Enhanced microglial dynamics and a paucity of tau seeding in the amyloid plaque microenvironment contribute to cognitive resilience in Alzheimer's disease.

Asymptomatic Alzheimer's disease (AsymAD) describes the status of individuals with preserved cognition but identifiable Alzheimer's disease (AD) brain pathology (i.e., beta-amyloid (Aß) deposits, neuritic plaques, and neurofibrillary tangles) at autopsy. In this study, we investigated the postmortem brains of a cohort of AsymAD subjects to gain insight into the mechanisms underlying resilience to AD pathology and cognitive decline. Our results showed that AsymAD cases exhibit enrichment in core plaques, decreased filamentous plaque accumulation, and increased plaque-surrounding microglia. Less pathological tau aggregation in dystrophic neurites was found in AsymAD brains than in AD brains, and tau seeding activity was comparable to that in healthy brains. We used spatial transcriptomics to characterize the plaque niche further and revealed autophagy, endocytosis, and phagocytosis as the pathways associated with the genes upregulated in the AsymAD plaque niche. Furthermore, the levels of ARP2 and CAP1, which are actin-based motility proteins that participate in the dynamics of actin filaments to allow cell motility, were increased in the microglia surrounding amyloid plaques in AsymAD cases. Our findings suggest that the amyloid-plaque microenvironment in AsymAD cases is characterized by the presence of microglia with highly efficient actin-based cell motility mechanisms and decreased tau seeding compared with that in AD brains. These two mechanisms can potentially protect against the toxic cascade initiated by Aß, preserving brain health, and slowing AD pathology progression.

Association of second antibiotic dose delays on mortality in patients with septic shock.

OBJECTIVE: Determine whether a delay in the administration of the second dose of antibiotics is associated with an increased risk of mortality for patients admitted with septic shock. DESIGN: Retrospective, observational evaluation. SETTING: Regional multicenter evaluation including four institutions in western Pennsylvania. PATIENTS: A total of 905 patients were included in this study who met the criteria for septic shock. Patients that did not receive a second dose of antibiotics, were transferred from an outside facility, or expected death within six hours of hospital admission were excluded. INTERVENTIONS: The frequency of second antibiotic dose administration delay was determined. A delay was defined as a delay greater than or equal to 25% of the antibiotic dosing interval. MEASUREMENTS AND MAIN RESULTS: A delay in second antibiotic dose administration was found in 181 (20%) of patients. Patients with a delay in the administration of second dose antibiotics had a higher mortality rate (35%) than patients without a delay (26%) (p =0.018). Patients with and without a delay in the administration of second-dose antibiotics had similar median 28-day vasopressor free days (median = 26.0, IQR = 2.0). Differences in the distribution of the 28-day vasopressor free days between groups resulted in the achievement of statistical significance (Mann-Whitney U = 57,294.5, z = -2.690, p = 0.006). There was no difference in 28-day ventilator-free days between groups. A delay in the administration of second dose antibiotics led to a longer in-hospital length of stay (9 days vs. 7 days; p = 0.022) and a longer ICU length of stay than patients without a delay (5 days vs. 3 days; p = 0.007). CONCLUSIONS: Delays in second antibiotic dose administration in septic shock patients were present but lower than previous studies. These delays were associated with increased mortality, increased ICU and hospital length of stay.

Noninvasive Ventilation or CPAP in the Initial Treatment Phase of Small Infants With Respiratory Failure.

BACKGROUND: Respiratory failure in infants is a common reason for admission to the pediatric ICU (PICU). Although high-flow nasal cannula (HFNC) is the preferred first-line treatment at our institution, some infants require CPAP or noninvasive ventilation (NIV). Here we report our experience using CPAP/NIV in infants < 10 kg. METHODS: We conducted a retrospective review of infants < 10 kg treated with CPAP/NIV in our PICUs between July 2017-May 2021 in the initial phase of treatment. Demographic, support type and settings, vital signs, pulse oximetry, and intubation data were extracted from the electronic health record. We compared subjects successfully treated with CPAP/NIV with those who required intubation. RESULTS: We studied 62 subjects with median (interquartile range) age 96 [6.5-308] d and weight 4.5 (3.4-6.6) kg. Of these, 22 (35%) required intubation. There were no significant differences in demographics, medical history, primary interface, pre-CPAP/NIV support, and device used to deliver CPAP/NIV. HFNC was used in 57 (92%) subjects before escalation to CPAP/NIV. Subjects who failed CPAP/NIV were less likely to have bronchiolitis (27% vs 60%, P = .040), less likely to be discharged from the hospital to home (68% vs 93%, P = .02), had a longer median hospital length of stay (LOS) (26.9 [21-50.5] d vs 10.4 [5.6-28.4] d, P = .002), and longer median ICU LOS (14.6 [7.9-25.2] d vs 5.8 [3.8-12.4] d, P = .004). Initial vital signs and FIO2 were similar, but SpO2 was lower and FIO2 higher at 6 h and 12 h after support initiation for subjects who failed CPAP/NIV. Initial CPAP/NIV settings were similar, but subjects who failed CPAP/NIV had higher maximum and final inspiratory/expiratory pressure. CONCLUSIONS: Most infants who failed initial HFNC support were successfully managed without intubation using NIV or CPAP. Bronchiolitis was associated with a lower rate of CPAP/NIV failure, whereas lower SpO2 and higher FIO2 levels were associated with higher rates of intubation.

A Common OXTR Risk Variant Alters Regulation of Gene Expression by DNA Hydroxymethylation in Pregnant Human Myometrium.

Postpartum hemorrhage, or excessive bleeding after birth, is a leading cause of maternal morbidity. A major cause of postpartum hemorrhage is uterine atony, tiring of the uterus which leads to ineffective contractions. Uterine contractions depend on oxytocin signaling in the myometrium, which in turn depends on expression of the oxytocin receptor (OXTR). Both genetic and epigenetic factors related to the oxytocin receptor are associated with risk of postpartum hemorrhage, but a mechanism relating these factors to oxytocin receptor activity in myometrium remains unclear. We report a genetic by epigenetic interaction whereby the relationship between DNA hydroxymethylation and OXTR gene expression depends on a common OXTR gene variant (rs53576). We also provide evidence that a similar genetic by epigenetic interaction using blood-derived DNA methylation is associated with relevant clinical outcomes: quantity of oxytocin administration and odds for postpartum hemorrhage. These results provide new avenues for predicting how women will respond to pharmacological agents in the prevention and treatment of postpartum hemorrhage.

ACR Appropriateness Criteria® Workup of Pleural Effusion or Pleural Disease.

Pleural effusions are categorized as transudative or exudative, with transudative effusions usually reflecting the sequala of a systemic etiology and exudative effusions usually resulting from a process localized to the pleura. Common causes of transudative pleural effusions include congestive heart failure, cirrhosis, and renal failure, whereas exudative effusions are typically due to infection, malignancy, or autoimmune disorders. This document summarizes appropriateness guidelines for imaging in four common clinical scenarios in patients with known or suspected pleural effusion or pleural disease. The American College of Radiology Appropriateness Criteria are evidence-based guidelines for specific clinical conditions that are reviewed annually by a multidisciplinary expert panel. The guideline development and revision process support the systematic analysis of the medical literature from peer reviewed journals. Established methodology principles such as Grading of Recommendations Assessment, Development, and Evaluation or GRADE are adapted to evaluate the evidence. The RAND/UCLA Appropriateness Method User Manual provides the methodology to determine the appropriateness of imaging and treatment procedures for specific clinical scenarios. In those instances where peer reviewed literature is lacking or equivocal, experts may be the primary evidentiary source available to formulate a recommendation.

Marine eDNA sampling from submerged surfaces with paint rollers.

Environmental DNA (eDNA) analyses of species present in marine environments is the most effective biological diversity measurement tool currently available. eDNA sampling methods are an intrinsically important part of the eDNA biodiversity analysis process. Identification and development of eDNA sampling methods that are as rapid, affordable, versatile and practical as possible will improve rates of detection of marine species. Optimal outcomes of eDNA biodiversity surveys come from studies employing high levels of sampling replication, so any methods that make sampling faster and cheaper will improve scientific outcomes. eDNA sampling methods that can be applied more widely will also enable sampling from a greater range of marine surface micro-habitats, resulting in detection of a wider range of organisms. In this study, we compared diversity detection by several methods for sampling eDNA from submerged marine surfaces: polyurethane foam, nylon swabs, microfibre paint rollers, and sediment scoops. All of the methods produced a diverse range of species identifications, with >250 multicellular species represented by eDNA at the study site. We found that widely-available small paint rollers were an effective, readily available and affordable method for sampling eDNA from underwater marine surfaces. This approach enables the sampling of marine eDNA using extended poles, or potentially by remotely operated vehicles, where surface sampling by hand is impractical.

ACR Appropriateness Criteria® Workup of pleural effusion or pleural disease

Pleural effusions are categorized as transudative or exudative, with transudative effusions usually reflecting the sequala of a systemic etiology and exudative effusions usually resulting from a process localized to the pleura. Common causes of transudative pleural effusions include congestive heart failure, cirrhosis, and renal failure, whereas exudative effusions are typically due to infection, malignancy, or autoimmune disorders. This document summarizes appropriateness guidelines for imaging in four common clinical scenarios in patients with known or suspected pleural effusion or pleural disease. The American College of Radiology Appropriateness Criteria are evidence-based guidelines for specific clinical conditions that are reviewed annually by a multidisciplinary expert panel. The guideline development and revision process support the systematic analysis of the medical literature from peer reviewed journals. Established methodology principles such as Grading of Recommendations Assessment, Development, and Evaluation or GRADE are adapted to evaluate the evidence. The RAND/UCLA Appropriateness Method User Manual provides the methodology to determine the appropriateness of imaging and treatment procedures for specific clinical scenarios. In those instances where peer reviewed literature is lacking or equivocal, experts may be the primary evidentiary source available to formulate a recommendation.

A novel induced pluripotent stem cell model of Schwann cell differentiation reveals NF2 - related gene regulatory networks of the extracellular matrix.

Schwann cells are vital to development and maintenance of the peripheral nervous system and their dysfunction has been implicated in a range of neurological and neoplastic disorders, including NF2 -related schwannomatosis. We developed a novel human induced pluripotent stem cell (hiPSC) model to study Schwann cell differentiation in health and disease. We performed transcriptomic, immunofluorescence, and morphological analysis of hiPSC derived Schwann cell precursors (SPCs) and terminally differentiated Schwann cells (SCs) representing distinct stages of development. To validate our findings, we performed integrated, cross-species analyses across multiple external datasets at bulk and single cell resolution. Our hiPSC model of Schwann cell development shared overlapping gene expression signatures with human amniotic mesenchymal stem cell (hAMSCs) derived SCs and in vivo mouse models, but also revealed unique features that may reflect species-specific aspects of Schwann cell biology. Moreover, we identified gene co-expression modules that are dynamically regulated during hiPSC to SC differentiation associated with ear and neural development, cell fate determination, the NF2 gene, and extracellular matrix (ECM) organization. By cross-referencing results between multiple datasets, we identified new genes potentially associated with NF2 expression. Our hiPSC model further provides a tractable platform for studying Schwann cell development in the context of human disease.

1q amplification and PHF19 expressing high-risk cells are associated with relapsed/refractory multiple myeloma.

Multiple Myeloma is an incurable plasma cell malignancy with a poor survival rate that is usually treated with immunomodulatory drugs (iMiDs) and proteosome inhibitors (PIs). The malignant plasma cells quickly become resistant to these agents causing relapse and uncontrolled growth of resistant clones. From whole genome sequencing (WGS) and RNA sequencing (RNA-seq) studies, different high-risk translocation, copy number, mutational, and transcriptional markers can be identified. One of these markers, PHF19, epigenetically regulates cell cycle and other processes and is already studied using RNA-seq. In this study, we generate a large (325,025 cells and 49 patients) single cell multi-omic dataset and jointly quantify ATAC- and RNA-seq for each cell and matched genomic profiles for each patient. We identify an association between one plasma cell subtype with myeloma progression that we call relapsed/refractory plasma cells (RRPCs). These cells are associated with chromosome 1q alterations, TP53 mutations, and higher expression of PHF19. We also identify downstream regulation of cell cycle inhibitors in these cells, possible regulation by the transcription factor (TF) PBX1 on chromosome 1q, and determine that PHF19 may be acting primarily through this subset of cells.

Ventromedial hypothalamic nucleus subset stimulates tissue thermogenesis via preoptic area outputs.

OBJECTIVE: Hypothalamic signals potently stimulate energy expenditure by engaging peripheral mechanisms to restore energy homeostasis. Previous studies have identified several critical hypothalamic sites (e.g. preoptic area (POA) and ventromedial hypothalamic nucleus (VMN)) that could be part of an interconnected neurocircuit that controls tissue thermogenesis and essential for body weight control. However, the key neurocircuit that can stimulate energy expenditure has not yet been established. METHODS: Here, we investigated the downstream mechanisms by which VMN neurons stimulate adipose tissue thermogenesis. We manipulated subsets of VMN neurons acutely as well as chronically and studied its effect on tissue thermogenesis and body weight control, using Sf1Cre and Adcyap1Cre mice and measured physiological parameters under both high-fat diet and standard chow diet conditions. To determine the node efferent to these VMN neurons, that is involved in modulating energy expenditure, we employed electrophysiology and optogenetics experiments combined with measurements using tissue-implantable temperature microchips. RESULTS: Activation of the VMN neurons that express the steroidogenic factor 1 (Sf1; VMNSf1 neurons) reduced body weight, adiposity and increased energy expenditure in diet-induced obese mice. This function is likely mediated, at least in part, by the release of the pituitary adenylate cyclase-activating polypeptide (PACAP; encoded by the Adcyap1 gene) by the VMN neurons, since we previously demonstrated that PACAP, at the VMN, plays a key role in energy expenditure control. Thus, we then shifted focus to the subpopulation of VMNSf1 neurons that contain the neuropeptide PACAP (VMNPACAP neurons). Since the VMN neurons do not directly project to the peripheral tissues, we traced the location of the VMNPACAP neurons' efferents. We identified that VMNPACAP neurons project to and activate neurons in the caudal regions of the POA whereby these projections stimulate tissue thermogenesis in brown and beige adipose tissue. We demonstrated that selective activation of caudal POA projections from VMNPACAP neurons induces tissue thermogenesis, most potently in negative energy balance and activating these projections lead to some similar, but mostly unique, patterns of gene expression in brown and beige tissue. Finally, we demonstrated that the activation of the VMNPACAP neurons' efferents that lie at the caudal POA are necessary for inducing tissue thermogenesis in brown and beige adipose tissue. CONCLUSIONS: These data indicate that VMNPACAP connections with the caudal POA neurons impact adipose tissue function and are important for induction of tissue thermogenesis. Our data suggests that the VMNPACAP → caudal POA neurocircuit and its components are critical for controlling energy balance by activating energy expenditure and body weight control.

-A machine learning model to predict surgical site infection after surgery of lower extremity fractures.

PURPOSE: This study aimed to develop machine learning algorithms for identifying predictive factors associated with the risk of postoperative surgical site infection in patients with lower extremity fractures. METHODS: A machine learning analysis was conducted on a dataset comprising 1,579 patients who underwent surgical fixation for lower extremity fractures to create a predictive model for risk stratification of postoperative surgical site infection. We evaluated different clinical and demographic variables to train four machine learning models (neural networks, boosted generalised linear model, naïve bayes, and penalised discriminant analysis). Performance was measured by the area under the curve score, Youdon's index and Brier score. A multivariate adaptive regression splines (MARS) was used to optimise predictor selection. RESULTS: The final model consisted of five predictors. (1) Operating room time, (2) ankle region, (3) open injury, (4) body mass index, and (5) age. The best-performing machine learning algorithm demonstrated a promising predictive performance, with an area under the ROC curve, Youdon's index, and Brier score of 77.8%, 62.5%, and 5.1%-5.6%, respectively. CONCLUSION: The proposed predictive model not only assists surgeons in determining high-risk factors for surgical site infections but also empowers patients to closely monitor these factors and take proactive measures to prevent complications. Furthermore, by considering the identified predictors, this model can serve as a reference for implementing preventive measures and reducing postoperative complications, ultimately enhancing patient outcomes. However, further investigations involving larger datasets and external validations are required to confirm the reliability and applicability of our model.

Generation and study of Am(IV) by temperature-controlled electron pulse radiolysis.

First-of-a-kind temperature-controlled electron pulse radiolysis experiments facilitated the radiation-induced formation of Am(IV) in concentrated (6.0 M) HNO3, and enabled the derivation of Arrhenius and Eyring activation parameters for instigating the radical reaction between NO3˙ and Am(III).

A common polymorphism in the Intelectin-1 gene influences mucus plugging in severe asthma.

By incompletely understood mechanisms, type 2 (T2) inflammation present in the airways of severe asthmatics drives the formation of pathologic mucus which leads to airway mucus plugging. Here we investigate the molecular role and clinical significance of intelectin-1 (ITLN-1) in the development of pathologic airway mucus in asthma. Through analyses of human airway epithelial cells we find that ITLN1 gene expression is highly induced by interleukin-13 (IL-13) in a subset of metaplastic MUC5AC+ mucus secretory cells, and that ITLN-1 protein is a secreted component of IL-13-induced mucus. Additionally, we find ITLN-1 protein binds the C-terminus of the MUC5AC mucin and that its deletion in airway epithelial cells partially reverses IL-13-induced mucostasis. Through analysis of nasal airway epithelial brushings, we find that ITLN1 is highly expressed in T2-high asthmatics, when compared to T2-low children. Furthermore, we demonstrate that both ITLN-1 gene expression and protein levels are significantly reduced by a common genetic variant that is associated with protection from the formation of mucus plugs in T2-high asthma. This work identifies an important biomarker and targetable pathways for the treatment of mucus obstruction in asthma.

Timing of intraoperative neurophysiological monitoring (IONM) recovery and clinical recovery after termination of pediatric spinal deformity surgery due to loss of IONM signals.

BACKGROUND CONTEXT: Intraoperative neurophysiological monitoring (IONM) is used to reduce the risk of spinal cord injury during pediatric spinal deformity surgery. Significant reduction and/or loss of IONM signals without immediate recovery may lead the surgeon to acutely abort the case. The timing of when monitorable signals return remains largely unknown. PURPOSE: The goal of this study was to investigate the correlation between IONM signal loss, clinical examination, and subsequent normalization of IONM signals after aborted pediatric spinal deformity surgery to help determine when it is safe to return to the operating room. STUDY DESIGN/SETTING: This is a multicenter, multidisciplinary, retrospective study of pediatric patients (<18 years old) undergoing spinal deformity surgery whose surgery was aborted due to a significant reduction or loss of IONM potentials. PATIENT SAMPLE: Sixty-six patients less than 18 years old who underwent spinal deformity surgery that was aborted due to IONM signal loss were enrolled into the study. OUTCOME MEASURES: IONM data, operative reports, and clinical examinations were investigated to determine the relationship between IONM loss, clinical examination, recovery of IONM signals, and clinical outcome. METHODS: Information regarding patient demographics, deformity type, clinical history, neurologic and ambulation status, operative details, IONM information (eg, quality of loss [SSEPs, MEPs], laterality, any recovery of signals, etc.), intraoperative wake-up test, postoperative neurologic exam, postoperative imaging, and time to return to the operating were all collected. All factors were analyzed and compared with univariate and multivariate analysis using appropriate statistical analysis. RESULTS: Sixty-six patients were enrolled with a median age of 13 years [IQR 11-14], and the most common sex was female (42/66, 63.6%). Most patients had idiopathic scoliosis (33/66, 50%). The most common causes of IONM loss were screw placement (27/66, 40.9%) followed by rod correction (19/66, 28.8%). All patients had either complete bilateral (39/66, 59.0%), partial bilateral (10/66, 15.2%) or unilateral (17/66, 25.8%) MEP loss leading to termination of the case. Overall, when patients were returned to the operating room 2 weeks postoperatively, nearly 75% (40/55) had monitorable IONM signals. Univariate analysis demonstrated that bilateral SSEP loss (p=.019), bilateral SSEP and MEP loss (p=.022) and delayed clinical neurologic recovery (p=.008) were significantly associated with having unmonitorable IONM signals at repeat surgery. Multivariate regression analysis demonstrated that delayed clinical neurologic recovery (> 72 hours) was significantly associated with unmonitorable IONM signals when returned to the operating room (p=.006). All patients ultimately made a full neurologic recovery. CONCLUSIONS: In children whose spinal deformity surgery was aborted due to intraoperative IONM loss, there was a strong correlation between combined intraoperative SSEP/MEP loss, the magnitude of IONM loss, the timing of clinical recovery, and the time of electrophysiological IONM recovery. The highest likelihood of having a prolonged postoperative neurological deficit and undetectable IONM signals upon return to the OR occurs with bilateral complete loss of SSEPs and MEPs.

Accelerated epigenetic age is associated with whole-brain functional connectivity and impaired cognitive performance in older adults.

While chronological age is a strong predictor for health-related risk factors, it is an incomplete metric that fails to fully characterize the unique aging process of individuals with different genetic makeup, neurodevelopment, and environmental experiences. Recent advances in epigenomic array technologies have made it possible to generate DNA methylation-based biomarkers of biological aging, which may be useful in predicting a myriad of cognitive abilities and functional brain network organization across older individuals. It is currently unclear which cognitive domains are negatively correlated with epigenetic age above and beyond chronological age, and it is unknown if functional brain organization is an important mechanism for explaining these associations. In this study, individuals with accelerated epigenetic age (i.e. AgeAccelGrim) performed worse on tasks that spanned a wide variety of cognitive faculties including both fluid and crystallized intelligence (N = 103, average age = 68.98 years, 73 females, 30 males). Additionally, fMRI connectome-based predictive models suggested a mediating mechanism of functional connectivity on epigenetic age acceleration-cognition associations primarily in medial temporal lobe and limbic structures. This research highlights the important role of epigenetic aging processes on the development and maintenance of healthy cognitive capacities and function of the aging brain.

Primate conservation: A public issue?

Nonhuman primates (primates) are one of the most endangered mammalian taxa in the world. In the Global North, primates are considered exotic species and, as such, humans' impact on primate conservation and responsibility to protect primates is often ignored. This view differs from the spectrum of relations and attitudes of humans that live in connection to primates, which can include viewing these animals as culturally/religiously significant, cohabitors of forests, nuisances, or sources of protein. While conservationists argue that primates deserve our protection, the conservation crisis facing primates is rarely framed as a public issue, in contrast to other global crises, such as climate change. However, over half of the world's human population lives within 100 km of primate habitat. Thus, humans and primates share the same environments. We suggest leveraging a holistic approach, such as One Health, that considers the interconnectedness of primates, humans, and their shared environments, through the lens of public anthropology. By approaching primate conservation as an intersectional issue that affects and is affected by humans, researchers and conservationists can identify strategies that simultaneously protect primates and address global inequities that frequently affect people in primate range countries. Reflexive research practices further allow academics to consider the broader impact of their ecological research through means such as publicly accessible dissemination of results, equitable capacity-building of high-quality personnel in primate range countries, and social activism. The use of inter-, multi-, and transdisciplinary concepts and methodology can address the intersectional challenges associated with implementing ethical and sustainable primate conservation measures.

Multiscale Modeling of Plutonium Radiation Chemistry in Nitric Acid Solutions. 1. Cobalt-60 Gamma Irradiation of Pu(IV).

Careful manipulation of the plutonium oxidation states is essential in the study and utilization of its rich redox chemistry. To achieve this level of control, a comprehensive mechanistic understanding of radiation-induced plutonium redox chemistry is critical due to the unavoidable exposure of plutonium to ionizing radiation fields, both inherent and from in-process applications. To this end, we have developed an experimentally evaluated multiscale computer model for the prediction of gamma radiation-induced Pu(IV) redox chemistry in concentrated nitric acid solutions (1.0, 3.0, and 6.0 M). Under these acidic, aqueous solution conditions, cobalt-60 gamma irradiation afforded marginal net conversion of Pu(IV) to Pu(VI), the extent of which was dependent on the concentration of HNO3 and absorbed gamma dose. Multiscale calculations, which are in excellent agreement with experimental data, indicate that this observation is due to a combination of inherent plutonium disproportionation reactions and several radiation-induced processes, including redox cycling between Pu(IV) and Pu(III), as achieved by the reduction of Pu(IV) by nitrous acid and hydrogen peroxide, the oxidation of Pu(III) by nitrate and hydroxyl radicals, and the sequential oxidation of Pu(IV) to Pu(V) and Pu(VI) by the remaining available yield of nitrate radicals.

Improving ecosystem health in highly altered river basins: a generalized framework and its application to the Mississippi-Atchafalaya River Basin.

Continued large-scale public investment in declining ecosystems depends on demonstrations of "success". While the public conception of "success" often focuses on restoration to a pre-disturbance condition, the scientific community is more likely to measure success in terms of improved ecosystem health. Using a combination of literature review, workshops and expert solicitation we propose a generalized framework to improve ecosystem health in highly altered river basins by reducing ecosystem stressors, enhancing ecosystem processes and increasing ecosystem resilience. We illustrate the use of this framework in the Mississippi-Atchafalaya River Basin (MARB) of the central United States (U.S.), by (i) identifying key stressors related to human activities, and (ii) creating a conceptual ecosystem model relating those stressors to effects on ecosystem structure and processes. As a result of our analysis, we identify a set of landscape-level indicators of ecosystem health, emphasizing leading indicators of stressor removal (e.g., reduced anthropogenic nutrient inputs), increased ecosystem function (e.g., increased water storage in the landscape) and increased resilience (e.g., changes in the percentage of perennial vegetative cover). We suggest that by including these indicators, along with lagging indicators such as direct measurements of water quality, stakeholders will be better able to assess the effectiveness of management actions. For example, if both leading and lagging indicators show improvement over time, then management actions are on track to attain desired ecosystem condition. If, however, leading indicators are not improving or even declining, then fundamental challenges to ecosystem health remain to be addressed and failure to address these will ultimately lead to declines in lagging indicators such as water quality. Although our model and indicators are specific to the MARB, we believe that the generalized framework and the process of model and indicator development will be valuable in an array of altered river basins.

Nationwide Case-Control Analysis of Merkel Cell Carcinoma and Associated Skin Cancer Comorbidities: An Examination of the All of Us Database.

Introduction Merkel cell carcinoma is an aggressive neuroendocrine tumor that is related to immunosuppression and the Merkel cell polyomavirus. It is more common on the head and neck and has been associated with other skin malignancies such as basal cell carcinoma, squamous cell carcinoma, and melanoma. However, there has never been a nationwide investigation that quantifies Merkel cell carcinoma's connection with these subgroups. Methods Utilizing the National Institutes of Health's All of Us open-access database, a retrospective study was conducted by filtering for Merkel cell carcinoma through the International Classification of Diseases, 9th and 10th Clinical Modification codes 209.* and C4A.*, respectively. This led to the inclusion of 41 patients in the study, with each instance compared to four control patients without merkel cell carcinoma, matched by age, race, and gender. The data's demographics and skin cancer co-morbidities were collected and evaluated with odds ratios and 95% confidence intervals using Wald's method. Results In patients with merkel cell carcinoma, a statistically significant gradient of increasing risk for developing basal cell carcinoma (Odds Ratio, 11.63; 95% Confidence Interval, 4.30-31.45; P < 0.0001), squamous cell carcinoma (Odds Ratio, 15.09; 95% Confidence Interval, 3.87-58.84; P = 0.0001), and melanoma (Odds Ratio, 27.94; 95% Confidence Interval, 3.26-239.48; P = 0.0024) was observed. The race/ethnicity demographics showed that 85.4% of the patients were white, and they were at the highest risk of developing merkel cell carcinoma. However, the study has limitations, such as the inability to identify the stage of merkel cell carcinoma among patients and the lack of consideration for other confounding variables. Conclusion The study examines the link between merkel cell carcinoma and other skin malignancies, underscoring the need for more national research to better understand the underlying causes that contribute to this link. The findings also indicate the possibility of sample bias in the All of Us database, emphasizing the need to assess the patient population's representativeness in such investigations.