bluuebunny/crossref_metadata_2025_split huggingface dataset:
Pharmacokinetic Characterisation and Comparison of Bioavailability of Intranasal Fentanyl, Transmucosal, and Intravenous Administration through a Three-Way Crossover Study in 24 Healthy Volunteers
Authors: Nardi-Hiebl S. , Ndieyira J. W. , Al Enzi Y. , Al Akkad W. , Koch T. , Geldner G. , Reyher C. , Eberhart L. H. J. 
Published: November 2021

Background. For more than 60 years, the synthetic opioid fentanyl has been widely used in anaesthesia and analgesia. While the intravenous formulation is primarily used for general anaesthesia and intensive care settings, the drug’s high lipophilic properties also allow various noninvasive routes of administration. Published data suggest that intranasal administration is also attractive for use as intranasal patient-controlled analgesia (PCA). A newly developed intranasal fentanyl formulation containing 47 μg fentanyl, intravenous fentanyl, and oral transmucosal fentanyl citrate were characterised, and bioavailability was compared to assess the suitability of the intranasal formulation for an intranasal PCA product. Methods. 27 healthy volunteers were enrolled in a single-centre, open-label, randomised (order of treatments), single-dose study in a three-period crossover design. The pharmacokinetics of one intranasal puff of fentanyl formulation (47 μg, 140 mL per puff), one short intravenous infusion of 50 μg fentanyl, and one lozenge with an integrated applicator (200 μg fentanyl) were studied, and bioavailability was calculated. Blood samples were collected over 12 hours, and plasma concentrations of fentanyl were determined by HPLC with MS/MS detection. Results. 24 volunteers completed the study. The geometric mean of AUC0-tlast was the highest with oral transmucosal administration (1106 h

∗

pg/ml, CV% = 32.86), followed by intravenous (672 h

∗

pg/ml, CV% = 32.18) and intranasal administration (515 h

∗

pg/ml, CV% = 30.10). Cmax was 886 pg/ml (CV% = 59.38) for intravenous, 338 pg/ml (CV% = 45.61) for intranasal, and 310 pg/ml (CV% = 29.58) for oral transmucosal administration. tmax was shortest for intravenous administration (0.06 h, SD = 0.056), followed by intranasal (0.21 h, SD = 0.078) and oral transmucosal administration (1.20 h, SD = 0.763). Dose-adjusted absolute bioavailability was determined to be 74.70% for the intranasal formulation and 41.25% for the oral transmucosal product. In total, 38 adverse events (AEs) occurred. Fourteen AEs were potentially related to the investigational items. No serious AE occurred. Conclusion. Pharmacokinetic parameters and bioavailability of the investigated intranasal fentanyl indicated suitability for its intended use as an intranasal PCA option.
Comparison of Clinical Features between the High and Low Serum KL-6 Patients with Acute Exacerbation of Interstitial Lung Diseases
Authors: Tagami Yoichi , Hara Yu , Murohashi Kota , Nagasawa Ryo , Nishikawa Yurika , Tanaka Meiro , Aoki Ayako , Tanaka Katsushi , Nakashima Kentaro , Watanabe Keisuke , Horita Nobuyuki , Kobayashi Nobuaki , Yamamoto Masaki , Kudo Makoto , Okudela Koji , Kaneko Takeshi 
Published: November 2021

Background. Serum Krebs von den Lungen-6 (KL-6) measurement is widely used to assess disease activity or prognosis in patients with interstitial lung diseases (ILDs). However, the clinical differences between high and low serum KL-6 levels at the time of acute exacerbation (AE) of ILD are not well known. Methods. Clinical parameters including age, sex, Charlson Comorbidity Index score (CCIS), blood biomarkers, high-resolution CT findings, and disease mortality were retrospectively compared between high and low KL-6 (cutoff value: 1000 U/mL) patients at the time of diagnosis of AE of ILDs. Results. Thirty-eight high serum KL-6 and 57 low serum KL-6 patients were included. There was no significant difference in 6-month mortality between them (

P

= 0.685), whereas serum lactate dehydrogenase was a significant predictor of 6-month mortality in the high serum KL-6 patients (odds ratio (OR): 1.006; 95% confidence interval (CI): 1.003–1.009;

P

< 0.001), and CCIS (OR: 1.502; 95% CI: 1.242–1.838;

P

< 0.001) and sex (OR: 5.751; 95% CI: 1.121–105.163;

P

= 0.033) were significant predictors in low serum KL-6 patients. In addition, the incidences of congestive heart failure, symptomatic chronic pulmonary disease, cerebrovascular disease, and second metastatic solid tumours were significantly higher in nonsurvivors with low serum KL-6 than in other groups (

P

< 0.05). Conclusions. The clinical features in patients with AEs of ILDs may differ depending on the serum KL-6 level, and clinicopathological examination according to this subtyping guided by the serum KL-6 level is essential.
Network Analysis Identifies Regulators of Basal-Like Breast Cancer Reprogramming and Endocrine Therapy Vulnerability
Authors: Choi Sea R. , Hwang Chae Young , Lee Jonghoon , Cho Kwang-Hyun 
Published: November 2021

Abstract

Basal-like breast cancer is the most aggressive breast cancer subtype with the worst prognosis. Despite its high recurrence rate, chemotherapy is the only treatment for basal-like breast cancer, which lacks expression of hormone receptors. In contrast, luminal A tumors express ERα and can undergo endocrine therapy for treatment. Previous studies have tried to develop effective treatments for basal-like patients using various therapeutics but failed due to the complex and dynamic nature of the disease. In this study, we performed a transcriptomic analysis of patients with breast cancer to construct a simplified but essential molecular regulatory network model. Network control analysis identified potential targets and elucidated the underlying mechanisms of reprogramming basal-like cancer cells into luminal A cells. Inhibition of BCL11A and HDAC1/2 effectively drove basal-like cells to transition to luminal A cells and increased ERα expression, leading to increased tamoxifen sensitivity. High expression of BCL11A and HDAC1/2 correlated with poor prognosis in patients with breast cancer. These findings identify mechanisms regulating breast cancer phenotypes and suggest the potential to reprogram basal-like breast cancer cells to enhance their targetability.

Significance:
A network model enables investigation of mechanisms regulating the basal-to-luminal transition in breast cancer, identifying BCL11A and HDAC1/2 as optimal targets that can induce basal-like breast cancer reprogramming and endocrine therapy sensitivity.
Metabolic Biomarker Discovery for Risk of Peripheral Artery Disease Compared With Coronary Artery Disease: Lipoprotein and Metabolite Profiling of 31 657 Individuals From 5 Prospective Cohorts
Authors: Tikkanen Emmi , Jägerroos Vilma , Holmes Michael V. , Sattar Naveed , Ala‐Korpela Mika , Jousilahti Pekka , Lundqvist Annamari , Perola Markus , Salomaa Veikko , Würtz Peter 
Published: November 2021

Background
Peripheral artery disease (PAD) and coronary artery disease (CAD) represent atherosclerosis in different vascular beds. We used detailed metabolic biomarker profiling to identify common and discordant biomarkers and clarify pathophysiological differences for these vascular diseases.

Methods and Results

We used 5 prospective cohorts from Finnish population (FINRISK 1997, 2002, 2007, and 2012, and Health 2000; n=31 657; median follow‐up time of 14 years) to estimate associations between >200 metabolic biomarkers and incident PAD and CAD. Metabolic biomarkers were measured with nuclear magnetic resonance, and disease events were obtained from nationwide hospital records. During the follow‐up, 498 incident PAD and 2073 incident CAD events occurred. In age‐ and sex‐adjusted Cox models, apolipoproteins and cholesterol measures were robustly associated with incident CAD (eg, hazard ratio [HR] per SD for higher apolipoprotein B/A‐1 ratio, 1.30; 95% CI, 1.25–1.36), but not with incident PAD (HR per SD for higher apolipoprotein B/A‐1 ratio, 1.04; 95% CI, 0.95–1.14;
P
heterogeneity
<0.001). In contrast, triglyceride levels in low‐density lipoprotein and high‐density lipoprotein were associated with both end points (
P
heterogeneity
>0.05). Lower proportion of polyunsaturated fatty acids relative to total fatty acids, and higher concentrations of monounsaturated fatty acids, glycolysis‐related metabolites, and inflammatory protein markers were strongly associated with incident PAD, and many of these associations were stronger for PAD than for CAD (
P
heterogeneity
<0.001). Most differences in metabolic profiles for PAD and CAD remained when adjusting for traditional risk factors.

Conclusions
The metabolic biomarker profile for future PAD risk is distinct from that of CAD. This may represent pathophysiological differences.
Myocardial Strain and Association With Clinical Outcomes in Danon Disease: A Model for Monitoring Progression of Genetic Cardiomyopathies
Authors: Bui Quan M. , Hong Kimberly N. , Kraushaar Megan , Ma Gary S. , Brambatti Michela , Kahn Andrew M. , Battiha Carol Elias , Boynton Kylie , Storm Garrett , Mestroni Luisa , Taylor Matthew R. G. , DeMaria Anthony N. , Adler Eric A. 
Published: November 2021

Background
Myocardial strain can identify subclinical left ventricular dysfunction in various cardiac diseases, but its association with clinical outcomes in genetic cardiomyopathies remains unknown. Herein, we assessed myocardial strain in patients with Danon disease (DD), a rare X‐linked autophagic disorder that causes severe cardiac manifestations.

Methods and Results

Echocardiographic images were reviewed and used to calculate myocardial strain from a retrospective, international registry of patients with DD. Regression analyses were performed to evaluate for an association of global longitudinal strain (GLS) and ejection fraction with the composite outcome (death, ventricular assist device, heart transplantation, and implantable cardioverter defibrillator for secondary prevention). A total of 22 patients with DD (male 14 [63.6%], median age 16.5 years) had sufficient echocardiograms for analysis. Absolute GLS was reduced with a mean of 12.2% with an apical‐sparing pattern observed. Univariable regression for GLS and composite outcome showed an odds ratio of 1.32 (95% CI, 1.02–1.71) with
P
=0.03. For receiver operating characteristic analysis, the areas under the curve for GLS and ejection fraction were 0.810 (
P
=0.02) and 0.605 (
P
=0.44), respectively. An absolute GLS cutoff of 10.0% yielded a true positive rate of 85.7% and false positive rate of 13.3%.

Conclusions
In this cohort of patients with DD, GLS may be a useful assessment of myocardial function and may predict clinical outcomes. This study highlights the potential use of myocardial strain phenotyping to monitor disease progression and potentially to predict clinical outcomes in DD and other genetic cardiomyopathies.
Dietary and Circulating Long‐Chain Omega‐3 Polyunsaturated Fatty Acids and Mortality Risk After Myocardial Infarction: A Long‐Term Follow‐Up of the Alpha Omega Cohort
Authors: Pertiwi Kamalita , Küpers Leanne K. , de Goede Janette , Zock Peter L. , Kromhout Daan , Geleijnse Johanna M. 
Published: November 2021

Background
Habitual intake of long‐chain omega‐3 fatty acids, especially eicosapentaenoic and docosahexaenoic acid (EPA+DHA) from fish, has been associated with a lower risk of fatal coronary heart disease (CHD) in population‐based studies. Whether that is also the case for patients with CHD is not yet clear. We studied the associations of dietary and circulating EPA+DHA and alpha‐linolenic acid, a plant‐derived omega‐3 fatty acids, with long‐term mortality risk after myocardial infarction.

Methods and Results

We analyzed data from 4067 Dutch patients with prior myocardial infarction aged 60 to 80 years (79% men, 86% on statins) enrolled in the Alpha Omega Cohort from 2002 to 2006 (baseline) and followed through 2018. Baseline intake of fish and omega‐3 fatty acids were assessed through a validated 203‐item food frequency questionnaire and circulating omega‐3 fatty acids were assessed in plasma cholesteryl esters. Hazard ratios (HRs) with 95% CIs were obtained from Cox regression analyses. During a median follow‐up period of 12 years, 1877 deaths occurred, of which 515 were from CHD and 834 from cardiovascular diseases. Dietary intake of EPA+DHA was significantly inversely associated with only CHD mortality (HR, 0.69 [0.52–0.90] for >200 versus ≤50 mg/d; HR, 0.92 [0.86–0.98] per 100 mg/d). Similar results were obtained for fish consumption (HR
CHD
, 0.74 [0.53–1.03] for >40 versus ≤5 g/d;
P
trend
: 0.031). Circulating EPA+DHA was inversely associated with CHD mortality (HR, 0.71 [0.53–0.94] for >2.52% versus ≤1.29%; 0.85 [0.77–0.95] per 1‐SD) and also with cardiovascular diseases and all‐cause mortality. Dietary and circulating alpha‐linolenic acid were not significantly associated with mortality end points.

Conclusions
In a cohort of Dutch patients with prior myocardial infarction, higher dietary and circulating EPA+DHA and fish intake were consistently associated with a lower CHD mortality risk.

Registration

URL:
https://www.clinicaltrials.gov
; Unique identifier: NCT03192410.
Thrombectomy With and Without Computed Tomography Perfusion Imaging in the Early Time Window: A Pooled Analysis of Patient-Level Data
Authors: Jadhav Ashutosh P. , Goyal Mayank , Ospel Johanna , Campbell Bruce C. , Majoie Charles B.L.M. , Dippel Diederik W. , White Phil , Bracard Serge , Guillemin Francis , Davalos Antoni , Hill Michael D. , Demchuk Andrew M. , Brown Scott , Saver Jeffrey L. , Muir Keith W. , Mitchell Peter , Desai Shashvat M. , Jovin Tudor G. 
Published: November 2021

Background:
The optimal imaging paradigm for endovascular thrombectomy (EVT) patient selection in early time window (0–6 hours) treated acute ischemic stroke patients remains uncertain. We aimed to compare post-EVT outcomes between patients who underwent prerandomization basic (noncontrast computed tomography [CT], CT angiography only) versus additional advanced imaging (computed tomography perfusion [CTP] imaging) and to determine the association of performance of prerandomization CTP imaging with clinical outcomes.

Methods:
The HERMES collaboration (Highly Effective Reperfusion Evaluated in Multiple Endovascular Stroke Trials) pooled patient-level data from randomized controlled trials comparing EVT with usual care for acute ischemic stroke due to anterior circulation large vessel occlusion. Good functional outcome, defined as modified Rankin Scale score 0 to 2 at 90 days, was compared between randomized patients with and without CTP baseline imaging. Univariable and multivariable binary logistic regression analysis was performed to determine the association of baseline CTP imaging and good functional outcome.

Results:
We analyzed 1348 patients 610 (45.3%) of whom underwent CTP prerandomization. The benefit of EVT compared with best medical management was maintained irrespective of the baseline imaging paradigm (90-day modified Rankin Scale score 0–2 in EVT versus control patients: with CTP: 46.0% (137/298) versus 28.9% (88/305), without CTP: 44.1% (162/367) versus 27.3% (100/366). Performance of CTP baseline imaging compared with baseline noncontrast CT and CT angiography only yielded similar rates of good outcome (odds ratio, 1.05 [95% CI, 0.82–1.33], adjusted odds ratio, 1.04, [95% CI, 0.80–1.35]).

Conclusions:
Rates of good functional outcome were similar among patients in whom CTP was or was not performed, and EVT treatment effect in the 0- to 6-hour time window was similar in patients with and without baseline CTP imaging.
Mapping Covid-19 Governance in Lebanon: Territories of Sectarianism and Solidarity
Authors: Harb Mona , Gharbieh Ahmad , Fawaz Mona , Dayekh Luna 
Published: November 2021

Abstract
Many states, including Lebanon, have used the Covid-19 pandemic as an occasion to reassert their power and to consolidate their policing and repressive apparatuses. We are far from a seamless scenario, however. Rather than a mere reproduction of the sectarian political system, we argue in this paper that the governance of the pandemic in Lebanon reveals tensions between powerful political parties, weakened public agencies, as well as multiple solidarity groups with diverging aspirations, colliding over the imagined future of the country. Using various sources of information (broadcast, print and online news media, social media), we build a database of the types of actors and the categories of actions across locations, and analyze the territorial and political variations of the governance of the pandemic. The paper demonstrates that the Covid-19 response in Lebanon operates through ongoing negotiations over the national territory in which timid yet visible aspirations for a non-sectarian country confront sectarian territorialities through back-and-forth cycles.
Observing, Measuring, and Assessing the Consequences of Snow Drought
Authors: Gottlieb Alexander R. , Mankin Justin S. 
Published: November 2021

Abstract
Warmer and shorter winters from climate change will reduce snowpacks in most seasonally snow-covered regions of the world, with consequences for freshwater availability in spring and summer when people and ecosystems demand water most. Recent record-low snowpacks, such as those in the winters of 2013/14 and 2014/15 in the western United States, have led to a surge in research on “snow droughts,” which are pointed to as harbingers of global warming that pose significant societal hazards. Yet, despite the importance of understanding snow droughts to best prepare for their attendant impacts, the concept remains amorphous, with no agreed-upon definition of what they are, how best to measure them, and how such snow droughts connect to warm-season impacts. These knowledge gaps limit our understanding of the risks posed by snow droughts in the present and future, and thus our preparedness for their differential impacts on freshwater resources. To address these issues, we compile a hemispheric ensemble of in situ, satellite, and reanalysis snowpack datasets. We use this ensemble to evaluate the scientific challenges and uncertainties arising from differences in defining and measuring snow droughts, and to identify opportunities to leverage this information to better understand the significance of snow droughts. We show that a clearer quantification of what constitutes a snow drought, including its uncertainties, improves our ability to anticipate costly and disruptive warm-season droughts, which is vital for informing risk management and adaptation to changing snow regimes.
Feasibility of Umbilical Hernia Repair Under Local Anesthesia and Monitored Anesthesia Care at a Veteran Affairs Hospital
Authors: Loss Lindsey , Meier Jennie , Phung Tri , Ordonez Javier , Huerta Sergio 
Published: November 2021

Background Local anesthesia (LA) for open umbilical hernia tissue repair (OUHTR) is not widely utilized in academic centers in the United States. We hypothesize that LA for OUHTR is feasible in a veteran patient population. Methods From 2015 to 2019, 449 umbilical hernias were repaired at our institution utilizing a standardized technique in veteran patients. OUHTR was included in this analysis (n = 283). Since 2017, 18.7% (n = 53) UH were repaired under LA. We compared outcomes and operative times between general anesthesia and LA in patients undergoing OUHTR. Univariable and multivariable analyses were performed to determine significance. Results The entire cohort was composed of older (56.3 ± 12.1 years), White (75.5%), obese (body mass index [BMI] = 32.3 ± 4.6 kg/m2) men (98.0%). The average hernia size for the entire cohort was 2.42 ± 1.2 cm. The groups were similar in age and BMI. Patients with higher American Society of Anesthesiologists (ASA) (Odds ratio [OR] 3.1; 95% CI 1.5-6.8) and cardiovascular disease (OR 2.7; 95% CI 1.0-7.2) were more likely to receive LA. Recurrence (0.0% vs 6.0%; P = .9) and 30-day complications (6.0% vs 13%; P = .9) were similar between LA and GA after correcting for hernia size. Operating room times were reduced in the LA group (17.7 minutes; P < .05). None of the patients with LA required postanesthesia care unit for recovery. The patients who received LA reported being comfortable (78.9% of patients), with the worst reported pain being 2.4 ± 2.4 (out of a scale of 10), and 94.7% would elect to receive LA if they had another hernia repair. Conclusion Patients who received LA had more cardiac disease and a higher ASA. Complications were similar between both groups. LA reduced operating room times. Patients were satisfied with LA.
Safety and Clinical Value of Prophylactic Ureteral Stenting Before Cytoreductive Surgery With Hyperthermic Intraperitoneal Chemotherapy
Authors: Hanna David N. , Hermina Andrew , Bradley Emma , Ghani Muhammad O. , Mina Alexander , Bailey Christina E. , Idrees Kamran , Magge Deepa 
Published: November 2021

Background Prophylactic ureteral stents (PUS) are typically placed prior to complex abdominal or pelvic operations at the surgeon’s discretion to help facilitate detection of iatrogenic ureteral injury. However, its usefulness and safety in the setting of cytoreductive surgery with hyperthermic intraperitoneal chemotherapy (CRS-HIPEC) have not been examined. This study aims to evaluate the potential clinical value and risk profile of prophylactic ureteral stent placement prior to CRS-HIPEC. Methods We performed a single-institutional retrospective analysis of 145 patients who underwent CRS-HIPEC from 2013 to 2021. Demographic and operative characteristics were compared between patients who underwent PUS placement and those that did not. Ureteral stent–related complications were evaluated. Results Of the 145 patients included in the analysis, 124 underwent PUS placement. There were no significant differences in patient demographics, medical comorbidities, or tumor characteristics. Additionally, PUS placement did not significantly increase operative time and was not associated with increased pelvic organ resection. However, patients who underwent prophylactic ureteral stenting had significantly higher peritoneal carcinomatosis index score (15.1 vs 9.1, P =.002) and increased rate of ureteral complications (24.2% vs 14.3%, P =.04), which led to lengthened hospital stay (13.2 days vs 8.1 days, P = .03). Notably, the sole ureteral injury and three cases of hydronephrosis were seen in patients who underwent PUS. Conclusion Prophylactic ureteral stent placement in patients undergoing CRS-HIPEC may be useful, particularly in patients with predetermined extensive pelvic disease. However, PUS placement is not without potential morbidity and should be selectively considered in patients for whom benefits outweigh the risks.