Groundwater is a hidden global keystone ecosystem.

Groundwater is a vital ecosystem of the global water cycle, hosting unique biodiversity and providing essential services to societies. Despite being the largest unfrozen freshwater resource, in a period of depletion by extraction and pollution, groundwater environments have been repeatedly overlooked in global biodiversity conservation agendas. Disregarding the importance of groundwater as an ecosystem ignores its critical role in preserving surface biomes. To foster timely global conservation of groundwater, we propose elevating the concept of keystone species into the realm of ecosystems, claiming groundwater as a keystone ecosystem that influences the integrity of many dependent ecosystems. Our global analysis shows that over half of land surface areas (52.6%) has a medium-to-high interaction with groundwater, reaching up to 74.9% when deserts and high mountains are excluded. We postulate that the intrinsic transboundary features of groundwater are critical for shifting perspectives towards more holistic approaches in aquatic ecology and beyond. Furthermore, we propose eight key themes to develop a science-policy integrated groundwater conservation agenda. Given ecosystems above and below the ground intersect at many levels, considering groundwater as an essential component of planetary health is pivotal to reduce biodiversity loss and buffer against climate change.

Care Fragmentation, Social Determinants of Health, and Postoperative Mortality in Older Veterans.

INTRODUCTION: Veterans Affairs Surgical Quality Improvement Program (VASQIP) benchmarking algorithms helped the Veterans Health Administration (VHA) reduce postoperative mortality. Despite calls to consider social risk factors, these algorithms do not adjust for social determinants of health (SDoH) or account for services fragmented between the VHA and the private sector. This investigation examines how the addition of SDoH change model performance and quantifies associations between SDoH and 30-d postoperative mortality. METHODS: VASQIP (2013-2019) cohort study in patients ≥65 y old with 2-30-d inpatient stays. VASQIP was linked to other VHA and Medicare/Medicaid data. 30-d postoperative mortality was examined using multivariable logistic regression models, adjusting first for clinical variables, then adding SDoH. RESULTS: In adjusted analyses of 93,644 inpatient cases (97.7% male, 79.7% non-Hispanic White), higher proportions of non-veterans affairs care (adjusted odds ratio [aOR] = 1.02, 95% CI = 1.01-1.04) and living in highly deprived areas (aOR = 1.15, 95% CI = 1.02-1.29) were associated with increased postoperative mortality. Black race (aOR = 0.77, CI = 0.68-0.88) and rurality (aOR = 0.87, CI = 0.79-0.96) were associated with lower postoperative mortality. Adding SDoH to models with only clinical variables did not improve discrimination (c = 0.836 versus c = 0.835). CONCLUSIONS: Postoperative mortality is worse among Veterans receiving more health care outside the VA and living in highly deprived neighborhoods. However, adjusting for SDoH is unlikely to improve existing mortality-benchmarking models. Reduction efforts for postoperative mortality could focus on alleviating care fragmentation and designing care pathways that consider area deprivation. The adjusted survival advantage for rural and Black Veterans may be of interest to private sector hospitals as they attempt to alleviate enduring health-care disparities.

Epigenetic modulation of myeloid cell functions in HIV and SARS-CoV-2 infection.

Myeloid cells play a vital role in innate immune responses as they recognize and phagocytose pathogens like viruses, present antigens, produce cytokines, recruit other immune cells to combat infections, and contribute to the attenuation of immune responses to restore homeostasis. Signal integration by pathogen recognition receptors enables myeloid cells to adapt their functions by a network of transcription factors and chromatin remodelers. This review provides a brief overview of the subtypes of myeloid cells and the main epigenetic regulation mechanisms. Special focus is placed on the epigenomic alterations in viral nucleic acids of HIV and SARS-CoV-2 along with the epigenetic changes in the host's myeloid cell compartment. These changes are important as they lead to immune suppression and promote the progression of the disease. Finally, we highlight some promising examples of 'epidrugs' that modulate the epigenome of immune cells and could be used as therapeutics for viral infections.

Differential impact of high-salt levels in vitro and in vivo on macrophage core functions.

The consumption of processed food is on the rise leading to huge intake of excess dietary salt, which strongly correlates with development of hypertension, often leading to cardiovascular diseases such as stroke and heart attack, as well as activation of the immune system. The effect of salt on macrophages is especially interesting as they are able to sense high sodium levels in tissues leading to transcriptional changes. In the skin, macrophages were shown to influence lymphatic vessel growth which, in turn, enables the transport of excess salt and thereby prevents the development of high blood pressure. Furthermore, salt storage in the skin has been linked to the onset of pro-inflammatory effector functions of macrophages in pathogen defence. However, there is only little known about the mechanisms which are involved in changing macrophage function to salt exposure. Here, we characterize the response of macrophages to excess salt both in vitro and in vivo. Our results validate and strengthen the notion that macrophages exhibit chemotactic migration in response to salt gradients in vitro. Furthermore, we demonstrate a reduction in phagocytosis and efferocytosis following acute salt challenge in vitro. While acute exposure to a high-salt diet in vivo has a less pronounced impact on macrophage core functions such as phagocytosis, our data indicate that prolonged salt challenge may exert a distinct effect on the function of macrophages. These findings suggest a potential role for excessive salt sensing by macrophages in the manifestation of diseases related to high-salt diets and explicitly highlight the need for in vivo work to decipher the physiologically relevant impact of excess salt on tissue and cell function.

A landscape assessment of CTSA evaluators and their work in the CTSA consortium, 2021 survey findings.

This article presents a landscape assessment of the findings from the 2021 Clinical and Translational Science Award (CTSA) Evaluators Survey. This survey was the most recent iteration of a well established, national, peer-led systematic snapshot of the CTSA evaluators, their skillsets, listed evaluation resources, preferred methods, and identified best practices. Three questions guided our study: who are the CTSA evaluators, what competencies do they share and how is their work used within hubs. We describe our survey process (logistics of development, deployment, and differences in historical context with prior instruments); and present its main findings. We provide specific recommendations for evaluation practice in two main categories (National vs Group-level) including, among others, the need for a national, strategic plan for evaluation as well as enhanced mentoring and training of the next generation of evaluators. Although based on the challenges and opportunities currently within the CTSA Consortium, takeaways from this study constitute important lessons with potential for application in other large evaluation consortia. To our knowledge, this is the first time 2021 survey findings are disseminated widely, to increase transparency of the CTSA evaluators' work and to motivate conversations within hub and beyond, as to how best to leverage existent evaluative capacity.

Evaluating novel biodegradable polymer matrix fertilizers for nitrogen-efficient agriculture.

Enhanced efficiency fertilizers (EEFs) can reduce nitrogen (N) losses in temperate agriculture but are less effective in the tropics. We aimed to design a new EEF and evaluate their performance in simple-to-complex tests with tropical soils and crops. We melt-extruded urea at different loadings into biodegradable polymer matrix composites using biodegradable polyhydroxyalkanoate (PHA) or polybutylene adipate-co-terephthalate (PBAT) polymers with urea distributed throughout the pellet. These contrast with commercially coated EEF that have a polymer-coated urea core. We hypothesized that matrix fertilizers would have an intermediate N release rate compared to fast release from urea or slow release from coated EEF. Nitrogen release rates in water and sand-soil columns confirmed that the matrix fertilizer formulations had a more progressive N release than a coated EEF. A more complex picture emerged from testing sorghum [Sorghum bicolor (L.) Moench] grown to maturity in large soil pots, as the different formulations resulted in minor differences in plant N accumulation and grain production. This confirms the need to consider soil interactions, microbial processes, crop physiology, and phenology for evaluating fertilizer performance. Promisingly, crop δ15N signatures emerged as an integrated measure of efficacy, tracking likely N conversions and losses. The three complementary evaluations combine the advantages of standardized high-throughput screening and more resource-intensive and realistic testing in a plant-soil system. We conclude that melt-blended biodegradable polymer matrix fertilizers show promise as EEF because they can be designed toward more abiotically or more microbially driven N release by selecting biopolymer type and N loading rate.

Presentation Acuity and Surgical Outcomes for Patients With Health Insurance Living in Highly Deprived Neighborhoods.

Importance: Insurance coverage expansion has been proposed as a solution to improving health disparities, but insurance expansion alone may be insufficient to alleviate care access barriers. Objective: To assess the association of Area Deprivation Index (ADI) with postsurgical textbook outcomes (TO) and presentation acuity for individuals with private insurance or Medicare. Design, Setting, and Participants: This cohort study used data from the National Surgical Quality Improvement Program (2013-2019) merged with electronic health record data from 3 academic health care systems. Data were analyzed from June 2022 to August 2023. Exposure: Living in a neighborhood with an ADI greater than 85. Main Outcomes and Measures: TO, defined as absence of unplanned reoperations, Clavien-Dindo grade 4 complications, mortality, emergency department visits/observation stays, and readmissions, and presentation acuity, defined as having preoperative acute serious conditions (PASC) and urgent or emergent cases. Results: Among a cohort of 29 924 patients, the mean (SD) age was 60.6 (15.6) years; 16 424 (54.9%) were female, and 13 500 (45.1) were male. A total of 14 306 patients had private insurance and 15 618 had Medicare. Patients in highly deprived neighborhoods (5536 patients [18.5%]), with an ADI greater than 85, had lower/worse odds of TO in both the private insurance group (adjusted odds ratio [aOR], 0.87; 95% CI, 0.76-0.99; P = .04) and Medicare group (aOR, 0.90; 95% CI, 0.82-1.00; P = .04) and higher odds of PASC and urgent or emergent cases. The association of ADIs greater than 85 with TO lost significance after adjusting for PASC and urgent/emergent cases. Differences in the probability of TO between the lowest-risk (ADI ≤85, no PASC, and elective surgery) and highest-risk (ADI >85, PASC, and urgent/emergent surgery) scenarios stratified by frailty were highest for very frail patients (Risk Analysis Index ≥40) with differences of 40.2% and 43.1% for those with private insurance and Medicare, respectively. Conclusions and Relevance: This study found that patients living in highly deprived neighborhoods had lower/worse odds of TO and higher presentation acuity despite having private insurance or Medicare. These findings suggest that insurance coverage expansion alone is insufficient to overcome health care disparities, possibly due to persistent barriers to preventive care and other complex causes of health inequities.

Social Determinants of Health and Surgical Desirability of Outcome Ranking in Older Veterans.

Importance: Evaluating how social determinants of health (SDOH) influence veteran outcomes is crucial, particularly for quality improvement. Objective: To measure associations between SDOH, care fragmentation, and surgical outcomes using a Desirability of Outcome Ranking (DOOR). Design, Setting, And Participants: This was a cohort study of US veterans using data from the Veterans Affairs (VA) Surgical Quality Improvement Program (VASQIP; 2013-2019) limited to patients aged 65 years or older with inpatient stays between 2 and 30 days, merged with multiple data sources, including Medicare. Race and ethnicity data were retrieved from VASQIP, Medicare and Medicaid beneficiary summary files, the Veterans Health Administration Corporate Data Warehouse, and the United States Veterans Eligibility Trends and Statistics file. Data were analyzed between September 2023 and February 2024. Exposure: Living in a highly deprived neighborhood (Area Deprivation Index >85), race and ethnicity used as a social construct, rurality, and care fragmentation (percentage of non-VA care days). Main Outcomes and Measures: DOOR is a composite, patient-centered ranking of 26 outcomes ranging from no complication (1, best) to 90-day mortality or near-death complications (6, worst). A series of proportional odds regressions was used to assess the impact of SDOH and care fragmentation adjusted for clinical risk factors, including presentation acuity (presenting with preoperative acute serious conditions and urgent or emergent surgical procedures). Results: The cohort had 93 644 patients (mean [SD] age, 72.3 [6.2] years; 91 443 [97.6%] male; 74 624 [79.7%] White). Veterans who identified as Black (adjusted odds ratio [aOR], 1.06; 95% CI, 1.02-1.10; P = .048) vs White and veterans with higher care fragmentation (per 20% increase in VA care days relative to all care days: aOR, 1.01; 95% CI, 1.01-1.02; P < .001) were associated with worse (higher) DOOR scores until adjusting for presentation acuity. Living in rural geographic areas was associated with better DOOR scores than living in urban areas (aOR, 0.93; 95% CI, 0.91-0.96; P < .001), and rurality was associated with lower presentation acuity (preoperative acute serious conditions: aOR, 0.88; 95% CI, 0.81-0.95; P = .001). Presentation acuity was higher in veterans identifying as Black, living in deprived neighborhoods, and with increased care fragmentation. Conclusions and Relevance: Veterans identifying as Black and veterans with greater proportions of non-VA care had worse surgical outcomes. VA programs should direct resources to reduce presentation acuity among Black veterans, incentivize veterans to receive care within the VA where possible, and better coordinate veterans' treatment and records between care sources.

Social Determinants of Long-Term Opioid Use Following Total Knee Arthroplasty.

Total knee arthroplasty (TKA) risks persistent pain and long-term opioid use (LTO). The role of social determinants of health (SDoH) in LTO is not well established. We hypothesized that SDoH would be associated with postsurgical LTO after controlling for relevant demographic and clinical variables. This study utilized data from the Veterans Affairs Surgical Quality Improvement Program, VA Corporate Data Warehouse, and Centers for Medicare and Medicaid Services, including Veterans aged ≥ 65 who underwent elective TKA between 2013 and 2019 with no postsurgical complications or history of significant opioid use. LTO was defined as > 90 days of opioid use beginning within 90 days postsurgery. SDoH variables included the Area Deprivation Index, rurality, and housing instability in the last 12 months identified via medical record screener or International Classification of Diseases, Tenth Revision codes. Multivariable risk adjustment models controlled for demographic and clinical characteristics. Of the 9,064 Veterans, 97% were male, 84.2% white, mean age was 70.6 years, 46.3% rural, 11.2% living in highly deprived areas, and 0.9% with a history of homelessness/housing instability. Only 3.7% (n = 336) developed LTO following TKA. In a logistic regression model of only SDoH variables, housing instability (odds ratio [OR] = 2.38, 95% confidence interval [CI]: 1.09-5.22) and rurality conferred significant risk for LTO. After adjusting for demographic and clinical variables, LTO was only associated with increasing days of opioid supply in the year prior to surgery (OR = 1.52, 95% CI: 1.43-1.63 per 30 days) and the initial opioid fill (OR = 1.07; 95% CI: 1.06-1.08 per day). Our primary hypothesis was not supported; however, our findings do suggest that patients with housing instability may present unique challenges for postoperative pain management and be at higher risk for LTO.

Erratum: Toward standardization, harmonization, and integration of social determinants of health data: A Texas Clinical and Translational Science Award institutions collaboration - CORRIGENDUM.

[This corrects the article DOI: 10.1017/cts.2024.2.].

Toward standardization, harmonization, and integration of social determinants of health data: A Texas Clinical and Translational Science Award institutions collaboration.

Introduction: The focus on social determinants of health (SDOH) and their impact on health outcomes is evident in U.S. federal actions by Centers for Medicare & Medicaid Services and Office of National Coordinator for Health Information Technology. The disproportionate impact of COVID-19 on minorities and communities of color heightened awareness of health inequities and the need for more robust SDOH data collection. Four Clinical and Translational Science Award (CTSA) hubs comprising the Texas Regional CTSA Consortium (TRCC) undertook an inventory to understand what contextual-level SDOH datasets are offered centrally and which individual-level SDOH are collected in structured fields in each electronic health record (EHR) system potentially for all patients. Methods: Hub teams identified American Community Survey (ACS) datasets available via their enterprise data warehouses for research. Each hub's EHR analyst team identified structured fields available in their EHR for SDOH using a collection instrument based on a 2021 PCORnet survey and conducted an SDOH field completion rate analysis. Results: One hub offered ACS datasets centrally. All hubs collected eleven SDOH elements in structured EHR fields. Two collected Homeless and Veteran statuses. Completeness at four hubs was 80%-98%: Ethnicity, Race; < 10%: Education, Financial Strain, Food Insecurity, Housing Security/Stability, Interpersonal Violence, Social Isolation, Stress, Transportation. Conclusion: Completeness levels for SDOH data in EHR at TRCC hubs varied and were low for most measures. Multiple system-level discussions may be necessary to increase standardized SDOH EHR-based data collection and harmonization to drive effective value-based care, health disparities research, translational interventions, and evidence-based policy.

Microglia rescue neurons from aggregate-induced neuronal dysfunction and death through tunneling nanotubes.

Microglia are crucial for maintaining brain health and neuron function. Here, we report that microglia establish connections with neurons using tunneling nanotubes (TNTs) in both physiological and pathological conditions. These TNTs facilitate the rapid exchange of organelles, vesicles, and proteins. In neurodegenerative diseases like Parkinson's and Alzheimer's disease, toxic aggregates of alpha-synuclein (α-syn) and tau accumulate within neurons. Our research demonstrates that microglia use TNTs to extract neurons from these aggregates, restoring neuronal health. Additionally, microglia share their healthy mitochondria with burdened neurons, reducing oxidative stress and normalizing gene expression. Disrupting mitochondrial function with antimycin A before TNT formation eliminates this neuroprotection. Moreover, co-culturing neurons with microglia and promoting TNT formation rescues suppressed neuronal activity caused by α-syn or tau aggregates. Notably, TNT-mediated aggregate transfer is compromised in microglia carrying Lrrk22(Gly2019Ser) or Trem2(T66M) and (R47H) mutations, suggesting a role in the pathology of these gene variants in neurodegenerative diseases.

Early postnatal high-dose fat-soluble enteral vitamin A supplementation for moderate or severe bronchopulmonary dysplasia or death in extremely low birthweight infants (NeoVitaA): a multicentre, randomised, parallel-group, double-blind, placebo-controlled, investigator-initiated phase 3 trial.

BACKGROUND: Vitamin A plays a key role in lung development, but there is no consensus regarding the optimal vitamin A dose and administration route in extremely low birthweight (ELBW) infants. We aimed to assess whether early postnatal additional high-dose fat-soluble enteral vitamin A supplementation versus placebo would lower the rate of moderate or severe bronchopulmonary dysplasia or death in ELBW infants receiving recommended basic enteral vitamin A supplementation. METHODS: This prospective, multicentre, randomised, parallel-group, double-blind, placebo-controlled, investigator-initiated phase 3 trial conducted at 29 neonatal intensive care units in Austria and Germany assessed early high-dose enteral vitamin A supplementation (5000 international units [IU]/kg per day) or placebo (peanut oil) for 28 days in ELBW infants. Eligible infants had a birthweight of more than 400 g and less than 1000 g; gestational age at birth of 32+0 weeks postmenstrual age or younger; and the need for mechanical ventilation, non-invasive respiratory support, or supplemental oxygen within the first 72 h of postnatal age after admission to the neonatal intensive care unit. Participants were randomly assigned by block randomisation with variable block sizes (two and four). All participants received basic vitamin A supplementation (1000 IU/kg per day). The composite primary endpoint was moderate or severe bronchopulmonary dysplasia or death at 36 weeks postmenstrual age, analysed in the intention-to-treat population. This trial was registered with EudraCT, 2013-001998-24. FINDINGS: Between March 2, 2015, and Feb 27, 2022, 3066 infants were screened for eligibility at the participating centres. 915 infants were included and randomly assigned to the high-dose vitamin A group (n=449) or the control group (n=466). Mean gestational age was 26·5 weeks (SD 2·0) and mean birthweight was 765 g (162). Moderate or severe bronchopulmonary dysplasia or death occurred in 171 (38%) of 449 infants in the high-dose vitamin A group versus 178 (38%) of 466 infants in the control group (adjusted odds ratio 0·99, 95% CI 0·73-1·55). The number of participants with at least one adverse event was similar between groups (256 [57%] of 449 in the high-dose vitamin A group and 281 [60%] of 466 in the control group). Serum retinol concentrations at baseline, at the end of intervention, and at 36 weeks postmenstrual age were similar in the two groups. INTERPRETATION: Early postnatal high-dose fat-soluble enteral vitamin A supplementation in ELBW infants was safe, but did not change the rate of moderate or severe bronchopulmonary dysplasia or death and did not substantially increase serum retinol concentrations. FUNDING: Deutsche Forschungsgemeinschaft and European Clinical Research Infrastructures Network (ECRIN).

UNC93B1 variants underlie TLR7-dependent autoimmunity.

UNC93B1 is critical for trafficking and function of nucleic acid-sensing Toll-like receptors (TLRs) TLR3, TLR7, TLR8, and TLR9, which are essential for antiviral immunity. Overactive TLR7 signaling induced by recognition of self-nucleic acids has been implicated in systemic lupus erythematosus (SLE). Here, we report UNC93B1 variants (E92G and R336L) in four patients with early-onset SLE. Patient cells or mouse macrophages carrying the UNC93B1 variants produced high amounts of TNF-α and IL-6 and upon stimulation with TLR7/TLR8 agonist, but not with TLR3 or TLR9 agonists. E92G causes UNC93B1 protein instability and reduced interaction with TLR7, leading to selective TLR7 hyperactivation with constitutive type I IFN signaling. Thus, UNC93B1 regulates TLR subtype-specific mechanisms of ligand recognition. Our findings establish a pivotal role for UNC93B1 in TLR7-dependent autoimmunity and highlight the therapeutic potential of targeting TLR7 in SLE.