bluuebunny/crossref_metadata_2025_split huggingface dataset:
Verapamil inhibits Kir2.3 channels by binding to the pore and interfering with PIP2 binding
Authors: Xynogalos Panagiotis , Rahm Ann-Kathrin , Fried Sebastian , Chasan Safak , Scherer Daniel , Seyler Claudia , Katus Hugo A. , Frey Norbert , Zitron Edgar 
Published: November 2022

Abstract
The inwardly rectifying potassium current of the cardiomyocyte (IK1) is the main determinant of the resting potential. Ion channels Kir2.1, Kir2.2, and Kir2.3 form tetramers and are the molecular correlate of macroscopic IK1 current. Verapamil is an antiarrhythmic drug used to suppress atrial and ventricular arrhythmias. Its primary mechanism of action is via blocking calcium channels. In addition, it has been demonstrated to block IK1 current and the Kir2.1 subunit. Its effect on other subunits that contribute to IK1 current has not been studied to date. We therefore analyzed the effect of verapamil on the Kir channels 2.1, 2.2, and 2.3 in the Xenopus oocyte expression system. Kir2.1, Kir2.2, and Kir2.3 channels were heterologously expressed in Xenopus oocytes. Respective currents were measured with the voltage clamp technique and the effect of verapamil on the current was measured. At a concentration of 300 µM, verapamil inhibited Kir2.1 channels by 41.36% ± 2.7 of the initial current, Kir2.2 channels by 16.51 ± 3.6%, and Kir2.3 by 69.98 ± 4.2%. As a verapamil effect on kir2.3 was a previously unknown finding, we analyzed this effect further. At wash in with 300 µM verapamil, the maximal effect was seen within 20 min of the infusion. After washing out with control solution, there was only a partial current recovery. The current reduction from verapamil was the same at − 120 mV (73.2 ± 3.7%), − 40 mV (85.5 ± 6.5%), and 0 mV (61.5 ± 10.6%) implying no voltage dependency of the block. Using site directed mutations in putative binding sites, we demonstrated a decrease of effect with pore mutant E291A and absence of verapamil effect for D251A. With mutant I214L, which shows a stronger affinity for PIP2 binding, we observed a normalized current reduction to 61.9 ± 0.06% of the control current, which was significantly less pronounced compared to wild type channels. Verapamil blocks Kir2.1, Kir2.2, and Kir2.3 subunits. In Kir2.3, blockade is dependent on sites E291 and D251 and interferes with activation of the channel via PIP2. Interference with these sites and with PIP2 binding has also been described for other Kir channels blocking drugs. As Kir2.3 is preferentially expressed in atrium, a selective Kir2.3 blocking agent would constitute an interesting antiarrhythmic concept.
Rapid LC–MS assay for targeted metabolite quantification by serial injection into isocratic gradients
Authors: Groves Ryan A. , Chan Carly C. Y. , Wildman Spencer D. , Gregson Daniel B. , Rydzak Thomas , Lewis Ian A. 
Published: November 2022

Abstract
Liquid chromatography mass spectrometry (LC–MS) has emerged as a mainstream strategy for metabolomics analyses. One advantage of LC–MS is that it can serve both as a biomarker discovery tool and as a platform for clinical diagnostics. Consequently, it offers an exciting opportunity to potentially transition research studies into real-world clinical tools. One important distinction between research versus diagnostics-based applications of LC–MS is throughput. Clinical LC–MS must enable quantitative analyses of target molecules in hundreds or thousands of samples each day. Currently, the throughput of these clinical applications is limited by the chromatographic gradient lengths, which—when analyzing complex metabolomics samples—are difficult to conduct in under ~ 3 min per sample without introducing serious quantitative analysis problems. To address this shortcoming, we developed sequential quantification using isotope dilution (SQUID), an analytical strategy that combines serial sample injections into a continuous isocratic mobile phase to maximize throughput. SQUID uses internal isotope-labelled standards to correct for changes in LC–MS response factors over time. We show that SQUID can detect microbial polyamines in human urine specimens (lower limit of quantification; LLOQ = 106 nM) with less than 0.019 normalized root mean square error. Moreover, we show that samples can be analyzed in as little as 57 s. We propose SQUID as a new, high-throughput LC–MS tool for quantifying small sets of target biomarkers across large cohorts.
Graphical Abstract
Prevalence trends and individual patterns of ADHD medication use in pregnancy in Norway and Sweden, 2010–2019
Authors: Cohen Jacqueline M. , Srinivas Chaitra , Furu Kari , Cesta Carolyn E. , Reutfors Johan , Karlstad Øystein 
Published: November 2022

AbstractPurposeThis study aimed to describe recent trends in ADHD medication use in pregnancy in Norway and Sweden, including prevalence, individual characteristics, and patterns of use.MethodsWe studied ADHD medication use (amphetamine, dexamphetamine, methylphenidate, atomoxetine, lisdexamfetamine, guanfacine) by year and age in pregnancies from 2010 to 2019 identified from the medical birth registers (gestational age ≥ 22 weeks) linked to prescribed drug registers (Norway,N = 577,116; Sweden,N = 1,118,988). We compared characteristics of those who used any ADHD medication in pregnancy to no use in pregnancy. Discontinuation was defined as no use after first trimester.ResultsADHD medication use increased from 2010 to 2019 by 3.0 users per 1000 pregnancies in Norway (from 2.5 to 5.5/1000) and by 6.3 per 1000 in Sweden (from 1.6 to 7.9/1000), mainly driven by methylphenidate and since 2015 by lisdexamfetamine. Medication use has increased among pregnant individuals of all age groups, with higher use among the youngest. Pregnant individuals who used ADHD medication were less likely to be married/cohabiting, more likely be nulliparous and to smoke. They had particularly high use of co-medication with antidepressants, anxiolytics/hypnotics, and opioids: 42% in Norway and 65% in Sweden used at least one additional class of psychotropic medication. Most individuals discontinued ADHD medication in pregnancy (85% Norway, 78% Sweden).ConclusionADHD medication use during pregnancy increased in Norway and Sweden in the last decade. However, discontinuation rates during pregnancy were high. Those who used ADHD medication had more risk factors for pregnancy complications including low parity, smoking, and other psychotropic drug use.
Environmental and Anthropogenic Factors Shape the Skin Bacterial Communities of a Semi-Arid Amphibian Species
Authors: Bates K. A. , Friesen J. , Loyau A. , Butler H. , Vredenburg V. T. , Laufer J. , Chatzinotas A. , Schmeller D. S. 
Published: November 2022

Abstract
The amphibian skin microbiome is important in maintaining host health, but is vulnerable to perturbation from changes in biotic and abiotic conditions. Anthropogenic habitat disturbance and emerging infectious diseases are both potential disrupters of the skin microbiome, in addition to being major drivers of amphibian decline globally. We investigated how host environment (hydrology, habitat disturbance), pathogen presence, and host biology (life stage) impact the skin microbiome of wild Dhofar toads (Duttaphrynus dhufarensis) in Oman. We detected ranavirus (but not Batrachochytrium dendrobatidis) across all sampling sites, constituting the first report of this pathogen in Oman, with reduced prevalence in disturbed sites. We show that skin microbiome beta diversity is driven by host life stage, water source, and habitat disturbance, but not ranavirus infection. Finally, although trends in bacterial diversity and differential abundance were evident in disturbed versus undisturbed sites, bacterial co-occurrence patterns determined through network analyses revealed high site specificity. Our results therefore provide support for amphibian skin microbiome diversity and taxa abundance being associated with habitat disturbance, with bacterial co-occurrence (and likely broader aspects of microbial community ecology) being largely site specific.
Upper tract urothelial carcinoma in Germany: epidemiological data and surgical treatment trends in a total population analysis from 2006 to 2019
Authors: Herout Roman , Baunacke Martin , Flegar Luka , Borkowetz Angelika , Reicherz Alina , Koch Rainer , Kraywinkel Klaus , Thomas Christian , Groeben Christer , Huber Johannes 
Published: November 2022

Abstract
Purpose
To report contemporary epidemiological data and treatment trends for upper tract urothelial carcinoma (UTUC) in Germany over a 14-year period.

Methods
We analyzed data from the nationwide German hospital billing database and the German cancer registry from 2006 to 2018/2019. The significance of changes over time was evaluated via regression analysis. Survival outcomes were calculated using the Kaplan–Meier method.

Results
There was a non-significant increase in the age-standardized incidence rate from 2.5/100,000 in 2006 to 2.9/100.000 in 2018. 13% of patients presented with lymph node metastasis and 7.6% of patients presented with distant metastasis at primary diagnosis. The 5-year overall survival was estimated at 45% and the 10-year overall survival at 32%. Endoscopic biopsies of the renal pelvis and ureter as well as ureteroscopies with excision/destruction of UTUC all increased significantly over the study period. The number of radical nephroureterectomies (RNU) for UTUC steadily increased from 1643 cases in 2006 to 2238 cases in 2019 (p < 0.005) with a shift from open surgery towards minimally invasive surgery. Complex reconstructive procedures like ileal ureter replacement or autotransplantation are rarely performed for urothelial carcinoma of the ureter.

Conclusion
Diagnostic and therapeutic procedures for UTUC have increased and minimally invasive nephroureterectomy is the predominant approach concerning radical surgery in 2019.
Histogram equalization using a selective filter
Authors: Dyke Roberto M. , Hormann Kai 
Published: November 2022

AbstractMany popular modern image processing software packages implement a naïve form of histogram equalization. This implementation is known to produce histograms that are not truly uniform. While exact histogram equalization techniques exist, these may produce undesirable artifacts in some scenarios. In this paper we consider the link between the established continuous theory for global histogram equalization and its discrete implementation, and we formulate a novel histogram equalization technique that builds upon and considerably improves the naïve approach. We show that we can linearly interpolate the cumulative distribution of a low-bit image by approximately dequantizing its intensities using a selective box filter. This helps to distribute the intensities more evenly. The proposed algorithm is subsequently evaluated and compared with existing works in the literature. We find that the method is capable of producing an equalized histogram that has a high entropy, while distances between similar intensities are preserved. The described approach has implications on several related image processing problems, e.g., edge detection.
Real-world comparative effectiveness of ARNI versus ACEi/ARB in HF with reduced or mildly reduced ejection fraction
Authors: Fu Michael , Pivodic Aldina , Käck Oskar , Costa-Scharplatz Madlaina , Dahlström Ulf , Lund Lars H. 
Published: November 2022

Abstract
Aims
Sacubitril/valsartan is a first-in-class angiotensin receptor–neprilysin inhibitor (ARNI) with a class-1 guideline recommendation. We assessed the real-world effectiveness of ARNI versus angiotensin-converting enzyme inhibitor/angiotensin receptor blocker (ACEi/ARB) on all-cause and cardiovascular (CV)-related mortality and hospitalizations in heart failure (HF) with reduced or mildly reduced ejection fraction (EF).

Methods
Patient-level clinical, laboratory, drug dispensation, hospitalization, and mortality data were derived from the Swedish Heart Failure Registry (SwedeHF) and interlinked databases (1 April 2016–31 December 2020). Eligible ARNI:ACEi/ARB patients (n = 7275:24,604) had a left ventricular EF < 50%. Mortality and hospitalizations with ARNI (≤ 3 months pre-/post-1 April 2016 index [SwedeHF]; n = 1506) versus ACEi/ARB (≤ 3 months post-index; n = 17,108) were assessed using propensity score matching (1:1 ratio) with clinical variables, and sensitivity analysis (1:2/1:3 with, and 1:2 without clinical variables).

Results
ARNI induced a 23% reduction in all-cause mortality versus ACEi/ARB (1:1 hazard ratio [HR; 95% confidence interval (CI)]: 0.77 [0.63–0.95], p = 0.013), and a non-significant 23% relative risk reduction in CV-related mortality (0.77 [0.54–1.09], p = 0.13), but no difference in all-cause or CV-related hospitalization (1.02 [0.91–1.13]; p = 0.76; 1.01 [0.91–1.15]; p = 0.84, respectively). Sensitivity analyses confirmed all-cause mortality was reduced for ARNI versus ACEi/ARB (HR 0.90 [95% CI 0.82–0.99], p = 0.026), but not CV-related mortality (HR 1.04 [95% CI 0.89–1.22], p = 0.63).

Conclusions
In this nationwide real-world study including a population of patients with HF with reduced or mildly reduced EF, ARNI as part of guideline-led Swedish clinical practice was associated with a statistically significant relative risk reduction in all-cause mortality compared with ACEi/ARB.
Beta-3 adrenergic receptor overexpression reverses aortic stenosis–induced heart failure and restores balanced mitochondrial dynamics
Authors: Pun-García Andrés , Clemente-Moragón Agustín , Villena-Gutierrez Rocio , Gómez Monica , Sanz-Rosa David , Díaz-Guerra Anabel , Prados Belén , Medina Juan Pablo , Montó Fermí , Ivorra Maria Dolores , Márquez-López Cristina , Cannavo Alessandro , Bernal Juan A. , Koch Walter J. , Fuster Valentin , de la Pompa José Luis , Oliver Eduardo , Ibanez Borja 
Published: November 2022

AbstractAortic stenosis (AS) is associated with left ventricular (LV) hypertrophy and heart failure (HF). There is a lack of therapies able to prevent/revert AS-induced HF. Beta3 adrenergic receptor (β3AR) signaling is beneficial in several forms of HF. Here, we studied the potential beneficial effect of β3AR overexpression on AS-induced HF. Selective β3AR stimulation had a positive inotropic effect. Transgenic mice constitutively overexpressing human β3AR in the heart (c-hβ3tg) were protected from the development of HF in response to induced AS, and against cardiomyocyte mitochondrial dysfunction (fragmented mitochondria with remodeled cristae and metabolic reprogramming featuring altered substrate use). Similar beneficial effects were observed in wild-type mice inoculated with adeno-associated virus (AAV9) inducing cardiac-specific overexpression of human β3AR before AS induction. Moreover, AAV9-hβ3AR injection into wild-type mice at late disease stages, when cardiac hypertrophy and metabolic reprogramming are already advanced, reversed the HF phenotype and restored balanced mitochondrial dynamics, demonstrating the potential of gene-therapy-mediated β3AR overexpression in AS. Mice with cardiac specific ablation of Yme1l (cYKO), characterized by fragmented mitochondria, showed an increased mortality upon AS challenge. AAV9-hβ3AR injection in these mice before AS induction reverted the fragmented mitochondria phenotype and rescued them from death. In conclusion, our results step out that β3AR overexpression might have translational potential as a therapeutic strategy in AS–induced HF.
Conceptualization, use, and outcomes associated with compassion in the care of people with multiple sclerosis: a scoping review
Authors: Simpson Robert , Posa Stephanie , Bruno Tania , Simpson Sharon , Wasilewski Marina B. , Robinson Lawrence R. , Munce Sarah , Bayley Mark , Feinstein Anthony 
Published: November 2022

Abstract
Objective
Compassion is widely regarded as an important component of high-quality healthcare. However, its conceptualization, use, and associated outcomes in the care of people with multiple sclerosis (PwMS) have not been synthesized. The aim of this review is to scope the peer reviewed academic literature on the conceptualization, use, and outcomes associated with compassion in the care of PwMS.

Methods
Studies were eligible for inclusion if reporting primary research data from quantitative, qualitative, or mixed-methods studies on the conceptualization, use, and outcomes associated with compassion in the care of PwMS. Relevant studies were identified through searching five electronic databases (CINAHL, Cochrane Library, EMBASE, MEDLINE, and PsycINFO) in January 2022. We followed the guidance outlined in the Joanna Briggs Institute (JBI) manual for evidence synthesis, and also referred to the Preferred Reporting Items for Systematic Reviews and Meta-analyses extension for Scoping Reviews Checklist (PRISMA-ScR). Simple descriptive methods were used to chart quantitative findings, and a descriptive approach with basic content analysis was employed to describe qualitative findings.

Results
Fifteen studies were included (participant n = 1722): eight quantitative, six mixed-methods, one exclusively qualitative. Synthesized qualitative data revealed that PwMS conceptualize compassion as involving self-kindness, agency, and acceptance. PwMS report using self-compassion in response to unpleasant sensations and experiences. Quantitative findings suggest that compassion may mediate benefit finding, reduced distress, and improved quality of life (QoL) in PwMS, that those with the condition may become more compassionate through time, and that self-compassion specifically can be increased through training in mindfulness. In this context, greater self-compassion in PwMS correlates with less depression and fatigue, better resilience and QoL. Among studies, self-compassion was the most common outcome measure for PwMS.

Conclusions
A nascent literature exists on the conceptualization, use, and outcomes associated with compassion in the care of PwMS. Further research is required to better understand what compassion means to PwMS and those caring for them. However, self-compassion can be cultivated among PwMS and may be helpful for managing unpleasant somatic symptoms and in benefit finding. Impact on other health outcomes is less clear. The use of compassion by health care providers in the care of PwMS is unstudied.
Antiplatelet and anticoagulant therapy in patients with submacular hemorrhage caused by neovascular age-related macular degeneration
Authors: Weber Constance , Bertelsmann Maria , Kiy Zoe , Stasik Isabel , Holz Frank G. , Liegl Raffael 
Published: November 2022

Abstract

Purpose
Patients with extensive submacular hemorrhage (SMH) caused by age-related macular degeneration (AMD) have a poor visual prognosis despite surgical intervention. Systemic blood-thinning drugs, which are commonly prescribed in the same age group, are known to increase the risk of severe hemorrhage in many parts of the body. This study aimed to investigate whether systemic blood-thinning drugs have an impact on the severity of SMH and if there are differences between the different types of blood-thinning medication.

Methods
We reviewed the medical records of patients who suffered from surgically treated SMH between 2020 and 2022. All patients received a full ophthalmologic examination upon presentation including best-corrected visual acuity (BCVA) and optical coherence tomography. Other characteristics that were recorded included size of hemorrhage, blood-thinning therapy, and reason for intake.

Results
A total of 115 patients with a mean age of 82 years were included in this retrospective analysis. Eighty-three patients (72.2%) were on blood-thinning therapy. The mean size of SMH was 32.01 mm2. Mean BCVA at initial presentation was 1.63 logMAR and 1.59 logMAR 1 year after surgery. The size of SMH was significantly larger in patients on blood-thinning medication (35.92 mm2 vs. 21.91 mm2) (p = 0.001) and their BCVA postoperatively was worse with 1.68 logMAR compared to 1.30 logMAR after 1 year (p = 0.503). Patients with vitamin K antagonists had larger SMH size and worse outcomes regarding BCVA compared to direct oral anticoagulants.

Conclusion
Blood thinners in patients with AMD affect the severity of SMH. Consequently, the indication for their intake should be critically evaluated.
When is a postmortem examination carried out? A retrospective analysis of all Swedish deaths 1999–2018
Authors: Tamsen Fredrik , Alafuzoff Irina 
Published: November 2022

AbstractThe objective of this study was to assess who is merited an autopsy in Sweden. Data from the Swedish cause of death (COD) registry over a period of 20 years was retrieved and analysed. A multinominal logistic regression analysis was performed to identify the variables that were most strongly associated with the performance of a clinical or forensic autopsy (CA/FA).A definite COD, i.e. a COD based on autopsy findings, was registered in 12.6% of all deceased during the investigated period. In the remaining cases, the COD was presumed by the clinicians. Being male, born in the Nordic region, dying in a private residence, and unnatural death were most strongly associated with the performance of CA/FA. In contrast, being female, dying from dementia, dying at a nursing home, being born outside of Europe, or living in a small city or rural area seldom led to the performance of CA/FA.The above is certainly surprising as an autopsy provides an opportunity to investigate the cause of death, validate clinical diagnoses, detect unexpected aberrations, audit health care, and provide feedback to clinicians to facilitate their continuing education.