Correction: Long-term Follow-up and Safety of Patients after an Upfront Therapy with Letrozole for Early Breast Cancer in Routine Clinical Care - The PreFace Study.

[This corrects the article DOI: 10.1055/a-2238-3153.].

Long-term Follow-up and Safety of Patients after an Upfront Therapy with Letrozole for Early Breast Cancer in Routine Clinical Care - The PreFace Study.

Introduction: Adjuvant treatment of patients with early-stage breast cancer (BC) should include an aromatase inhibitor (AI). Especially patients with a high recurrence risk might benefit from an upfront therapy with an AI for a minimum of five years. Nevertheless, not much is known about the patient selection for this population in clinical practice. Therefore, this study analyzed the prognosis and patient characteristics of postmenopausal patients selected for a five-year upfront letrozole therapy. Patients and Methods: From 2009 to 2011, 3529 patients were enrolled into the adjuvant phase IV PreFace clinical trial (NCT01908556). Postmenopausal hormone receptor-positive BC patients, for whom an upfront five-year therapy with letrozole (2.5 mg/day) was indicated, were eligible. Disease-free survival (DFS), overall survival (OS) and safety in relation to patient and tumor characteristics were assessed. Results: 3297 patients started letrozole therapy. The majority of patients (n = 1639, 57%) completed the five-year treatment. 34.5% of patients continued with endocrine therapy after the mandated five-year endocrine treatment. Five-year DFS rates were 89% (95% CI: 88-90%) and five-year OS rates were 95% (95% CI: 94-96%). In subgroup analyses, DFS rates were 83%, 84% and 78% for patients with node-positive disease, G3 tumor grading, and pT3 tumors respectively. The main adverse events (any grade) were pain and hot flushes (66.8% and 18.3% of patients). Conclusions: The risk profile of postmenopausal BC patients selected for a five-year upfront letrozole therapy showed a moderate recurrence and death risk. However, in subgroups with unfavorable risk factors, prognosis warrants an improvement, which might be achieved with novel targeted therapies.

Development of a sensitive real-time quaking-induced conversion (RT-QuIC) assay for application in prion-infected blood.

Efforts to prevent human-to-human transmission of variant Creutzfeldt-Jakob disease (vCJD) by contaminated blood would be aided by the development of a sensitive diagnostic test that could be routinely used to screen blood donations. As blood samples from vCJD patients are extremely rare, here we describe the optimisation of real-time quaking-induced conversion (RT-QuIC) for detection of PrPSc (misfolded prion protein, a marker of prion infection) in blood samples from an established large animal model of vCJD, sheep experimentally infected with bovine spongiform encephalopathy (BSE). Comparative endpoint titration experiments with RT-QuIC, miniaturized bead protein misfolding cyclic amplification (mb-PMCA) and intracerebral inoculation of a transgenic mouse line expressing sheep PrP (tgOvARQ), demonstrated highly sensitive detection of PrPSc by RT-QuIC in a reference sheep brain homogenate. Upon addition of a capture step with iron oxide beads, the RT-QuIC assay was able to detect PrPSc in whole blood samples from BSE-infected sheep up to two years before disease onset. Both RT-QuIC and mb-PMCA also demonstrated sensitive detection of PrPSc in a reference vCJD-infected human brain homogenate, suggesting that either assay may be suitable for application to human blood samples. Our results support the further development and evaluation of RT-QuIC as a diagnostic or screening test for vCJD.

Sweet and sour synergy: exploring the antibacterial and antibiofilm activity of acetic acid and vinegar combined with medical-grade honeys.

Oxymel, a combination of honey and vinegar, has been used as a remedy for wounds and infections in historical and traditional medical settings. While honey is now clinically used to treat infected wounds, this use of a complex, raw natural product (NP) mixture is unusual in modern western medicine. Research into the antimicrobial activity of NPs more usually focuses on finding a single active compound. The acetic acid in vinegar is known to have antibacterial activity at low concentrations and is in clinical use to treat burn wound infections. Here, we investigated the potential for synergistic activity of different compounds present in a complex ingredient used in historical medicine (vinegar) and in an ingredient mixture (oxymel). We conducted a systematic review to investigate published evidence for antimicrobial effects of vinegars against human pathogenic bacteria and fungi. No published studies have explicitly compared the activity of vinegar with that of a comparable concentration of acetic acid. We then characterized selected vinegars by HPLC and assessed the antibacterial and antibiofilm activity of the vinegars and acetic acid, alone and in combination with medical-grade honeys, against Pseudomonas aeruginosa and Staphylococcus aureus. We found that some vinegars have antibacterial activity that exceeds that predicted by their acetic acid content alone, but that this depends on the bacterial species being investigated and the growth conditions (media type, planktonic vs. biofilm). Pomegranate vinegars may be particularly interesting candidates for further study. We also conclude that there is potential for acetic acid, and some vinegars, to show synergistic antibiofilm activity with manuka honey.

Climate-driven variation in dispersal ability predicts responses to forest fragmentation in birds.

Species sensitivity to forest fragmentation varies latitudinally, peaking in the tropics. A prominent explanation for this pattern is that historical landscape disturbance at higher latitudes has removed fragmentation-sensitive species or promoted the evolution of more resilient survivors. However, it is unclear whether this so-called extinction filter is the dominant driver of geographic variation in fragmentation sensitivity, particularly because climatic factors may also cause latitudinal gradients in dispersal ability, a key trait mediating sensitivity to habitat fragmentation. Here we combine field survey data with a morphological proxy for avian dispersal ability (hand-wing index) to assess responses to forest fragmentation in 1,034 bird species worldwide. We find that fragmentation sensitivity is strongly predicted by dispersal limitation and that other factors-latitude, body mass and historical disturbance events-have relatively limited explanatory power after accounting for species differences in dispersal. We also show that variation in dispersal ability is only weakly predicted by historical disturbance and more strongly associated with intra-annual temperature fluctuations (seasonality). Our results suggest that climatic factors play a dominant role in driving global variation in the impacts of forest fragmentation, emphasizing the need for more nuanced environmental policies that take into account local context and associated species traits.

Scientists' warning on population.

Humanity must commit to transformative change on all levels in order to address the climate emergency and biodiversity collapse. In particular, stabilizing and ultimately reducing the human population size is necessary to ensure the long-term wellbeing of our species and other life on Earth. We show how this transition can be accomplished in an equitable framework that promotes human rights. Specifically, we issue a global appeal for women and men to have at most one child and call for policy-makers to implement population policies that improve education for girls and young women and ensure the availability of high-quality family-planning services.

Glimmers of hope in large carnivore recoveries.

In the face of an accelerating extinction crisis, scientists must draw insights from successful conservation interventions to uncover promising strategies for reversing broader declines. Here, we synthesize cases of recovery from a list of 362 species of large carnivores, ecologically important species that function as terminal consumers in many ecological contexts. Large carnivores represent critical conservation targets that have experienced historical declines as a result of direct exploitation and habitat loss. We examine taxonomic and geographic variation in current extinction risk and recovery indices, identify conservation actions associated with positive outcomes, and reveal anthropogenic threats linked to ongoing declines. We find that fewer than 10% of global large carnivore populations are increasing, and only 12 species (3.3%) have experienced genuine improvement in extinction risk, mostly limited to recoveries among marine mammals. Recovery is associated with species legislation enacted at national and international levels, and with management of direct exploitation. Conversely, ongoing declines are robustly linked to threats that include habitat modification and human conflict. Applying lessons from cases of large carnivore recovery will be crucial for restoring intact ecosystems and maintaining the services they provide to humans.

Subclinical infection occurs frequently following low dose exposure to prions by blood transfusion.

Infectious prion diseases have very long incubation periods, and the role that subclinical infections play in transmission, persistence and re-emergence of these diseases is unclear. In this study, we used a well-established model of vCJD (sheep experimentally infected with bovine spongiform encephalopathy, BSE) to determine the prevalence of subclinical infection following exposure by blood transfusion from infected donors. Many recipient sheep survived for years post-transfusion with no clinical signs and no disease-associated PrP (PrPSc) found in post mortem tissue samples by conventional tests. Using a sensitive protein misfolding cyclic amplification assay (PMCA), we found that the majority of these sheep had detectable PrPSc in lymph node samples, at levels approximately 105-106 times lower than in equivalent samples from clinically positive sheep. Further testing revealed the presence of PrPSc in other tissues, including brain, but not in blood samples. The results demonstrate that subclinical infection is a frequent outcome of low dose prion infection by a clinically relevant route for humans (blood transfusion). The long term persistence of low levels of infection has important implications for prion disease control and the risks of re-emergent infections in both humans and animals.

Zafirlukast Induces VHL- and HIF-2α-Dependent Oxidative Cell Death in 786-O Clear Cell Renal Carcinoma Cells.

Mutations in the Von Hippel-Lindau (VHL) gene are the driving force in many forms of clear cell renal cell carcinoma (ccRCC) and promote hypoxia-inducible factor (HIF)-dependent tumor proliferation, metastasis and angiogenesis. Despite the progress that has already been made, ccRCC generally remain resistant to conventional therapies and ccRCC patients suffer from metastasis and acquired resistance, highlighting the need for novel therapeutic options. Cysteinyl leukotriene receptor 1 (CysLTR1) antagonists, like zafirlukast, are administered in bronchial asthma to control eicosanoid signaling. Intriguingly, long-term use of zafirlukast decreases cancer risk and leukotriene receptor antagonists inhibit tumor growth, but the mechanisms still remain unexplored. Therefore, we aim to understand the mechanisms of zafirlukast-mediated cell death in ccRCC cells. We show that zafirlukast induces VHL-dependent and TNFα-independent non-apoptotic and non-necroptotic cell death in ccRCC cells. Cell death triggered by zafirlukast could be rescued with antioxidants and the PARP-1 inhibitor Olaparib, and additionally relies on HIF-2α. Finally, MG-132-mediated proteasome inhibition sensitized VHL wild-type cells to zafirlukast-induced cell death and inhibition of HIF-2α rescued zafirlukast- and MG-132-triggered cell death. Together, these results highlight the importance of VHL, HIF and proteasomal degradation in zafirlukast-induced oxidative cell death with potentially novel therapeutic implications for ccRCC.

The evolution, ecology, and conservation of hummingbirds and their interactions with flowering plants.

The ecological co-dependency between plants and hummingbirds is a classic example of a mutualistic interaction: hummingbirds rely on floral nectar to fuel their rapid metabolisms, and more than 7000 plant species rely on hummingbirds for pollination. However, threats to hummingbirds are mounting, with 10% of 366 species considered globally threatened and 60% in decline. Despite the important ecological implications of these population declines, no recent review has examined plant-hummingbird interactions in the wider context of their evolution, ecology, and conservation. To provide this overview, we (i) assess the extent to which plants and hummingbirds have coevolved over millions of years, (ii) examine the mechanisms underlying plant-hummingbird interaction frequencies and hummingbird specialization, (iii) explore the factors driving the decline of hummingbird populations, and (iv) map out directions for future research and conservation. We find that, despite close associations between plants and hummingbirds, acquiring evidence for coevolution (versus one-sided adaptation) is difficult because data on fitness outcomes for both partners are required. Thus, linking plant-hummingbird interactions to plant reproduction is not only a major avenue for future coevolutionary work, but also for studies of interaction networks, which rarely incorporate pollinator effectiveness. Nevertheless, over the past decade, a growing body of literature on plant-hummingbird networks suggests that hummingbirds form relationships with plants primarily based on overlapping phenologies and trait-matching between bill length and flower length. On the other hand, species-level specialization appears to depend primarily on local community context, such as hummingbird abundance and nectar availability. Finally, although hummingbirds are commonly viewed as resilient opportunists that thrive in brushy habitats, we find that range size and forest dependency are key predictors of hummingbird extinction risk. A critical direction for future research is to examine how potential stressors - such as habitat loss and fragmentation, climate change, and introduction of non-native plants - may interact to affect hummingbirds and the plants they pollinate.

Negative producer price differentials in Federal Milk Marketing Orders: Explanations, implications, and policy options.

In Federal Milk Marketing Orders (FMMO), which use multiple component pricing schemas, farmers are paid for delivered quantity of butterfat, protein, and other solids, plus a producer price differential (PPD). The PPD captures the difference between the total handler obligations to the pool and the total component value of milk. In 2020, record negative PPD caused widespread frustration among dairy farmers. The primary objective of this research was to provide a comprehensive analysis of factors that affect PPD and to quantify their relative importance. We examined FMMO data from the past 10 yr including prices, utilizations, and tests. By decomposing the PPD, we were able to isolate the drivers of negative values. We found that long-term trends in usage, most importantly declining beverage milk and rising component tests, including both butterfat and protein, have substantially reduced PPD over the past decade. Class I milk pricing reform of 2018 exacerbated negative PPD in 2020, but we found that the PPD would have been negative even without that reform. The greatest contributor to recent negative PPD was the spread between cheese and milk powder prices, caused by shifts in demand due to the COVID-19 pandemic and USDA intervention cheese purchases. A range of policy modifications proposed to address negative PPD was evaluated.

Producing wood at least cost to biodiversity: integrating Triad and sharing-sparing approaches to inform forest landscape management.

Forest loss and degradation are the greatest threats to biodiversity worldwide. Rising global wood demand threatens further damage to remaining native forests. Contrasting solutions across a continuum of options have been proposed, yet which of these offers most promise remains unresolved. Expansion of high-yielding tree plantations could free up forest land for conservation provided this is implemented in tandem with stronger policies for conserving native forests. Because plantations and other intensively managed forests often support far less biodiversity than native forests, a second approach argues for widespread adoption of extensive management, or 'ecological forestry', which better simulates natural forest structure and disturbance regimes - albeit with compromised wood yields and hence a need to harvest over a larger area. A third, hybrid suggestion involves 'Triad' zoning where the landscape is divided into three sorts of management (reserve, ecological/extensive management, and intensive plantation). Progress towards resolving which of these approaches holds the most promise has been hampered by the absence of a conceptual framework and of sufficient empirical data formally to identify the most appropriate landscape-scale proportions of reserves, extensive, and intensive management to minimize biodiversity impacts while meeting a given level of demand for wood. In this review, we argue that this central challenge for sustainable forestry is analogous to that facing food-production systems, and that the land sharing-sparing framework devised to establish which approach to farming could meet food demand at least cost to wild species can be readily adapted to assess contrasting forest management regimes. We develop this argument in four ways: (i) we set out the relevance of the sharing-sparing framework for forestry and explore the degree to which concepts from agriculture can translate to a forest management context; (ii) we make design recommendations for empirical research on sustainable forestry to enable application of the sharing-sparing framework; (iii) we present overarching hypotheses which such studies could test; and (iv) we discuss potential pitfalls and opportunities in conceptualizing landscape management through a sharing-sparing lens. The framework we propose will enable forest managers worldwide to assess trade-offs directly between conservation and wood production and to determine the mix of management approaches that best balances these (and other) competing objectives. The results will inform ecologically sustainable forest policy and management, reduce risks of local and global extinctions from forestry, and potentially improve a valuable sector's social license to operate.

Preclinical transmission of prions by blood transfusion is influenced by donor genotype and route of infection.

Variant Creutzfeldt-Jakob disease (vCJD) is a human prion disease resulting from zoonotic transmission of bovine spongiform encephalopathy (BSE). Documented cases of vCJD transmission by blood transfusion necessitate on-going risk reduction measures to protect blood supplies, such as leucodepletion (removal of white blood cells, WBCs). This study set out to determine the risks of prion transmission by transfusion of labile blood components (red blood cells, platelets, plasma) commonly used in human medicine, and the effectiveness of leucodepletion in preventing infection, using BSE-infected sheep as a model. All components were capable of transmitting prion disease when donors were in the preclinical phase of infection, with the highest rates of infection in recipients of whole blood and buffy coat, and the lowest in recipients of plasma. Leucodepletion of components (<106 WBCs/unit) resulted in significantly lower transmission rates, but did not completely prevent transmission by any component. Donor PRNP genotype at codon 141, which is associated with variation in incubation period, also had a significant effect on transfusion transmission rates. A sensitive protein misfolding cyclic amplification (PMCA) assay, applied to longitudinal series of blood samples, identified infected sheep from 4 months post infection. However, in donor sheep (orally infected), the onset of detection of PrPSc in blood was much more variable, and generally later, compared to recipients (intravenous infection). This shows that the route and method of infection may profoundly affect the period during which an individual is infectious, and the test sensitivity required for reliable preclinical diagnosis, both of which have important implications for disease control. Our results emphasize that blood transfusion can be a highly efficient route of transmission for prion diseases. Given current uncertainties over the prevalence of asymptomatic vCJD carriers, this argues for the maintenance and improvement of current measures to reduce the risk of transmission by blood products.

A forest loss report card for the world's protected areas.

Protected areas are a key tool in the conservation of global biodiversity and carbon stores. We conducted a global test of the degree to which more than 18,000 terrestrial protected areas (totalling 5,293,217 km2) reduce deforestation in relation to unprotected areas. We also derived indices that quantify how well countries' forests are protected, both in terms of forested area protected and effectiveness of protected areas at reducing deforestation, in relation to vertebrate species richness, aboveground forest carbon biomass and background deforestation rates. Overall, protected areas did not eliminate deforestation, but reduced deforestation rates by 41%. Protected area deforestation rates were lowest in small reserves with low background deforestation rates. Critically, we found that after adjusting for effectiveness, only 6.5%-rather than 15.7%-of the world's forests are protected, well below the Aichi Convention on Biological Diversity's 2020 Target of 17%. We propose that global targets for protected areas should include quantitative goals for effectiveness in addition to spatial extent.

#Eggs: social and online media-derived perceptions of egg-laying hen housing.

Enormous quantities of data are generated through social and online media in the era of Web 2.0. Understanding consumer perceptions or demand efficiently and cost effectively remains a focus for economists, retailer/consumer sciences, and production industries. Most of the efforts to understand demand for food products rely on reports of past market performance along with survey data. Given the movement of content-generation online to lay users via social media, the potential to capture market-influencing shifts in sentiment exists in online data. This analysis presents a novel approach to studying consumer perceptions of production system attributes using eggs and laying hen housing, which have received significant attention in recent years. The housing systems cage-free and free-range had the greatest number of online hits in the searches conducted, compared with the other laying hen housing types. Less online discussion surrounded enriched cages, which were found by other methods/researchers to meet many key consumer preferences. These results, in conjunction with insights into net sentiment and words associated with different laying hen housing in online and social media, exemplify how social media listening may complement traditional methods to inform decision-makers regarding agribusiness marketing, food systems, management, and regulation. Employing web-derived data for decision-making within agrifood firms offers the opportunity for actionable insights tailored to individual businesses or products.

Beverage milk consumption patterns in the United States: Who is substituting from dairy to plant-based beverages?

This research used a survey of 995 US households to explore how dairy milk and plant-based beverage substitutes were consumed. Long-term trends of declining beverage milk consumption have been exacerbated in recent years by increasing consumption of plant-based beverages. Although beverage milk consumption has been declining, total dairy consumption in the United States continues to increase, driven by growth in sales of cheese, butter, and yogurt. Using k-means cluster analysis, 3 consumption clusters for US households were identified. The largest cluster, consisting of 61.6% of households, consumed dairy milk with some regularity and consumed little or no plant-based beverages. A second cluster, flexitarian households, consisting of 15.6% of respondent households, frequently consumed both dairy milk and plant-based beverages. The third cluster, plant-based consumers, consisting of 22.8% of households, consumed almost exclusively plant-based beverages. Examining differences in demographics between clusters, flexitarian households were larger, more likely to include young children, more likely to include a vegetarian or vegan, and more liberal than traditional dairy-consuming households. Plant-based households had many similarities to flexitarian households. The flexitarian and plant-based clusters were willing to substitute plant-based beverages for dairy milk for almost all consumption uses.

Online procurement of pet supplies and willingness to pay for veterinary telemedicine.

Changing consumer shopping behaviors, and specifically the shift towards online procurement of goods and services, have altered the retail landscape of nearly all goods, including pet products and services. Whilst it is known and commonly discussed that less retail business for products and medications is being conducted in clinics than in the past, it is not well documented where that commerce is now taking place, and by what customer segments. For cats, dogs, and other pets, specialty food and food in general was purchased by a high percentage of respondents at the physical store. Sixteen-percent of dog owners, 17 % of cat owners and 14 % of other animal owners purchased prescription food at the veterinarian. Ten percent of dog owners, 10 % of cat owners, and 9 % of other animal owners purchased prescription food from the physical store. A high percentage of cat and dog owners purchased flea and tick preventative, heartworm preventative and prescription medications at the veterinarian, followed by the physical store. Using a choice experiment, both dog and cat owners were willing-to-pay a statistically significant positive amount for having their veterinarian, or a veterinarian in their community (who was not their veterinarian) on the veterinary telemedicine call or video when compared to a veterinarian from outside the community. In relation to the willingness to pay (WTP) for a telemedicine veterinary consultation with a veterinarian outside of the pet owners' community, dog owners were willing to pay $38.04 more for a telemedicine veterinary consultation with their regular veterinarian, and $13.38 more for a telemedicine veterinary consultation with a veterinarian in the dog owners' community. Cat owners had a WTP of $38.12 per call or visit for having their veterinarian as the consultant which was statistically higher than their WTP for a veterinarian in their community, $12.74 when compared to a veterinarian outside their community. When comparing the mean price adjusted WTP between cat and dog owners, there were not any statistically significant differences found. Quantifying pet owner willingness to pay for commonly discussed attributes of telemedicine, such as whether a local veterinarian is consulted (versus a veterinarian from outside the community), facilitates veterinary practice management decision making as practices adjust product and service offerings to meet the changing consumer demand of pet owners in today's marketplace.

Public Perceptions of Veterinarians from Social and Online Media Listening.

The public perception of the veterinary medicine profession is of increasing concern given the mounting challenges facing the industry, ranging from student debt loads to mental health implications arising from compassion fatigue, euthanasia, and other challenging aspects of the profession. This analysis employs social media listening and analysis to discern top themes arising from social and online media posts referencing veterinarians. Social media sentiment analysis is also employed to aid in quantifying the search results, in terms of whether they are positivity/negativity associated. From September 2017-November 2019, over 1.4 million posts and 1.7 million mentions were analyzed; the top domain in the search results was Twitter (74%). The mean net sentiment associated with the search conducted over the time period studied was 52%. The top terms revealed in the searches conducted revolved mainly around care of or concern for pet animals. The recognition of challenges facing the veterinary medicine profession were notably absent, except for the mention of suicide risks. While undeniably influenced by the search terms selected, which were directed towards client-clinic related verbiage, a relative lack of knowledge regarding veterinarians' roles in human health, food safety/security, and society generally outside of companion animal care was recognized. Future research aimed at determining the value of veterinarians' contributions to society and, in particular, in the scope of One Health, may aid in forming future communication and education campaigns.