Search

Synthetic opioids like fentanyl have improved the standard of care for many patients in the clinical setting, but their abuse leads to tens of thousands of overdose deaths annually. The current opioid epidemic underscores a critical need for insights into the physiological effects of fentanyl on vital functions. High doses of opioids in small mammals cause opioid-induced respiratory depression (OIRD) leading to hypoventilation, hypoxemia, and hypercapnia. In addition, opioids can also increase the alveolar to arterial oxygen (A-a) gradient and airway dysfunction. However, little is known about the physiologic effects of sub-lethal doses of opioids in large mammals. Here we report the effects of a sub-lethal dose range of fentanyl (25–125 μg/kg; IV) on vital physiologic functions over 90 min (min) and withdrawal-like behaviors over the subsequent 4 h (h) in adult female goats (n = 13). Fentanyl induced decreases in breathing frequency in the first few min post-injection, but then led to a sustained increase in tidal volume, total ventilation, and blood pressure with a reduced heart rate for ≥90 min. These ventilatory changes resulted in time-dependent arterial hypocapnia and hypoxemia and an increased alveolar to arterial oxygen gradient ∼30 min post-injection indicative of impaired gas exchange in the lung. The predominant effects of fentanyl on breathing were stimulatory, underscored by an increased rate of rise of the diaphragm muscle activity and increased activation of upper airway, intercostal and abdominal muscles. Beginning 90 min post-injection we also quantified withdrawal-like behaviors over 4 h, demonstrating dose- and time-dependent increases in locomotor, biting, itching, and pawing behaviors. We conclude that fentanyl at sublethal doses induces multiple physiologic and behavior changes that emerge along different time courses suggesting multiple independent mechanisms underlying effects of opioids.

One of the main causes of the dismal prognosis in patients who survive the initial bleeding after aneurysmal subarachnoidal hemorrhage is the delayed cerebral ischaemia caused by vasospasm. Studies suggest that cerebral magnesium and pH may potentially play a role in the pathophysiology of this adverse event. Using phosphorous magnetic resonance spectrocopy (31P-MRS), we calculated the cerebral magnesium (Mg) and pH levels in 13 patients who suffered from aSAH. The values between the group that developed clinically significant vasospasm (n = 7) and the group that did not (n = 6) were compared. The results of this study show significantly lower cerebral Mg levels (p = 0.019) and higher pH levels (p < 0.001) in the cumulative group (all brain voxels together) in patients who developed clinically significant vasospasm. Further clinical studies on a larger group of carefully selected patients are needed in order to predict clinically significant vasospasm.

Rationale & objectiveChronic kidney disease (CKD) is complicated by abnormalities that reflect disruption in filtration, tubular, and endocrine functions of the kidney. Our aim was to explore the relationship of specific laboratory result abnormalities and hypertension with the estimated glomerular filtration rate (eGFR) and albuminuria CKD staging framework.Study designCross-sectional individual participant-level analyses in a global consortium.Setting & study populations17 CKD and 38 general population and high-risk cohorts.Selection criteria for studiesCohorts in the CKD Prognosis Consortium with data for eGFR and albuminuria, as well as a measurement of hemoglobin, bicarbonate, phosphorus, parathyroid hormone, potassium, or calcium, or hypertension.Data extractionData were obtained and analyzed between July 2015 and January 2018.Analytical approachWe modeled the association of eGFR and albuminuria with hemoglobin, bicarbonate, phosphorus, parathyroid hormone, potassium, and calcium values using linear regression and with hypertension and categorical definitions of each abnormality using logistic regression. Results were pooled using random-effects meta-analyses.ResultsThe CKD cohorts (n=254,666 participants) were 27% women and 10% black, with a mean age of 69 (SD, 12) years. The general population/high-risk cohorts (n=1,758,334) were 50% women and 2% black, with a mean age of 50 (16) years. There was a strong graded association between lower eGFR and all laboratory result abnormalities (ORs ranging from 3.27 [95% CI, 2.68-3.97] to 8.91 [95% CI, 7.22-10.99] comparing eGFRs of 15 to 29 with eGFRs of 45 to 59mL/min/1.73m2), whereas albuminuria had equivocal or weak associations with abnormalities (ORs ranging from 0.77 [95% CI, 0.60-0.99] to 1.92 [95% CI, 1.65-2.24] comparing urinary albumin-creatinine ratio > 300 vs < 30mg/g).LimitationsVariations in study era, health care delivery system, typical diet, and laboratory assays.ConclusionsLower eGFR was strongly associated with higher odds of multiple laboratory result abnormalities. Knowledge of risk associations might help guide management in the heterogeneous group of patients with CKD.

ImportanceEarly identification of individuals at elevated risk of developing chronic kidney disease (CKD) could improve clinical care through enhanced surveillance and better management of underlying health conditions.ObjectiveTo develop assessment tools to identify individuals at increased risk of CKD, defined by reduced estimated glomerular filtration rate (eGFR).Design, setting, and participantsIndividual-level data analysis of 34 multinational cohorts from the CKD Prognosis Consortium including 5 222 711 individuals from 28 countries. Data were collected from April 1970 through January 2017. A 2-stage analysis was performed, with each study first analyzed individually and summarized overall using a weighted average. Because clinical variables were often differentially available by diabetes status, models were developed separately for participants with diabetes and without diabetes. Discrimination and calibration were also tested in 9 external cohorts (n = 2 253 540).ExposuresDemographic and clinical factors.Main outcomes and measuresIncident eGFR of less than 60 mL/min/1.73 m2.ResultsAmong 4 441 084 participants without diabetes (mean age, 54 years, 38% women), 660 856 incident cases (14.9%) of reduced eGFR occurred during a mean follow-up of 4.2 years. Of 781 627 participants with diabetes (mean age, 62 years, 13% women), 313 646 incident cases (40%) occurred during a mean follow-up of 3.9 years. Equations for the 5-year risk of reduced eGFR included age, sex, race/ethnicity, eGFR, history of cardiovascular disease, ever smoker, hypertension, body mass index, and albuminuria concentration. For participants with diabetes, the models also included diabetes medications, hemoglobin A1c, and the interaction between the 2. The risk equations had a median C statistic for the 5-year predicted probability of 0.845 (interquartile range [IQR], 0.789-0.890) in the cohorts without diabetes and 0.801 (IQR, 0.750-0.819) in the cohorts with diabetes. Calibration analysis showed that 9 of 13 study populations (69%) had a slope of observed to predicted risk between 0.80 and 1.25. Discrimination was similar in 18 study populations in 9 external validation cohorts; calibration showed that 16 of 18 (89%) had a slope of observed to predicted risk between 0.80 and 1.25.Conclusions and relevanceEquations for predicting risk of incident chronic kidney disease developed from more than 5 million individuals from 34 multinational cohorts demonstrated high discrimination and variable calibration in diverse populations. Further study is needed to determine whether use of these equations to identify individuals at risk of developing chronic kidney disease will improve clinical care and patient outcomes.

Background There are no available lifetime risk estimates of lower-extremity peripheral artery disease (PAD). Methods and Results Using data from 6 US community-based cohorts and the vital statistics, we estimated the prevalence and incidence of PAD, defined as an ankle-brachial index

BACKGROUND:There is growing interest in the use of multiplexed aptamer-based assays for large-scale proteomic studies. However, the analytic, short- and long-term variation of the measured proteins is largely uncharacterized. METHODS:We quantified 4001 plasma protein analytes from 42 participants in the Atherosclerosis Risk in Communities (ARIC) Study in split samples and at multiple visits using a multiplexed modified aptamer assay. We calculated the CV, Spearman correlation, and intraclass correlation (ICC) between split samples and evaluated the short-term (4-9 weeks) and long-term (approximately 20 years) variability using paired t-tests with log-transformed protein concentrations and Bonferroni-corrected significance thresholds. We performed principal component (PC) analysis of protein analyte concentrations and evaluated their associations with age, sex, race, and estimated glomerular filtration rate (eGFR). RESULTS:The mean baseline age was 57 years at the first visit, 43% of participants were male and 57% were white. Among 3693 protein analytes that passed quality control, half (n = 1846) had CVs < 5.0%, Spearman correlations > 0.89, and ICCs > 0.96 among the split samples. Over the short term, only 1 analyte had a statistically significant difference between the 2 time points, whereas, over approximately 20 years, 866 analytes (23.4%) had statistically significant differences (P < 1.4 × 10-5, 681 increased, 185 decreased). PC1 had high correlations with age (-0.73) and eGFR (0.60). PC2 had moderate correlation with male sex (0.18) and white race (0.31). CONCLUSIONS:Multiplexed modified aptamer technology can assay thousands of proteins with excellent precision. Our results support the potential for large-scale studies of the plasma proteome over the lifespan.

Abstract Background Proteins and metabolites are essential for many biological functions and often linked through enzymatic or transport reactions. Individual molecules have been associated with all-cause mortality. Many of these are correlated and might jointly represent pathways or endophenotypes involved in diseases. Results We present an integrated analysis of proteomics and metabolomics via a local dimensionality reduction clustering method. We identified 224 modules of correlated proteins and metabolites in the Atherosclerosis Risk in Communities (ARIC) study, a general population cohort of older adults (N = 4046, mean age 75.7, mean eGFR 65). Many of the modules displayed strong cross-sectional associations with demographic and clinical characteristics. In comprehensively adjusted analyses, including fasting plasma glucose, history of cardiovascular disease, systolic blood pressure and kidney function among others, 60 modules were associated with mortality. We transferred the network structure to the African American Study of Kidney Disease and Hypertension (AASK) (N = 694, mean age 54.5, mean mGFR 46) and identified mortality associated modules relevant in this disease specific cohort. The four mortality modules relevant in both the general population and CKD were all a combination of proteins and metabolites and were related to diabetes / insulin secretion, cardiovascular disease and kidney function. Key components of these modules included N-terminal (NT)-pro hormone BNP (NT-proBNP), Sushi, Von Willebrand Factor Type A, EGF And Pentraxin (SVEP1), and several kallikrein proteases. Conclusion Through integrated biomarkers of the proteome and metabolome we identified functions of (patho-) physiologic importance related to diabetes, cardiovascular disease and kidney function.

Abstract Background Overlap syndromes of anti-NMDA receptor encephalitis and MOG-mediated demyelination have been reported. In this case we provide a long-term longitudinal follow-up of clinical and imaging characteristics as well as of antibody dynamics. Case presentation We report a 32-year-old male patient who presented with psychosis, decreased consciousness and movement disorders and was tested positive for anti-NMDA receptor antibodies. Forty-four months after symptom onset and diagnosis of autoimmune encephalitis, he suffered from relapse. At this time, the patient developed anti-MOG and anti-Caspr2 antibodies. Treatment with plasmapheresis, steroids and rituximab eventually led to substantial clinical and radiological improvement. Anti-Caspr2 antibodies persisted, anti-NMDA receptor antibodies decreased, while anti-MOG antibodies turned negative again. Conclusion We provide long-term longitudinal follow-up of a patient with anti-NMDA receptor encephalitis who developed triple antibody positivity at the time of relapse. Antibody dynamics were associated with clinical disease course.

Abstract Objective Newer antidiabetic medications such as sodium‐glucose co‐transporter 2 inhibitors (SGLT2i) and glucagon‐like peptide 1 receptor agonists (GLP1RA) result in weight loss in clinical trials. However, the real‐world effectiveness remains unclear. The magnitude of weight change associated with antidiabetic medication using real‐world data was examined. Methods Patients with diabetes who initiated SGLT2i (n = 906), GLP1RA (n = 782), dipeptidyl peptidase‐4 inhibitors (DPP4i, n = 1881), or sulfonylureas (n = 3255) in Geisinger Health System were identified. Outcomes were percent weight change per year and time to 5% weight loss. Propensity scores were used to account for differences across groups. Results The mean ± SD age of patients was 57.5 ± 14.1 years, 3381 (49.5%) were female, and 6450 (94.5%) had body mass index ≥25 kg/m2. Compared with sulfonylureas, newer antidiabetic medications were associated with significant weight loss (−3.2% [95% confidence interval: −3.8%, −2.6%] per year for SGLT2i; −2.9% [−3.6%, −2.3%] per year for GLP1RA; and −1.7% [−2.1%, −1.3%] per year for DPP4i). SGLT2i and GLP1RA were also associated with significant weight loss compared with DPP4i. Among patients with overweight or obesity, SGLT2i and GLP1RA users were more likely to achieve 5% weight loss compared with sulfonylureas and DPP4i. Conclusions In real‐world practice, SGLT2i and GLP1RA were associated with significant weight loss compared with sulfonylureas and DPP4i. These results may further motivate uptake of SGLT2i and GLP1RA, especially among patients who were overweight or had obesity.

BackgroundGBM research is constantly assessing potential valuable prognostic biomarkers to better understand the disease and prognosticate future outcomes. Measuring temporal muscle thickness (TMT) has appeared to be a promising new surrogate marker for skeletal muscle mass and sarcopenia, which further indicates frailty and predicts overall survival (OS). The aim of this study was to determine its usefulness as a prognostic marker in patients with high-grade glioma compared to functional status scales.MethodsTMT was measured in preoperative axial T1-weighted contrast-enhanced magnetic resonance images in 277 patients who received surgical treatment of newly diagnosed WHO III and IV gliomas in our institution between 2015 and 2020. Clinical Frailty Scale (CFS) and Karnofsky Performance Scale (KPS) were assessed preoperatively and during a follow-up visit.ResultsFemale gender has shown significant correlation with TMT, while TMT did not correlate with preoperative and follow-up functional scores, age, WHO classification, IDH mutation, MGMT promoter methylation, EGFR and ATRX expression, or 1p/19q co-deletion. No significant prognostic value of TMT could be shown in 6, 12, and 24 months OS, while changes in CFS and KPS proved to have a significant impact.ConclusionOnly female gender, but no other clinical, histological, or molecular marker showed any interrelation with TMT. Functional scores outclass measuring TMT as a reliable prognostic factor for predicting OS in patients with high-grade glioma.

Abstract Renewable power generation from wind and solar energy is strongly dependent on the weather. To plan future sustainable energy systems that are robust to weather variability, a better understanding of why and when periods of low wind and solar power output occur is valuable. We call such periods of low wind speed and insolation “Dunkelflauten”, the German word for “dark wind lulls”. In this article, we analyse the meteorological conditions during Dunkelflauten in Germany by applying the concept of weather regimes. Weather regimes are quasi‐stationary, recurrent and persistent large‐scale circulation patterns that explain multi‐day atmospheric variability (5–15 days). We use a regime definition that allows us to distinguish four different types of blocked regimes, characterized by high‐pressure situations in the North Atlantic‐European region. We find that Dunkelflauten in Germany occur mainly in winter when the solar power output is low due to the seasonal cycle of solar irradiance and wind power output drops for several consecutive days. A high‐pressure system over Germany, associated with the European Blocking regime, is responsible for most of the Dunkelflauten. Dunkelflauten during the Greenland Blocking regime are associated with colder temperatures than usual, causing higher electricity demand, and would present a particular challenge as space heating becomes electrified in the future. Furthermore, we show that Dunkelflauten occur predominantly when a weather regime is well established and persists longer than usual. Our study provides novel insight into the occurrence and meteorological characteristics of Dunkelflauten, which is essential for planning resilient energy systems and supporting grid operators to prepare for potential shortages in supply.

AbstractZebra Mussels (Dreissena polymorpha) were introduced into the US in the 1980s and have since spread throughout the country with concomitant impacts on aquatic ecosystems. We placed 20 m transects in a variety of sediment types and collected data on sediment size, mussel coverage (the percent of the bottom covered by mussels), and the presence of macrophytes within 0.25 m2 quadrats in White Bear Lake, MN. To assess the degree of Zebra Mussel aggregation, we calculated Morisita’s index of dispersion (Iδ) at four levels of spatial scale − 0.25 m2, 1 m2, 4 m2, and 40 m2. Understanding the pattern of aggregation in Zebra Mussels is crucial in detecting early invasions, monitoring populations, and attempting to eradicate them. There was greater Zebra Mussel coverage within quadrats with coarser substrates (gravel/cobble and mixed sediment – including rock and boulders) compared to those with finer substrates (silt and sand). Macrophyte coverage did not significantly influence Zebra Mussel coverage on the lake bed sediments. Spatial scale had a large impact on the measure of mussel aggregation. Zebra Mussels in sand and silt had the highest degree of aggregation and high levels of macrophytes resulted in greater degrees of aggregation on the lake bed sediments. Zebra mussel coverage measured at larger spatial scales generally resulted in lower aggregation values, across both sediment types and levels of macrophyte coverage. The appropriate selection of spatial scale for sampling or observation is critical when upscaling local density to lake populations.

IntroductionThe understanding of the pathophysiology of multiple sclerosis (MS) has evolved alongside the characterization of cytokines and chemokines in cerebrospinal fluid (CSF) and serum. However, the complex interplay of pro- and anti-inflammatory cytokines and chemokines in different body fluids in people with MS (pwMS) and their association with disease progression is still not well understood and needs further investigation. Therefore, the aim of this study was to profile a total of 65 cytokines, chemokines, and related molecules in paired serum and CSF samples of pwMS at disease onset.MethodsMultiplex bead-based assays were performed and baseline routine laboratory diagnostics, magnetic resonance imaging (MRI), and clinical characteristics were assessed. Of 44 participants included, 40 had a relapsing–remitting disease course and four a primary progressive MS.ResultsThere were 29 cytokines and chemokines that were significantly higher in CSF and 15 in serum. Statistically significant associations with moderate effect sizes were found for 34 of 65 analytes with sex, age, CSF, and MRI parameters and disease progression.DiscussionIn conclusion, this study provides data on the distribution of 65 different cytokines, chemokines, and related molecules in CSF and serum in newly diagnosed pwMS.

A Review of: Laakso, M., Matthias, L., & Jahn, N. (2021). Open is not forever: A study of vanished open access journals. Journal of the Association for Information Science & Technology, 72(9), 1099–1112. https://doi.org/10.1002/asi.24460 Objective – To determine the number of open access journals that have vanished from the web and to summarize their publishing lifespan, geographical and disciplinary characteristics. Design – A descriptive research study. Setting – The internet and internet archive. Subjects – Open access journals. Methods – To identify vanished open access (OA) journals, vanished was defined by the authors as “a journal that published at least one volume as immediate OA after which production ceased, and the journal, together with the published full-text documents, disappeared from the web.” If the journal content partially existed, it would be considered as vanished if