Groundwater-dependent ecosystem map exposes global dryland protection needs.

Groundwater is the most ubiquitous source of liquid freshwater globally, yet its role in supporting diverse ecosystems is rarely acknowledged1,2. However, the location and extent of groundwater-dependent ecosystems (GDEs) are unknown in many geographies, and protection measures are lacking1,3. Here, we map GDEs at high-resolution (roughly 30 m) and find them present on more than one-third of global drylands analysed, including important global biodiversity hotspots4. GDEs are more extensive and contiguous in landscapes dominated by pastoralism with lower rates of groundwater depletion, suggesting that many GDEs are likely to have already been lost due to water and land use practices. Nevertheless, 53% of GDEs exist within regions showing declining groundwater trends, which highlights the urgent need to protect GDEs from the threat of groundwater depletion. However, we found that only 21% of GDEs exist on protected lands or in jurisdictions with sustainable groundwater management policies, invoking a call to action to protect these vital ecosystems. Furthermore, we examine the linkage of GDEs with cultural and socio-economic factors in the Greater Sahel region, where GDEs play an essential role in supporting biodiversity and rural livelihoods, to explore other means for protection of GDEs in politically unstable regions. Our GDE map provides critical information for prioritizing and developing policies and protection mechanisms across various local, regional or international scales to safeguard these important ecosystems and the societies dependent on them.

Feasibility of remote monitoring for fatal coronary heart disease using Apple Watch ECGs.

Background: Fatal coronary heart disease (FCHD) is often described as sudden cardiac death (affects >4 million people/year), where coronary artery disease is the only identified condition. Electrocardiographic artificial intelligence (ECG-AI) models for FCHD risk prediction using ECG data from wearable devices could enable wider screening/monitoring efforts. Objectives: To develop a single-lead ECG-based deep learning model for FCHD risk prediction and assess concordance between clinical and Apple Watch ECGs. Methods: An FCHD single-lead ("lead I" from 12-lead ECGs) ECG-AI model was developed using 167,662 ECGs (50,132 patients) from the University of Tennessee Health Sciences Center. Eighty percent of the data (5-fold cross-validation) was used for training and 20% as a holdout. Cox proportional hazards (CPH) models incorporating ECG-AI predictions with age, sex, and race were also developed. The models were tested on paired clinical single-lead and Apple Watch ECGs from 243 St. Jude Lifetime Cohort Study participants. The correlation and concordance of the predictions were assessed using Pearson correlation (R), Spearman correlation (ρ), and Cohen's kappa. Results: The ECG-AI and CPH models resulted in AUC = 0.76 and 0.79, respectively, on the 20% holdout and AUC = 0.85 and 0.87 on the Atrium Health Wake Forest Baptist external validation data. There was moderate-strong positive correlation between predictions (R = 0.74, ρ = 0.67, and κ = 0.58) when tested on the 243 paired ECGs. The clinical (lead I) and Apple Watch predictions led to the same low/high-risk FCHD classification for 99% of the participants. CPH prediction correlation resulted in an R = 0.81, ρ = 0.76, and κ = 0.78. Conclusion: Risk of FCHD can be predicted from single-lead ECGs obtained from wearable devices and are statistically concordant with lead I of a 12-lead ECG.

Costal margin reconstruction for slipping rib syndrome: Outcomes of more than 500 cases and advancements beyond earlier sutured repair technique.

Objectives: To evaluate results of sutured repair for slipping rib syndrome (SRS), identify failure points, and discuss technique modifications to improve outcomes through costal margin reconstruction (CMR). Methods: Patients undergoing repair of SRS between February 2019 and February 2024 at an academic referral institution were retrospectively analyzed. Pain scores, quality of life, pain medication use, and reoperations were evaluated pre- and postoperatively at 1 and 6 months. In patients failing sutured repair we identified specific failure points and devised a new CMR technique to overcome them. Subsequent CMR patients were followed at 1, 6, 12, 18, and 24 months using the same outcome measures. Results: Four hundred forty-nine patients underwent repair. Two hundred forty-one patients underwent sutured repair with revision required in 66. Median time to revision was 14 months. CMR was developed and performed in 247 patients. In CMR patients, preoperative mean pain score of 7.5 out of 10 dropped postoperatively to 4.0, 2.5, 1.9, 1.3, and 0.9 at 1, 6, 12, 18, and 24 months, respectively (P < .001). Mean quality of life of 38% improved to 73%, 83%, 88%, 93%, and 95% at the same intervals (P < .001). Preoperatively, 29% of patients chronically used opioid medications. Opioid use dropped postoperatively to 11%, 4%, 4%, 0%, and 0% at the same intervals. Use of nonopioid medications followed a similar pattern. One CMR patient required full revision. Conclusions: SRS is a debilitating, but correctable disorder. Improved pain and quality of life, reduction in chronic opioid use, and freedom from revision surgery suggest that CMR should be considered the standard operation for SRS.

Protocol for optimizing surface expression and speed in coaggregation assays using K562 cells and subsequent analysis with a CoAg Index.

Coaggregation assays using K562 cells have been extensively employed to study how cell adhesion molecules mediate specificity between different populations. Here we describe how to prepare K562 cells, optimize electroporation conditions, calibrate antibodies used for protein detection, determine the surface expression of desired adhesion molecules, and considerations for the rotational force to be applied during the assay. We also detail procedures for analyzing coaggregates using our established CoAggregation (CoAg) Index. For complete details on the use and execution of this protocol, please refer to Bisogni et al.1.

Combining Nuclear Medicine With Other Modalities: Future Prospect for Multimodality Imaging.

This meeting report summarizes a consultants meeting that was held at International Atomic Energy Agency Headquarters, Vienna, in July 2022 to provide an update on the development of multimodality imaging by combining nuclear medicine imaging agents with other nonradioactive molecular probes and/or biomedical imaging techniques.

Improving access to buprenorphine for rural veterans in a learning health care system.

OBJECTIVE: To describe a learning health care system research process designed to increase buprenorphine prescribing for the treatment of opioid use disorder (OUD) in rural primary care settings within U.S. Department of Veterans Affairs (VA) treatment facilities. DATA SOURCES AND STUDY SETTING: Using national administrative data from the VA Corporate Data Warehouse, we identified six rural VA health care systems that had improved their rate of buprenorphine prescribing within primary care from 2015 to 2020 (positive deviants). We conducted qualitative interviews with leaders, clinicians, and staff involved in buprenorphine prescribing within primary care from these sites to inform the design of an implementation strategy. STUDY DESIGN: Qualitative interviews to inform implementation strategy development. DATA COLLECTION/EXTRACTION METHODS: Interviews were audio-recorded, transcribed verbatim, and coded by a primary coder and secondary reviewer. Analysis utilized a mixed inductive/deductive approach. To develop an implementation strategy, we matched clinical needs identified within interviews with resources and strategies participants had utilized to address these needs in their own sites. PRINCIPAL FINDINGS: Interview participants (n = 30) identified key clinical needs and strategies for implementing buprenorphine in rural, primary care settings. Common suggestions included the need for clinical mentorship or a consult service, buprenorphine training, and educational resources. Building upon interview findings and in partnership with a clinical team, we developed an implementation strategy composed of an engaging case-based training, an audit and feedback process, and educational resources (e.g., Buprenorphine Frequently Asked Questions, Rural Care Model Infographic). CONCLUSIONS: We describe a learning health care system research process that leveraged national administrative data, health care provider interviews, and clinical partnership to develop an implementation strategy to encourage buprenorphine prescribing in rural primary care settings.

Screening for Unhealthy Alcohol Use Among Patients With Multiple Chronic Conditions in Primary Care.

Introduction: Unhealthy alcohol use increases the risk for and exacerbation of chronic health conditions. As such, screening, prevention, and management of unhealthy alcohol use is especially critical to improving health outcomes for patients with multiple chronic health conditions. It is unclear to what extent multiple chronic condition status is a barrier to screening for unhealthy alcohol use in the primary care setting. The authors hypothesized that patients with multiple chronic conditions would be at lower odds of being screened for unhealthy alcohol use than patients without multiple chronic conditions. Methods: The authors performed a secondary analysis of electronic health record data for patients from 67 primary care practices in Virginia (2020-2023). Using the Center for Medicare and Medicaid Services' chronic disease framework, they classified patients by multiple chronic condition status: no multiple chronic conditions, physical multiple chronic conditions, mental health multiple chronic conditions, and physical and mental health multiple chronic conditions. They used multiple logistic regressions with an added practice-level random effect to analyze the relationship between multiple chronic condition status and the odds of receiving an alcohol-related assessment, of being screened for unhealthy alcohol use with a U.S. Preventive Services Task Force-recommended instrument, and of screening positive for unhealthy alcohol use within the past 2 years. Results: Within a final cohort of n=11,789, a total of 6,796 patients (58%) had multiple chronic conditions (29% physical multiple chronic conditions, 4% mental health multiple chronic conditions, and 25% physical and mental health multiple chronic conditions). In all, 69% of patients were screened for unhealthy alcohol use, whereas 16% were screened with a U.S. Preventive Services Task Force-recommended instrument, and 7% screened positive for unhealthy alcohol use. Patients with physical and mental health multiple chronic conditions had 0.9 times lower odds of receiving any screening for unhealthy alcohol use than those with no multiple chronic conditions (95% CI=0.8, 1.0; p=0.0240), whereas patients with only physical multiple chronic conditions or only mental health multiple chronic conditions had similar odds. There was no difference in the odds of being screened with a U.S. Preventive Services Task Force-recommended instrument on the basis of multiple chronic condition status. Patients with mental health multiple chronic conditions and physical and mental health multiple chronic conditions had 1.8 and 1.5 times greater odds of screening positive for unhealthy alcohol use, respectively (95% CI=1.3, 2.7; p=0.0014 and 95% CI=1.2, 1.8; p=0.0003). Conclusions: Although patients with chronic mental health conditions were more likely to screen positive for unhealthy alcohol use than patients without multiple chronic conditions, Virginia primary care patients with physical and mental health multiple chronic conditions were less likely to receive an alcohol-related assessment during the past 2 years. Given the overall modest rate of screening with a U.S. Preventive Services Task Force-recommended instrument, further efforts are needed to create the conditions for high-quality alcohol-related preventive service delivery in primary care, particularly for patients with high complexity and/or mental health conditions.

Cardiovascular Clinical Trials in the Asia-Pacific Region.

This Viewpoint discusses the potential challenges to the operational conduct of clinical trials in the Asia-Pacific region, where there is a high rate of cardiovascular disease, and provides possible solutions.

Ocean warming and acidification adjust inter- and intra-specific variability in the functional trait expression of polar invertebrates.

Climate change is known to affect the distribution and composition of species, but concomitant alterations to functionally important aspects of behaviour and species-environment relations are poorly constrained. Here, we examine the ecosystem ramifications of changes in sediment-dwelling invertebrate bioturbation behaviour-a key process mediating nutrient cycling-associated with near-future environmental conditions (+ 1.5 °C, 550 ppm [pCO2]) for species from polar regions experiencing rapid rates of climate change. We find that responses to warming and acidification vary between species and lead to a reduction in intra-specific variability in behavioural trait expression that adjusts the magnitude and direction of nutrient concentrations. Our analyses also indicate that species behaviour is not predetermined, but can be dependent on local variations in environmental history that set population capacities for phenotypic plasticity. We provide evidence that certain, but subtle, aspects of inter- and intra-specific variation in behavioural trait expression, rather than the presence or proportional representation of species per se, is an important and under-appreciated determinant of benthic biogeochemical responses to climate change. Such changes in species behaviour may act as an early warning for impending ecological transitions associated with progressive climate forcing.

Altered extracellular matrix correlates with an immunosuppressive tumor microenvironment and disease progression in younger adults with oral cavity squamous cell carcinoma.

Introduction: Oral cavity squamous cell carcinoma (OSCC) occurs most frequently in patients >60 years old with a history of tobacco and alcohol use. Epidemiological studies describe increased incidence of OSCC in younger adults (<45 years). Despite its poor prognosis, knowledge of OSCC tumor microenvironment (TME) characteristics in younger adults is scarce and could help inform possible resistance to emerging treatment options. Methods: Patients with OSCC were evaluated using TCGA-HNSC (n=121) and a stage and subsite-matched institutional cohort (n=8) to identify differential gene expression focusing on the extracellular matrix (ECM) and epithelial-mesenchymal transition (EMT) processes in younger (≤45 years) vs. older adults (≥60 years). NanoString nCounter analysis was performed using isolated total RNA from formalin-fixed paraffin-embedded (FFPE) tumor samples. Stained tumor slides from young and old OSCC patients were evaluated for CD8+ T-cell counts using immunohistochemistry. Results: Younger OSCC patients demonstrated significantly increased expression of ECM remodeling and EMT process genes, as well as TME immunosuppression. Gene set enrichment analyses demonstrated increased ECM pathways and concurrent decreased immune pathways in young relative to old patients. Transcripts per million of genetic markers involved in ECM remodeling including LAMB3, VCAN, S100A9, COL5A1, and ITGB2 were significantly increased in tumors of younger vs. older patients (adjusted p-value < 0.10). Young patient TMEs demonstrated a 2.5-fold reduction in CD8+ T-cells as compared to older patients (p < 0.05). Conclusion: Differential gene expression impacting ECM remodeling and TME immunosuppression may contribute to disease progression in younger adult OSCC and has implications on response to evolving treatment modalities, such as immune checkpoint inhibitor therapy.

Slaying the Serpent: A Research Agenda to Expand Intervention Development and Accelerate Guinea Worm Eradication Efforts.

Dracunculiasis, also known as Guinea worm disease, is targeted to become the second human disease and first parasitic infection to be eradicated. The global Guinea Worm Eradication Program (GWEP), through community-based interventions, reduced the burden of disease from an estimated 3.5 million cases per year in 1986 to only 13 human cases in 2022. Despite progress, in 2012 Guinea worm disease was detected in domesticated dogs and later in domesticated cats and baboons. Without previous development of any Guinea worm therapeutics, diagnostic tests to detect pre-patent Guinea worm infection, or environmental surveillance tools, the emergence of Guinea worm disease in animal hosts-a threat to eradication-motivated an assessment of evidence gaps and research opportunities. This gap analysis informed the refinement of a robust research agenda intended to generate new evidence and identify additional tools for national GWEPs and to better align the global GWEP with a 2030 Guinea worm eradication certification target. This paper outlines the rationale for the development and expansion of the global GWEP Research Agenda and summarizes the results of the gap analysis that was conducted to identify Guinea worm-related research needs and opportunities. We describe five work streams informed by the research gap analysis that underpin the GWEP Research Agenda and address eradication endgame challenges through the employment of a systems-informed One Health approach. We also discuss the infrastructure in place to disseminate new evidence and monitor research results as well as plans for the continual review of evidence and research priorities.

Factors Influencing Community Engagement during Guinea Worm and Polio Eradication Endgames in Chad: Recommendations for "Last Mile" Programming.

Community engagement is a strategy commonly used in health and development programming. Many disease eradication programs engage with communities through different structures and mechanisms to detect, report, contain, and respond to the diseases they target. Qualitative operational research was conducted in a district of Chad co-endemic for both dracunculiasis (i.e., Guinea worm disease) and circulating vaccine-derived poliovirus to reveal factors influencing community engagement behavior in the context of eradication-related programming. Women and men from six communities and stakeholders from the local, district, and central levels were recruited to participate in focus group discussions and semi-structured in-depth interviews. A thematic analysis was performed to identify barriers and facilitators of community engagement. Barriers to community engagement included mistrust in exogenously established health program initiatives (i.e., initiatives designed by partners external to targeted program communities) resulting from negative past experiences with external entities and community groups and the lure of profit-motivating community engagement. Subgroup and intersectionality analyses revealed that gender and other identities influence whether and to what extent certain members of the community engage in a meaningful way. Facilitators of community engagement included leadership and the influence of authorities and leaders in community participation, perceived benefits of being engaged with community-based initiatives, and use of incentives to enhance community participation. Study findings may be used to inform the refinement of community engagement approaches in Chad and learning agendas for other "last mile" disease eradication programs.

THE CLASSIFICATION OF HIATAL SHAPES AND ITS USE AS A MARKER FOR COMPLEXITY, OPERATIVE INTERVENTIONS, AND RECURRENCE.

BACKGROUND: Diaphragmatic reconstruction is a vital, but challenging component of hiatal hernia and anti-reflux surgery. Results are optimized by minimizing axial tension along the esophagus, assessed with intra-abdominal length, and radial tension across the hiatus, which has not been standardized. We categorized hiatal openings into four shapes, as a surrogate for radial tension, to correlate their association with operative interventions and recurrence. METHODS: We retrospectively reviewed all primary hiatal hernias (≥3cm) repaired at a single center between 2010-2020. Patients with intra-operative hiatal photos with at least one year of follow up were included. The hiatal openings were classified into four shapes: slit, inverted teardrop, "D", and oval and ordered in this manner of hypothesized increased complexity and tension. RESULTS: A total of 239 patients were studied, with 113 (47%) having a recurrence. Age (p<0.001), proportion of paraesophageal hernias (p<0.001), hernia axial length (p<0.001), and hiatal width (p<0.001) all increased as shape progressed from slit to inverted teardrop to 'D" to oval. Mesh (p=0.003) and relaxing incisions (p<0.001) were more commonly employed in more advanced shapes, "D" and ovals. However, recurrence (p=0.88) did not correlate with hiatal shape. CONCLUSION: Four different hiatal shapes are commonly seen during hernia repair. These shapes represent a spectrum of hernia chronicity and complexity necessitating increased use of operative measures but not correlating with recurrence. While failing to be a direct marker for recurrence risk, hiatal shape may serve as an intra-operative tool to inform surgeons of the potential need for additional hiatal interventions.

The phenotypic and genotypic spectrum of individuals with mono- or biallelic ANK3 variants.

ANK3 encodes ankyrin-G, a protein involved in neuronal development and signaling. Alternative splicing gives rise to three ankyrin-G isoforms comprising different domains with distinct expression patterns. Mono- or biallelic ANK3 variants are associated with non-specific syndromic intellectual disability in 14 individuals (seven with monoallelic and seven with biallelic variants). In this study, we describe the clinical features of 13 additional individuals and review the data on a total of 27 individuals (16 individuals with monoallelic and 11 with biallelic ANK3 variants) and demonstrate that the phenotype for biallelic variants is more severe. The phenotypic features include language delay (92%), autism spectrum disorder (76%), intellectual disability (78%), hypotonia (65%), motor delay (68%), attention deficit disorder (ADD) or attention deficit hyperactivity disorder (ADHD) (57%), sleep disturbances (50%), aggressivity/self-injury (37.5%), and epilepsy (35%). A notable phenotypic difference was presence of ataxia in three individuals with biallelic variants, but in none of the individuals with monoallelic variants. While the majority of the monoallelic variants are predicted to result in a truncated protein, biallelic variants are almost exclusively missense. Moreover, mono- and biallelic variants appear to be localized differently across the three different ankyrin-G isoforms, suggesting isoform-specific pathological mechanisms.

Bacillus subtilis-derived peptides disrupt quorum sensing and biofilm assembly in multidrug-resistant Staphylococcus aureus.

Multidrug-resistant Staphylococcus aureus is one of the most clinically important pathogens in the world, with infections leading to high rates of morbidity and mortality in both humans and animals. The ability of S. aureus to form biofilms protects cells from antibiotics and promotes the transfer of antibiotic resistance genes; therefore, new strategies aimed at inhibiting biofilm growth are urgently needed. Probiotic species, including Bacillus subtilis, are gaining interest as potential therapies against S. aureus for their ability to reduce S. aureus colonization and virulence. Here, we search for strains and microbially derived compounds with strong antibiofilm activity against multidrug-resistant S. aureus by isolating and screening Bacillus strains from a variety of agricultural environments. From a total of 1,123 environmental isolates, we identify a single strain B. subtilis 6D1, with a potent ability to inhibit biofilm growth, disassemble mature biofilm, and improve antibiotic sensitivity of S. aureus biofilms through an Agr quorum sensing interference mechanism. Biochemical and molecular networking analysis of an active organic fraction revealed multiple surfactin isoforms, and an uncharacterized peptide was driving this antibiofilm activity. Compared with commercial high-performance liquid chromatography grade surfactin obtained from B. subtilis, we show these B. subtilis 6D1 peptides are significantly better at inhibiting biofilm formation in all four S. aureus Agr backgrounds and preventing S. aureus-induced cytotoxicity when applied to HT29 human intestinal cells. Our study illustrates the potential of exploring microbial strain diversity to discover novel antibiofilm agents that may help combat multidrug-resistant S. aureus infections and enhance antibiotic efficacy in clinical and veterinary settings. IMPORTANCE: The formation of biofilms by multidrug-resistant bacterial pathogens, such as Staphylococcus aureus, increases these microorganisms' virulence and decreases the efficacy of common antibiotic regimens. Probiotics possess a variety of strain-specific strategies to reduce biofilm formation in competing organisms; however, the mechanisms and compounds responsible for these phenomena often go uncharacterized. In this study, we identified a mixture of small probiotic-derived peptides capable of Agr quorum sensing interference as one of the mechanisms driving antibiofilm activity against S. aureus. This collection of peptides also improved antibiotic killing and protected human gut epithelial cells from S. aureus-induced toxicity by stimulating an adaptive cytokine response. We conclude that purposeful strain screening and selection efforts can be used to identify unique probiotic strains that possess specially desired mechanisms of action. This information can be used to further improve our understanding of the ways in which probiotic and probiotic-derived compounds can be applied to prevent bacterial infections or improve bacterial sensitivity to antibiotics in clinical and agricultural settings.

American Rhinologic Society Expert Practice Statement: Indications and Recommendations for Septoplasty in Children.

The goal of this American Rhinologic Society Expert Practice Statement (EPS) is to provide recommendations and guidance through evidence-based consensus statements regarding pediatric septoplasty. This EPS was developed following the previously published methodology and approval process. The topics of interest included appropriate indications, safety and efficacy, timing, relevant quality of life instruments, and surgical techniques. Following a modified Delphi approach, six statements were developed, five of which reached consensus and one that did not. These statements and accompanying evidence are summarized along with an assessment of future needs.

A liver immune rheostat regulates CD8 T cell immunity in chronic HBV infection.

Chronic hepatitis B virus (HBV) infection affects 300 million patients worldwide1,2, in whom virus-specific CD8 T cells by still ill-defined mechanisms lose their function and cannot eliminate HBV-infected hepatocytes3-7. Here we demonstrate that a liver immune rheostat renders virus-specific CD8 T cells refractory to activation and leads to their loss of effector functions. In preclinical models of persistent infection with hepatotropic viruses such as HBV, dysfunctional virus-specific CXCR6+ CD8 T cells accumulated in the liver and, as a characteristic hallmark, showed enhanced transcriptional activity of cAMP-responsive element modulator (CREM) distinct from T cell exhaustion. In patients with chronic hepatitis B, circulating and intrahepatic HBV-specific CXCR6+ CD8 T cells with enhanced CREM expression and transcriptional activity were detected at a frequency of 12-22% of HBV-specific CD8 T cells. Knocking out the inhibitory CREM/ICER isoform in T cells, however, failed to rescue T cell immunity. This indicates that CREM activity was a consequence, rather than the cause, of loss in T cell function, further supported by the observation of enhanced phosphorylation of protein kinase A (PKA) which is upstream of CREM. Indeed, we found that enhanced cAMP-PKA-signalling from increased T cell adenylyl cyclase activity augmented CREM activity and curbed T cell activation and effector function in persistent hepatic infection. Mechanistically, CD8 T cells recognizing their antigen on hepatocytes established close and extensive contact with liver sinusoidal endothelial cells, thereby enhancing adenylyl cyclase-cAMP-PKA signalling in T cells. In these hepatic CD8 T cells, which recognize their antigen on hepatocytes, phosphorylation of key signalling kinases of the T cell receptor signalling pathway was impaired, which rendered them refractory to activation. Thus, close contact with liver sinusoidal endothelial cells curbs the activation and effector function of HBV-specific CD8 T cells that target hepatocytes expressing viral antigens by means of the adenylyl cyclase-cAMP-PKA axis in an immune rheostat-like fashion.