bluuebunny/crossref_metadata_2025_split huggingface dataset:
Metformin and risk of age-related macular degeneration in individuals with type 2 diabetes: a retrospective cohort study
Authors: Gokhale Krishna M , Adderley Nicola J , Subramanian Anuradhaa , Lee Wen Hwa , Han Diana , Coker Jesse , Braithwaite Tasanee , Denniston Alastair K , Keane Pearse A , Nirantharakumar Krishnarajah 
Published: February 2022

BackgroundAge-related macular degeneration (AMD) in its late stages is a leading cause of sight loss in developed countries. Some previous studies have suggested that metformin may be associated with a reduced risk of developing AMD, but the evidence is inconclusive.AimsTo explore the relationship between metformin use and development of AMD among patients with type 2 diabetes in the UK.MethodsA large, population-based retrospective open cohort study with a time-dependent exposure design was carried out using IQVIA Medical Research Data, 1995–2019. Patients aged ≥40 with diagnosed type 2 diabetes were included.The exposed group was those prescribed metformin (with or without any other antidiabetic medications); the comparator (unexposed) group was those prescribed other antidiabetic medications only. The exposure status was treated as time varying, collected at 3-monthly time intervals.Extended Cox proportional hazards regression was used to calculate the adjusted HRs for development of the outcome, newly diagnosed AMD.ResultsA total of 173 689 patients, 57% men, mean (SD) age 62.8 (11.6) years, with incident type 2 diabetes and a record of one or more antidiabetic medications were included in the study. Median follow-up was 4.8 (IQR 2.3–8.3, range 0.5–23.8) years. 3111 (1.8%) patients developed AMD. The adjusted HR for diagnosis of AMD was 1.02 (95% CI 0.92 to 1.12) in patients prescribed metformin (with or without other antidiabetic medications) compared with those prescribed any other antidiabetic medication only.ConclusionWe found no evidence that metformin was associated with risk of AMD in primary care patients requiring treatment for type 2 diabetes.
Health research priorities for wildland firefighters: a modified Delphi study with stakeholder interviews
Authors: Pelletier Chelsea , Ross Christopher , Bailey Katherine , Fyfe Trina M , Cornish Katie , Koopmans Erica 
Published: February 2022

ObjectivesThe increase in global wildland fire activity has accelerated the urgency to understand health risks associated with wildland fire suppression. The aim of this project was to identify occupational health research priorities for wildland firefighters and related personnel.DesignIn order to identify, rank and rate health research priorities, we followed a modified Delphi approach. Data collection involved a two-stage online survey followed by semi-structured interviews.SettingBritish Columbia, Canada.ParticipantsParticipants included any current or past wildland firefighter or individuals engaged in related roles. There were 132 respondents to the first survey. Responses to the first survey were analysed to produce 10 research topics which were ranked by 75 participants in the second survey (response rate: 84%).Primary and secondary outcome measuresThe primary outcome was the identification, ranking and level of agreement of research priorities through a two-round online survey. We contextualised these findings through deductive and inductive qualitative content analysis of semi-structured interviews.ResultsThe most important research priorities identified were (% consensus): effects of smoke inhalation on respiratory health (89%), fatigue and sleep (80%), mental health (78%), stress (76%) and long-term risk of disease (67%). Interviews were completed with 14 individuals. Two main themes were developed from an inductive content analysis of interview transcripts: (1) understanding the dynamic risk environment; and (2) organisational fit of mitigation strategies.ConclusionsParticipants expressed a general concern with the unknown mental and physical health impacts of their jobs, including the long-term risk of morbidity and mortality. Future research must address knowledge gaps in our understanding of the health impacts of wildland fire and work to develop appropriate mitigation strategies while considering the needs of workers and unpredictable workplace environment.Trial registration numberOpen Science Framework, https://osf.io/ugz4s/
Effect of intravenous thrombolysis before endovascular therapy on outcome according to collateral status: insight from the ETIS Registry
Authors: Anadani Mohammad , Januel Anne-Christine , Finitsis Stephanos , Clarençon Frédéric , Richard Sébastien , Marnat Gaultier , Bourcier Romain , Sibon Igor , Dargazanli Cyril , Arquizan Caroline , Blanc Raphael , Lapergue Bertrand , Consoli Arturo , Eugene Francois , Vannier Stephane , Caroff Jildaz , Denier Christian , Boulanger Marion , Gauberti Maxime , Rouchaud Aymeric , Macian Montoro Francisco , Rosso Charlotte , Ben Hassen Wagih , Turc Guillaume , Ozkul-Wermester Ozlem , Papagiannaki Chrysanthi , Albucher Jean François , Le Bras Anthony , Evain Sarah , Wolff Valerie , Pop Raoul , Timsit Serge , Gentric Jean-Christophe , Bourdain Frederic , Veunac Louis , de Havenon Adam , Liebeskind David S , Maier Benjamin , Gory Benjamin 
Published: February 2022

BackgroundIt is unknown whether collateral status modifies the effect of pretreatment intravenous thrombolysis (IVT) on the outcomes of patients with large vessel occlusions treated with endovascular therapy (EVT). We aimed to assess whether collateral status modifies the effect of IVT on the outcomes of EVT in clinical practice.MethodsWe used data from the ongoing prospective multicentric Endovascular Treatment in Ischemic Stroke (ETIS) Registry in France. Patients with anterior circulation proximal large vessel occlusions treated with EVT within 6 hours of symptom onset were enrolled. Patients were divided into two groups based on pretreatment with IVT. The two groups were matched based on baseline characteristics. We tested the interaction between collateral status and IVT in unadjusted and adjusted models.ResultsA total of 1589 patients were enrolled in the study, of whom 55% received IVT. Using a propensity score matching method, 724 no IVT patients were matched to 549 IVT patients. In propensity score weighted analysis, IVT was associated with higher odds of early neurological improvement (OR 1.74; 95% CI 1.33 to 2.26), favorable functional outcome (OR 1.66; 95% CI 1.23 to 2.24), excellent functional outcome (OR 2.04; 95% CI 1.47 to 2.83), and successful reperfusion (OR 2.18; 95% CI 1.51 to 3.16). IVT was not associated with mortality or hemorrhagic complications. There was no interaction between collateral status and IVT association with any of the outcomes.ConclusionsCollateral status does not modify the effect of pretreatment IVT on the efficacy and safety outcomes of EVT.
Transvascular in vivo microscopy of the subarachnoid space
Authors: Anagnostakou Vania , Epshtein Mark , Ughi Giovanni J , King Robert M , Valavanis Antonios , Puri Ajit S , Gounis Matthew J 
Published: February 2022

BackgroundThe micro-architectonics of the subarachnoid space (SAS) remain partially understood and largely ignored, likely the result of the inability to image these structures in vivo. We explored transvascular imaging with high-frequency optical coherence tomography (HF-OCT) to interrogate the SAS.MethodsIn vivo HF-OCT was performed in 10 dogs in both the posterior and anterior cerebral circulations. The conduit vessels used were the basilar, anterior spinal, and middle and anterior cerebral arteries through which the perivascular SAS was imaged. The HF-OCT imaging probe was introduced via a microcatheter and images were acquired using a contrast injection (3.5 mL/s) for blood clearance. Segmentation and three-dimensional rendering of HF-OCT images were performed to study the different configurations and porosity of the subarachnoid trabeculae (SAT) as a function of location.ResultsOf 13 acquisitions, three were excluded due to suboptimal image quality. Analysis of 15 locations from seven animals was performed showing six distinct configurations of arachnoid structures in the posterior circulation and middle cerebral artery, ranging from minimal presence of SAT to dense networks and membranes. Different locations showed predilection for specific arachnoid morphologies. At the basilar bifurcation, a thick, fenestrated membrane had a unique morphology. SAT average thickness was 100 µm and did not vary significantly based on location. Similarly, the porosity of the SAT averaged 91% and showed low variability.ConclusionWe have demonstrated the feasibility to image the structures of the SAS with transvascular HF-OCT. Future studies are planned to further map the SAT to increase our understanding of their function and possible impact on neurovascular pathologies.
Dose-dependent effects of high intensity focused ultrasound on compound action potentials in an ex vivo rodent peripheral nerve model: comparison to local anesthetics
Authors: Anderson Thomas Anthony , Delgado Jorge , Sun Sharon , Behzadian Negin , Vilches-Moure Jose , Szlavik Robert B , Butts-Pauly Kim , Yeomans David 
Published: February 2022

BackgroundIn animal models, focused ultrasound can reversibly or permanently inhibit nerve conduction, suggesting a potential role in managing pain. We hypothesized focused ultrasound’s effects on action potential parameters may be similar to those of local anesthetics.MethodsIn an ex vivo rat sciatic nerve model, action potential amplitude, area under the curve, latency to 10% peak, latency to 100% peak, rate of rise, and half peak width changes were assessed after separately applying increasing focused ultrasound pressures or concentrations of bupivacaine and ropivacaine. Focused ultrasound’s effects on nerve structure were examined histologically.ResultsIncreasing focused ultrasound pressures decreased action potential amplitude, area under the curve, and rate of rise, increased latency to 10% peak, and did not change latency to 100% peak or half peak width. Increasing local anesthetic concentrations decreased action potential amplitude, area under the curve, and rate of rise and increased latency to 10% peak, latency to 100% peak, and half peak width. At the highest focused ultrasound pressures, nerve architecture was altered compared with controls.DiscussionWhile some action potential parameters were altered comparably by focused ultrasound and local anesthetics, there were small but notable differences. It is not evident if these differences may lead to differences in clinical pain effects when focused ultrasound is applied in vivo or if focused ultrasound pressures that result in clinically relevant changes damage nerve structures. Given the potential advantages of a non-invasive technique for managing pain conditions, further investigation may be warranted in an in vivo pain model.
Bowhead whale calf detections in the western Beaufort sea during the open water season, 2012–2019
Authors: Clarke J.T. , Ferguson M.C. , Okkonen S.R. , Brower A.A. , Willoughby A.L. 
Published: February 2022

Successful reproduction is essential to a species existence. Here we summarize Bering–Chukchi–Beaufort (BCB) bowhead whale (Balaena mysticetus Linnaeus, 1758) calf distribution, ratio of calf to adult sightings, and encounter rate from data collected during line–transect aerial surveys conducted from July to October 2012–2019 in the western Beaufort Sea (140°W–157°W). During 223,000 on effort km, a total of 274 calves were seen: 100 in summer (July–August) and 174 in fall (September–October), compared with nearly 3,200 non-calves. Calves were widely distributed in the study area in August and September, with distribution in July largely east of 150°W and distribution in October west of 143°W. Calf ratios and encounter rates appear to follow a 3–4 year cycle. Most calves (240/274; 88%) were seen near an adult assumed to be the maternal female, but 9% (26/274) of all calves were observed unaccompanied at the surface and 3% (8/274) were observed with large whales at the surface but not close by. Of the total calves detected, 60% (165/274) were observed after circling was initiated, highlighting the importance of closely investigating all bowhead whale sightings if identification of calves is critical to project goals. Bowhead whale calf data from the eastern Beaufort Sea and Amundsen Gulf in August 2019 are also summarized.
LoRa Networking Techniques for Large-scale and Long-term IoT: A Down-to-top Survey
Authors: Li Chenning , Cao Zhichao 
Published: February 2022

Low-Power Wide-Area Networks (LPWANs) are an emerging Internet-of-Things (IoT) paradigm, which caters to large-scale and long-term sensory data collection demand. Among the commercialized LPWAN technologies, LoRa (Long Range) attracts much interest from academia and industry due to its open-source physical (PHY) layer and standardized networking stack. In the flourishing LoRa community, many observations and countermeasures have been proposed to understand and improve the performance of LoRa networking in practice. From the perspective of the LoRa networking stack; however, we lack a whole picture to comprehensively understand what has been done or not and reveal what the future trends are.
This survey proposes a taxonomy of a two-dimensional (i.e., networking layers, performance metrics) to categorize and compare the cutting-edge LoRa networking techniques. One dimension is the layered structure of the LoRa networking stack. From down to the top, we have the PHY layer, Link layer, Media-access Control (MAC) layer, and Application (App) layer. In each layer, we focus on the three most representative layer-specific research issues for fine-grained categorizing. The other dimension is LoRa networking performance metrics, including range, throughput, energy, and security. We compare different techniques in terms of these metrics and further overview the open issues and challenges, followed by our observed future trends. According to our proposed taxonomy, we aim at clarifying several ways to achieve a more effective LoRa networking stack and find more LoRa applicable scenarios, leading to a brand-new step toward a large-scale and long-term IoT.
Mitochondrial Creatine Kinase Attenuates Pathologic Remodeling in Heart Failure
Authors: Keceli Gizem , Gupta Ashish , Sourdon Joevin , Gabr Refaat , Schär Michael , Dey Swati , Tocchetti Carlo G. , Stuber Annina , Agrimi Jacopo , Zhang Yi , Leppo Michelle , Steenbergen Charles , Lai Shenghan , Yanek Lisa R. , O’Rourke Brian , Gerstenblith Gary , Bottomley Paul A. , Wang Yibin , Paolocci Nazareno , Weiss Robert G. 
Published: February 2022

Background:
Abnormalities in cardiac energy metabolism occur in heart failure (HF) and contribute to contractile dysfunction, but their role, if any, in HF-related pathologic remodeling is much less established. CK (creatine kinase), the primary muscle energy reserve reaction which rapidly provides ATP at the myofibrils and regenerates mitochondrial ADP, is down-regulated in experimental and human HF. To test the hypotheses that pathologic remodeling in human HF is related to impaired cardiac CK energy metabolism and that rescuing CK attenuates maladaptive hypertrophy in experimental HF.

Methods:
First, in 27 HF patients and 14 healthy subjects, we measured cardiac energetics and left ventricular remodeling using noninvasive magnetic resonance 31P spectroscopy and magnetic resonance imaging, respectively. Second, we tested the impact of metabolic rescue with cardiac-specific overexpression of either Ckmyofib (myofibrillar CK) or Ckmito (mitochondrial CK) on HF-related maladaptive hypertrophy in mice.

Results:
In people, pathologic left ventricular hypertrophy and dilatation correlate closely with reduced myocardial ATP levels and rates of ATP synthesis through CK. In mice, transverse aortic constriction-induced left ventricular hypertrophy and dilatation are attenuated by overexpression of CKmito, but not by overexpression of CKmyofib. CKmito overexpression also attenuates hypertrophy after chronic isoproterenol stimulation. CKmito lowers mitochondrial reactive oxygen species, tissue reactive oxygen species levels, and upregulates antioxidants and their promoters. When the CK capacity of CKmito-overexpressing mice is limited by creatine substrate depletion, the protection against pathologic remodeling is lost, suggesting the ADP regenerating capacity of the CKmito reaction rather than CK protein per se is critical in limiting adverse HF remodeling.

Conclusions:
In the failing human heart, pathologic hypertrophy and adverse remodeling are closely related to deficits in ATP levels and in the CK energy reserve reaction. CKmito, sitting at the intersection of cardiac energetics and redox balance, plays a crucial role in attenuating pathologic remodeling in HF.

REGISTRATION:

URL:
https://www.clinicaltrials.gov
; Unique identifier: NCT00181259.
Research Goes Red: Early Experience With a Participant-Centric Registry
Authors: Gilchrist Susan C. , Hall Jennifer L. , Khandelwal Abha , Hidalgo Bertha , Aggarwal Brooke , Kinzy Claire , Mallya Pratheek , Conners Katie , Stevens Laura M. , Alger Heather M. , Mehta Laxmi , Wexler Laura , Mega Jessica L. , Hernandez Adrian , Hayes Sharonne N. , Mieres Jennifer H. , Jessup Mariell , Roger Veronique L. 
Published: February 2022

Rationale:
Cardiovascular disease remains the leading cause of death in women. To address its determinants including persisting cardiovascular risk factors amplified by sex and race inequities, novel personalized approaches are needed grounded in the engagement of participants in research and prevention.

Objective:
To report on a participant-centric and personalized dynamic registry designed to address persistent gaps in understanding and managing cardiovascular disease in women.

Methods and Results:
The American Heart Association and Verily launched the Research Goes Red registry (RGR) in 2019, as an online research platform available to consenting individuals over the age of 18 years in the United States. RGR aims to bring participants and researchers together to expand knowledge by collecting data and providing an open-source longitudinal dynamic registry for conducting research studies. As of July 2021, 15 350 individuals have engaged with RGR. Mean age of participants was 48.0 48.0±0.2 years with a majority identifying as female and either non-Hispanic White (75.7%) or Black (10.5%). In addition to 6 targeted health surveys, RGR has deployed 2 American Heart Association-sponsored prospective clinical studies based on participants’ areas of interest. The first study focuses on perimenopausal weight gain, developed in response to a health concerns survey. The second study is designed to test the use of social media campaigns to increase awareness and participation in cardiovascular disease research among underrepresented millennial women.

Conclusions:
RGR is a novel online participant-centric platform that has successfully engaged women and provided critical data on women’s heart health to guide research. Priorities for the growth of RGR are centered on increasing reach and diversity of participants, and engaging researchers to work within their communities to leverage the platform to address knowledge gaps and improve women’s health.
Patient-Specific TBX5-G125R Variant Induces Profound Transcriptional Deregulation and Atrial Dysfunction
Authors: van Ouwerkerk Antoinette F. , Bosada Fernanda M. , van Duijvenboden Karel , Houweling Arjan C. , Scholman Koen T. , Wakker Vincent , Allaart Cornelis P. , Uhm Jae-Sun , Mathijssen Inge B. , Baartscheer Ton , Postma Alex V. , Barnett Phil , Verkerk Arie O. , Boukens Bastiaan J. , Christoffels Vincent M. 
Published: February 2022

Background:
The pathogenic missense variant p.G125R in TBX5 (T-box transcription factor 5) causes Holt–Oram syndrome (also known as hand–heart syndrome) and early onset of atrial fibrillation. Revealing how an altered key developmental transcription factor modulates cardiac physiology in vivo will provide unique insights into the mechanisms underlying atrial fibrillation in these patients.

Methods:

We analyzed ECGs of an extended family pedigree of Holt–Oram syndrome patients. Next, we introduced the TBX5-p.G125R variant in the mouse genome (
Tbx5

G125R

) and performed electrophysiologic analyses (ECG, optical mapping, patch clamp, intracellular calcium measurements), transcriptomics (single-nuclei and tissue RNA sequencing), and epigenetic profiling (assay for transposase-accessible chromatin using sequencing, H3K27ac [histone H3 lysine 27 acetylation] CUT&RUN [cleavage under targets and release under nuclease sequencing]).

Results:

We discovered high incidence of atrial extra systoles and atrioventricular conduction disturbances in Holt–Oram syndrome patients.
Tbx5

G125R/+

mice were morphologically unaffected and displayed variable RR intervals, atrial extra systoles, and susceptibility to atrial fibrillation, reminiscent of TBX5-p.G125R patients. Atrial conduction velocity was not affected but systolic and diastolic intracellular calcium concentrations were decreased and action potentials were prolonged in isolated cardiomyocytes of
Tbx5

G125R/+

mice compared with controls. Transcriptional profiling of atria revealed the most profound transcriptional changes in cardiomyocytes versus other cell types, and identified over a thousand coding and noncoding transcripts that were differentially expressed. Epigenetic profiling uncovered thousands of TBX5-p.G125R-sensitive, putative regulatory elements (including enhancers) that gained accessibility in atrial cardiomyocytes. The majority of sites with increased accessibility were occupied by Tbx5. The small group of sites with reduced accessibility was enriched for DNA-binding motifs of members of the SP (specificity protein) and KLF (Krüppel-like factor) families of transcription factors. These data show that Tbx5-p.G125R induces changes in regulatory element activity, alters transcriptional regulation, and changes cardiomyocyte behavior, possibly caused by altered DNA binding and cooperativity properties.

Conclusions:
Our data reveal that a disease-causing missense variant in TBX5 induces profound changes in the atrial transcriptional regulatory network and epigenetic state in vivo, leading to arrhythmia reminiscent of those seen in human TBX5-p.G125R variant carriers.