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Abstract Mesenchymal stromal cells (MSCs) are multipotent adult stem cells which possess immunomodulatory and repair capabilities. In this study, we investigated whether MSC therapy could modulate inflammation and lung damage in the lungs of Scnn1b-transgenic mice overexpressing the β-subunit of the epithelial sodium channel (β-ENaC), a model with features of Cystic Fibrosis lung disease. Human bone marrow derived MSC cells were intravenously delivered to mice, prior to collection of bronchoalveolar lavage (BALF) and tissue. BALF analysis revealed a significant reduction in inflammatory cells after MSC administration, with both monocytic cells and neutrophils significantly reduced. Pro-inflammatory cytokines keratinocyte-derived chemokine (KC) and osteopontin were also significantly reduced. Histological tissue analysis revealed a reduction in emphysema in Scnn1b-TG mice treated with MSCs and consistent with these findings, improvements in lung function after MSC therapy were observed. Furthermore, MSCs enhanced Ki67 staining in alveolar cells, which may indicate regeneration of the destroyed parenchyma. Mechanistically, restoration of peroxisome proliferator-activated receptor-γ (PPARγ) expression and its transcriptional program were identified after MSC treatment. Our data demonstrate that MSC therapy can reduce inflammation, damage, and lung function decline in the chronically inflamed lung of Scnn1b-Tg mice, suggesting that MSCs may provide an effective tool in the treatment of muco-obstructive diseases such as cystic fibrosis.

Abstract Background To assess proportions of metastatic recurrence in women initially diagnosed with non-metastatic breast cancer by stage at diagnosis, breast cancer subtype, calendar period and age. Methods A systematic search of MEDLINE and Web of Science databases (January 2010–12 May 2022) was conducted. Studies reporting the proportion of distant metastatic recurrence in women with non-metastatic breast cancer were identified and outcomes and characteristics were extracted. Risk of bias was assessed independently by two reviewers. Random-effects meta-analyses of proportions were used to calculate pooled estimates and 95% confidence intervals (CIs). Results 193 studies covering over 280,000 patients were included in the main analysis. Pooled proportions of metastatic recurrence increased with longer median follow-up time from 12.2% (95% CI 10.5–14.0%) at 1–4 years post diagnosis, 14.3% (95% CI 12.9–15.7%) at 5–9 years to 23.3% (95% CI 20.1–26.8) at 10 years or more. Regional variation was observed with pooled estimates ranging from 11.0% (95% CI 8.5–13.7%) in Europe to 26.4% (95% CI 16.7–37.4%) in Africa (1–4 years follow-up). Proportions of recurrence were higher in studies with diagnosis before 2000 (22.2%, 95% CI 15.1–30.3) compared to studies with diagnosis from 2000 onwards (12.8%, 95% CI 11.7–14.0). At 1–4 years median follow-up, pooled proportions of metastatic recurrence were higher in women with hormone receptor negative (15.2%, 95% CI 12.0–18.7%) compared with receptor positive disease (9.6%, 95% CI 6.2–13.6%) and in women with locally advanced (33.2%, 95% CI 24.7–42.3%) relative to early disease at initial diagnosis (4.8%, 95% CI 2.5–7.8%). Proportions were higher in those under 50 years compared with 70+ years, 18.6% (95% CI 15.9–21.4%) versus 13.3% (95% CI 9.2, 18.0%), respectively. Heterogeneity was high in all meta-analyses and results should be interpreted with caution. Conclusions Higher proportions of metastatic recurrence in patients initially diagnosed at an advanced stage and in earlier calendar period emphasises the importance of early detection and treatment advancements. As the global number of breast cancer survivors increases, research and health policy efforts should be directed towards timely diagnosis and access to effective treatments and care. Study registration: PROSPERO CRD42022314500.

Background: In small children with left atrioventricular valve dysfunction, valve repair is preferred but some will require valve replacement. No prosthetic valve has growth potential, bioprostheses have poor durability, and mechanical prostheses have high rates of thromboembolic and hemorrhagic complications. We reviewed our experience with a modified bovine jugular vein valve designed for use in the right ventricular outflow tract (Melody valve, Medtronic) and compared this with contemporary mechanical valve replacement. Methods: We reviewed outcomes of all left-sided atrioventricular valve replacements (AVVR) performed between January 2017 and April 2023 on patients with biventricular circulation less than 5 years old at time of surgery, N = 19. We compared mortality and major morbidity outcomes between mechanical AVVR (mAVVR, n = 14) and Melody AVVR (MAVVR, n=5). Results: MAVVR was performed on younger and smaller patients (5.7 ± 4.2 vs 28.4 ± 22.3 months, P = .002; 6 ± 1.7 vs10 ± 5.1 kg, P = .01). There were 2 early and 1 late death in the mAVVR group, and none in the MAVVR group. There was a trend towards more hemorrhagic and neurologic complications in the mAVVR group (P = .1, 0.28, respectively). Conclusions: In this small series, despite its use in younger and smaller patients, our preliminary experience with the Melody valve compares favorably with our contemporaneous outcomes with mechanical prostheses by way of simpler anticoagulation management with a trend towards better overall outcomes.

Abstract Understanding of newborn immune ontogeny in the first week of life will enable age-appropriate strategies for safeguarding vulnerable newborns against infectious diseases. Here we conducted an observational study exploring the immunological profile of infants longitudinally throughout their first week of life. Our Expanded Program on Immunization - Human Immunology Project Consortium (EPIC-HIPC) studies the epigenetic regulation of systemic immunity using small volumes of peripheral blood samples collected from West African neonates on days of life (DOL) 0, 1, 3, and 7. Genome-wide DNA methylation and single nucleotide polymorphism markers are examined alongside matched transcriptomic and flow cytometric data. Integrative analysis reveals that a core network of transcription factors mediates dynamic shifts in neutrophil-to-lymphocyte ratios (NLR), which are underpinned by cell-type specific methylation patterns in the two cell types. Genetic variants are associated with lower NLRs at birth, and healthy newborns with lower NLRs at birth are more likely to subsequently develop sepsis. These findings provide valuable insights into the early-life determinants of immune system development.

IntroductionSince the early 2000s, the video game industry has seen extraordinary booms in product development and market growth, with the total number of video game players globally reaching 2.69 billion by the end of 2020. Despite the rapid growth of the industry, there is little recent data investigating the time adult video game players spend sedentary playing video games and the time they spent engaged in physical activity. The purpose of this quantitative, cross-sectional, non-experimental survey study is to describe the frequency and duration of video game play and physical activity in adult video game players.MethodsParticipants completed an online survey, evaluating their demographic and health history information, video game play, and physical activity behaviors.ResultsThe study used data from a total of 221 participants (Males = 153, Females = 68). The mean age of the participants was 27.29 (SD 7.27) years. Of the 221 participants, 145 identified as casual players, 50 amateurs, 24 semi-professionals, and 2 professionals. The participants spent over five days per week and an average of 26.56 h per week playing video games. Personal computers were reported to have the longest duration of play of the four platforms investigated (17.59 h per week). The total amount of time participants spent engaged in cumulative moderate-to-vigorous physical activity (MVPA) was an average of 15.43 (SD 16.79) hours per week. The majority of this time was spent engaged in occupational physical activity (5.11 h per week). Participants spent 2.39 h per week engaged in leisure time MVPA.ConclusionOur results indicate an increase in VG play compared to 2018, suggesting United States adult video game players may be more at risk for detrimental effects to their physical health. This could be attributed to the habits formed during the COVID-19 pandemic, the influences from video genre game play mechanics, and the social aspects of playing video games with friends. Future research should focus on developing research methodologies that will objectively measure adult video game player frequencies and durations in video game play alongside extensive observation of different video gameplay mechanic genres and their relationships with physical activity.

We consider how the ongoing recovery of baleen whale populations requires improved understanding when managing the largest commercial fishery in the Southern Ocean, the fishery for Antarctic krill. Baleen whales already represent one of the major consumers of krill, and as such compete with the fishery. However, they are not explicitly included either in the monitoring programme or the krill fisheries management approach of the Commission for the Conservation of Antarctic Marine Living Resources (CCAMLR). Individual baleen whales are at direct mortality risk from ship strike, entanglement, or by-catch. In addition, sub-lethal impacts on individuals, albeit with population-level consequences, via decreased body condition and reproductive rates, may arise from local depletion of prey and prey-field disturbance that increases whale energetic costs. Mitigating these risks requires that baleen whales, including those species not yet recovered, are fully integrated into management procedures. A vital issue will be to facilitate the ongoing recovery of blue, fin and sei whales, populations of which are still heavily depleted relative to their pre-whaling abundance. Part of the answer to this will be how CCAMLR resolves outstanding issues related to its newly emerging revised krill fishery management framework. Management of the krill fishery is data-poor, with much of the scientific support reliant upon data that are now decades old. The decision rules for determining sustainable yields need careful re-evaluation, given they were negotiated at a time when baleen whales were rarely observed, and krill fishery catches were low in relation to the estimated available krill biomass. The Antarctic marine ecosystem is spatially and temporally dynamic, and is changing, yet CCAMLR still assumes a static system. An explicit commitment to collect up-to-date monitoring data about krill and baleen whales is vital to help inform the revised management framework. Precaution argues that catch levels should not increase until adequate data are available for effective management. Knowledge about the status of baleen whales will inevitably require close collaboration with the International Whaling Commission.

Summary: Water-soluble Fe4L44− cages can be synthesized in a multicomponent self-assembly process exploiting functionalized trigonal ligands, FeII salts, and water-soluble sulfonated formylpyridine components. The cages are soluble in purely aqueous solution and display an overall 4− charge, but are capable of binding suitably sized non-coordinating anions in the host cavity despite their anionic nature. Anions such as PF6− or AsF6− occupy the internal cavity, whereas anions that are too small (BF4−) or too large (NTf2−) are not encapsulated. The external anionic charge and sterically blocked ligand cores limit the exchange rate of bound anions, as no exchange is seen over a period of weeks with the anion-filled cages, and internalization of added PF6− by an empty cage takes multiple weeks, despite the strong affinity of the cavity for PF6− ions. In the future, this recognition mechanism could be used to control release of anions for environmental applications.

Global biodiversity declines require a step change in monitoring frameworks to properly track and diagnose population trends. National weather surveillance radar (WSR) networks offer high spatial (ca. 1-10 km) and temporal (5–10 min) resolution data collected over regional and decadal scales, with well-supported infrastructure that holds great promise for the study of biodiversity. However, WSR datasets pose new challenges for ecologists due to their format, volume, and three-dimensional spatial structure. Here, we define a novel approach to the processing of WSR data to produce a product that can be used to interrogate trends in aerial biodiversity (abundance or diversity) at and across individual ground-level sites. From the full volume of WSR data collected approximately every six minutes we extract vertical columns of WSR observations above sites to compare against standardised nocturnal macro-moth monitoring data at ground level. The results show that there is strong agreement between the WSR-derived proxy of biodiversity in the air column and ground-level measurements of abundance and diversity in nocturnal moth communities. The columnar product operates on a biologically relevant scale with a diameter of 5 km, although column dimensions can easily be customised, and can be deployed at any site within a WSR's observable range. These findings have the potential to unlock past and present WSR observations for widespread application to existing and novel ecological questions and can be applied to weather radar networks around the world.

IntroductionPrior studies suggest lymphopenia following radiation therapy may impact toxicity and cancer control. Chronic radiation-related lymphopenia (RRL) has been noted in prostate cancer patients treated with conventionally fractionated pelvic radiation therapy. The impact of utilizing hypofractionated high integral dose therapies such as stereotactic body radiation therapy (SBRT) on RRL is less well characterized. This prospective study sought to evaluate the impact of prostate SBRT plus or minus supplemental pelvic nodal radiation (PNI) on RRL.MethodsBetween 2012 and 2023, serial serum absolute lymphocyte counts (ALCs) were measured in 226 men treated at MedStar Georgetown with robotic SBRT using the CyberKnife® (CK) (36.25 Gy in 5 fractions) alone or CK (19.5 Gy in 3 fractions) followed by supplemental PNI using VMAT (37.5–45.0 Gy in 15–25 fractions) per an institutional protocol (IRB#: 2012-1175). Baseline ALC (k/μL) was measured 1–2 hours prior to robotic SBRT and at each follow-up appointment (1, 3, 6, 9, 12, 18, and 24 months post-treatment). Lymphopenia was graded using the CTCAEv.4: Grade 1 (0.8-1.0 k/μL), Grade 2 (0.5-0.8 k/μL), Grade 3 (0.2-0.5 k/μL) and Grade 4 (

Abstract Background Primary osteoarthritis (OA) occurs without identifiable underlying causes such as previous injuries or specific medical conditions. Age is a major contributing factor to OA, and as one ages, various joint tissues undergo gradual change, including degeneration of the articular cartilage, alterations in subchondral bone (SCB) morphology, and inflammation of the synovium. Methods We investigated the prevalence of primary OA in aged, genetically diverse UM-HET3 mice. Articular cartilage (AC) integrity and SCB morphology were assessed in 182 knee joints of 22-25 months old mice using the Osteoarthritis Research Society International (OARSI) scoring system and micro-CT, respectively. Additionally, we explored the effects of methylene blue (MB) and mitoquinone (MitoQ), two agents that affect mitochondrial function, on the prevalence and progression of OA during aging. Results Aged UM-HET3 mice showed a high prevalence of primary OA in both sexes. Significant positive correlations were found between cumulative AC (cAC) scores and synovitis in both sexes, and osteophyte formation in female mice. Ectopic chondrogenesis did not show significant correlations with cAC scores. Significant direct correlations were found between AC scores and inflammatory markers in chondrocytes, including matrix metalloproteinase-13, inducible nitric oxide synthase, and the NLR family pyrin domain containing-3 inflammasome in both sexes, indicating a link between OA severity and inflammation. Additionally, markers of cell cycle arrest, such as p16 and β-galactosidase, also correlated with AC scores. In male mice, no significant correlations were found between SCB morphology traits and cAC scores, while in female mice, significant correlations were found between cAC scores and tibial SCB plate bone mineral density. Notably, MB and MitoQ treatments influenced the disease's progression in a sex-specific manner. MB treatment significantly reduced cAC scores at the medial knee joint, while MitoQ treatment reduced cAC scores, but these did not reach significance. Conclusions Our study provides comprehensive insights into the prevalence and progression of primary OA in aged UM-HET3 mice, highlighting the sex-specific effects of MB and MitoQ treatments. The correlations between AC scores and various pathological factors underscore the multifaceted nature of OA and its association with inflammation and subchondral bone changes.

Abstract Creatine chemical exchange saturation transfer (CrCEST) MRI is an emerging high resolution and noninvasive method for measuring muscle specific oxidative phosphorylation (OXPHOS). However, CrCEST measurements are sensitive to changes in muscle pH, which might confound the measurement and interpretation of creatine recovery time (τCr). Even with the same prescribed exercise stimulus, the extent of acidification and hence its impact on τCr is expected to vary between individuals. To address this issue, a method to measure pH pre- and post-exercise and its impact on CrCEST MRI with high temporal resolution is needed. In this work, we integrate carnosine 1H- magnetic resonance spectroscopy (MRS) and 3D CrCEST to establish “mild” and “moderate/intense” exercise stimuli. We then test the dependence of CrCEST recovery time on pH using different exercise stimuli. This comprehensive metabolic imaging protocol will enable personalized, muscle specific OXPHOS measurements in both healthy aging and myriad other disease states impacting muscle mitochondria.

Abstract Climate change is a looming threat to marine life, creating an urgent need to develop climate-informed conservation strategies. The Climate Risk Index for Biodiversity was designed to assess the climate risk for marine species in a manner that supports decision-making. Yet, its regional application remains to be explored. Here, we use it to evaluate climate risk for ~2000 species in the northwest Atlantic Ocean, a marine warming hotspot, to explore its capacity to inform climate-considered fisheries management. Under high emissions, harvested species, especially those with the highest economic value, have a disproportionate risk of projected exposure to hazardous climate conditions but benefit the most from emission mitigation. By mapping critical risk areas for 90 fish stocks, we pinpoint locations likely to require additional intervention, such as in the southern Gulf of St. Lawrence for Atlantic cod. Finally, we demonstrate how evaluating climate risk geographically and understanding how it arises can support short- and long-term fisheries management and conservation objectives under climate change.

PURPOSECancer recurrence is an important long-term outcome of cancer survivors that is often not routinely collected and recorded by population-based registries. In this study, we review population-based studies to determine the current availability, landscape, and infrastructure of long-term outcomes, particularly metastatic recurrence, in women initially diagnosed with nonmetastatic breast cancer (MBC).METHODSWe reviewed the literature to identify studies that used population-based registry data to examine the distribution of metastatic recurrence in women diagnosed with non-MBC. Data on outcomes and methods of ascertainment were extracted. Registry infrastructure including sources and funding was also reviewed.RESULTSA total of 23 studies from 11 registries in eight countries spanning Europe, North America, and Oceania were identified and included in the review. Most studies were retrospective in nature and collected recurrence data only for ad hoc studies rather than as part of their routine registration. Definition of recurrence and data sources varied considerably across studies: the cancer-free time interval between the start of follow-up and risk window ranged from the diagnosis of primary tumor (n = 7) to 6 months from diagnosis (n = 1); the start of follow-up differed between initial diagnosis (n = 16) and treatment (n = 7).CONCLUSIONCancer surveillance should encompass outcomes among survivors for research and monitoring. Studies are underway, but more are needed. Cancer registries should be supported to routinely collect recurrence data to allow complete evaluation of MBC as an outcome to be conducted and inform health care providers and researchers of the prognosis of both nonmetastatic and metastatic patients with breast cancer.

Abstract Complex alumina parts were printed using vat photopolymerization (VPP), which is a stereolithography‐based additive manufacturing (AM) technique used to shape ceramic preforms, or green parts. The critical flaw size was determined using classical fracture mechanics techniques. The strength and fracture toughness were measured and compared to flaws detected in x‐ray computed tomography (XCT or CT) distributions as well as the fracture surfaces. The strength was lower compared traditionally made alumina, and that is due to layering effects, slurry defects, and printing defects. The critical flaw size from fracture mechanics was 206 µm. XCT has high enough resolution to detect the critical flaw size and much smaller features, where the average flaw size observed in CT scans was around 80–100 µm. The fracture surfaces indicate that flaws causing failure are larger than that of the critical flaw size (∼300 µm), but fracture surfaces do not show definitive features compared to traditionally made ceramics. Since XCT can observe flaws smaller than the critical flaw size, this method can be used as a screening technique.

Background: Little is known regarding the characteristics, treatment patterns, and outcomes in patients with adult congenital heart disease (ACHD) admitted to cardiac intensive care units (CICUs). Objectives: The authors sought to better define the contemporary epidemiology, treatment patterns, and outcomes of ACHD admissions in the CICU. Methods: The Critical Care Cardiology Trials Network is a multicenter network of CICUs in North America. Participating centers contributed prospective data from consecutive admissions during 2-month annual snapshots from 2017 to 2022. We analyzed characteristics and outcomes of admissions with ACHD compared with those without ACHD. Multivariable logistic regression was used to assess mortality in ACHD vs non-ACHD admissions. Results: Of 23,299 CICU admissions across 42 sites, there were 441 (1.9%) ACHD admissions. Shunt lesions were most common (46.1%), followed by right-sided lesions (29.5%) and complex lesions (28.7%). ACHD admissions were younger (median age 46 vs 67 years) than non-ACHD admissions. ACHD admissions were more commonly for heart failure (21.3% vs 15.7%, P

Craniomaxillofacial (CMF) reconstruction is a challenging clinical dilemma. It often necessitates skin replacement in the form of autologous graft or flap surgery, which differ from one another based on hypodermal/dermal content. Unfortunately, both approaches are plagued by scarring, poor cosmesis, inadequate restoration of native anatomy and hair, alopecia, donor site morbidity, and potential for failure. Therefore, new reconstructive approaches are warranted, and tissue engineered skin represents an exciting alternative. In this study, we demonstrated the reconstruction of CMF full-thickness skin defects using intraoperative bioprinting (IOB), which enabled the repair of defects via direct bioprinting of multiple layers of skin on immunodeficient rats in a surgical setting. Using a newly formulated patient-sourced allogenic bioink consisting of both human adipose-derived extracellular matrix (adECM) and stem cells (ADSCs), skin loss was reconstructed by precise deposition of the hypodermal and dermal components under three different sets of animal studies. adECM, even at a very low concentration such as 2 % or less, has shown to be bioprintable via droplet-based bioprinting and exhibited de novo adipogenic capabilities both in vitro and in vivo. Our findings demonstrate that the combinatorial delivery of adECM and ADSCs facilitated the reconstruction of three full-thickness skin defects, accomplishing near-complete wound closure within two weeks. More importantly, both hypodermal adipogenesis and downgrowth of hair follicle-like structures were achieved in this two-week time frame. Our approach illustrates the translational potential of using human-derived materials and IOB technologies for full-thickness skin loss.

Abstract Background Approximating the recent phylogeny of N phased haplotypes at a set of variants along the genome is a core problem in modern population genomics and central to performing genome-wide screens for association, selection, introgression, and other signals. The Li & Stephens (LS) model provides a simple yet powerful hidden Markov model for inferring the recent ancestry at a given variant, represented as an $$N \times N$$ N × N distance matrix based on posterior decodings. Results We provide a high-performance engine to make these posterior decodings readily accessible with minimal pre-processing via an easy to use package kalis, in the statistical programming language R. kalis enables investigators to rapidly resolve the ancestry at loci of interest and developers to build a range of variant-specific ancestral inference pipelines on top. kalis exploits both multi-core parallelism and modern CPU vector instruction sets to enable scaling to hundreds of thousands of genomes. Conclusions The resulting distance matrices accessible via kalis enable local ancestry, selection, and association studies in modern large scale genomic datasets.

Communities and their surrounding landscapes are intricately interconnected. This is evident in the Intermountain West of the United States of America, where large cities sit within vast landscapes otherwise containing small rural communities with farm, forest, and rangeland. Climate change and other stresses increase the tensions along the gradient of urban to rural communities and landscapes, and theoretical frameworks are needed to conceptualize regime shifts within these social-ecological systems. We propose a framework called Guided Transformation (GT) that translates new knowledge into action by incorporating diverse perspectives and values that prioritize community and environmental well-being. Guided Transformation combines elements from social, ecological, and technological systems (SETS) theory, resilience theory, and sustainability transitions research. In this manuscript, we outline the GT framework and its relationship to related theory and literature, and we then provide three case studies that demonstrate the application of the GT framework. The first case study is in the upper Rio Grande watershed in New Mexico, where innovative governance strategies are addressing the challenge of wildfire and watershed protection. The second is in eastern Washington and the Yakima Basin, where drought drove innovation in the form of an integrated water management plan that is now helping to meet the needs of both farmers and fish in the basin. In the final case study, we discuss work on the Navajo Nation addressing food, energy, and water security and Indigenous sovereignty through solar greenhouse technology.

The disorder and heterogeneity of low-molecular-weight amyloid-beta oligomers (AβOs) underlie their participation in multiple modes of cellular dysfunction associated with the etiology of Alzheimer’s disease (AD). The lack of specified conformational states in these species complicates efforts to select or design small molecules to targeting discrete pathogenic states. Furthermore, targeting AβOs alone may be therapeutically insufficient, as AD progresses as a multifactorial, self-amplifying cascade. To address these challenges, we have screened the activity of seven new candidates that serve as Paramagnetic Amyloid Ligand (PAL) candidates. PALs are bifunctional small molecules that both remodel the AβO structure and localize a potent antioxidant that mimics the activity of SOD within live cells. The candidates are built from either a stilbene or curcumin scaffold with nitroxyl moiety to serve as catalytic antioxidants. Measurements of PAL AβO binding and remolding along with assessments of bioactivity allow for the extraction of useful SAR information from screening data. One candidate (HO-4450; PMT-307), with a six-membered nitroxyl ring attached to a stilbene ring, displays the highest potency in protecting against cell-derived Aβ. A preliminary low-dose evaluation in AD model mice provides evidence of modest treatment effects by HO-4450. The results for the curcumin PALs demonstrate that the retention of the native curcumin phenolic groups is advantageous to the design of the hybrid PAL candidates. Finally, the PAL remodeling of AβO secondary structures shows a reasonable correlation between a candidate’s bioactivity and its ability to reduce the fraction of antiparallel β-strand.

This case report presents a novel, non-pharmacological treatment of Type 2 Diabetes in a 46-year-old male, demonstrating improvements in blood chemistry and psychometric markers after 8 treatments using a Mind-Body Intervention (MBI) called Neuro-Emotional Technique (NET). The patient presented with a diagnosis of Type 2 Diabetes (T2D), pain, psychosocial indicators of stress and anxiety, and a score of 4 on the ACE-Q (Adverse Childhood Experiences Questionnaire) that is consistent with a predisposition to chronic disease and autoimmune disorders. Glucose levels for this patient were above normal levels (typically between 10-15mmol/L where optimal range is between 4-10mmol/L) for at least two months prior to the 4-week NET intervention period, despite the standard use of conventional antidiabetic medications (insulin injections). The patient exhibited numerous indictors of chronic stress that were hypothesised to be underlying his medical diagnosis and a series of 8 NET treatments over a period of 4 weeks was recommended. Psychometric tests and glucose measurements were recorded at baseline (prior to treatment), 4 weeks (at the conclusion of treatment) and at 8 weeks (4 weeks following the conclusion of treatment). Results show that glucose levels were reduced, and self-reported measures of depression, anxiety, stress, distress and pain all decreased from high and extreme levels to within normal ranges after 4 weeks, with ongoing improvement at 8 weeks. McEwen described the concept of allostatic load and the disruptive effects that cumulative stress can have on both mental and physical health. It is hypothesized that NET reduces allostatic load thereby fortifying homeostasis and the salutogenic stress response mechanisms involved in recovery from chronic illness, possibly via the Psycho-Immune-Neuroendocrine (PINE) network. Further studies with larger sample sizes are required to establish whether these results could be extrapolated to a wider population, however the results of this case suggest that it may be beneficial to consider co-management of T2D with an MBI such as NET.

Abstract Given the importance of coastal upwelling systems to ocean productivity, fisheries, and biogeochemical cycles, their response to climate change is of great interest. However, there is no consensus on future productivity changes in these systems, which may be controlled by multiple drivers including wind‐driven and geostrophic transport, stratification, and source water properties. Here we use an ensemble of regional ocean projections and recently developed upwelling indices for the California Current System to disentangle these sometimes‐competing influences. Some changes are consistent among models (e.g., decreased mixed layer depth), while for others there is a lack of agreement even on the direction of future change (e.g., nitrate concentration in upwelled waters). Despite models' diverging projections of productivity changes, they agree that those changes are predominantly driven by subsurface nitrate concentrations, not by upwelling strength. Our results highlight the need for more attention to processes governing subsurface nutrient changes, not just upwelling strength.

Abstract There are few effective treatments for small cell lung cancer (SCLC) underscoring the need for innovative therapeutic approaches. This study focuses on exploiting telomerase, a critical SCLC dependency as a therapeutic target. A prominent characteristic of SCLC is their reliance on telomerase activity, a key enzyme essential for their continuous proliferation. Here we utilize a nucleoside analog, 6-Thio-2’-deoxyguanosine (6TdG) currently in phase II clinical trials, that is preferentially incorporated by telomerase into telomeres leading to telomere dysfunction. Using preclinical mouse and human derived models we find low intermittent doses of 6TdG inhibit tumor growth and reduce metastatic burden. Anti-tumor efficacy correlates with a reduction in a subpopulation of cancer initiating like cells (CICs) identified by their expression of L1CAM/CD133 and highest telomerase activity. 6TdG treatment also leads to activation of innate and adaptive anti-tumor responses. Mechanistically, 6TdG depletes CICs and induces type-I interferon signaling leading to tumor immune visibility by activating tumor cell STING signaling. We also observe increased sensitivity to irradiation after 6TdG treatment in both syngeneic and humanized SCLC xenograft models both of which are dependent on the presence of host immune cells. This study underscores the immune-enhancing and metastasis-reducing effects of 6TdG, employing a range of complementary in vitro and in vivo SCLC preclinical models providing a potential therapeutic approach to SCLC.

The use of an agonist-antagonist muscle pair for myoelectric control of a transtibial prosthesis requires normalizing the myoelectric signals and identifying their co-contraction signature. Extensive literature has explored the relationship between body posture and lower-limb muscle activation level using surface electromyography (EMG), but it is unknown how these relationships hold after amputation. Using a virtual tracking task, this study compares the effect of three different calibration postures (seated, standing, dynamic) on user tracking ability while in two tracking postures (seated, standing) for 18 able-bodied (AB) subjects and 9 subjects with transtibial (TT) amputation. As expected, AB subjects produced statistically significant differences in muscle activation for gastrocnemius (GAS) when seated vs. standing during calibration (p = 8.8e-4), but not for tibialis anterior (TA) (p = 0.76). TT subjects, however, showed no significant differences in GAS or TA between seated and standing (p = 0.90, 0.60 respectively). It was also determined that normalizing EMG by the global maximum signal observed (standard in biomechanic analysis) is undesirable for myoelectric control. For best general results with this framework, calibration in both seated and dynamic postures is recommended, taking the normalization information from the seated posture and the narrowest co-contraction slopes from the two.

Background: Autoantibodies are commonly used as biomarkers in autoimmune diseases, but there are limitations. For example, autoantibody biomarkers have poor sensitivity or specificity in systemic lupus erythematosus and do not exist in the spondyloarthropathies, impairing diagnosis and treatment. While autoantibodies suitable for strong biomarkers may not exist in these conditions, another possibility is that technology has limited their discovery. The purpose of this study was to use a novel high-density peptide array that enables the evaluation of IgG binding to every possible linear antigen in the entire human peptidome, as well as a novel machine learning approach that incorporates ELISA validation predictability in order to discover autoantibodies that could be developed into sensitive and specific markers of lupus or spondyloarthropathy. Methods: We used a peptide array containing the human peptidome, several viral peptidomes, and key post-translational modifications (6 million peptides) to quantify IgG binding in lupus, spondyloarthropathy, rheumatoid arthritis, Sjögren’s disease, and control sera. Using ELISA data for 70 peptides, we performed a random forest analysis that evaluated multiple array features to predict which peptides might be good biomarkers, as confirmed by ELISA. We validated the peptide prediction methodology in rheumatoid arthritis and COVID-19, conditions for which the antibody repertoire is well-understood, and then evaluated IgG binding by ELISA to peptides that we predicted would be highly bound specifically in lupus or spondyloarthropathy. Results: Our methodology performed well in validation studies, but peptides predicted to be highly and specifically bound in lupus or spondyloarthropathy could not be confirmed by ELISA. Conclusions: In a comprehensive evaluation of the entire human peptidome, highly sensitive and specific IgG autoantibodies were not identified in lupus or spondyloarthropathy. Thus, the pathogenesis of lupus and spondyloarthropathy may not depend upon unique autoantigens, and other types of molecules should be sought as optimal biomarkers in these conditions.

This study examined invasive cervical cancer (ICC) incidence trends in British Columbia (BC) by age and stage-at-diagnosis relative to World Health Organization ICC elimination targets (4 per 100,000 persons). Incident ICC cases (1971–2017) were obtained from the BC Cancer Registry. Annual age-standardized incidence rates (ASIRs) per 100,000 persons were generated using the direct method. ASIRs were examined among all ages 15+ years and eight age groups using Joinpoint Regression with the Canadian 2011 standard population. Standardized rate ratios (SRRs) compared stage II–IV (late) versus stage I (early) ASIRs by age (2010–2017). ICC ASIRs did not reach the elimination target. ASIRs declined from 18.88 to 7.08 per 100,000 persons (1971–2017). Stronger declines were observed among ages 45+ years, with the largest decline among ages 70–79 years (AAPC = −3.2%, 95% CI = −3.9% to −2.6%). Among ages 25–69 years, varying levels of attenuation in declining trends and stabilization were observed since the 1980s. SRRs indicated higher rates of late-stage ICC among ages 55+ years (SRR−55–69 years = 1.34, 95% CI = 1.08–1.71). Overall, ICC incidence declined in BC since 1971 but did not reach the elimination target. The pace of decline varied across age groups and increased with age. Continued efforts are needed to progress cervical cancer elimination among all age groups.

Background: The successful implementation of an equitable lung cancer screening program requires consideration of factors that influence accessibility to screening services. Methods: Using lung cancer cases in British Columbia (BC), Canada, as a proxy for a screen-eligible population, spatial access to 36 screening sites was examined using geospatial mapping and vehicle travel time from residential postal code at diagnosis to the nearest site. The impact of urbanization and Statistics Canada’s Canadian Index of Multiple Deprivation were examined. Results: Median travel time to the nearest screening site was 11.7 min (interquartile range 6.2–23.2 min). Urbanization was significantly associated with shorter drive time (p < 0.001). Ninety-nine percent of patients with ≥60 min drive times lived in rural areas. Drive times were associated with sex, ethnocultural composition, situational vulnerability, economic dependency, and residential instability. For example, the percentage of cases with drive times ≥60 min among the least deprived situational vulnerability group was 4.7% versus 44.4% in the most deprived group. Conclusions: Populations at risk in rural and remote regions may face more challenges accessing screening services due to increased travel times. Drive times increased with increasing sociodemographic and economic deprivations highlighting groups that may require support to ensure equitable access to lung cancer screening.

Abstract Objectives To assess the cost-effectiveness of cetuximab in combination with chemotherapy fluorouracil, oxaliplatin, and leucovorin (FOLFOX) or fluorouracil, irinotecan and leucovorin (FOLFIRI) compared to standard chemotherapy alone as a first-line treatment for metastatic colorectal cancer (mCRC) with positive KRAS wild type patients in Indonesia. Methods A cost-utility analysis applying Markov model was constructed, with a societal perspective. Clinical evidence was derived from published clinical trials. Direct medical costs were gathered from hospital billings. Meanwhile, direct non-medical costs, indirect costs, and utility data were collected by directly interviewing patients. We applied 3% discount rate for both costs and outcomes. Probabilistic sensitivity analysis was performed to explore the model’s uncertainty. Additionally, using payer perspective, budget impact analysis was estimated to project the financial impact of treatment coverage. Results There was no significant difference in life years gained (LYG) between cetuximab plus FOLFOX/FOLFIRI and chemotherapy alone. The incremental QALY was only one month, and the incremental cost-effectiveness ratio (ICER) was approximately IDR 3 billion/QALY for cetuximab plus chemotherapy. Using 1–3 GDP per capita (IDR 215 million or USD 14,350) as the current threshold, the cetuximab plus chemotherapy was not cost-effective. The budget impact analysis resulted that if cetuximab plus chemotherapy remain included in the benefits package under the Indonesian national health insurance (NHI) system, the payer would need more than IDR 1 trillion for five years. Conclusions The combination of cetuximab and chemotherapy for mCRC is unlikely cost-effective and has a substantial financial impact on the system.

Abstract A global decline in seagrass populations has led to renewed calls for their conservation as important providers of biogenic and foraging habitat, shoreline stabilization and carbon storage. Eelgrass (Zostera marina) occupies the largest geographic range among seagrass species spanning a commensurately broad spectrum of environmental conditions. In Canada, eelgrass is managed as a single phylogroup despite occurring across three oceans and a range of ocean temperatures and salinity gradients. Previous research has focused on applying relatively few markers to reveal population structure of eelgrass, whereas a whole‐genome approach is warranted to investigate cryptic structure among populations inhabiting different ocean basins and localized environmental conditions. We used a pooled whole‐genome re‐sequencing approach to characterize population structure, gene flow and environmental associations of 23 eelgrass populations ranging from the Northeast United States to Atlantic, subarctic and Pacific Canada. We identified over 500,000 SNPs, which when mapped to a chromosome‐level genome assembly revealed six broad clades of eelgrass across the study area, with pairwise FST ranging from 0 among neighbouring populations to 0.54 between Pacific and Atlantic coasts. Genetic diversity was highest in the Pacific and lowest in the subarctic, consistent with colonization of the Arctic and Atlantic oceans from the Pacific less than 300 kya. Using redundancy analyses and two climate change projection scenarios, we found that subarctic populations are predicted to be potentially more vulnerable to climate change through genomic offset predictions. Conservation planning in Canada should thus ensure that representative populations from each identified clade are included within a national network so that latent genetic diversity is protected, and gene flow is maintained. Northern populations, in particular, may require additional mitigation measures given their potential susceptibility to a rapidly changing climate.

Background:. Social media use has grown across healthcare delivery and practice, with dramatic changes occurring in response to the coronavirus (COVID-19) pandemic. The purpose of this study was to conduct a comprehensive systematic review to determine the current landscape of social media use by (1) orthopaedic surgery residencies/fellowship training programs and (2) individual orthopaedic surgeons and the change in use over time. Methods:. We searched 3 electronic databases (PubMed, MEDLINE, and Embase) from their inception to April 2022 for all studies that analyzed the use of social media in orthopaedic surgery. Two reviewers independently determined study eligibility, rated study quality, and extracted data. Methodology was in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. Results:. Twenty-eight studies were included, of which 11 analyzed social media use by orthopaedic surgery residency and fellowship training programs and 17 examined its use by individual orthopaedic surgeons. Among residency and fellowship programs, Instagram was identified as the most common platform used, with 42% to 88% of programs reporting program-specific Instagram accounts, followed by Twitter/X (20%-52%) and Facebook (10%-38%). Social media was most commonly used by programs for recruitment and information dissemination to prospective residency applicants (82% and 73% of included studies, respectively). After the start of the COVID-19 pandemic, there was a 620% and 177% increase in the number of training programs with Instagram and Twitter/X accounts, respectively. Individual use of social media ranged from 1.7% to 76% (Twitter/X), 10% to 73% (Facebook), 0% to 61% (Instagram), 22% to 61% (LinkedIn), and 6.5% to 56% (YouTube). Conclusions:. Instagram, Twitter/X, and Facebook are the premier platforms that patients, residency applicants, and institutions frequent. With the continued growth of social media use anticipated, it will be critical for institutions and individuals to create and abide by guidelines outlining respectful and professional integration of social media into practice. Level of Evidence:. Level IV.

Monitoring trends in large mammal populations is a fundamental component of wildlife management and conservation. However, direct estimates of population size and vital rates of large mammals can be logistically challenging and expensive. Indicators that reflect trends in abundance, therefore, can be valuable tools for supporting population monitoring. Polar bears have a relatively simple life history such that a few key variables may be effective indicators for tracking changes in body condition and recruitment that affect abundance. Direct estimates of polar bear abundance are difficult to obtain due to their large home ranges in remote Arctic habitats. Changes in abundance associated with environmental conditions appear to affect polar bears largely via effects on female body condition which influence reproduction and cub survival (i.e., recruitment). Loss of sea ice habitat is further limiting researcher access for population monitoring creating a need for alternative approaches. Here we used relationships established from eight years (2008–2017) of data collected on 439 polar bears in the Chukchi Sea, to transform previously published individual-based relationships with annually available sea ice, atmospheric circulation, and prey body condition variables to predict annual mean body condition and recruitment during 2018–2022. Although annual sample sizes were limited for verifying predicted body condition and recruitment via techniques such as cross-validation, in most cases predicted annual means were closely correlated with observed means for 2008–2017. Summer sea ice and prey body condition remained within or increased relative to levels observed during 2008–2017 and predicted polar bear body condition and recruitment during 2018–2022 were largely within or above observed annual means during 2008–2017. A lack of trend in environmental and ecological variables or polar bear body condition and recruitment metrics during 2008–2022 is suggestive that the Chukchi Sea polar bear population was likely stable during this time. Our results provide support for developing models that predict important population parameters of large mammals based on environmental and ecological indicators. Given that trend information is lacking for 10 of the 19 recognized polar bear populations and is outdated for others, the use of environmental and ecological indicators may be particularly useful for augmenting direct estimates of polar bear vital rates in between periods of data collection. Although demographic assessments for polar bears have primarily focused on correlations with sea ice availability, our study and others highlight that prey health is also an important indicator of polar bear population status.

The aim of this study was to determine which characteristics of recreational, collegiate, and professional endurance athletes were associated with training changes due to COVID-19 safety restrictions. A Qualtrics survey was distributed to endurance athletes around the world from June 2020 to February 2021. Significant differences between athlete characteristics and changes in training status were determined using a Chi-squared test (significance p < 0.05). Approximately 66% of the 331 endurance athletes changed their training due to restrictions. Significant group differences were found for age, sex, prior coaching status, prior use of a training program, and athlete primary sport compared to the whole sample. Understanding these factors may allow athletes/coaches to approach training in a different way to help minimize or prevent the effects of detraining for a greater portion of athletes should a COVID-19 variant or any other pandemic emerge in the future.

Abstract Background The pediatric patient-reported outcomes version of the common terminology criteria for adverse event measure was developed and validated for use in pediatric cancer clinical trials to better capture the symptom experiences through direct self-report. The study aim was to develop and validate a Swahili language version of the patient-reported outcomes version of the common terminology criteria for adverse event measure. Methods The pediatric version of 15 core symptom adverse events, and the corresponding questions, were selected from the patient-reported outcomes version of the common terminology criteria for adverse event library, then forward and back translated into Swahili by bilingual translators. The translated items were further refined using concurrent cognitive interviewing. Each round of interviews included five children, ages 8–17 years-old, receiving cancer therapy at Bugando Medical Centre, the cancer referral hospital for Northwest Tanzania, and continued until at least 80% of participants understood the question. Results Three rounds of cognitive interviews were completed involving 13 patients and 5 caregivers. Among patients, 50% of questions (19/38) were fully comprehended after the first interview round. Two Adverse Events (anxiety and peripheral neuropathy) were the most difficult for participants to understand, associated with education level and experience. Goal comprehension was achieved after three rounds of interviews with no further revisions required. All parents in the first cognitive interview group comprehended the survey, with no additional revisions. Conclusion A Swahili patient-reported outcomes version of the common terminology criteria for adverse event was effective in eliciting patient-reported Adverse Events related to cancer treatment, with good comprehension for children aged 8–17 years. This survey is important to incorporate patient self-reporting of symptomatic toxicities and is an effective tool to increase capacity for pediatric cancer clinical trials throughout East Africa, further reducing global disparities in cancer care.

Abstract Despite the numerous hydrological, geological, and ecological benefits produced by floodplain landscapes, floodplains continue to be degraded by human activities at a much higher rate than other landscape types. This large-scale landscape modification has been widely recognized, yet a comprehensive, national dataset quantifying the degree to which human activities are responsible for this degradation has not previously been evaluated. In this research, we analyze floodplain integrity for the contiguous United States by spatially quantifying the impact of anthropogenic stressors on almost 80,000 floodplain units. We demonstrate the prevalence of human modifications through widely available geospatial datasets, which we use to quantify indicators of floodplain integrity for five essential floodplain functions of flood attenuation, groundwater storage, habitat provision, sediment regulation, and organics and solute regulation. Our results show that floodplain degradation is spatially heterogeneous and that the integrity of nearly 70% of floodplains in the United States is poor. We highlight that quantifying the integrity of spatially explicit floodplain elements can allow for restoration efforts to be targeted to the areas in most desperate need of preservation.

Understanding groundwater-dependent ecosystems (i.e., areas with a relatively shallow water table that plays a major role in supporting vegetation health) is key to sustaining water resources in the western United States. Groundwater-dependent ecosystems (GDEs) in Colorado have non-pristine temporal and spatial patterns, compared to agro-ecosystems, which make it difficult to quantify how these ecosystems are impacted by changes in water availability. The goal of this study is to examine how key hydrosocial parameters perturb GDE water use in time and in space. The temporal approach tests for the additive impacts of precipitation, surface water discharge, surface water mass balance as a surrogate for surface–groundwater exchange, and groundwater depth on the monthly Landsat normalized difference vegetation index (NDVI). The spatial approach tests for the additive impacts of river confluences, canal augmentation, development, perennial tributary confluences, and farmland modification on temporally integrated NDVI. Model results show a temporal trend (monthly, 1984–2019) is identifiable along segments of the Arkansas River at resolutions finer than 10 km. The temporal impacts of river discharge correlate with riparian water use sooner in time compared to precipitation, but this result is spatially variable and dependent on the covariates tested. Spatially, areal segments of the Arkansas River that have confluences with perennial streams have increased cumulative vegetation density. Quantifying temporal and spatial dependencies between the sources and effects of GDEs could aid in preventing the loss of a vulnerable ecosystem to increased water demand, changing climate, and evolving irrigation methodologies.

Summary: Coronavirus disease 2019 (COVID-19) remains a significant public health threat due to the ability of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants to evade the immune system and cause breakthrough infections. Although pathogenic coronaviruses such as SARS-CoV-2 and Middle East respiratory syndrome (MERS)-CoV lead to severe respiratory infections, how these viruses affect the chromatin proteomic composition upon infection remains largely uncharacterized. Here, we use our recently developed integrative DNA And Protein Tagging methodology to identify changes in host chromatin accessibility states and chromatin proteomic composition upon infection with pathogenic coronaviruses. SARS-CoV-2 infection induces TP53 stabilization on chromatin, which contributes to its host cytopathic effect. We mapped this TP53 stabilization to the SARS-CoV-2 spike and its propensity to form syncytia, a consequence of cell-cell fusion. Differences in SARS-CoV-2 spike variant-induced syncytia formation modify chromatin accessibility, cellular senescence, and inflammatory cytokine release via TP53. Our findings suggest that differences in syncytia formation alter senescence-associated inflammation, which varies among SARS-CoV-2 variants.

Genomic data provides useful information for public health practice, particularly when combined with epidemiologic data. However, sampling bias is a concern because inferences from nonrandom data can be misleading. In March 2021, the Washington State Department of Health, USA, partnered with submitting and sequencing laboratories to establish sentinel surveillance for SARS-CoV-2 genomic data. We analyzed available genomic and epidemiologic data during presentinel and sentinel periods to assess representativeness and timeliness of availability. Genomic data during the presentinel period was largely unrepresentative of all COVID-19 cases. Data available during the sentinel period improved representativeness for age, death from COVID-19, outbreak association, long-term care facility–affiliated status, and geographic coverage; timeliness of data availability and captured viral diversity also improved. Hospitalized cases were underrepresented, indicating a need to increase inpatient sampling. Our analysis emphasizes the need to understand and quantify sampling bias in phylogenetic studies and continue evaluation and improvement of public health surveillance systems.

pdacR is an open-source R package and web-based platform that enables community exploration of pancreatic ductal adenocarcinoma (PDAC) gene expression datasets. pdacR is used to interrogate the specificities of popular PDAC molecular subtypes.

Background: We aimed to evaluate midterm patient-reported outcomes and reoperation rates following rotator cuff repair in patients with either rheumatoid arthritis (RA) or other inflammatory arthritis (nonRA-IA) diagnoses. Methods: We identified all patients with either RA or nonRA-IA who underwent a rotator cuff repair at our institution between 2008 and 2018. IA diagnoses included RA, systemic lupus erythematosus, psoriatic arthritis, and other unspecified inflammatory arthritis. We compiled a cohort of 51 shoulders, with an average follow-up time of 7.0 years. The average age was 60 years (range 39-81), and 55% of patients were female. Patients were contacted via phone to obtain patient-reported outcomes surveys. Univariate linear regression was used to evaluate associations between patient characteristics and outcomes. Results: A review of preoperative radiographs demonstrated that 50% of patients presented with some degree of glenohumeral joint inflammatory degeneration. At the final follow-up, the mean visual analog score for pain was 2 (range 0-8), and the mean American Shoulder and Elbow Surgeons score (ASES) was 77 (standard deviation [SD] = 19). The mean subjective shoulder value was 75% (SD = 22%), and the average satisfaction was 9 (SD 1.9). The mean Patient-Reported Outcomes Measurement Information System upper extremity score was 41 (SD = 10.6). Female sex and a complete tear (vs. partial) were both associated with lower ASES scores, whereas no other characteristics were associated with postoperative ASES scores. The 5-year Kaplan-Meier survival estimate free of reoperation was 91.8% (95% confidence interval 83.0-99.8). Conclusions: Rotator cuff repair in patients with RA or other inflammatory arthritis diagnoses resulted in satisfactory patient-reported outcomes that seem comparable to rotator cuff repair when performed in the general population. Furthermore, reoperations were rare, with a 5-year survival rate free of reoperation for any reason of over 90%. Altogether, an inflammatory arthritis diagnosis should not preclude by itself attempted rotator cuff repair surgery in these patients.

Non-volitional control, such as finite-state machine (FSM) impedance control, does not directly incorporate user intent signals, while volitional control, like direct myoelectric control (DMC), relies on these signals. This paper compares the performance, capabilities, and perception of FSM impedance control to DMC on a robotic prosthesis for subjects with and without transtibial amputation. It then explores, using the same metrics, the feasibility and performance of the combination of FSM impedance control and DMC across the full gait cycle, termed Hybrid Volitional Control (HVC). After calibration and acclimation with each controller, subjects walked for two minutes, explored the control capabilities, and completed a questionnaire. FSM impedance control produced larger average peak torque (1.15 Nm/kg) and power (2.05 W/kg) than DMC (0.88 Nm/kg and 0.94 W/kg). The discrete FSM, however, caused non-standard kinetic and kinematic trajectories, while DMC yielded trajectories qualitatively more similar to able-bodied biomechanics. While walking with HVC, all subjects successfully achieved ankle push-off and were able to modulate the magnitude of push-off via the volitional input. Unexpectedly, however, HVC behaved either more similarly to FSM impedance control or to DMC alone, rather than in combination. Both DMC and HVC, but not FSM impedance control, allowed subjects to achieve unique activities such as tip-toe standing, foot tapping, side-stepping, and backward walking. Able-bodied subject (N=6) preferences were split amongst the controllers, while all transtibial subjects (N=3) preferred DMC. Desired performance and ease of use showed the highest correlations with overall satisfaction (0.81 and 0.82, respectively).

Abstract Objective Continuous ambulatory peritoneal dialysis (CAPD) and hemodialysis (HD) are main modalities for end stage renal disease (ESRD) patients, and those have been covered by National Health Insurance (NHI) scheme since 2014 in Indonesia. This study aims to update the cost-effectiveness model of CAPD versus HD in Indonesia setting. Results Compared to HD, CAPD provides good value for money among ESRD patients in Indonesia. Using societal perspective, the total costs were IDR 1,348,612,118 (USD 95,504) and IDR 1,368,447,750 (USD 96,908), for CAPD and HD, respectively. The QALY was slightly different between two modalities, 4.79 for CAPD versus 4.22 for HD. The incremental cost-effectiveness ratio (ICER) yields savings of IDR 34,723,527/QALY (USD 2460).

Abstract Background Maize-infecting viruses are known to inflict significant agronomic yield loss throughout the world annually. Identification of known or novel causal agents of disease prior to outbreak is imperative to preserve food security via future crop protection efforts. Toward this goal, a large-scale metagenomic approach utilizing high throughput sequencing (HTS) was employed to identify novel viruses with the potential to contribute to yield loss of graminaceous species, particularly maize, in North America. Results Here we present four novel viruses discovered by HTS and individually validated by Sanger sequencing. Three of these viruses are RNA viruses belonging to either the Betaflexiviridae or Tombusviridae families. Additionally, a novel DNA virus belonging to the Geminiviridae family was discovered, the first Mastrevirus identified in North American maize. Conclusions Metagenomic studies of crop and crop-related species such as this may be useful for the identification and surveillance of known and novel viral pathogens of crops. Monitoring related species may prove useful in identifying viruses capable of infecting crops due to overlapping insect vectors and viral host-range to protect food security.

Follicular lymphoma can transform to a more aggressive histology. Here, the authors use bulk and single cell analysis to create a 26 marker panel which could be used to profile FL samples and predict the risk of transformation using flow cytometry.

Abstract Background Historically, the focus of cost-effectiveness analyses has been on the costs to operate and deliver interventions after their initial design and launch. The costs related to design and implementation of interventions have often been omitted. Ignoring these costs leads to an underestimation of the true price of interventions and biases economic analyses toward favoring new interventions. This is especially true in low- and middle-income countries (LMICs), where implementation may require substantial up-front investment. This scoping review was conducted to explore the topics, depth, and availability of scientific literature on integrating implementation science into economic evaluations of health interventions in LMICs. Methods We searched Web of Science and PubMed for papers published between January 1, 2010, and December 31, 2021, that included components of both implementation science and economic evaluation. Studies from LMICs were prioritized for review, but papers from high-income countries were included if their methodology/findings were relevant to LMIC settings. Results Six thousand nine hundred eighty-six studies were screened, of which 55 were included in full-text review and 23 selected for inclusion and data extraction. Most papers were theoretical, though some focused on a single disease or disease subset, including: mental health (n = 5), HIV (n = 3), tuberculosis (n = 3), and diabetes (n = 2). Manuscripts included a mix of methodology papers, empirical studies, and other (e.g., narrative) reviews. Authorship of the included literature was skewed toward high-income settings, with 22 of the 23 papers featuring first and senior authors from high-income countries. Of nine empirical studies included, no consistent implementation cost outcomes were measured, and only four could be mapped to an existing costing or implementation framework. There was also substantial heterogeneity across studies in how implementation costs were defined, and the methods used to collect them. Conclusion A sparse but growing literature explores the intersection of implementation science and economic evaluation. Key needs include more research in LMICs, greater consensus on the definition of implementation costs, standardized methods to collect such costs, and identifying outcomes of greatest relevance. Addressing these gaps will result in stronger links between implementation science and economic evaluation and will create more robust and accurate estimates of intervention costs. Trial registration The protocol for this manuscript was published on the Open Science Framework. It is available at: https://osf.io/ms5fa/ (DOI: 10.17605/OSF.IO/32EPJ).

The occurrences of summer hypoxia in coastal California Current can significantly affect the benthic and pelagic habitat and lead to complex ecosystem changes. Model-simulated hypoxia in this region is strongly spatially heterogeneous, and its future changes show uncertainties depending on the model used. Here, we used an ensemble of the new generation Earth system models to examine the present-day and future changes of summer hypoxia in this region. We applied model-specific thresholds combined with empirical bias adjustments of the dissolved oxygen variance to identify hypoxia. We found that, although simulated dissolved oxygen in the subsurface varies across the models both in mean state and variability, after necessary bias adjustments, the ensemble shows reasonable hypoxia frequency compared with a hindcast in terms of spatial distribution and average frequency in the coastal region. The models project increases in hypoxia frequency under warming, which is in agreement with deoxygenation projected consistently across the models for the coastal California Current. This work demonstrated a practical approach of using the multi-model ensemble for regional studies while presenting methodology limitations and gaps in observations and models to improve these limitations.

Abstract Contemporary analyses of insect population trends are based, for the most part, on a large body of heterogeneous and short‐term datasets of diurnal species that are representative of limited spatial domains. This makes monitoring changes in insect biomass and biodiversity difficult. What is needed is a method for monitoring that provides a consistent, high‐resolution picture of insect populations through time over large areas during day and night. Here, we explore the use of X‐band weather surveillance radar (WSR) for the study of local insect populations using a high‐quality, multi‐week time series of nocturnal moth light trapping data. Specifically, we test the hypotheses that (i) unsupervised data‐driven classification algorithms can differentiate meteorological and biological phenomena, (ii) the diversity of the classes of bioscatterers are quantitatively related to the diversity of insects as measured on the ground and (iii) insect abundance measured at ground level can be predicted quantitatively based on dual‐polarization Doppler WSR variables. Adapting the quasi‐vertical profile analysis method and data clustering techniques developed for the analysis of hydrometeors, we demonstrate that our bioscatterer classification algorithm successfully differentiates bioscatterers from hydrometeors over a large spatial scale and at high temporal resolutions. Furthermore, our results also show a clear relationship between biological and meteorological scatterers and a link between the abundance and diversity of radar‐based bioscatterer clusters and that of nocturnal aerial insects. Thus, we demonstrate the potential utility of this approach for landscape scale monitoring of biodiversity.

Using high-resolution stable isotope and microstructure analyses of otoliths, this study reveals that sardine populations in the western and eastern North Pacific have different early life metabolic and growth rates that respond contrastingly to temperature variations. These findings could explain observations of different responses in these populations to decadal-scale temperature anomalies.

Patients treated with Aurora kinase inhibitors experience dose-limiting neutropenia while other cytopenias are rare. Here, Chou et al. show that this cell-type specific side effect is partly explained by loss of drug efflux pump expression during neutrophil differentiation.

Identification of host antiviral restriction factors could provide targets for antiviral therapy. Here, using a genome-wide CRISPR screen, the authors identify the glycosyltransferase B3GAT1 as a host protein which, when ectopically overexpressed, restricts influenza virus infection in vitro and in mice, as well as other viruses relying on sialic acid for entry.