Search

Background Heparin anticoagulation has been used successfully for cardiopulmonary bypass (CPB). However, an alternative anticoagulant approach is desirable due to the cases of heparin-induced thrombocytopenia. Dabigatran provides anticoagulation for an in vitro model of simulated CPB. The current analysis tests the hypothesis that dabigatran provides sufficient anticoagulation for CPB in intact rabbits. Methods Nonlinear mixed effects models were used to estimate dabigatran parameters for a two-compartment pharmacokinetic model in 10 New Zealand White rabbits. A dabigatran infusion designed to maintain a plasma concentration of 90 µg/ml was run throughout CPB based on the pharmacokinetics. Animals were subjected to sternotomy and anticoagulated with IV dabigatran (six animals) or heparin (four animals). Rabbits were cannulated centrally using the right atrium and ascending aorta and CPB was maintained for 120 min. Measurement of activated clotting time, thromboelastometric reaction time, and blood gases were performed during CPB. Then, the animals were euthanized, and the brain and one kidney were removed for histology. Sections of the arterial filters were inspected using electron microscopy. Results The observed dabigatran concentrations during CPB were greater than the target concentration, ranging from 137 ± 40 μg/ml at 5 min of CPB to 428 ± 150 μg/ml at 60 min, and 295 ± 35 μg/ml at 120 min. All rabbits completed 2 h of CPB without visible thrombosis. In the two groups, reaction time values were elevated, reaching 10,262 ± 4,198 s (dabigatran group) and 354 ± 141 s (heparin group) at 120 min of CPB. Brains and kidneys showed no evidence of thrombosis or ultrastructural damage. Sections of the arterial line filter showed minimal or no fibrin. There was no significant difference in outcomes between dabigatran- and heparin-treated animals. Conclusions In this first-use, proof-of-concept study, the authors have shown that dabigatran provides acceptable anticoagulation similar to heparin to prevent thrombosis using a rabbit CPB model. Editor’s Perspective What We Already Know about This Topic What This Article Tells Us That Is New

Introduction: Popliteal artery aneurysms are in most cases asymptomatic but cause significant complications if ruptured. An acute popliteal aneurysm rupture is relatively rare, and few cases have been documented secondary to blunt trauma. Common presenting signs and symptoms include distal limb ischemia and absent dorsalis pedis pulses. Timely management and recognition of this rare presentation are crucial as this condition can result in limb loss or death if not treated in a timely manner. Case Report: An 80-year-old man with history of hypertension presented to the emergency department complaining of inability to feel sensation below his left knee after falling from ground level. Physical examination was pertinent for bounding radial and femoral pulses bilaterally, although absent dorsalis pedis and posterior tibial pulses to the left lower extremity. Computed tomography angiography identified occlusion of the left superficial femoral arterial lumen associated with a ruptured popliteal aneurysm, approximately eight centimeters in size. He immediately received unfractionated heparin and was admitted to the hospital for left medial thigh exploration and decompressive dermatofasciotomy. Conclusion: After confirmation of popliteal aneurysmal rupture with advanced imaging, heparinization and vascular surgery consultation are critical steps that should be taken to prevent limb loss.

Summary Background 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. Methods 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 . Findings 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. Interpretation 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. Funding Merck Sharp and Dohme, a subsidiary of Merck, Kenilworth, NJ, USA.

In this paper, I discuss common endogeneity problems found in entrepreneurship research. I show how entrepreneurship researchers, particularly those working with observational data, typically face several specific endogeneity threats in a given study. I then show through a series of simulated of datasets instrument variable approaches that effectively address endogeneity in a variety of research designs. I discuss best-practice recommendations for integrating instrument variables into entrepreneurship research at the study design phase, and outline potential sources for instruments.

ImportanceEvidence on the effectiveness and safety of COVID-19 therapies across a diverse population with varied risk factors is needed to inform clinical practice.ObjectiveTo assess the safety of neutralizing monoclonal antibodies (nMAbs) for the treatment of COVID-19 and their association with adverse outcomes.Design, Setting, and ParticipantsThis retrospective cohort study included 167 183 patients from a consortium of 4 health care systems based in California, Minnesota, Texas, and Utah. The study included nonhospitalized patients 12 years and older with a positive COVID-19 laboratory test collected between November 9, 2020, and January 31, 2022, who met at least 1 emergency use authorization criterion for risk of a poor outcome.ExposureFour nMAb products (bamlanivimab, bamlanivimab-etesevimab, casirivimab-imdevimab, and sotrovimab) administered in the outpatient setting.Main Outcomes and MeasuresClinical and SARS-CoV-2 genomic sequence data and propensity-adjusted marginal structural models were used to assess the association between treatment with nMAbs and 4 outcomes: all-cause emergency department (ED) visits, hospitalization, death, and a composite of hospitalization or death within 14 days and 30 days of the index date (defined as the date of the first positive COVID-19 test or the date of referral). Patient index dates were categorized into 4 variant epochs: pre-Delta (November 9, 2020, to June 30, 2021), Delta (July 1 to November 30, 2021), Delta and Omicron BA.1 (December 1 to 31, 2021), and Omicron BA.1 (January 1 to 31, 2022).ResultsAmong 167 183 patients, the mean (SD) age was 47.0 (18.5) years; 95 669 patients (57.2%) were female at birth, 139 379 (83.4%) were White, and 138 900 (83.1%) were non-Hispanic. A total of 25 241 patients received treatment with nMAbs. Treatment with nMAbs was associated with lower odds of ED visits within 14 days (odds ratio [OR], 0.76; 95% CI, 0.68-0.85), hospitalization within 14 days (OR, 0.52; 95% CI, 0.45-0.59), and death within 30 days (OR, 0.14; 95% CI, 0.10-0.20). The association between nMAbs and reduced risk of hospitalization was stronger in unvaccinated patients (14-day hospitalization: OR, 0.51; 95% CI, 0.44-0.59), and the associations with hospitalization and death were stronger in immunocompromised patients (hospitalization within 14 days: OR, 0.31 [95% CI, 0.24-0.41]; death within 30 days: OR, 0.13 [95% CI, 0.06-0.27]). The strength of associations of nMAbs increased incrementally among patients with a greater probability of poor outcomes; for example, the ORs for hospitalization within 14 days were 0.58 (95% CI, 0.48-0.72) among those in the third (moderate) risk stratum and 0.41 (95% CI, 0.32-0.53) among those in the fifth (highest) risk stratum. The association of nMAb treatment with reduced risk of hospitalizations within 14 days was strongest during the Delta variant epoch (OR, 0.37; 95% CI, 0.31-0.43) but not during the Omicron BA.1 epoch (OR, 1.29; 95% CI, 0.68-2.47). These findings were corroborated in the subset of patients with viral genomic data. Treatment with nMAbs was associated with a significant mortality benefit in all variant epochs (pre-Delta: OR, 0.16 [95% CI, 0.08-0.33]; Delta: OR, 0.14 [95% CI, 0.09-0.22]; Delta and Omicron BA.1: OR, 0.10 [95% CI, 0.03-0.35]; and Omicron BA.1: OR, 0.13 [95% CI, 0.02-0.93]). Potential adverse drug events were identified in 38 treated patients (0.2%).Conclusions and RelevanceIn this study, nMAb treatment for COVID-19 was safe and associated with reductions in ED visits, hospitalization, and death, although it was not associated with reduced risk of hospitalization during the Omicron BA.1 epoch. These findings suggest that targeted risk stratification strategies may help optimize future nMAb treatment decisions.

Glaciers are unique indicators of climate change. While recent global-scale glacier decline has been attributed to anthropogenic forcing, direct links between human-induced climate warming and extreme glacier mass-loss years have not been documented. Here we apply event attribution methods to document this at the regional scale, targeting the highest mass-loss years (2011 and 2018) across New Zealand’s Southern Alps. Glacier mass balance is simulated using temperature and precipitation from multiple climate model ensembles. We estimate extreme mass loss was at least six times (2011) and ten times (2018) (>90% confidence) more likely to occur with anthropogenic forcing than without. This increased likelihood is driven by present-day temperatures ~1.0 °C above the pre-industrial average, confirming a connection between anthropogenic emissions and high annual ice loss. These results suggest that as warming and extreme heat events continue and intensify, there will be an increasingly visible human fingerprint on extreme glacier mass-loss years in the coming decades. Detecting a human role in a given year of extreme glacier mass loss is difficult at regional scales. Event attribution methods estimate that two extreme mass-loss years in the New Zealand Southern Alps, 2011 and 2018, were at least six and ten times more likely with anthropogenic climate warming.

Wide adoption of electronic health records (EHRs) has raised the expectation that data obtained during routine clinical care, termed “real-world” data, will be accumulated across health care systems and analyzed on a large scale to produce improvements in patient outcomes and the use of health care resources. To facilitate a learning health system, EHRs must contain clinically meaningful structured data elements that can be readily exchanged, and the data must be of adequate quality to draw valid inferences. At the present time, the majority of EHR content is unstructured and locked into proprietary systems that pose significant challenges to conducting accurate analyses of many clinical outcomes. This article details the current state of data obtained at the point of care and describes the changes necessary to use the EHR to build a learning health system.

Despite our best intentions, physically salient but entirely task-irrelevant stimuli can sometimes capture our attention. With learning, it is possible to more efficiently ignore such stimuli, although specifically how the visual system accomplishes this remains to be clarified. Using a sample of young-adult participants, we examined the time course of eye movements to targets and distractors. We replicate a reduced frequency of eye movements to the distractor when appearing in a location at which distractors are frequently encountered. This reduction was observed even for the earliest saccades, when selection tends to be most stimulus-driven. When the distractor appeared at the high-probability location, saccadic reaction time was slowed specifically for distractor-going saccades, suggesting a slowing of priority accumulation at this location. In the event that the distractor was fixated, disengagement from the distractor was also faster when it appeared in the high-probability location. Both proactive and reactive mechanisms of distractor suppression work together to minimize attentional capture by frequently-encountered distractors.

Slope failures in high plasticity clay deposits are common occurrences in many parts of the world. In western and central Alabama, expansive Prairie clays are commonly found, and shallow slope failures have occurred in both fill and cut slopes containing these high plasticity clays. The objective of this study was to examine the effects of suction and the use of nonlinear strength envelopes on the embankment stability of a section of highway AL-5. The testing program consisted of fifteen ring shear tests performed using a Bromhead Ring Shear Device. The results of the tests were used to develop both linear and nonlinear fully softened and residual strength envelopes. The saturated strength envelopes are then used in a limit equilibrium slope stability analysis with and without the effects of suction. The results show stability (factor of safety &gt, 1) for all cases except the residual friction angle without suction. Given these results, large slope failures are unlikely to occur in this area, but surficial failures and deformations due to creep may be possible. These results demonstrate the importance of considering the effects of suction and nonlinear strength envelopes when examining the potential for shallow slope failures in high plasticity clays.

Slope failures in roadway embankments are common occurrences and can lead to traffic disruptions and large costs to repair damage. In areas with high-plasticity clays, special attention must be paid to characterizing both the stratigraphy and the potential for strength loss. This study demonstrates the use of an integrated site characterization approach, which seeks to utilize results from geotechnical and geophysical tests to understand the behavior of a landslide in west Alabama. The timing and mechanism of the initial failure causing the preexisting shear plane at this site are not known. Results from electrical resistivity and seismic geophysical tests are integrated with information from borings and index tests to develop a representative cross-section for the landslide, and torsional ring shear results are used to measure the drained fully softened and residual strengths. Both the limit equilibrium (LEM) and strength reduction method (SRM) analyses are used to examine possible failure mechanisms. The results show good agreement between noncircular LEM and SRM analyses and indicate that the initial failure was likely due to undrained loading of the clay. Analyses utilizing the residual drained strength envelopes produce FS values significantly lower than 1 indicating the slope to be unstable when soil on the failure plane exists at the residual state. Sensitivity analyses suggest that the combined effect of lowering the water table and strength recovery may explain the intermittent nature of movements.

Importance: This three-part study characterizes the widespread implementation of telehealth during the first year of the COVID-19 pandemic, giving us insight into the role of telehealth as we enter a stage of “new normal” healthcare delivery in the U.S. Objective: The COVID-19 Telehealth Impact Study was designed to describe the natural experiment of telehealth adoption during the pandemic. Using a large claims data stream and surveys of providers and patients, we studied telehealth in all 50 states to inform healthcare leaders. Design, Setting, Participants: In March 2020, the MITRE Corporation and Mayo Clinic founded the COVID-19 Healthcare Coalition (C19HCC), to respond to the pandemic. We report trends using a dataset of over 2 billion healthcare claims covering over 50% of private insurance activity in the U.S. (January 2019-December 2020), along with key elements from our provider survey (July-August 2020) and patient survey (November 2020 - February 2021). Main Outcomes and Measures: There was rapid and widespread adoption of telehealth in Spring 2020 with over 12 million telehealth claims in April 2020, accounting for 49.4% of total health care claims. Providers and patients expressed high levels of satisfaction with telehealth. 75% of providers indicated that telehealth enabled them to provide quality care. 84% of patients agreed that quality of their telehealth visit was good. Results: Peak levels of telehealth use varied widely among states ranging from 74.9% in Massachusetts to 25.4% in Mississippi. Every clinical discipline saw a steep rise with the largest claims volume in behavioral health. Provision of care by out-of-state provider was common at 6.5% (October-December 2020). Providers reported multiple modalities of telehealth care delivery. 74% of patients indicated they will use telehealth services in the future. Conclusions and Relevance: Innovation shown by providers and patients during this period of rapid telehealth expansion constitutes a great natural experiment in care delivery with evidence supporting widespread clinical adoption and satisfaction on the part of both patients and clinicians. The authors encourage continued broad access to telehealth over the next 12 months to allow telehealth best practices to emerge, creating a more effective and resilient system of care delivery.

In 1995, a geotechnical experimentation site was established in rural Lee County, Alabama near the area often referred to as Spring Villa. The Auburn University National Geotechnical Experimentation Site (AUNGES) site is situated near the southern terminus of the Appalachian Piedmont Physiographic province. The site consists of two sub sites, one that is a thick profile of residual soil and the other is an outcrop of fractured weathered quartzite. Extensive site investigation has been conducted at the site by many agencies and researchers using a wide array of in-situ soil tests. Foundations, excavations, and retaining structures have been constructed and load tested at the AUNGES. This paper summarizes all the work conducted at the site since its inception. Maps that detail the location of all in-situ tests and structures tested were generated. Representative profiles are included that relate early site investigation, between 1995 and 2005, and contemporary work done after 2010 are generated based on the results of piezocone, dilatometer, standard penetration, and shear wave velocity tests.

Two excavations were instrumented at the Auburn National Geotechnical Experimentation Site (NGES) in Opelika, AL. The excavations were constructed approximately 6 m deep × 30 m long with a vertical face. The primary goal of this experiment was to determine the boundary conditions that resulted in failure of the excavation. In doing so, conclusions were drawn regarding the accuracy of common laboratory test methods for estimating the strength properties of residual soil. The instrumentation plan was designed to monitor real-time pore water pressures (positive and negative) surrounding the excavation throughout the course of each 1-year test period. Time-lapse cameras were used to identify when failures occurred, and the approximate geometry of the failure planes. Undisturbed soil samples were taken during the subsurface exploration and used in conjunction with previous soil test results to accurately define the material properties and layering based on common laboratory test methods. In addition to common laboratory tests, unsaturated triaxial tests were also conducted, and soil-water characteristic curves were measured to further define the unsaturated properties of the soil. In both excavations, failure was observed along a similar plane, which began at the bottom of the excavation, and propagated to the surface (approximately 2 m behind the face of the excavation) along existing tension cracks that developed during the construction of the excavation. Based on these results, recommendations are provided as related to the most appropriate test methods for determining the strength properties of residual soil for use in geotechnical design.

Background The expansion of telehealth use during the COVID-19 pandemic increased access to health care services for many US residents. This is particularly true for provider-to-patient telehealth communication. In rural communities, telehealth can increase access to health care services that would otherwise be limited due to geographic and distance barriers. The adoption of telehealth in rural communities, however, has been hindered by technology barriers, lack of community awareness, and lack of provider buy-in. The purpose of this study was to explore community-identified approaches to improving telehealth access in rural North Central Washington. Objective The aim of this study was to identify, group, and rate approaches to expanding and integrating telehealth in rural communities in North Central Washington. Methods We used group concept mapping, a participant-engaged, mixed method approach, to explore participant perspectives and preferences. Purposively sampled participants were community leaders and stakeholders in rural North Central Washington. Participants brainstormed strategies for implementing and expanding community telehealth access in their community and sorted them into conceptually similar groups. Strategies were then rated by participants in terms of potential impact, feasibility, and the cost of implementation. Quantitative analyses included multidimensional scaling and hierarchical cluster analysis to produce a cluster map and pattern match graph for interpreting the community members’ ideas and preferences. Results Participant brainstorming yielded 70 strategies for implementing telehealth in rural North Central Washington. Strategies were individually sorted into groups (point map stress value 0.21), producing a 6-cluster solution. The clusters were “Community infrastructure,” “Ensuring access to telehealth technology,” “Technology infrastructure for telehealth,” “Training/awareness of telehealth,” “State- and policy-level considerations,” and “Health care systems engagement and delivery.” Participants rated “Training/awareness of telehealth” and “Health care systems engagement and delivery” to be highly impactful and feasible approaches. The “Training/awareness of telehealth” cluster included strategies such as educating community members that telehealth is an easy, reliable, convenient, and private way to access health care and providing community training on how to access health care remotely. The latter cluster, “Health care systems engagement and delivery,” included approaches that were ranked as highly feasible and impactful, such as engaging with clinics and providers on overcoming barriers to implementing telehealth services or ensuring that local health clinic staff is on board with telehealth as an alternative platform to provide services. Conclusions Strategies identified and rated by participants incorporate the importance of community engagement in telehealth implementation, including educating community members about telehealth and engaging with community health clinics to facilitate use by providers. Community partners in North Central Washington will use these findings, along with additional community survey data, broadband speed test data, and provider input, to increase access to telehealth in their rural and remote communities. Conflicts of Interest None declared.

The land ice contribution to global mean sea level rise has not yet been predicted 1 using ice sheet and glacier models for the latest set of socio-economic scenarios, nor using coordinated exploration of uncertainties arising from the various computer models involved. Two recent international projects generated a large suite of projections using multiple models 2–8, but primarily used previous-generation scenarios 9 and climate models 10, and could not fully explore known uncertainties. Here we estimate probability distributions for these projections under the new scenarios 11,12 using statistical emulation of the ice sheet and glacier models. We find that limiting global warming to 1.5 degrees Celsius would halve the land ice contribution to twenty-first-century sea level rise, relative to current emissions pledges. The median decreases from 25 to 13 centimetres sea level equivalent (SLE) by 2100, with glaciers responsible for half the sea level contribution. The projected Antarctic contribution does not show a clear response to the emissions scenario, owing to uncertainties in the competing processes of increasing ice loss and snowfall accumulation in a warming climate. However, under risk-averse (pessimistic) assumptions, Antarctic ice loss could be five times higher, increasing the median land ice contribution to 42 centimetres SLE under current policies and pledges, with the 95th percentile projection exceeding half a metre even under 1.5 degrees Celsius warming. This would severely limit the possibility of mitigating future coastal flooding. Given this large range (between 13 centimetres SLE using the main projections under 1.5 degrees Celsius warming and 42 centimetres SLE using risk-averse projections under current pledges), adaptation planning for twenty-first-century sea level rise must account for a factor-of-three uncertainty in the land ice contribution until climate policies and the Antarctic response are further constrained.

The only complete inventory of New Zealand glaciers was based on aerial photography starting in 1978. While there have been partial updates using 2002 and 2009 satellite data, most glaciers are still represented by the 1978 outlines in contemporary global glacier databases. The objective of this project is to establish an updated glacier inventory for New Zealand. We have used Landsat 8 OLI satellite imagery from February and March 2016 for delineating clean glaciers using a semi-automatic band ratio method and debris-covered glaciers using a maximum likelihood classification. The outlines have been checked against Sentinel-2 MSI data, which have a higher resolution. Manual post processing was necessary due to misclassifications (e.g. lakes, clouds), mapping in shadowed areas, and combining the clean and debris-covered parts into single glaciers. New Zealand glaciers cover an area of 794 ± 34 km2 in 2016 with a debris-covered area of 10%. Of the 2918 glaciers, seven glaciers are >10 km2 while 71% is 2. The debris cover on those largest glaciers is >40%. Only 15 glaciers are located on the North Island. For a selection of glaciers, we were able to calculate the area reduction between the 1978 and 2016 inventories.

© Author(s) 2016. Quantitative palaeoclimate reconstructions provide data for evaluating the mechanisms of past, natural climate variability. Geometries of former mountain glaciers, constrained by moraine mapping, afford the opportunity to reconstruct palaeoclimate, due to the close relationship between ice extent and local climate. In this study, we present results from a series of experiments using a 2-D coupled energy balance-ice flow model that investigate the palaeoclimate significance of Last Glacial Maximum moraines within nine catchments in the central North Island, New Zealand. We find that the former ice limits can be simulated when present-day temperatures are reduced by between 4 and 7°C, if precipitation remains unchanged from present. The spread in the results between the nine catchments is likely to represent the combination of chronological and model uncertainties. The majority of catchments targeted require temperature decreases of 5.1 to 6.3°C to simulate the former glaciers, which represents our best estimate of the temperature anomaly in the central North Island, New Zealand, during the Last Glacial Maximum. A decrease in precipitation of up to 25% from present, as suggested by proxy evidence and climate models, increases the magnitude of the required temperature changes by up to 0.8°C. Glacier model experiments using reconstructed topographies that exclude the volume of post-glacial (< 15 ka) volcanism generally increased the magnitude of cooling required to simulate the former ice limits by up to 0.5°C. Our palaeotemperature estimates expand the spatial coverage of proxy-based quantitative palaeoclimate reconstructions in New Zealand. Our results are also consistent with independent, proximal temperature reconstructions from fossil groundwater and pollen assemblages, as well as similar glacier modelling reconstructions from the central Southern Alps, which suggest air temperatures were ca. 6°C lower than present across New Zealand during the Last Glacial Maximum.

Chlamydia suis is an important, highly prevalent, and diverse obligate intracellular pathogen infecting pigs. In order to investigate the prevalence and diversity of C. suis in the U.S., 276 whole blood samples from feral swine were collected as well as 109 fecal swabs and 60 whole blood samples from domestic pigs. C. suis-specific peptide ELISA identified anti-C. suis antibodies in 13.0% of the blood of feral swine (26/276) and 80.0% of the domestic pigs (48/60). FRET-qPCR and DNA sequencing found C. suis DNA in 99.1% of the fecal swabs (108/109) and 21.7% of the whole blood (13/60) of the domestic pigs, but not in any of the assayed blood samples (0/267) in feral swine. Phylogenetic comparison of partial C. suis ompA gene sequences and C. suis-specific multilocus sequencing typing (MLST) revealed significant genetic diversity of the C. suis identified in this study. Highly genetically diverse C. suis strains are prevalent in domestic pigs in the USA. As crowding strongly enhances the frequency and intensity of highly prevalent Chlamydia infections in animals, less population density in feral swine than in domestic pigs may explain the significantly lower C. suis prevalence in feral swine. A future study is warranted to obtain C. suis DNA from feral swine to perform genetic diversity of C. suis between commercial and feral pigs.

Acute bacterial endocarditis is a rapid, difficult to manage, and frequently lethal disease. Potent antibiotics often cannot efficiently kill Staphylococcus aureus that colonizes the heart’s valves. S. aureus relies on virulence factors to evade therapeutics and the host’s immune response, usurping the host’s clotting system by activating circulating prothrombin with staphylocoagulase and von Willebrand factor–binding protein. An insoluble fibrin barrier then forms around the bacterial colony, shielding the pathogen from immune cell clearance. Targeting virulence factors may provide previously unidentified avenues to better diagnose and treat endocarditis. To tap into this unused therapeutic opportunity, we codeveloped therapeutics and multimodal molecular imaging to probe the host-pathogen interface. We introduced and validated a family of small-molecule optical and positron emission tomography (PET) reporters targeting active thrombin in the fibrin-rich environment of bacterial colonies. The imaging agents, based on the clinical thrombin inhibitor dabigatran, are bound to heart valve vegetations in mice. Using optical imaging, we monitored therapy with antibodies neutralizing staphylocoagulase and von Willebrand factor–binding protein in mice with S. aureus endocarditis. This treatment deactivated bacterial defenses against innate immune cells, decreased in vivo imaging signal, and improved survival. Aortic or tricuspid S. aureus endocarditis in piglets was also successfully imaged with clinical PET/magnetic resonance imaging. Our data map a route toward adjuvant immunotherapy for endocarditis and provide efficient tools to monitor this drug class for infectious diseases.

Remote sensing observations of the Mariner 10 and MESSENGER spacecraft have shown the existence of atomic (H) and molecular (H2) hydrogen in the exosphere around Mercury. However, to date the hydrogen number densities could only be estimated indirectly from exospheric models, based on Lyman-α radiances for H and the H2 detection threshold of the Mariner 10 occultation experiment. Here we show the first in-situ measured altitude-density profile of atomic H, derived from magnetic field observations by MESSENGER. Our results reveal an extended H corona with densities decreasing from 1000 − 100 cm−3 between 2 − 8 Mercury radii. These densities are 2-3 orders of magnitude larger than previously predicted, but in good agreement with the Lyman-α radiances. The large H densities result from the dissociation of H2. We can reproduce the observed H densities using an exospheric model which includes ionization, dissociation and recombination, that allows us to constrain the H2 surface density to ∼ 5×10^5 cm−3. This is two orders of magnitude smaller than the previously assumed upper limit.