Integrating experiments to predict interactive cue effects on spring phenology with warming.

Climate change has advanced plant phenology globally 4-6 d °C-1 on average. Such shifts are some of the most reported and predictable biological impacts of rising temperatures. Yet as climate change has marched on, phenological shifts have appeared muted over recent decades - failing to match simple predictions of an advancing spring with continued warming. The main hypothesis for these changing trends is that interactions between spring phenological cues - long-documented in laboratory environments - are playing a greater role in natural environments due to climate change. Here, we argue that accurately linking shifts observed in long-term data to underlying phenological cues is slowed by biases in observational studies and limited integration of insights from laboratory studies. We synthesize seven decades of laboratory experiments to quantify how phenological cue-space has been studied and how treatments compare with shifts caused by climate change. Most studies focus on one cue, limiting our ability to make accurate predictions, but some well-studied forest species offer opportunities to advance forecasting. We outline how greater integration of controlled-environment studies with long-term data could drive a new generation of laboratory experiments, built on physiological insights, that would transform our fundamental understanding of phenology and improve predictions.

Spatial and temporal shifts in photoperiod with climate change.

Climate change causes both temporal (e.g. advancing spring phenology) and geographic (e.g. range expansion poleward) species shifts, which affect the photoperiod experienced at critical developmental stages ('experienced photoperiod'). As photoperiod is a common trigger of seasonal biological responses - affecting woody plant spring phenology in 87% of reviewed studies that manipulated photoperiod - shifts in experienced photoperiod may have important implications for future plant distributions and fitness. However, photoperiod has not been a focus of climate change forecasting to date, especially for early-season ('spring') events, often assumed to be driven by temperature. Synthesizing published studies, we find that impacts on experienced photoperiod from temporal shifts could be orders of magnitude larger than from spatial shifts (1.6 h of change for expected temporal vs 1 min for latitudinal shifts). Incorporating these effects into forecasts is possible by leveraging existing experimental data; we show that results from growth chamber experiments on woody plants often have data relevant for climate change impacts, and suggest that shifts in experienced photoperiod may increasingly constrain responses to additional warming. Further, combining modeling approaches and empirical work on when, where and how much photoperiod affects phenology could rapidly advance our understanding and predictions of future spatio-temporal shifts from climate change.

A simple explanation for declining temperature sensitivity with warming.

Recently, multiple studies have reported declining phenological sensitivities (∆ days per ℃) with higher temperatures. Such observations have been used to suggest climate change is reshaping biological processes, with major implications for forecasts of future change. Here, we show that these results may simply be the outcome of using linear models to estimate nonlinear temperature responses, specifically for events that occur after a cumulative thermal threshold is met-a common model for many biological events. Corrections for the nonlinearity of temperature responses consistently remove the apparent decline. Our results show that rising temperatures combined with linear estimates based on calendar time produce the observations of declining sensitivity-without any shift in the underlying biology. Current methods may thus undermine efforts to identify when and how warming will reshape biological processes.

T cells isolated from patients with checkpoint inhibitor-resistant melanoma are functional and can mediate tumor regression.

Background: Almost half of the patients with metastatic melanoma obtain only short-term or no benefit at all from checkpoint inhibitor (CPI) immunotherapy. In this study, we investigated whether the immune system of patients progressing following CPI treatment was able to generate functional tumor-specific immune responses. Materials and methods: Tumor-infiltrating lymphocytes (TILs) were isolated and expanded from metastatic melanoma lesions which progressed during or after anti-programmed cell death protein 1 (PD)-1 and anti-Cytotoxic T-Lymphocyte Antigen 4 (CTLA-4) treatment. Tumor-specific immune responses were assessed with co-culture assays of TILs and autologous tumor cells. Results: TILs from 23 metastases of individual patients could be assessed for T cells recognition of autologous tumor cells. All metastases were progressive on or following anti-PD-1 (23/23, 100%), and the majority also after anti-CTLA-4 (17/23, 74%). Functional antitumor immune responses were detected in 19/23 patients (83%). Both CD8+ (in 18/23 patients, 78%) and CD4+ (in 16/23 patients, 70%) TILs were able to recognize autologous tumors. A large fraction of CD8+ TILs (median 23%, range 1.0%-84%) recognized tumor cells. This is similar to the cohorts of unselected patient populations with metastatic melanoma presented in previous studies. The localization of intratumoral immune infiltrates was heterogeneous among samples. In a phase I/II clinical trial, TILs were administered with lymphodepleting chemotherapy, pegIFNα2b and interleukin-2 to 12 patients with CPI-resistant melanoma. Out of 12 patients who previously failed CPI therapy, treatment with TILs resulted in two partial responses, of which one is ongoing. Conclusions: Tumor-reactive T cells appear to heavily infiltrate the tumor microenvironment of patients who failed previous CPI treatment. These patients can still respond to an infusion of unselected autologous TILs. Our results warrant further testing of novel immune re-activation strategies in melanoma patients who failed multiple CPI therapy.

Do patient access schemes for high-cost cancer drugs deliver value to society?-lessons from the NHS Cancer Drugs Fund.

BACKGROUND: The NHS Cancer Drugs Fund (CDF) was established in 2010 to reduce delays and improve access to cancer drugs, including those that had been previously appraised but not approved by NICE (National Institute for Health and Care Excellence). After 1.3 billion GBP expenditure, a UK parliamentary review in 2016 rationalized the CDF back into NICE. METHODS: This paper analyses the potential value delivered by the CDF according to six value criteria. This includes validated clinical benefits scales, cost-effectiveness criteria as defined by NICE and an assessment of real-world data. The analysis focuses on 29 cancer drugs approved for 47 indications that could be prescribed through the CDF in January 2015. RESULTS: Of the 47 CDF approved indications, only 18 (38%) reported a statistically significant OS benefit, with an overall median survival of 3.1 months (1.4-15.7 months). When assessed according to clinical benefit scales, only 23 (48%) and 9 (18%) of the 47 drug indications met ASCO and ESMO criteria, respectively. NICE had previously rejected 26 (55%) of the CDF approved indications because they did not meet cost-effectiveness thresholds. Four drugs-bevacizumab, cetuximab, everolimus and lapatinib-represented the bulk of CDF applications and were approved for a total of 18 separate indications. Thirteen of these indications were subsequently delisted by the CDF in January 2015 due to insufficient evidence for clinical benefit-data which were unchanged since their initial approval. CONCLUSIONS: We conclude the CDF has not delivered meaningful value to patients or society. There is no empirical evidence to support a 'drug only' ring fenced cancer fund relative to concomitant investments in other cancer domains such as surgery and radiotherapy, or other noncancer medicines. Reimbursement decisions for all drugs and interventions within cancer care should be made through appropriate health technology appraisal processes.

The use of cell culture platforms to identify novel markers of bone and dentin resorption.

OBJECTIVES: 1) To test the hypothesis that there would be proteomic differences in the composition of exosomes isolated from osteoclasts and odontoclasts and 2) to determine the clinical usefulness of these in vitro biomarker candidates. MATERIALS AND METHODS: Mouse bone marrow-derived precursors were cultured on either dentin or bone slices and allowed to mature and begin resorption. Exosomes were isolated from cell culture media and characterized by mass spectrometry. The proteomic data obtained from this in vitro study were compared with the data obtained from human samples in our previous work. RESULTS: There was a difference in the proteomic composition of exosomes from osteoclasts and odontoclasts. A total of 40 exosomal proteins were only present in osteoclast media, whereas six unique exosomal proteins were identified in odontoclast supernatants. Approximately 50% of exosomal proteins released by clastic cells in vitro can be found in oral fluids. CONCLUSION: Our data suggest that the mineralized matrix type plays a role in the final phenotypic characteristics of mouse clastic cells. Many in vitro biomarker candidates of bone and dentin resorption can also be found in human oral fluids, thus indicating that this approach may be a viable alternative in biomarker discovery.

Effects of different orthodontic retention protocols on the periodontal health of mandibular incisors.

OBJECTIVES: To test the following two hypotheses: 1) different types of retainers result in distinct levels of biomarkers in gingival crevicular fluid (GCF) and 2) the retainer bonded to all mandibular anterior teeth induces more detrimental outcomes to the periodontium. SETTING AND SAMPLE POPULATION: The Department of Orthodontics at the University of Florida. The population consisted of individuals in the retention phase of orthodontic treatment. MATERIAL AND METHODS: This was a cross-sectional study that enrolled 36 individuals. Subjects in group 1 had retainers bonded to the mandibular canines only. Group 2 consisted of individuals having retainers bonded to all mandibular anterior teeth. Group 3 included patients using mandibular removable retainers. After clinical examination, GCF was collected from the mandibular incisor and biomarker levels were compared between the groups. RESULTS: Plaque accumulation and gingivitis differed significantly among groups, with the highest median values in group 2 subjects. Pairwise comparison of the groups with respect to gingivitis showed significant differences between groups 1 and 2. Significant differences among groups were detected for RANKL, OPG, OPN, M-CSF, MMP-3, and MMP-9. The ratio RANKL/OPG was significantly higher in group 2 subjects, with pairwise comparisons indicating that groups 1 and 2 differed from group 3. CONCLUSION: An association was found between orthodontic retention groups and GCF biomarker levels, which should be further explored in longitudinal studies. The presence of retainers bonded to all anterior teeth seems to increase plaque accumulation and gingivitis.

Mountain uplift explains differences in Palaeogene patterns of mammalian evolution and extinction between North America and Europe.

Patterns of late Palaeogene mammalian evolution appear to be very different between Eurasia and North America. Around the Eocene-Oligocene (EO) transition global temperatures in the Northern Hemisphere plummet: following this, European mammal faunas undergo a profound extinction event (the Grande Coupure), while in North America they appear to pass through this temperature event unscathed. Here, we investigate the role of surface uplift to environmental change and mammalian evolution through the Palaeogene (66-23 Ma). Palaeogene regional surface uplift in North America caused large-scale reorganization of precipitation patterns, particularly in the continental interior, in accord with our combined stable isotope and ecometric data. Changes in mammalian faunas reflect that these were dry and high-elevation palaeoenvironments. The scenario of Middle to Late Eocene (50-37 Ma) surface uplift, together with decreasing precipitation in higher-altitude regions of western North America, explains the enigma of the apparent lack of the large-scale mammal faunal change around the EO transition that characterized western Europe. We suggest that North American mammalian faunas were already pre-adapted to cooler and drier conditions preceding the EO boundary, resulting from the effects of a protracted history of surface uplift.

Oxygen and hydrogen isotope evidence for a temperate climate 3.42 billion years ago.

Stable oxygen isotope ratios (delta(18)O) of Precambrian cherts have been used to establish much of our understanding of the early climate history of Earth and suggest that ocean temperatures during the Archaean era ( approximately 3.5 billion years ago) were between 55 degrees C and 85 degrees C (ref. 2). But, because of uncertainty in the delta(18)O of the primitive ocean, there is considerable debate regarding this conclusion. Examination of modern and ancient cherts indicates that another approach, using a combined analysis of delta(18)O and hydrogen isotopes (deltaD) rather than delta(18)O alone, can provide a firmer constraint on formational temperatures without independent knowledge of the isotopic composition of ambient waters. Here we show that delta(18)O and deltaD sampled from 3.42-billion-year-old Buck Reef Chert rocks in South Africa are consistent with formation from waters at varied low temperatures. The most (18)O-enriched Buck Reef Chert rocks record the lowest diagenetic temperatures and were formed in equilibrium with waters below approximately 40 degrees C. Geochemical and sedimentary evidence suggests that the Buck Reef Chert was formed in shallow to deep marine conditions, so our results indicate that the Palaeoarchaean ocean was isotopically depleted relative to the modern ocean and far cooler (

Does the cancer drugs fund lead to faster uptake of cost-effective drugs? A time-trend analysis comparing England and Wales.

BACKGROUND: The Cancer Drugs Fund (CDF) provides £200 million annually in England for 'anti-cancer' drugs. METHODS: We used a controlled pre-/post-intervention design to compare IMS Health dispensing data for 15 cancer drugs (2007-2012) in England vs Wales, stratified by pre-CDF NICE drug approval status (rejected, mixed recommendations, recommended, not appraised). RESULTS: The CDF was associated with increased prescribing in England for three of five drugs rejected or with mixed NICE recommendations. The prescribing volume ratios (PVR) ranged from 1.29 (95% CI 1.00, 1.67) for sorafenib to 3.28 (2.59, 4.14) for bevacizumab (NICE rejected) and 0.93 (0.81, 1.06) and 1.35 (1.21, 1.49) for sunitinib and imatinib respectively (mixed recommendations). Post CDF prescribing in England increased for both drugs awaiting NICE appraisal pre-CDF (lapatinib PVR=7.44 (5.81, 9.54), panitumumab PVR=5.40 (1.20, 24.42)) and subsequently rejected. The CDF was not associated with increased prescribing in England of NICE-recommended drugs. The three most recently launched, subsequently recommended drugs were adopted faster in Wales (from pazopanib PVR=0.51 (0.28, 0.96) to abiraterone PVR=0.78 (0.61-0.99)). INTERPRETATION: These data indicate that the CDF is used to access drugs deemed not cost-effective by NICE. The CDF did not expedite access to new cost-effective cancer agents prior to NICE approval.

Determination of trace elements in ibuprofen drug products using microwave-assisted acid digestion and inductively coupled plasma-mass spectrometry.

Trace elements are found in most drugs as a result of the drug formulation and drug production methods. An inductively coupled plasma-mass spectrometry method for the determination of 24 trace elements (Mg, Ti, V, Cr, Mn, Cu, Fe, Co, Ni, Zn, As, Se, Mo, Ru, Rh, Pd, Ag, Cd, Sb, Ba, Ir, Pt, Au, and Pb) in solid ibuprofen tablets was established in relation to the ICH Q3D(R1) guideline, to evaluate the possibility of linking trace elemental profiles to drug formulation strategies, and to differentiate between drug products based on the trace elemental profiles. Ten European ibuprofen drug products were evaluated (n=3). The sample preparation was performed by microwave-assisted acid digestion using only 10 mg of homogenized sample and 900 µL of a mix of 65% HNO3, 37% HCl, and 30% H2O2. Solid residuals primarily composed of insoluble SiO2 excipients were removed by centrifugation. Only concentrations of Mg, Fe, Ti, Mn, Cr, and Ni were detected above the limits of detection and did not exceed the ICH Q3D(R1) guideline permitted daily exposure limits. The trace elemental profiles were evaluated through principal component analysis. Three principal components describing 96% of the variance were useful in grouping the ibuprofen drug products, and the detected trace elemental remnants could be related to drug formulation and drug production strategies. An in-house quality control material was used in lack of certified reference materials and was in combination with spike recoveries used for method validation. Good spike recoveries (94-119%) were obtained for all measured trace elements except Mg. Mg showed acceptable spike recoveries (75-155%) for mid and high-spike concentrations, but poor recoveries (30-223%) were detected with low spike concentrations in spike matrices containing high amounts of Mg. Overall, the method is suggested applicable for solid drugs containing insoluble SiO2 excipients and drugs comparable to ibuprofen.

Perceptions of intermittent preventive treatment of malaria in pregnancy (IPTp) and barriers to adherence in Nasarawa and Cross River States in Nigeria.

BACKGROUND: Malaria during pregnancy is dangerous to both mother and foetus. Intermittent preventive treatment of malaria in pregnancy (IPTp) is a strategy where pregnant women in malaria-endemic countries receive full doses of sulphadoxine-pyrimethamine (SP), whether or not they have malaria. The Nigerian government adopted IPTp as a national strategy in 2005; however, major gaps affecting perception, uptake, adherence, and scale-up remain. METHODS: A cross-sectional study was conducted in peri-urban and rural communities in Nasarawa and Cross River States in Nigeria. Study instruments were based on the socio-ecological model and its multiple levels of influences, taking into account individual, community, societal, and environmental contexts of behaviour and social change. Women of reproductive age, their front-line care providers, and (in Nasarawa only) their spouses participated in focus group discussions and in-depth individual interviews. Facility sampling was purposive to include tertiary, secondary and primary health facilities. RESULTS: The study found that systems-based challenges (stockouts; lack of provider knowledge of IPTp protocols) coupled with individual women's beliefs and lack of understanding of IPT contribute to low uptake and adherence. Many pregnant women are reluctant to seek care for an illness they do not have. Those with malaria often prefer to self-medicate through drug shops or herbs, though those who seek clinic-based treatment trust their providers and willingly accept medicine prescribed. CONCLUSIONS: Failing to deliver complete IPTp to women attending antenatal care is a missed opportunity. While many obstacles are structural, programmes can target women, their communities and the health environment with specific interventions to increase IPTp uptake and adherence.

Donor-derived organ transplant transmission of coccidioidomycosis.

Coccidioidomycosis in solid organ transplant recipients most often occurs as a result of primary infection or reactivation of latent infection. Herein, we report a series of cases of transplant-related transmission of coccidioidomycosis from a single donor from a non-endemic region whose organs were transplanted to 5 different recipients. In all, 3 of the 5 recipients developed evidence of Coccidioides infection, 2 of whom had disseminated disease. The degree of T-cell immunosuppression and timing of antifungal therapy initiation likely contributed to development of disease and disease severity in these recipients. This case series highlights the importance of having a high index of suspicion for Coccidioides infection in solid organ transplant recipients, even if the donor does not have known exposure, given the difficulties of obtaining a detailed and accurate travel history from next-of-kin.

A Miocene to Pleistocene climate and elevation record of the Sierra Nevada (California).

Orographic precipitation of Pacific-sourced moisture creates a rain shadow across the central part of the Sierra Nevada (California) that contrasts with the southern part of the range, where seasonal monsoonal precipitation sourced to the south obscures this rain shadow effect. Orographic rainout systematically lowers the hydrogen isotope composition of precipitation (deltaD(ppt)) and therefore deltaD(ppt) reflects a measure of the magnitude of the rain shadow. Hydrogen isotope compositions of volcanic glass (deltaD(glass)) hydrated at the earth's surface provide a unique opportunity to track the elevation and precipitation history of the Sierra Nevada and adjacent Basin and Range Province. Analysis of 67 well dated volcanic glass samples from widespread volcanic ash-fall deposits located from the Pacific coast to the Basin and Range Province demonstrates that between 0.6 and 12.1 Ma the hydrogen isotope compositions of meteoric water displayed a large (>40 per thousand) decrease from the windward to the leeward side of the central Sierra Nevada, consistent with the existence of a rain shadow of modern magnitude over that time. Evidence for a Miocene-to-recent rain shadow of constant magnitude and systematic changes in the longitudinal climate and precipitation patterns strongly suggest that the modern first-order topographic elements of the Sierra Nevada characterized the landscape over at least the last 12 million years.

Estrogen protects lenses against cataract induced by transforming growth factor-beta (TGFbeta).

Cataract, already a major cause of visual impairment and blindness, is likely to become an increasing problem as the world population ages. In a previous study, we showed that transforming growth factor-beta (TGFP) induces rat lenses in culture to develop opacities and other changes that have many features of human subcapsular cataracts. Here we show that estrogen protects against cataract. Lenses from female rats are more resistant to TGFbeta-induced cataract than those from males. Furthermore, lenses from ovariectomized females show increased sensitivity to the damaging effects of TGFbeta and estrogen replacement in vivo, or exposure to estrogen in vitro, restores resistance. Sex-dependent and estrogen-related differences in susceptibility to cataract formation, consistent with a protective role for estrogen, have been noted in some epidemiological studies. The present study in the rat indicates that estrogen provides protection against cataract by countering the damaging effects of TGFbeP. It also adds to an increasing body of evidence that hormone replacement therapy protects postmenopausal women against various diseases.

A unified call to action from Australian nursing and midwifery leaders: ensuring that Black lives matter.

Nurses and midwives of Australia now is the time for change! As powerfully placed, Indigenous and non-Indigenous nursing and midwifery professionals, together we can ensure an effective and robust Indigenous curriculum in our nursing and midwifery schools of education. Today, Australia finds itself in a shifting tide of social change, where the voices for better and safer health care ring out loud. Voices for justice, equity and equality reverberate across our cities, our streets, homes, and institutions of learning. It is a call for new songlines of reform. The need to embed meaningful Indigenous health curricula is stronger now than it ever was for Australian nursing and midwifery. It is essential that nursing and midwifery leadership continue to build an authentic collaborative environment for Indigenous curriculum development. Bipartisan alliance is imperative for all academic staff to be confident in their teaching and learning experiences with Indigenous health syllabus. This paper is a call out. Now is the time for Indigenous and non-Indigenous nurses and midwives to make a stand together, for justice and equity in our teaching, learning, and practice. Together we will dismantle systems, policy, and practices in health that oppress. The Black Lives Matter movement provides us with a 'now window' of accepted dialogue to build a better, culturally safe Australian nursing and midwifery workforce, ensuring that Black Lives Matter in all aspects of health care.

Oxygen isotope zoning in garnet.

Oxygen isotope zoning was examined within garnet with the use of the stable isotope laser probe. Four metamorphic garnets from the regional metamorphic terrane in Vermont and the skarn deposit at Carr Fork, Utah, were examined and were found to be concentrically zoned in delta(18)O values. The largest variations in delta(18)O values were observed in the regional metamorphic garnets, where delta(18)O values change by 3 per mil from core to rim. These oxygen isotope zoning profiles reflect the changes in the delta(18)O values of the rocks during garnet growth, which are caused by infiltration of fluids and by dehydration reactions during metamorphism.

Oxygen isotope constraints on the origin of impact glasses from the cretaceous-tertiary boundary.

Laser-extraction oxygen isotope and major element analyses of individual glass spherules from Haitian Cretaceous-Tertiary boundary sediments demonstrate that the glasses fall on a mixing line between an isotopically heavy (delta(18)O = 14 per mil) high-calcium composition and an isotopically light (delta(18)O = 6 per mil) high-silicon composition. This trend can be explained by melting of heterogeneous source rocks during the impact of an asteroid (or comet) approximately 65 million years ago. The data indicate that the glasses are a mixture of carbonate and silicate rocks and exclude derivation of the glasses either by volcanic processes or as mixtures of sulfate-rich evaporate and silicate rocks.