprehensive assessment of regional observed changes was hindered by the range of metrics employed, underpinning datasets, and time periods examined. Here, using the Berkeley Earth temperature dataset and key heatwave metrics, we systematically examine regional and global observed heatwave trends. In almost all regions, heatwave frequency demonstrates the most rapid and significant change. A measure of cumulative heat shows significant increases almost everywhere since the 1950s, mainly driven by heatwave days. Trends in heatwave frequency, duration and cumulative heat have accelerated since the 1950s, and due to the high influence of variability we recommend regional trends are assessed over multiple decades. Our results provide comparable regional observed heatwave trends, on spatial and temporal scales necessary for understanding impacts. Heatwaves are expected to become more frequent and more intense under global warming, but how these trends differ on a regional scale is not well known. Here, the authors provide a comprehensive assessment of regional changes and show that most heat indicaters have increased since the 1950s.

Budding costume designer Lola lives an extraordinary life in San Francisco with her two dads and beloved dog, dating a punk rocker, but when the Bell twins return to the house next door Lola recalls both the friendship-ending fight with Calliope, a figure skater, and the childhood crush she had on Cricket.

Key Points The nuclear factor-κB (NF-κB)–inhibitor of NF-κB kinase (IKK) pathway can promote the growth and survival of many solid and haematological maligancies and therefore has the potential to provide numerous targets for novel anticancer therapies. Most attention has focused on the development of IKKβ inhibitors, but it is now clear that IKKβ has many NF-κB-independent functions and its inhibition could result in undesired effects. Although it is apparent that NF-κB subunits have important roles in tumorigenesis and the response to cancer therapy, their individual contributions have not been clearly defined. The NF-κB response is highly pleiotropic and the consequences of its activation can be context dependent. NF-κB is not always tumour promoting and it can exhibit tumour suppressor-like activities. Crosstalk with tumour-suppressor proteins, such as p53, provides an important mechanism for regulating NF-κB activity and function in cancer. Tumour suppressors can inhibit the tumour-promoting activities of NF-κB subunits while facilitating their ability to suppress cancer progression. Understanding the regulation and function of the NF-κB subunits in cancer provides opportunities for the development of new therapies and allows the better use of existing drugs that affect NF-κB–IKK activity. Nuclear factor-κB (NF-κB) has many functions in cancer, hence the need for drugs that can modulate its activity. In order to achieve this, Neil D. Perkins argues that the complex roles of the individual NF-κB subunits must be considered. It is only recently that the full importance of nuclear factor-κB (NF-κB) signalling to cancer development has been understood. Although much attention has focused on the upstream pathways leading to NF-κB activation, it is now becoming clear that the inhibitor of NF-κB kinases (IKKs), which regulate NF-κB activation, have many independent functions in tissue homeostasis and normal immune function that could compromise the clinical utility of IKK inhibitors. Therefore, if the NF-κB pathway is to be properly exploited as a target for both anticancer and anti-inflammatory drugs, it is appropriate to reconsider the complex roles of the individual NF-κB subunits.

Although most patients with epithelial ovarian cancer respond to frontline platinum-based chemotherapy, around 70% will relapse within 3 years. The phase 3 JAVELIN Ovarian 100 trial compared avelumab (anti-PD-L1 monoclonal antibody) in combination with chemotherapy followed by avelumab maintenance, or chemotherapy followed by avelumab maintenance, versus chemotherapy alone in patients with treatment-naive epithelial ovarian cancer. JAVELIN Ovarian 100 was a global, open-label, three-arm, parallel, randomised, phase 3 trial run at 159 hospitals and cancer treatment centres in 25 countries. Eligible women were aged 18 years and older with stage III–IV epithelial ovarian, fallopian tube, or peritoneal cancer (following debulking surgery, or candidates for neoadjuvant chemotherapy), and had an Eastern Cooperative Oncology Group performance status of 0 or 1. Patients were randomly assigned (1:1:1) via interactive response technology to receive chemotherapy (six cycles; carboplatin dosed at an area under the serum-concentration-time curve of 5 or 6 intravenously every 3 weeks plus paclitaxel 175 mg/m2 every 3 weeks or 80 mg/m2 once a week [investigators' choice]) followed by avelumab maintenance (10 mg/kg intravenously every 2 weeks; avelumab maintenance group); chemotherapy plus avelumab (10 mg/kg intravenously every 3 weeks) followed by avelumab maintenance (avelumab combination group); or chemotherapy followed by observation (control group). Randomisation was in permuted blocks of size six and stratified by paclitaxel regimen and resection status. Patients and investigators were masked to assignment to the two chemotherapy groups without avelumab at the time of randomisation until completion of the chemotherapy phase. The primary endpoint was progression-free survival assessed by blinded independent central review in all randomly assigned patients (analysed by intention to treat). Safety was analysed in all patients who received at least one dose of study treatment. This trial is registered with ClinicalTrials.gov, NCT02718417. The trial was fully enrolled and terminated at interim analysis due to futility, and efficacy is no longer being assessed. Between May 19, 2016 and Jan 23, 2018, 998 patients were randomly assigned (avelumab maintenance n=332, avelumab combination n=331, and control n=335). At the planned interim analysis (data cutoff Sept 7, 2018), prespecified futility boundaries were crossed for the progression-free survival analysis, and the trial was stopped as recommended by the independent data monitoring committee and endorsed by the protocol steering committee. Median follow-up for progression-free survival for all patients was 10·8 months (IQR 7·1–14·9); 11·1 months (7·0–15·3) for the avelumab maintenance group, 11·0 months (7·4–14·5) for the avelumab combination group, and 10·2 months (6·7–14·0) for the control group. Median progression-free survival was 16·8 months (95% CI 13·5–not estimable [NE]) with avelumab maintenance, 18·1 months (14·8–NE) with avelumab combination treatment, and NE (18·2 months–NE) with control treatment. The stratified hazard ratio for progression-free survival was 1·43 (95% CI 1·05–1·95; one-sided p=0·99) with the avelumab maintenance regimen and 1·14 (0·83–1·56; one-sided p=0·79) with the avelumab combination regimen, versus control treatment. The most common grade 3–4 adverse events were anaemia (69 [21%] patients in the avelumab maintenance group, 63 [19%] in the avelumab combination group, and 53 [16%] in the control group), neutropenia (91 [28%], 99 [30%], and 88 [26%]), and neutrophil count decrease (49 [15%], 45 [14%], and 59 [18%]). Serious adverse events of any grade occurred in 92 (28%) patients in the avelumab maintenance group, 118 (36%) in the avelumab combination group, and 64 (19%) in the control group. Treatment-related deaths occurred in one (<1%) patient in the avelumab maintenance group (due to atrial fibrillation) and one (<1%) patient in the avelumab combination group (due to disease progression). Although no new safety signals were observed, results do not support the use of avelumab in the frontline treatment setting. Alternative treatment regimens are needed to improve outcomes in patients with advanced epithelial ovarian cancer. Pfizer and Merck KGaA, Darmstadt, Germany.