Urothelial carcinomas of the upper urinary tract (UTUCs) are rare, with poorer stage-for-stage prognosis than urothelial carcinomas of the urinary bladder. No international consensus exists on the ...benefit of adjuvant chemotherapy for patients with UTUCs after nephroureterectomy with curative intent. The POUT (Peri-Operative chemotherapy versus sUrveillance in upper Tract urothelial cancer) trial aimed to assess the efficacy of systemic platinum-based chemotherapy in patients with UTUCs.
We did a phase 3, open-label, randomised controlled trial at 71 hospitals in the UK. We recruited patients with UTUC after nephroureterectomy staged as either pT2–T4 pN0–N3 M0 or pTany N1–3 M0. We randomly allocated participants centrally (1:1) to either surveillance or four 21-day cycles of chemotherapy, using a minimisation algorithm with a random element. Chemotherapy was either cisplatin (70 mg/m2) or carboplatin (area under the curve AUC4·5/AUC5, for glomerular filtration rate <50 mL/min only) administered intravenously on day 1 and gemcitabine (1000 mg/m2) administered intravenously on days 1 and 8; chemotherapy was initiated within 90 days of surgery. Follow-up included standard cystoscopic, radiological, and clinical assessments. The primary endpoint was disease-free survival analysed by intention to treat with a Peto-Haybittle stopping rule for (in)efficacy. The trial is registered with ClinicalTrials.gov, NCT01993979. A preplanned interim analysis met the efficacy criterion for early closure after recruitment of 261 participants.
Between June 19, 2012, and Nov 8, 2017, we enrolled 261 participants from 57 of 71 open study sites. 132 patients were assigned chemotherapy and 129 surveillance. One participant allocated chemotherapy withdrew consent for data use after randomisation and was excluded from analyses. Adjuvant chemotherapy significantly improved disease-free survival (hazard ratio 0·45, 95% CI 0·30–0·68; p=0·0001) at a median follow-up of 30·3 months (IQR 18·0–47·5). 3-year event-free estimates were 71% (95% CI 61–78) and 46% (36–56) for chemotherapy and surveillance, respectively. 55 (44%) of 126 participants who started chemotherapy had acute grade 3 or worse treatment-emergent adverse events, which accorded with frequently reported events for the chemotherapy regimen. Five (4%) of 129 patients managed by surveillance had acute grade 3 or worse emergent adverse events. No treatment-related deaths were reported.
Gemcitabine–platinum combination chemotherapy initiated within 90 days after nephroureterectomy significantly improved disease-free survival in patients with locally advanced UTUC. Adjuvant platinum-based chemotherapy should be considered a new standard of care after nephroureterectomy for this patient population.
Cancer Research UK.
➤ Heterotopic ossification occurs most commonly after joint arthroplasty, spinal cord injury, traumatic brain injury, blast trauma, elbow and acetabular fractures, and thermal injury.➤ The conversion ...of progenitor cells to osteogenic precursor cells as a result of cell-mediated interactions with the local tissue environment is affected by oxygen tension, pH, availability of micronutrients, and mechanical stimuli, and leads to heterotopic ossification.➤ Radiation and certain nonsteroidal anti-inflammatory medications are important methods of prophylaxis against heterotopic ossification.➤ Well-planned surgical excision can improve patient outcomes regardless of the joint involved or the initial cause of injury.➤ Future therapeutic strategies are focused on targeted inhibition of local factors and signaling pathways that catalyze ectopic bone formation.
Genomic instability is a hallmark of human cancers, including the 5% caused by human papillomavirus (HPV). Here we report a striking association between HPV integration and adjacent host genomic ...structural variation in human cancer cell lines and primary tumors. Whole-genome sequencing revealed HPV integrants flanking and bridging extensive host genomic amplifications and rearrangements, including deletions, inversions, and chromosomal translocations. We present a model of "looping" by which HPV integrant-mediated DNA replication and recombination may result in viral-host DNA concatemers, frequently disrupting genes involved in oncogenesis and amplifying HPV oncogenes E6 and E7. Our high-resolution results shed new light on a catastrophic process, distinct from chromothripsis and other mutational processes, by which HPV directly promotes genomic instability.
The current obesity pandemic results from a physiological imbalance in which energy intake chronically exceeds energy expenditure (EE), and prevention and treatment strategies remain generally ...ineffective. Approaches designed to increase EE have been informed by decades of experiments in rodent models designed to stimulate adaptive thermogenesis, a long-term increase in metabolism, primarily induced by chronic cold exposure. At the cellular level, thermogenesis is achieved through increased rates of futile cycling, which are observed in several systems, most notably the regulated uncoupling of oxidative phosphorylation from ATP generation by uncoupling protein 1, a tissue-specific protein present in mitochondria of brown adipose tissue (BAT). Physiological activation of BAT and other organ thermogenesis occurs through β-adrenergic receptors (AR), and considerable effort over the past 5 decades has been directed toward developing AR agonists capable of safely achieving a net negative energy balance while avoiding unwanted cardiovascular side effects. Recent discoveries of other BAT futile cycles based on creatine and succinate have provided additional targets. Complicating the current and developing pharmacological-, cold-, and exercise-based methods to increase EE is the emerging evidence for strong physiological drives toward restoring lost weight over the long term. Future studies will need to address technical challenges such as how to accurately measure individual tissue thermogenesis in humans; how to safely activate BAT and other organ thermogenesis; and how to sustain a negative energy balance over many years of treatment.
This work evaluates glacial dust as a source of sediment, and associated iron (Fe), to the Fe‐limited Gulf of Alaska (GoA). A reanalysis of GoA sediment data, using rare earth elements and thorium as ...provenance tracers, suggests a flux to the ocean surface of Copper River (AK) glacial dust, and associated Fe, that is comparable to the flux of dust from Asia, at least 1,000 km from the narrow mountain valley glacial dust source area. This work suggests dust from Asia may not be the largest source of Fe to the GoA. Dust models fail to accurately simulate this glacial dust transport because their coarse resolution underestimates wind speeds, and the dust flux. This work suggests that glacial dust fluxes may have been important in the geologic past (e.g., the last glacial maximum) from locations where there was more extensive coverage by glaciers than at present.
Plain Language Summary
The growth of phytoplankton, the base of the marine food web, is known to be limited by availability of the micronutrient iron in the Gulf of Alaska. We evaluated the importance of glacial dust in this region as a source of iron, and other trace metals, by using concentrations of the rare earth elements and thorium in particles as tracers of their geographic origin. We analyzed for these elements in glacial dust samples from the Copper River valley (Alaska), the largest source of glacier‐derived dust. Together with previously published concentrations for dust from Asia and volcanic material, we estimated the inputs of each source material to the sediments of the Gulf of Alaska. This information, together with published sediment mass accumulation rates, suggests an important contribution of Alaskan glacial dust and associated iron, to surface waters of the Gulf of Alaska, at least 1,000 km from the source. Dust models fail to accurately simulate this dust transport because their coarse spatial resolution substantially underestimates wind speeds. Glacial dust fluxes may have been important sources of iron in the geologic past (e.g., the Last Glacial Maximum) from New Zealand and South America, when there was more extensive glacial coverage.
Key Points
Copper River glacial dust contributes substantially to Gulf of Alaska sediments, and associated iron to surface waters
Dust models lack sufficient spatial resolution to accurately simulate the winds that drive the flux of glacial dust from narrow valleys
Glacial dust‐associated iron may have been important in the geologic past in times and locations with more extensive glacial coverage
Abstract
Continental-scale models of malaria climate suitability typically couple well-established temperature-response models with basic estimates of vector habitat availability using rainfall as a ...proxy. Here we show that across continental Africa, the estimated geographic range of climatic suitability for malaria transmission is more sensitive to the precipitation threshold than the thermal response curve applied. To address this problem we use downscaled daily climate predictions from seven GCMs to run a continental-scale hydrological model for a process-based representation of mosquito breeding habitat availability. A more complex pattern of malaria suitability emerges as water is routed through drainage networks and river corridors serve as year-round transmission foci. The estimated hydro-climatically suitable area for stable malaria transmission is smaller than previous models suggest and shows only a very small increase in state-of-the-art future climate scenarios. However, bigger geographical shifts are observed than with most rainfall threshold models and the pattern of that shift is very different when using a hydrological model to estimate surface water availability for vector breeding.
Objectives The Newcastle 85+ Study aims to systematically study the clinical, biological, and psychosocial attributes of an unselected cohort of 85 year olds and to examine subsequent health ...trajectories as the cohort ages; health at baseline is reported.Design Cross sectional analysis of baseline data from a cohort study.Setting Newcastle upon Tyne and North Tyneside primary care trusts, United Kingdom.Participants 1042 people born in 1921 and registered with the participating general practices.Main outcome measures Detailed health assessment and review of general practice records (disease, medication, and use of general practice services); participants could decline elements of the protocol. Results Of the 1453 eligible people, 851 (58.6%) were recruited to health assessment plus record review, 188 (12.9%) to record review only, and 3 (0.2%) to health assessment only. Data from record review are reported on a maximum of 1030 and from health assessment on a maximum of 853; individual denominators differ owing to withdrawal and missing values. Of the health assessment sample (n=853), 62.1% (n=530) were women and 10.4% (n=89) were in institutional care. The most prevalent diseases were hypertension (57.5%, 592/1030) and osteoarthritis (51.8%, 534/1030). Moderate or severe cognitive impairment was present in 11.7% (96/824) of participants, severe or profound urinary incontinence in 21.3% (173/813), hearing impairment in 59.6% (505/848), and visual impairment in 37.2% (309/831). Health assessment identified participants with possible disease but without a previous diagnosis in their medical record for hypertension (25.1%, 206/821), ischaemic heart disease (12.6%, 99/788), depression (6.9%, 53/772), dementia (6.7%, 56/840), and atrial fibrillation (3.8%, 30/788). Undiagnosed diabetes mellitus and thyroid disease were rare (1%, 7/717 and 6/762, respectively). A median of 3 (interquartile range 1-8) activities of daily living were undertaken with difficulty. Overall, 77.6% (646/832) of participants rated their health compared with others of the same age as good, very good, or excellent. High contact rates in the previous year with general practitioners (93.8%, 960/1024) were recorded. Women had significantly higher disease counts (medians: women 5, men 4; P=0.033) and disability scores (medians: women 4, men 2; P=0.0006) than men, but were less likely to have attended outpatient clinics in the previous three months (women 29% (150/524), men 37% (118/320), odds ratio 0.7, 95% confidence interval 0.5 to 0.9).Conclusions This large cohort of 85 year olds showed good levels of both self rated health and functional ability despite significant levels of disease and impairment. Hypertension, ischaemic heart disease, atrial fibrillation, depression, and dementia may be underdiagnosed. Notable differences were found between the sexes: women outnumbered men and had more disease and disability.
We present the set of deep Neutron Star Interior Composition Explorer (NICER) X-ray timing observations of the nearby rotation-powered millisecond pulsars PSRs J0437−4715, J0030+0451, J1231−1411, and ...J2124−3358, selected as targets for constraining the mass-radius relation of neutron stars and the dense matter equation of state (EoS) via modeling of their pulsed thermal X-ray emission. We describe the instrument, observations, and data processing/reduction procedures, as well as the series of investigations conducted to ensure that the properties of the data sets are suitable for parameter estimation analyses to produce reliable constraints on the neutron star mass-radius relation and the dense matter EoS. We find that the long-term timing and flux behavior and the Fourier-domain properties of the event data do not exhibit any anomalies that could adversely affect the intended measurements. From phase-selected spectroscopy, we find that emission from the individual pulse peaks is well described by a single-temperature hydrogen atmosphere spectrum, with the exception of PSR J0437−4715, for which multiple temperatures are required.
How cells maintain their size has been extensively studied under constant conditions. In the wild, however, cells rarely experience constant environments. Here, we examine how the 24-h circadian ...clock and environmental cycles modulate cell size control and division timings in the cyanobacterium Synechococcus elongatus using single-cell time-lapse microscopy. Under constant light, wild-type cells follow an apparent sizer-like principle. Closer inspection reveals that the clock generates two subpopulations, with cells born in the subjective day following different division rules from cells born in subjective night. A stochastic model explains how this behavior emerges from the interaction of cell size control with the clock. We demonstrate that the clock continuously modulates the probability of cell division throughout day and night, rather than solely applying an on–off gate to division, as previously proposed. Iterating between modeling and experiments, we go on to identify an effective coupling of the division rate to time of day through the combined effects of the environment and the clock on cell division. Under naturally graded light–dark cycles, this coupling narrows the time window of cell divisions and shifts divisions away from when light levels are low and cell growth is reduced. Our analysis allows us to disentangle, and predict the effects of, the complex interactions between the environment, clock, and cell size control.
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