Although contemporary society seems to promote the values of individualism and mobility, this engrossing book is dedicated to the notion that human lives are enriched by participation in a social ...community that is integrated into the natural landscape of a particular place. The 34 contributors—who include David Ehrenfeld, Lynn R. Miller, Wendell Berry, Deborah Tall, David W. Orr, Robert Swann, and Susan Witt, as well as other philosophers, scientists, activists, economists, historians, farmers and ranchers, sociologists, theologians, and political scientists—offer an array of social and ecological perspectives on the nature of "community." The editors, William Vitek and Wes Jackson, contend that a deeper understanding of communities is critical for the health of the planet and the human spirit. They offer a compelling collection of new and classic writings—many in the form of personal narrative—that extend E. F. Schumacher's ideas about the importance of human scale and Aldo Leopold's concept of biotic citizenship. Proposing eloquent defenses of community life and practical suggestions for becoming connected to others and native to a place, the writers explore the loss of community, the philosophical foundations of communities, and the current renewal of community life. **William Vitek** is associate professor of philosophy at Clarkson University. He is active in promoting working landscapes, rural communities, and local economies in northern New York. **Wes Jackson** is director and cofounder of the Land Institute in Salina, Kansas, and recent recipient of a Pew Conservation Scholars award and a MacArthur Fellowship. He is currently engaged in revitalizing Matfield Green, an abandoned farm community in Kansas.
Renal tubular epithelial cells (RTECs) perform the essential function of maintaining the constancy of body fluid composition and volume. Toxic, inflammatory, or hypoxic-insults to RTECs can cause ...systemic fluid imbalance, electrolyte abnormalities and metabolic waste accumulation- manifesting as acute kidney injury (AKI), a common disorder associated with adverse long-term sequelae and high mortality. Here we report the results of a kinome-wide RNAi screen for cellular pathways involved in AKI-associated RTEC-dysfunction and cell death. Our screen and validation studies reveal an essential role of Cdkl5-kinase in RTEC cell death. In mouse models, genetic or pharmacological Cdkl5 inhibition mitigates nephrotoxic and ischemia-associated AKI. We propose that Cdkl5 is a stress-responsive kinase that promotes renal injury in part through phosphorylation-dependent suppression of pro-survival transcription regulator Sox9. These findings reveal a surprising non-neuronal function of Cdkl5, identify a pathogenic Cdkl5-Sox9 axis in epithelial cell-death, and support CDKL5 antagonism as a therapeutic approach for AKI.
The nickel-based superalloy Inconel 718 (IN718) is an excellent candidate among the existing aerospace alloys for laser powder bed fusion (LPBF) manufacturing. LPBF IN718 has a preference for (001) ...growth, resulting in a non-uniform, anisotropic microstructure which translates into orthotropic mechanical behavior. The most common heat treatment applied to IN718 is AMS 5662. This treatment was developed 60 years ago for wrought and cast metal forming processes. The small grains and columnar grain structure of LPBF IN718 are not affected by treatments per AMS 5662. Recrystallization and the removal of scan strategy effects have big implications for the acceptance of AM parts. If parts can be heat treated to remove any OEM-related microstructural differences, then parts fabricated on different machines can be printed in any orientation and possess the same properties. This research studies the microstructure of LPBF IN718 as it evolves under an annealing treatment of 1160 ∘C for up to 8 hours. It was hypothesized and later confirmed that this higher-temperature annealing would mitigate the scan strategy effects and anisotropy resulting from the LPBF process. The grain size, shape, and recrystallization are compared throughout the evolution. Additionally, the X–Y and X–Z planes are compared to find a point at which the annealing process results in equiaxed, isotropic grains and the scan strategy effects are mitigated. An equiaxed microstructure was successfully achieved through recrystallization and grain growth, resulting in isotropic microstructure for each scan strategy that was considered. Isotropic mechanical properties were achieved following a modified annealing treatment at 1160 ∘C for 4 hours and validated via nanoindentation and tensile testing.
Abstract
Tree die-off, driven by extreme drought and exacerbated by a warming climate, is occurring rapidly across every wooded continent—threatening carbon sinks and other ecosystem services ...provided by forests and woodlands. Forecasting the spatial patterns of tree die-off in response to drought is a priority for the management and conservation of forested ecosystems under projected future hotter and drier climates. Several thresholds derived from drought-metrics have been proposed to predict mortality of
Pinus edulis,
a model tree species in many studies of drought-induced tree die-off. To improve future capacity to forecast tree mortality, we used a severe drought as a natural experiment. We compared the ability of existing mortality thresholds derived from four drought metrics (the Forest Drought Severity Index (FDSI), the Standardized Precipitation Evapotranspiration Index, and raw values of precipitation (PPT) and vapor pressure deficit, calculated using 4 km PRISM data) to predict areas of
P. edulis
die-off following an extreme drought in 2018 across the southwestern US. Using aerial detection surveys of tree mortality in combination with gridded climate data, we calculated the agreement between these four proposed thresholds and the presence and absence of regional-scale tree die-off using sensitivity, specificity, and the area under the curve (AUC). Overall, existing mortality thresholds tended to over predict the spatial extent of tree die-off across the landscape, yet some retain moderate skill in discriminating between areas that experienced and did not experience tree die-off. The simple PPT threshold had the highest AUC score (71%) as well as fair sensitivity and specificity, but the FDSI had the greatest sensitivity to die-off (85.9%). We highlight that empirically derived climate thresholds may be useful forecasting tools to identify vulnerable areas to drought induced die-off, allowing for targeted responses to future droughts and improved management of at-risk areas.
Understanding controls on the stable isotopic composition of precipitation and vapor in the West Pacific Warm Pool is vital for accurate representation of convective processes in models and correct ...interpretation of isotope‐based paleoclimate proxies, yet a lack of direct observational evidence precludes the utility of these isotopic tracers. Results from a measurement campaign at Manus Island, Papua New Guinea from 28 April to 8 May 2013 demonstrate variability in the stable isotopic composition (δD and δ18O) of precipitation and vapor in individual precipitation events and over a 10 day period. Isotope ratios in water vapor and precipitation progressively increased throughout the period of measurement, coincident with a transition from high to low regional convective activity. Vapor isotope ratios approached equilibrium with seawater during the quiescent period and likely reflected downwind advection of distilled vapor and re‐evaporation of rainfall during the period of regional convection. On a 5 min timescale across individual storms, isotope ratios in precipitation were strongly correlated with isotope ratios in surface vapor. However, individual precipitation isotope ratios were not strongly correlated with surface meteorological data, including precipitation rate, in all storms. Yet across all events, precipitation deuterium excess was negatively correlated with surface temperature, sea level pressure, and cloud base height and positively correlated with precipitation rate and relative humidity. Paired surface precipitation and vapor isotope ratios indicate condensation at boundary layer temperatures. The ratio of these paired values decreased with increasing precipitation rate during some precipitation events, suggesting rain re‐evaporation and precipitation in equilibrium with an isotopically distinct upper level moisture source. Results from the short campaign support the interpretation that isotope ratios in precipitation and vapor in the western tropical Pacific are indicators of regional convective intensity at the timescale of days to weeks. However, a nonstationary relationship between rain rate and stable isotope ratios in precipitation during individual convective events suggests that condensation, rain evaporation, moisture recycling, and regional moisture convergence do not always yield an amount effect relationship on intraevent timescales.
Key Points
Consistent amount effect is not observed in storms
Deuterium excess correlated with variables related to convective activity
Rain to vapor isotope ratios indicate rain evaporation and distinct upper level vapor sources
The Sr/Ca ratio of coral aragonite is used to reconstruct past sea surface temperature (SST). Twenty‐one laboratories took part in an interlaboratory study of coral Sr/Ca measurements. Results show ...interlaboratory bias can be significant, and in the extreme case could result in a range in SST estimates of 7°C. However, most of the data fall within a narrower range and the Porites coral reference material JCp‐1 is now characterized well enough to have a certified Sr/Ca value of 8.838 mmol/mol with an expanded uncertainty of 0.089 mmol/mol following International Association of Geoanalysts (IAG) guidelines. This uncertainty, at the 95% confidence level, equates to 1.5°C for SST estimates using Porites, so is approaching fitness for purpose. The comparable median within laboratory error is <0.5°C. This difference in uncertainties illustrates the interlaboratory bias component that should be reduced through the use of reference materials like the JCp‐1. There are many potential sources contributing to biases in comparative methods but traces of Sr in Ca standards and uncertainties in reference solution composition can account for half of the combined uncertainty. Consensus values that fulfil the requirements to be certified values were also obtained for Mg/Ca in JCp‐1 and for Sr/Ca and Mg/Ca ratios in the JCt‐1 giant clam reference material. Reference values with variable fitness for purpose have also been obtained for Li/Ca, B/Ca, Ba/Ca, and U/Ca in both reference materials. In future, studies reporting coral element/Ca data should also report the average value obtained for a reference material such as the JCp‐1.
Key Points
Twenty‐one labs have characterised the coral JCp‐1
The 95% confidence level equates to 1.5{degree sign}C for SST estimates
Uncertainty can be reduced through the use of reference materials like JCp‐1
PD-1 and PD-L1 inhibitors are active in metastatic urothelial carcinoma, but positive randomised data supporting their use as a first-line treatment are lacking. In this study we assessed outcomes ...with first-line pembrolizumab alone or combined with chemotherapy versus chemotherapy for patients with previously untreated advanced urothelial carcinoma.
KEYNOTE-361 is a randomised, open-label, phase 3 trial of patients aged at least 18 years, with untreated, locally advanced, unresectable, or metastatic urothelial carcinoma, with an Eastern Cooperative Oncology Group performance status of up to 2. Eligible patients were enrolled from 201 medical centres in 21 countries and randomly allocated (1:1:1) via an interactive voice-web response system to intravenous pembrolizumab 200 mg every 3 weeks for a maximum of 35 cycles plus intravenous chemotherapy (gemcitabine 1000 mg/m2 on days 1 and 8 and investigator's choice of cisplatin 70 mg/m2 or carboplatin area under the curve 5 on day 1 of every 3-week cycle) for a maximum of six cycles, pembrolizumab alone, or chemotherapy alone, stratified by choice of platinum therapy and PD-L1 combined positive score (CPS). Neither patients nor investigators were masked to the treatment assignment or CPS. At protocol-specified final analysis, sequential hypothesis testing began with superiority of pembrolizumab plus chemotherapy versus chemotherapy alone in the total population (all patients randomly allocated to a treatment) for the dual primary endpoints of progression-free survival (p value boundary 0·0019), assessed by masked, independent central review, and overall survival (p value boundary 0·0142), followed by non-inferiority and superiority of overall survival for pembrolizumab versus chemotherapy in the patient population with CPS of at least 10 and in the total population (also a primary endpoint). Safety was assessed in the as-treated population (all patients who received at least one dose of study treatment). This study is completed and is no longer enrolling patients, and is registered at ClinicalTrials.gov, number NCT02853305.
Between Oct 19, 2016 and June 29, 2018, 1010 patients were enrolled and allocated to receive pembrolizumab plus chemotherapy (n=351), pembrolizumab monotherapy (n=307), or chemotherapy alone (n=352). Median follow-up was 31·7 months (IQR 27·7–36·0). Pembrolizumab plus chemotherapy versus chemotherapy did not significantly improve progression-free survival, with a median progression-free survival of 8·3 months (95% CI 7·5–8·5) in the pembrolizumab plus chemotherapy group versus 7·1 months (6·4–7·9) in the chemotherapy group (hazard ratio HR 0·78, 95% CI 0·65–0·93; p=0·0033), or overall survival, with a median overall survival of 17·0 months (14·5–19·5) in the pembrolizumab plus chemotherapy group versus 14·3 months (12·3–16·7) in the chemotherapy group (0·86, 0·72–1·02; p=0·0407). No further formal statistical hypothesis testing was done. In analyses of overall survival with pembrolizumab versus chemotherapy (now exploratory based on hierarchical statistical testing), overall survival was similar between these treatment groups, both in the total population (15·6 months 95% CI 12·1–17·9 with pembrolizumab vs 14·3 months 12·3–16·7 with chemotherapy; HR 0·92, 95% CI 0·77–1·11) and the population with CPS of at least 10 (16·1 months 13·6–19·9 with pembrolizumab vs 15·2 months 11·6–23·3 with chemotherapy; 1·01, 0·77–1·32). The most common grade 3 or 4 adverse event attributed to study treatment was anaemia with pembrolizumab plus chemotherapy (104 30% of 349 patients) or chemotherapy alone (112 33% of 342 patients), and diarrhoea, fatigue, and hyponatraemia (each affecting four 1% of 302 patients) with pembrolizumab alone. Six (1%) of 1010 patients died due to an adverse event attributed to study treatment; two patients in each treatment group. One each occurred due to cardiac arrest and device-related sepsis in the pembrolizumab plus chemotherapy group, one each due to cardiac failure and malignant neoplasm progression in the pembrolizumab group, and one each due to myocardial infarction and ischaemic colitis in the chemotherapy group.
The addition of pembrolizumab to first-line platinum-based chemotherapy did not significantly improve efficacy and should not be widely adopted for treatment of advanced urothelial carcinoma.
Merck Sharp and Dohme, a subsidiary of Merck, Kenilworth, NJ, USA.
Although delayed hospital cooling has been demonstrated to improve outcome after cardiac arrest, in-field cooling started immediately after the return of spontaneous circulation may be more ...beneficial. The aims of the present pilot study were to assess the feasibility, safety, and effectiveness of in-field cooling.
We determined the effect on esophageal temperature, before hospital arrival, of infusing up to 2 L of 4 degrees C normal saline as soon as possible after resuscitation from out-of-hospital cardiac arrest. A total of 125 such patients were randomized to receive standard care with or without intravenous cooling. Of the 63 patients randomized to cooling, 49 (78%) received an infusion of 500 to 2000 mL of 4 degrees C normal saline before hospital arrival. These 63 patients experienced a mean temperature decrease of 1.24+/-1 degrees C with a hospital arrival temperature of 34.7 degrees C, whereas the 62 patients not randomized to cooling experienced a mean temperature increase of 0.10+/-0.94 degrees C (P<0.0001) with a hospital arrival temperature of 35.7 degrees C. In-field cooling was not associated with adverse consequences in terms of blood pressure, heart rate, arterial oxygenation, evidence for pulmonary edema on initial chest x-ray, or rearrest. Secondary end points of awakening and discharged alive from hospital trended toward improvement in ventricular fibrillation patients randomized to in-field cooling.
These pilot data suggest that infusion of up to 2 L of 4 degrees C normal saline in the field is feasible, safe, and effective in lowering temperature. We propose that the effect of this cooling method on neurological outcome after cardiac arrest be studied in larger numbers of patients, especially those whose initial rhythm is ventricular fibrillation.
The first interim analysis of the KEYNOTE-564 study showed improved disease-free survival with adjuvant pembrolizumab compared with placebo after surgery in patients with clear cell renal cell ...carcinoma at an increased risk of recurrence. The analysis reported here, with an additional 6 months of follow-up, was designed to assess longer-term efficacy and safety of pembrolizumab versus placebo, as well as additional secondary and exploratory endpoints.
In the multicentre, randomised, double-blind, placebo-controlled, phase 3 KEYNOTE-564 trial, adults aged 18 years or older with clear cell renal cell carcinoma with an increased risk of recurrence were enrolled at 213 hospitals and cancer centres in North America, South America, Europe, Asia, and Australia. Eligible participants had an Eastern Cooperative Oncology Group performance status of 0 or 1, had undergone nephrectomy 12 weeks or less before randomisation, and had not received previous systemic therapy for advanced renal cell carcinoma. Participants were randomly assigned (1:1) via central permuted block randomisation (block size of four) to receive pembrolizumab 200 mg or placebo intravenously every 3 weeks for up to 17 cycles. Randomisation was stratified by metastatic disease status (M0 vs M1), and the M0 group was further stratified by ECOG performance status and geographical region. All participants and investigators involved in study treatment administration were masked to the treatment group assignment. The primary endpoint was disease-free survival by investigator assessment in the intention-to-treat population (all participants randomly assigned to a treatment). Safety was assessed in the safety population, comprising all participants who received at least one dose of pembrolizumab or placebo. As the primary endpoint was met at the first interim analysis, updated data are reported without p values. This study is ongoing, but no longer recruiting, and is registered with ClinicalTrials.gov, NCT03142334.
Between June 30, 2017, and Sept 20, 2019, 994 participants were assigned to receive pembrolizumab (n=496) or placebo (n=498). Median follow-up, defined as the time from randomisation to data cutoff (June 14, 2021), was 30·1 months (IQR 25·7–36·7). Disease-free survival was better with pembrolizumab compared with placebo (HR 0·63 95% CI 0·50–0·80). Median disease-free survival was not reached in either group. The most common all-cause grade 3–4 adverse events were hypertension (in 14 3% of 496 participants) and increased alanine aminotransferase (in 11 2%) in the pembrolizumab group, and hypertension (in 13 3% of 498 participants) in the placebo group. Serious adverse events attributed to study treatment occurred in 59 (12%) participants in the pembrolizumab group and one (<1%) participant in the placebo group. No deaths were attributed to pembrolizumab.
Updated results from KEYNOTE-564 support the use of adjuvant pembrolizumab monotherapy as a standard of care for participants with renal cell carcinoma with an increased risk of recurrence after nephrectomy.
Merck Sharp & Dohme LLC, a subsidiary of Merck & Co, Inc, Rahway, NJ, USA.
The novel human coronavirus SARS-CoV-2 is a major ongoing global threat with huge economic burden. Like all respiratory viruses, SARS-CoV-2 initiates infection in the upper respiratory tract (URT). ...Infected individuals are often asymptomatic, yet highly infectious and readily transmit virus. A therapy that restricts initial replication in the URT has the potential to prevent progression of severe lower respiratory tract disease as well as limiting person-to-person transmission.
SARS-CoV-2 Victoria/01/2020 was passaged in Vero/hSLAM cells and virus titre determined by plaque assay. Challenge virus was delivered by intranasal instillation to female ferrets at 5.0 × 106 pfu/ml. Treatment groups received intranasal INNA-051, developed by Ena Respiratory. SARS-CoV-2 RNA was detected using the 2019-nCoV CDC RUO Kit and QuantStudio™ 7 Flex Real-Time PCR System. Histopathological analysis was performed using cut tissues stained with haematoxylin and eosin (H&E).
We show that prophylactic intra-nasal administration of the TLR2/6 agonist INNA-051 in a SARS-CoV-2 ferret infection model effectively reduces levels of viral RNA in the nose and throat. After 5 days post-exposure to SARS-CoV-2, INNA-051 significantly reduced virus in throat swabs (p=<0.0001) by up to a 24 fold (96% reduction) and in nasal wash (p=0.0107) up to a 15 fold (93% reduction) in comparison to untreated animals.
The results of our study support clinical development of a therapy based on prophylactic TLR2/6 innate immune activation in the URT, to reduce SARS-CoV-2 transmission and provide protection against COVID-19.
This work was funded by Ena Respiratory, Melbourne, Australia.
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