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Abstract The Network for Pancreatic Organ donors with Diabetes (nPOD) is the largest biorepository of human pancreata and associated immune organs from donors with type 1 diabetes (T1D), maturity-onset diabetes of the young (MODY), cystic fibrosis-related diabetes (CFRD), type 2 diabetes (T2D), gestational diabetes, islet autoantibody positivity (AAb+), and without diabetes. nPOD recovers, processes, analyzes, and distributes high-quality biospecimens, collected using optimized standard operating procedures, and associated de-identified data/metadata to researchers around the world. Herein describes the release of high-parameter genotyping data from this collection. 372 donors were genotyped using a custom precision medicine single nucleotide polymorphism (SNP) microarray. Data were technically validated using published algorithms to evaluate donor relatedness, ancestry, imputed HLA, and T1D genetic risk score. Additionally, 207 donors were assessed for rare known and novel coding region variants via whole exome sequencing (WES). These data are publicly-available to enable genotype-specific sample requests and the study of novel genotype:phenotype associations, aiding in the mission of nPOD to enhance understanding of diabetes pathogenesis to promote the development of novel therapies.

Abstract Background Leaf surface phenotypes can indicate plant health and relate to a plant’s adaptations to environmental stresses. Identifying these phenotypes using non-invasive techniques can assist in high-throughput phenotyping and can improve decision making in plant breeding. Identification of these surface phenotypes can also assist in stress identification. Incorporating surface phenotypes into leaf optical modelling can lead to improved biochemical parameter retrieval and species identification. Results In this paper, leaf surface phenotypes are characterized for 349 leaf samples based on polarized light reflectance measured at Brewster’s Angle, and microscopic observation. Four main leaf surface phenotypes (glossy wax, glaucous wax, high trichome density, and glabrous) were identified for the leaf samples. The microscopic and visual observations of the phenotypes were used as ground truth for comparison with the spectral classification. In addition to surface classification, the microscope images were used to assess cell size, shape, and cell cap aspect ratios; these surface attributes were not found to correlate significantly with spectral measurements obtained in this study. Using a quadratic discriminant analysis function, a series of 10,000 classifications were run with the data randomly split between training and testing datasets, with 150 and 199 samples, respectively. The average correct classification rate was 72.9% with a worst-case classification of 60.3%. Conclusions Leaf surface phenotypes were successfully correlated with spectral measurements that can be obtained remotely. Remote identification of these surface phenotypes will improve leaf optical modelling and biochemical parameter estimations. Phenotyping of leaf surfaces can inform plant breeding decisions and assist with plant health monitoring.

The Association for Cancer Immunotherapy (CIMT) celebrated the 20th anniversary of the CIMT Annual Meeting. CIMT2023 was held 3-5 May 2023 in Mainz, Germany. 1051 academic and clinical professionals from over 30 countries attended the meeting and discussed the latest advances in cancer immunology and immunotherapy research. This report summarizes the highlights of CIMT2023.

BackgroundDaily stressors are associated with cognitive decline and increased risk of heart disease, depression, and other debilitating chronic illnesses in midlife adults. Daily stressors tend to occur at home or at work and are more frequent in urban versus rural settings. Conversely, spending time in natural environments such as parks or forests, or even viewing nature-themed images in a lab setting, is associated with lower levels of perceived stress and is hypothesized to be a strong stress “buffer,” reducing perceived stress even after leaving the natural setting. However, many studies of daily stress have not captured environmental contexts and relied on end-of-day recall instead of in-the-moment data capture. With new technology, these limitations can be addressed to enhance knowledge of the daily stress experience. ObjectiveWe propose to use our novel custom-built Stress Reports in Variable Environments (STRIVE) ecological momentary assessment mobile phone app to measure the experience of daily stress of midlife adults in free-living conditions. Using our app to capture data in real time will allow us to determine (1) where and when daily stress occurs for midlife adults, (2) whether midlife adults’ daily stressors are linked to certain elements of the built and natural environment, and (3) how ecological momentary assessment measurement of daily stress is similar to and different from a modified version of the popular Daily Inventory of Stressful Events measurement tool that captures end-of-day stress reports (used in the Midlife in the United States [MIDUS] survey). MethodsWe will enroll a total of 150 midlife adults living in greater Indianapolis, Indiana, in this study on a rolling basis for 3-week periods. As those in underrepresented minority groups and low-income areas have previously been found to experience greater levels of stress, we will use stratified sampling to ensure that half of our study sample is composed of underrepresented minorities (eg, Black, American Indian, Hispanic, or Native Pacific Islanders) and approximately one-third of our sample falls within low-, middle-, and high-income brackets. ResultsThis project is funded by the National Institute on Aging from December 2022 to November 2024. Participant enrollment began in August 2023 and is expected to finish in July 2024. Data will be spatiotemporally analyzed to determine where and when stress occurs for midlife adults. Pictures of stressful environments will be qualitatively analyzed to determine the common elements of stressful environments. Data collected by the STRIVE app will be compared with retrospective Daily Inventory of Stressful Events data. ConclusionsCompleting this study will expand our understanding of midlife adults’ experience of stress in free-living conditions and pave the way for data-driven individual and community-based intervention designs to promote health and well-being in midlife adults. International Registered Report Identifier (IRRID)DERR1-10.2196/51845

The proportions and phenotypes of immune cell subsets in peripheral blood undergo continual and dramatic remodeling throughout the human life span, which complicates efforts to identify disease-associated immune signatures in type 1 diabetes (T1D). We conducted cross-sectional flow cytometric immune profiling on peripheral blood from 826 individuals (stage 3 T1D, their first-degree relatives, those with ≥2 islet autoantibodies, and autoantibody-negative unaffected controls). We constructed an immune age predictive model in unaffected participants and observed accelerated immune aging in T1D. We used generalized additive models for location, shape, and scale to obtain age-corrected data for flow cytometry and complete blood count readouts, which can be visualized in our interactive portal (ImmScape); 46 parameters were significantly associated with age only, 25 with T1D only, and 23 with both age and T1D. Phenotypes associated with accelerated immunological aging in T1D included increased CXCR3+ and programmed cell death 1–positive (PD-1+) frequencies in naive and memory T cell subsets, despite reduced PD-1 expression levels on memory T cells. Phenotypes associated with T1D after age correction were predictive of T1D status. Our findings demonstrate advanced immune aging in T1D and highlight disease-associated phenotypes for biomarker monitoring and therapeutic interventions.

The Middle East and North Africa (MENA) region has experienced more frequent and severe drought events in recent decades, leading to increasingly pressing concerns over already strained food and water security. An effective drought monitoring and early warning system is thus critical to support risk mitigation and management by countries in the region. Here we investigate the potential for assimilation of leaf area index (LAI) and soil moisture observations to improve the representation of the overall hydrological and carbon cycles and drought by an advanced land surface model. The results reveal that assimilating soil moisture does not meaningfully improve model representation of the hydrological and biospheric processes for this region, but instead it degrades the simulation of the interannual variation in evapotranspiration (ET) and carbon fluxes, mainly due to model weaknesses in representing prognostic phenology. However, assimilating LAI leads to greater improvement, especially for transpiration and carbon fluxes, by constraining the timing of simulated vegetation growth response to evolving climate conditions. LAI assimilation also helps to correct for the erroneous interaction between the prognostic phenology and irrigation during summertime, effectively reducing a large positive bias in ET and carbon fluxes. Independently assimilating LAI or soil moisture alters the categorization of drought, with the differences being greater for more severe drought categories. We highlight the vegetation representation in response to changing land use and hydroclimate as one of the key processes to be captured for building a successful drought early warning system for the MENA region.

The autoimmune pathogenesis of type 1 diabetes (T1D) involves cellular infiltration from innate and adaptive immune subsets into the islets of Langerhans within the pancreas; however, the direct cytotoxic killing of insulin-producing β-cells is thought to be mediated primarily by antigen-specific CD8+ T cells. Despite this direct pathogenic role, key aspects of their receptor specificity and function remain uncharacterized, in part, due to their low precursor frequency in peripheral blood. The concept of engineering human T cell specificity, using T cell receptor (TCR) and chimeric antigen receptor (CAR)-based approaches, has been demonstrated to improve adoptive cell therapies for cancer, but has yet to be extensively employed for modeling and treating autoimmunity. To address this limitation, we sought to combine targeted genome editing of the endogenous TCRα chain gene (TRAC) via CRISPR/Cas9 in combination with lentiviral vector (LV)-mediated TCR gene transfer into primary human CD8+ T cells. We observed that knockout (KO) of endogenous TRAC enhanced de novo TCR pairing, which permitted increased peptide:MHC-dextramer staining. Moreover, TRAC KO and TCR gene transfer increased markers of activation and effector function following activation, including granzyme B and interferon-γ production. Importantly, we observed increased cytotoxicity toward an HLA-A*0201+ human β-cell line by HLA-A*02:01 restricted CD8+ T cells engineered to recognize islet-specific glucose-6-phosphatase catalytic subunit (IGRP). These data support the notion of altering the specificity of primary human T cells for mechanistic analyses of autoreactive antigen-specific CD8+ T cells and are expected to facilitate downstream cellular therapeutics to achieve tolerance induction through the generation of antigen-specific regulatory T cells.

We demonstrate a heterogeneously integrated laser on silicon exhibiting a sub-20 kHz Lorentzian linewidth over a wavelength tuning range of 58 nm from 1350 to 1408 nm, which are record values to date for E-band integrated lasers in the literature. Wide wavelength tuning is achieved with an integrated Si ring-resonator-based Vernier mirror, which also significantly reduces the Lorentzian linewidth. Such a record performance leverages a mature heterogeneous III–V/Si platform and marks an important milestone in E-band optical fiber communications and in reaching visible wavelengths via second harmonic generation for optical atomic clock applications.

Abstract Representation of irrigation in Earth System Models has advanced over the past decade, yet large uncertainties persist in the effective simulation of irrigation practices, particularly over locations where the on‐ground practices and climate impacts are less reliably known. Here we investigate the utility of assimilating remotely sensed vegetation data for improving irrigation water use and associated fluxes within a land surface model. We show that assimilating optical sensor‐based leaf area index estimates significantly improves the simulation of irrigation water use when compared to the USGS ground reports. For heavily irrigated areas, assimilation improves the evaporative fluxes and gross primary production (GPP) simulations, with the median correlation increasing by 0.1–1.1 and 0.3–0.6, respectively, as compared to the reference datasets. Further, bias improvements in the range of 14–35 mm mo−1 and 10–82 g m−2 mo−1 are obtained in evaporative fluxes and GPP as a result of incorporating vegetation constraints, respectively. These results demonstrate that the use of remotely sensed vegetation data is an effective, observation‐informed, globally applicable approach for simulating irrigation and characterizing its impacts on water and carbon states.

This article draws together two trajectories of legal scholarship: the turn to the visual in legal studies and the emergence of the subfield of law and comics, or ‘graphic justice’. It does this via an analysis of superhero comics as fitting within a particular genealogy of the ius imaginum, or law of images. This is not to argue simply that superhero comics are dominated by narratives of law, justice and legality—they are—but rather that the very theatrical figure of the superhero and its encompassing of a dual persona is a presentation of a particular political theology of the image. The article analyses the way in which this political theology is rendered visible in Charles Soule’s Daredevil: Back in Black, highlighting the image of the superhero and its connection to both sovereignty and the biopolitics of personhood.

What does it mean to be human today in our globalised, technologised and hypermediated world? How do our modes of cultural representation relate to, affect and effect the role of being human? This special issue of Law, Technology and Humans seeks to explore the form of the comic as one means to address these questions. Comics are a means of cultural representation and discourse that not only reflect but refract — through their deployment of word and image, of grid and gutter, of both visual and textual mediation — the very means of human interaction and intersubjectivity. Arising out of the 2019 Graphic Justice Research Alliance conference, hosted by the School of Law and Criminology (now the School of Law and Society) at the University of the Sunshine Coast, Australia, the papers collected here examine not only the way in which comics and graphic art present narratives of law and justice, or representations of human rights and their abuses, but also the way in which comics in their form and multimodality call into question the law’s drawing of the boundaries of the human as it is challenged by its relation to the non-human, the environment and technology.

Abstract Background Troponin T (TnT) is a well-known risk factor for negative outcome in hemodialysis (HD) patients, but little is known about variation over time, and the impact of clinical and dialysis specific factors. This study investigated the effect of angiotensin II receptor blockade (ARB), short and long-term variation in TnT and associations with clinical parameters. Methods In this analysis based on the SAFIR-cohort (Clinical Trials ID: NCT00791830) 81 HD patients were randomized double-blind for placebo (n = 40) or angiotensin II receptor blocker (ARB) treatment (n = 41) with irbesartan (150–300 mg) and followed for 12 months with six serial measurements of TnT using a high-sensitivity assay. Results Fifty-four patients (67%) completed follow-up. Baseline TnT-medians (min-max) were (placebo/ARB): 45(14–295)/46(10–343) ng/L. ARB-treatment did not significantly affect mean TnT-levels over the 12-month study period. Median week-to-week and one-year TnT-variation (5th–95th-percentile range) using all samples regardless of intervention were: 0(− 14–10) ng/L (week-to-week) and 3(− 40–71) ng/L (12 months). Median TnT-amplitude, capturing the change from the lowest to the highest TnT-value observed during the one-year study period was 38% or 20.5 ng/L. Median ratios with 95% limits of agreement were: 1.00(0.73–1.37); P = 0.92 (1 week/baseline; n = 77) and 1.07(0.52–2.25); P = 0.19 (12 months/baseline; n = 54). Baseline TnT was positively correlated with diabetes, ultrafiltration volume, arterial stiffness, change in intradialytic total peripheral resistance and N-terminal pro b-type natriuretic peptide (NT-proBNP) and negatively correlated with hematocrit, residual renal function and change in intradialytic cardiac output. High baseline TnT was associated with a higher risk of admission and cardiovascular (CV) events during follow-up. Increase in TnT over time (ΔTnT = 12-months-baseline) was significantly associated with increase in left ventricular (LV) mass and NT-proBNP and decrease in LV ejection fraction and late intradialytic stroke volume. ΔTnT was not significantly associated with admissions, CV or intradialytic hypotensive events during follow-up. Admissions were significantly more likely with a high (TnT-amplitude> 20.5 ng/L) than a low TnT-amplitude. Peaks in TnT were less frequent in aspirin-treated patients. Conclusion ARB-treatment had no significant effect on TnT-levels. Week-to-week variation was generally low, yet over 12 months individual patients had considerable TnT fluctuations. Rise in TnT over time was significantly correlated with markers of cardiac deterioration. Trial registration ClinicalTrials.gov Identifier: NCT00791830 . Date of registration: November 17, 2008. EudraCT no: 2008–001267-11.

River ice, like open-water conditions, is an integral component of the cold-climate hydrological cycle. The annual succession of river ice formation, growth, decay and clearance can include low flows and ice jams, as well as midwinter and spring break-up events. Reports and associated data of river ice occurrence are often limited to single locations or regional assessments, are season-specific, and use readily available data. Within Canada, the National Hydrometric Program (NHP) operates a network of gauging stations with water level as the primary measured variable to derive discharge. In the late 1990s, the Water Science and Technology Directorate of Environment and Climate Change Canada initiated a long-term effort to compile, archive and extract river-ice-related information from NHP hydrometric records. This data article describes the original research data set produced by this near 20-year effort: the Canadian River Ice Database (CRID). The CRID holds almost 73 000 recorded variables from a subset of 196 NHP stations throughout Canada that were in operation within the period 1894 to 2015. Over 100 000 paper and digital files were reviewed, representing 10 378 station years of active operation. The task of compiling this database involved manual extraction and input of more than 460 000 data entries on water level, discharge, ice thickness, date, time and data quality rating. Guidelines on the data extraction, rating procedure and challenges are provided. At each location, time series of up to 15 variables specific to the occurrence of freeze-up and winter-low events, midwinter break-up, ice thickness, spring break-up, and maximum open-water level were compiled. This database follows up on several earlier efforts to compile information on river ice, which are summarized herein, and expands the scope and detail for use in Canadian river ice research and applications. Following the Government of Canada Open Data initiative, this original river ice data set is available at https://doi.org/10.18164/c21e1852-ba8e-44af-bc13-48eeedfcf2f4 (de Rham et al., 2020).

Regulatory T cell (Treg) adoptive cell therapy (ACT) represents an emerging strategy for restoring immune tolerance in autoimmune diseases. Tregs are commonly purified using a CD4+CD25+CD127lo/- gating strategy, which yields a mixed population: 1) cells expressing the transcription factors, FOXP3 and Helios, that canonically define lineage stable thymic Tregs and 2) unstable FOXP3+Helios- Tregs. Our prior work identified the autoimmune disease risk-associated locus and costimulatory molecule, CD226, as being highly expressed not only on effector T cells but also, interferon-γ (IFN-γ) producing peripheral Tregs (pTreg). Thus, we sought to determine whether isolating Tregs with a CD4+CD25+CD226- strategy yields a population with increased purity and suppressive capacity relative to CD4+CD25+CD127lo/- cells. After 14d of culture, expanded CD4+CD25+CD226- cells displayed a decreased proportion of pTregs relative to CD4+CD25+CD127lo/- cells, as measured by FOXP3+Helios- expression and the epigenetic signature at the FOXP3 Treg-specific demethylated region (TSDR). Furthermore, CD226- Tregs exhibited decreased production of the effector cytokines, IFN-γ, TNF, and IL-17A, along with increased expression of the immunoregulatory cytokine, TGF-β1. Lastly, CD226- Tregs demonstrated increased in vitro suppressive capacity as compared to their CD127lo/- counterparts. These data suggest that the exclusion of CD226-expressing cells during Treg sorting yields a population with increased purity, lineage stability, and suppressive capabilities, which may benefit Treg ACT for the treatment of autoimmune diseases.

Despite larger nonlinear coefficients, waveguide losses have prevented using semiconductors instead of dielectric materials for on-chip frequency-comb sources. By significantly reducing waveguide loss, ultra-low-threshold Kerr comb generation is demonstrated in a high-Q AlGaAs-on-insulator microresonator system.

Background: Central blood pressure (BP) assessed noninvasively considerably underestimates true invasively measured aortic BP in chronic kidney disease (CKD) patients. The difference between the estimated and the true aortic BP increases with decreasing estimated glomerular filtration rates (eGFR). The present study investigated whether aortic calcification affects noninvasive estimates of central BP. Methods: Twenty-four patients with CKD stage 4–5 undergoing coronary angiography and an aortic computed tomography scan were included (63% males, age [mean ± SD ] 53 ± 11 years, and eGFR 9 ± 5 mL/min/1.73 m2). Invasive aortic BP was measured through the angiography catheter, while non-invasive central BP was obtained using radial artery tonometry with a SphygmoCor® device. The Agatston calcium score (CS) in the aorta was quantified on CT scans using the CS on CT scans. Results: The invasive aortic systolic BP (SBP) was 152 ± 23 mm Hg, while the estimated central SBP was 133 ± 20 mm Hg. Ten patients had a CS of 0 in the aorta, while 14 patients had a CS >0 in the aorta. The estimated central SBP was lower than the invasive aortic SBP in patients with aortic calcification compared to patients without (mean difference 8 mm Hg, 95% CI 0.3–16; p = 0.04). The brachial SBP was lower than the aortic SBP in patients with aortic calcification compared to patients without (mean difference 10 mm Hg, 95% CI 2–19; p = 0.02). Conclusion: In patients with advanced CKD the presence of aortic calcification is associated with a higher difference between invasively measured central aortic BP and non-invasive estimates of central BP as compared to patients without calcifications.

Abstract: CXC chemokine receptor 4 (CXCR4) is overexpressed by a broad range of hematological disorders, and its interaction with CXC chemokine ligand 12 (CXCL12) is of central importance in the retention and chemoprotection of neoplastic cells in the bone marrow and lymphoid organs. In this article, we describe the biological evaluation of a new CXCR4-targeting and -antagonizing molecule (BAT1) that we designed and show that, when incorporated into a liposomal drug delivery system, it can be used to deliver cancer therapeutics at high levels to chronic lymphocytic leukemia (CLL) cells. CXCR4 targeting and antagonism by BAT1 were demonstrated alone and following its incorporation into liposomes (BAT1-liposomes). Antagonism of BAT1 against the CXCR4/CXCL12 interaction was demonstrated through signaling inhibition and function blocking: BAT1 reduced ERK phosphorylation and cell migration to levels equivalent to those seen in the absence of CXCL12 stimulation (P < .001). Specific uptake of BAT1-liposomes and delivery of a therapeutic cargo to the cell nucleus was seen within 3 hours of incubation and induced significantly more CLL cell death after 24 hours than control liposomes (P = .004). The BAT1 drug-delivery system is modular, versatile, and highly clinically relevant, incorporating elements of proven clinical efficacy. The combined capabilities to block CXCL12-induced migration and intracellular signaling while simultaneously delivering therapeutic cargo mean that the BAT1-liposome drug-delivery system could be a timely and relevant treatment of a range of hematological disorders, particularly because the therapeutic cargo can be tailored to the disease being treated.

Many precipitation-driven data products from land data assimilation systems support assessments of droughts, floods, and other societally-relevant land-surface processes. The accumulated precipitation used as input to these products has a significant impact on water budgets; however, the effects of daily distribution of precipitation on these products are not well known. A comparison of the Integrated Multi-satellite Retrievals for GPM (IMERG) and Climate Hazards Group InfraRed Precipitation with Stations version 2 (CHIRPS2) rainfall products over the continental United States (CONUS) was performed to quantify the impacts of the daily distribution of precipitation on biases and errors in soil moisture, runoff, and evapotranspiration (ET). Since the total accumulated precipitation between the IMERG and CHIRPS product differed, a third precipitation product, CHIRPS-to-IMERG (CHtoIM), was produced that used CHIRPS2 accumulated precipitation totals and the daily precipitation frequency distribution of IMERG. This new product supported a controlled analysis of the impact of precipitation frequency distribution on simulated hydrological fields. The CHtoIM had higher occurrences of precipitation in the 0–5 mm day−1 range, with a lower occurrence of dry days, which decreased soil moisture and surface runoff in the land-surface model. The surface soil layer had a tendency to reach saturation more often in the CHIRPS2 simulations, where the number of moderate to heavy precipitation days (>5 mm day−1) was increased. Using the blended CHtoIM product as input reduced errors in surface soil moisture by 5–15% when compared to Soil Moisture Active/Passive (SMAP) data. Similarly, ET errors were also slightly decreased (~2%) when compared to SSEBop data. Moderate changes in daily precipitation distributions had a quantifiable impact on soil moisture, runoff, and ET. These changes usually improved the model when compared to other modeled and observational datasets, but the magnitude of the improvements varied by region and time of year.

Category: Midfoot/Forefoot Introduction/Purpose: The superiority of Primary arthrodesis (PA) versus open reduction and internal fixation (ORIF) in Lisfranc injuries has been debated for decades. In recent years, researchers have attempted to use meta-analyses to reach a definitive conclusion. However, they have reached uncertain and contradicting conclusions when comparing these treatment options, which has led to more confusion. The goal of this paper is to navigate the primary source data of each meta-analyses to determine why different conclusions were reached and provide surgeons with more clarity on the comparable outcomes of PA and ORIF treatment options in Lisfranc injuries. Methods: A systematic literature review was conducted by searching for ‘meta-analysis’ AND ‘Lisfranc’ with keywords such as ‘ORIF’ OR ‘open reduction’ OR ‘Arthrodesis’ OR ‘fusion’. Five meta-analysis articles discussing PA and ORIF in Lisfranc injuries were identified. Study outcomes were extracted from each article for comparison. Contradicting conclusions were identified, and the primary sources used by each meta-analysis was analyzed. Results: All meta-analyses agreed that PA had lower rates of hardware removal and that there is no significant difference between PA and ORIF when considering revision surgery, anatomic reduction, postoperative infection, total complications, and patient satisfaction. However, contradicting conclusions were reached regarding functional patient outcomes such as return to duty, the American Orthopaedic Foot & Ankle Society (AOFAS) score, and visual analogue scale (VAS) score. Conclusion: PA has favorable rates of hardware removal compared to ORIF, while no difference between PA and ORIF was found for revision surgery, anatomic reduction, postoperative infection, total complications, and patient satisfaction.While certain meta-analyses had contradicting conclusion as to which treatment option is favorable for returning to duty, AOFAS score, and VAS score, it was determined there was no significant difference in PA and ORIF for return to work and VAS score. Repeat meta- analysis with truly equivocal outcomes would be necessary to reach a valid conclusion for return to full activity and AOFAS midfoot scores.

Category: Ankle; Bunion; Hindfoot; Lesser Toes; Midfoot/Forefoot Introduction/Purpose: There is a growing trend to perform surgical procedures at freestanding ambulatory surgical centers. No literature exists evaluating the rate of adverse events and overall safety of foot and ankle outpatient surgeries at a freestanding ambulatory surgery center (ASC). Methods: A retrospective review of all foot and ankle cases performed over a two year period at a single freestanding ASC. A total of 313 cases were performed. Adverse events are state-reported events that cause harm or lead to additional treatment. Using state-reported adverse events criteria and previous literature from hand and upper-extremity cases, we categorized our adverse events into seven categories: 1) infection requiring intravenous abx or return to the operating room, 2) postoperative transfer to a hospital, 3) wrong-site surgery, 4) retention of a foreign object, 5) postoperative symptomatic thromboembolism (DVT), 6) medication error, and 7) bleeding complications. Results: The overall rate of adverse events was 3.5% with 11 events identified over the two year period. There were a total of 10 infections and 1 symptomatic DVT. There were no cases that resulted in transfer to a hospital, hospital admission after discharge, medication error, bleeding complications, wrong-site procedures, or retained foreign bodies. Conclusion: Outpatient foot and ankle procedures are not without complications, but the overall rate of complications postoperatively is farly low (3.5%). Overall, foot and ankle surgeries can be performed safely in an outpatient setting at an ASC.

The human T lymphocyte compartment is highly dynamic over the course of a lifetime. Of the many changes, perhaps most notable is the transition from a predominantly naïve T cell state at birth to the acquisition of antigen-experienced memory and effector subsets following environmental exposures. These phenotypic changes, including the induction of T cell exhaustion and senescence, have the potential to negatively impact efficacy of adoptive T cell therapies (ACT). When considering ACT with CD4+CD25+CD127–/lo regulatory T cells (Tregs) for the induction of immune tolerance, we previously reported ex vivo expanded umbilical cord blood (CB) Tregs remained more naïve, suppressed responder T cells equivalently, and exhibited a more diverse T cell receptor (TCR) repertoire compared to expanded adult peripheral blood (APB) Tregs. Herein, we hypothesized that upon further characterization, we would observe increased lineage heterogeneity and phenotypic diversity in APB Tregs that might negatively impact lineage stability, engraftment capacity, and the potential for Tregs to home to sites of tissue inflammation following ACT. We compared the phenotypic profiles of human Tregs isolated from CB versus the more traditional source, APB. We conducted analysis of fresh and ex vivo expanded Treg subsets at both the single cell (scRNA-seq and flow cytometry) and bulk (microarray and cytokine profiling) levels. Single cell transcriptional profiles of pre-expansion APB Tregs highlighted a cluster of cells that showed increased expression of genes associated with effector and pro-inflammatory phenotypes (CCL5, GZMK, CXCR3, LYAR, and NKG7) with low expression of Treg markers (FOXP3 and IKZF2). CB Tregs were more diverse in TCR repertoire and homogenous in phenotype, and contained fewer effector-like cells in contrast with APB Tregs. Interestingly, expression of canonical Treg markers, such as FOXP3, TIGIT, and IKZF2, were increased in CB CD4+CD127+ conventional T cells (Tconv) compared to APB Tconv, post-expansion, implying perinatal T cells may adopt a default regulatory program. Collectively, these data identify surface markers (namely CXCR3) that could be depleted to improve purity and stability of APB Tregs, and support the use of expanded CB Tregs as a potentially optimal ACT modality for the treatment of autoimmune and inflammatory diseases.

Editors of several journals in the field of hydrology met during the General Assembly of the European Geosciences Union (EGU) in Vienna in April 2017. This event was a follow-up of similar meetings held in 2013 and 2015. These meetings enable the group of editors to review the current status of the journals and the publication process, and to share thoughts on future strategies. Journals were represented at the 2017 meeting by their editors, as shown in the list of authors. The main points on invigorating hydrological research through journal publications are communicated in this joint editorial published in the above journals.

Editors of several journals in the field of hydrology met during the General Assembly of the European Geosciences Union—EGU in Vienna in April 2017. This event was a follow-up of similar meetings held in 2013 and 2015. These meetings enable the group of editors to review the current status of the journals and the publication process, and to share thoughts on future strategies. Journals were represented at the 2017 meeting by their editors, as shown in the list of authors. The main points on invigorating hydrological research through journal publications are communicated in this joint editorial published in the above journals.

The effective applications of land surface models (LSMs) and hydrologic models pose a varied set of data input and processing needs, ranging from ensuring consistency checks to more derived data processing and analytics. This article describes the development of the Land surface Data Toolkit (LDT), which is an integrated framework designed specifically for processing input data to execute LSMs and hydrological models. LDT not only serves as a preprocessor to the NASA Land Information System (LIS), which is an integrated framework designed for multi-model LSM simulations and data assimilation (DA) integrations, but also as a land-surface-based observation and DA input processor. It offers a variety of user options and inputs to processing datasets for use within LIS and stand-alone models. The LDT design facilitates the use of common data formats and conventions. LDT is also capable of processing LSM initial conditions and meteorological boundary conditions and ensuring data quality for inputs to LSMs and DA routines. The machine learning layer in LDT facilitates the use of modern data science algorithms for developing data-driven predictive models. Through the use of an object-oriented framework design, LDT provides extensible features for the continued development of support for different types of observational datasets and data analytics algorithms to aid land surface modeling and data assimilation.

In this synthesis paper addressing hydrologic scaling and similarity, we posit that roadblocks in the search for universal laws of hydrology are hindered by our focus on computational simulation (the third paradigm) and assert that it is time for hydrology to embrace a fourth paradigm of data-intensive science. Advances in information-based hydrologic science, coupled with an explosion of hydrologic data and advances in parameter estimation and modeling, have laid the foundation for a data-driven framework for scrutinizing hydrological scaling and similarity hypotheses. We summarize important scaling and similarity concepts (hypotheses) that require testing; describe a mutual information framework for testing these hypotheses; describe boundary condition, state, flux, and parameter data requirements across scales to support testing these hypotheses; and discuss some challenges to overcome while pursuing the fourth hydrological paradigm. We call upon the hydrologic sciences community to develop a focused effort towards adopting the fourth paradigm and apply this to outstanding challenges in scaling and similarity.

The diversity in hydrologic models has historically led to great controversy on the correct approach to process-based hydrologic modeling, with debates centered on the adequacy of process parameterizations, data limitations and uncertainty, and computational constraints on model analysis. In this paper, we revisit key modeling challenges on requirements to (1) define suitable model equations, (2) define adequate model parameters, and (3) cope with limitations in computing power. We outline the historical modeling challenges, provide examples of modeling advances that address these challenges, and define outstanding research needs. We illustrate how modeling advances have been made by groups using models of different type and complexity, and we argue for the need to more effectively use our diversity of modeling approaches in order to advance our collective quest for physically realistic hydrologic models.

Accurate specification of the model error covariances in data assimilation systems is a challenging issue. Ensemble land data assimilation methods rely on stochastic perturbations of input forcing and model prognostic fields for developing representations of input model error covariances. This article examines the limitations of using a single forcing dataset for specifying forcing uncertainty inputs for assimilating snow depth retrievals. Using an idealized data assimilation experiment, the article demonstrates that the use of hybrid forcing input strategies (either through the use of an ensemble of forcing products or through the added use of the forcing climatology) provide a better characterization of the background model error, which leads to improved data assimilation results, especially during the snow accumulation and melt-time periods. The use of hybrid forcing ensembles is then employed for assimilating snow depth retrievals from the AMSR2 instrument over two domains in the continental USA with different snow evolution characteristics. Over a region near the Great Lakes, where the snow evolution tends to be ephemeral, the use of hybrid forcing ensembles provides significant improvements relative to the use of a single forcing dataset. Over the Colorado headwaters characterized by large snow accumulation, the impact of using the forcing ensemble is less prominent and is largely limited to the snow transition time periods. The results of the article demonstrate that improving the background model error through the use of a forcing ensemble enables the assimilation system to better incorporate the observational information.

Polyketides are a class of specialised metabolites synthesised by both eukaryotes and prokaryotes. These chemically and structurally diverse molecules are heavily used in the clinic and include frontline antimicrobial and anticancer drugs such as erythromycin and doxorubicin. To replenish the clinicians' diminishing arsenal of bioactive molecules, a promising strategy aims at transferring polyketide biosynthetic pathways from their native producers into the biotechnologically desirable host Escherichia coli. This approach has been successful for type I modular polyketide synthases (PKSs); however, despite more than 3 decades of research, the large and important group of type II PKSs has until now been elusive in E. coli. Here, we report on a versatile polyketide biosynthesis pipeline, based on identification of E. coli-compatible type II PKSs. We successfully express 5 ketosynthase (KS) and chain length factor (CLF) pairs-e.g., from Photorhabdus luminescens TT01, Streptomyces resistomycificus, Streptoccocus sp. GMD2S, Pseudoalteromonas luteoviolacea, and Ktedonobacter racemifer-as soluble heterodimeric recombinant proteins in E. coli for the first time. We define the anthraquinone minimal PKS components and utilise this biosynthetic system to synthesise anthraquinones, dianthrones, and benzoisochromanequinones (BIQs). Furthermore, we demonstrate the tolerance and promiscuity of the anthraquinone heterologous biosynthetic pathway in E. coli to act as genetically applicable plug-and-play scaffold, showing it to function successfully when combined with enzymes from phylogenetically distant species, endophytic fungi and plants, which resulted in 2 new-to-nature compounds, neomedicamycin and neochaetomycin. This work enables plug-and-play combinatorial biosynthesis of aromatic polyketides using bacterial type II PKSs in E. coli, providing full access to its many advantages in terms of easy and fast genetic manipulation, accessibility for high-throughput robotics, and convenient biotechnological scale-up. Using the synthetic and systems biology toolbox, this plug-and-play biosynthetic platform can serve as an engine for the production of new and diversified bioactive polyketides in an automated, rapid, and versatile fashion.

Umbilical cord blood is a traditional and convenient source of cells for hematopoietic stem cell transplantation. Thymic regulatory T cells (Tregs) are also present in cord blood, and there is growing interest in the use of autologous Tregs to provide a low-risk, fully human leukocyte antigen (HLA)-matched cell product for treating autoimmune diseases, such as type 1 diabetes. Here, we describe a good manufacturing practice (GMP)-compatible Treg expansion protocol using fluorescence-activated cell sorting, resulting in a mean 2,092-fold expansion of Tregs over a 16-day culture for a median yield of 1.26 × 109 Tregs from single-donor cryopreserved units. The resulting Tregs passed prior clinical trial release criteria for Treg purity and sterility, including additional rigorous assessments of FOXP3 and Helios expression and epigenetic analysis of the FOXP3 Treg-specific demethylated region (TSDR). Compared with expanded adult peripheral blood Tregs, expanded cord blood Tregs remained more naive, as assessed by continued expression of CD45RA, produced reduced IFN-γ following activation, and effectively inhibited responder T cell proliferation. Immunosequencing of the T cell receptor revealed a remarkably diverse receptor repertoire within cord blood Tregs that was maintained following in vitro expansion. These data support the feasibility of generating GMP-compliant Tregs from cord blood for adoptive cell transfer therapies and highlight potential advantages in terms of safety, phenotypic stability, autoantigen specificity, and tissue distribution.