bluuebunny/crossref_metadata_2025 huggingface dataset:
Investigating the marginal and herd effects of COVID-19 vaccination for reducing case fatality rate: Evidence from the United States
Authors: Li Tenglong , Wang Zilong , He Shuyue , Chen Ying
Published: March 2023

Vaccination campaigns have been rolled out in most countries to increase the vaccination coverage and protect against case mortality during the ongoing pandemic. To evaluate the effectiveness of COVID-19 vaccination, it is vital to disentangle the herd effect from the marginal effect and parameterize them separately in a model. To demonstrate this, we study the relationship between the COVID-19 vaccination coverage and case fatality rate (CFR) based on a U.S. vaccination coverage at county level, with daily records from March 11th, 2021 to Jan 26th, 2022 for 3109 U.S. counties. Using segmented regression, we discovered three breakpoints of the vaccination coverage, at which the herd effects could potentially exist. Controlling for county heterogeneity, we found the size of the marginal effect was not constant but actually enlarged as the vaccination coverage increased, and only the herd effect at the first breakpoint was statistically significant, which implied indirect benefit of vaccination may exist at the early stage of a vaccination campaign. Our results have demonstrated that public health researchers should carefully differentiate and quantify the herd and marginal effects in analyzing vaccination data, to better inform vaccination campaign strategies as well as evaluate vaccination effectiveness.
Phosphorylation controls spatial and temporal activities of motor-PRC1 complexes to complete mitosis
Authors: Gluszek-Kustusz Agata , Craske Benjamin , Legal Thibault , McHugh Toni , Welburn Julie P.I.
Published: March 2023

During mitosis, spindle architecture alters as chromosomes segregate to daughter cells. The microtubule crosslinker Protein Required for Cytokinesis 1 (PRC1) is essential for spindle stability, chromosome segregation and completion of cytokinesis, but how it recruits motors to the central spindle to coordinate the segregation of chromosomes is unknown. Here, we combine structural and cell biology approaches to show that the human CENP-E motor, which is essential for chromosome capture and alignment by microtubules, binds to PRC1 through a conserved hydrophobic motif. This binding mechanism is also used by Kinesin-4 Kif4A:PRC1. Usingin vitroreconstitution, we demonstrate that CENP-E slides antiparallel PRC1-crosslinked microtubules. We find that the regulation of CENP-E -PRC1 interaction is spatially and temporally coupled with relocalization to overlapping microtubules in anaphase. Finally, we demonstrate that the PRC1:microtubule motor interaction is essential in anaphase to control chromosome partitioning, retain central spindle integrity and ensure cytokinesis. Taken together our findings reveal the molecular basis for the cell cycle regulation of motor-PRC1 complexes to couple chromosome segregation and cytokinesis.
Superposition of target structures enables design of bi-stable RNA molecules with deep learning
Authors: Blum Christopher F. , Kolkhof Petra , Kollmann Markus
Published: March 2023

The ability to design RNA molecules with specific structures and functions could facilitate research and developments in biotechnology, biology and pharmacy. Here we present a flexible RNA design framework based on deep learning that locally optimizes sequences by gradient-guided search methods. We demonstrate its effectiveness by designing bi-stable RNA molecules by superimposing conformer target structures.
Pharmacologic Activation of a Compensatory Integrated Stress Response Kinase Promotes Mitochondrial Remodeling in PERK-deficient Cells
Authors: Perea Valerie , Baron Kelsey R. , Dolina Vivian , Aviles Giovanni , Rosarda Jessica D. , Guo Xiaoyan , Kampmann Martin , Wiseman R. Luke
Published: March 2023

The integrated stress response (ISR) comprises the eIF2α kinases PERK, GCN2, HRI, and PKR, which induce translational and transcriptional signaling in response to diverse insults. Deficiencies in PERK signaling lead to mitochondrial dysfunction and contribute to the pathogenesis of numerous diseases. We define the potential for pharmacologic activation of compensatory eIF2α kinases to rescue ISR signaling and promote mitochondrial adaptation in PERK-deficient cells. We show that the HRI activator BtdCPU and GCN2 activator halofuginone promote ISR signaling and rescue ER stress sensitivity in PERK-deficient cells. However, BtdCPU induces mitochondrial depolarization, leading to mitochondrial fragmentation and activation of the OMA1-DELE1-HRI signaling axis. In contrast, halofuginone promotes mitochondrial elongation and adaptive mitochondrial respiration, mimicking regulation induced by PERK. This shows halofuginone can compensate for deficiencies in PERK signaling and promote adaptive mitochondrial remodeling, highlighting the potential for pharmacologic ISR activation to mitigate mitochondrial dysfunction and motivating the pursuit of highly-selective ISR activators.
Identification of chemotherapy targets reveals a nucleus-to-mitochondria ROS sensing pathway
Authors: Zhang Junbing , Simpson Claire M. , Berner Jacqueline , Chong Harrison B. , Fang Jiafeng , Sahin Zehra Ordulu , Weiss-Sadan Tom , Possemato Anthony P. , Harry Stefan , Takahashi Mariko , Yang Tzu-yi , Richter Marianne , Patel Himani , Smith Abby E. , Carlin Alexander D. , Hubertus de Groot Adriaan F. , Wolf Konstantin , Shi Lei , Wei Ting-Yu , Dürr Benedikt R. , Chen Nicholas J. , Vornbäumen Tristan , Wichmann Nina O. , Pooladanda Venkatesh , Matoba Yuske , Kumar Shaan , Kim Eugene , Bouberhan Sara , Olivia Esther , Rueda Bo , Bardeesy Nabeel , Liau Brian , Lawrence Michael , Stokes Matt P. , Beausoleil Sean A. , Bar-Peled Liron
Published: March 2023

Multiple chemotherapies are proposed to cause cell death in part by increasing the steady-state levels of cellular reactive oxygen species (ROS). However, for most of these drugs exactly how the resultant ROS function and are sensed is poorly understood. In particular, it’s unclear which proteins the ROS modify and their roles in chemotherapy sensitivity/resistance. To answer these questions, we examined 11 chemotherapies with an integrated proteogenomic approach identifying many unique targets for these drugs but also shared ones including ribosomal components, suggesting one mechanism by which chemotherapies regulate translation. We focus on CHK1 which we find is a nuclear H2O2sensor that promotes an anti-ROS cellular program. CHK1 acts by phosphorylating the mitochondrial-DNA binding protein SSBP1, preventing its mitochondrial localization, which in turn decreases nuclear H2O2. Our results reveal a druggable nucleus-to-mitochondria ROS sensing pathway required to resolve nuclear H2O2accumulation, which mediates resistance to platinum-based chemotherapies in ovarian cancers.
Intragenic DNA inversions expand bacterial coding capacity
Authors: Chanin Rachael B. , West Patrick T. , Park Ryan M. , Wirbel Jakob , Green Gabriella Z. M. , Miklos Arjun M. , Gill Matthew O. , Hickey Angela S. , Brooks Erin F. , Bhatt Ami S.
Published: March 2023

Bacterial populations that originate from a single bacterium are not strictly clonal. Often, they contain subgroups with distinct phenotypes. Bacteria can generate heterogeneity through phase variation: a preprogrammed, reversible mechanism that alters gene expression levels across a population. One well studied type of phase variation involves enzyme-mediated inversion of specific intergenic regions of genomic DNA. Frequently, these DNA inversions flip the orientation of promoters, turning ON or OFF adjacent coding regions within otherwise isogenic populations. Through this mechanism, inversion can affect fitness, survival, or group dynamics. Here, we develop and apply bioinformatic approaches to discover thousands of previously undescribed phase-variable regions in prokaryotes using long-read datasets. We identify ‘intragenic invertons’, a surprising new class of invertible elements found entirely within genes, in bacteria and archaea. To date, inversions within single genes have not been described. Intragenic invertons allow a gene to encode two or more versions of a protein by flipping a DNA sequence within the coding region, thereby increasing coding capacity without increasing genome size. We experimentally characterize specific intragenic invertons in the gut commensalBacteroides thetaiotaomicron, presenting a ‘roadmap’ for investigating this new gene-diversifying phenomenon.

One-Sentence Summary

Intragenic DNA inversions, identified using long-read sequencing datasets, are found in many phyla across the prokaryotic tree of life.
Nitric oxide regulates metabolism in murine stress erythroid progenitors to promote recovery during inflammatory anemia
Authors: Ruan Baiye , Chen Yuanting , Trimidal Sara , Koo Imhoi , Qian Fenghua , Cai Jingwei , Mcguigan John , Hall Molly A. , Patterson Andrew D. , Prabhu K. Sandeep , Paulson Robert F.
Published: March 2023

Inflammation skews bone marrow hematopoiesis increasing the production of myeloid effector cells at the expense of steady-state erythropoiesis. A compensatory stress erythropoiesis response is induced to maintain homeostasis until inflammation is resolved. In contrast to steady-state erythroid progenitors, stress erythroid progenitors (SEPs) utilize signals induced by inflammatory stimuli. However, the mechanistic basis for this is not clear. Here we reveal a nitric oxide (NO)-dependent regulatory network underlying two stages of stress erythropoiesis, namely proliferation, and the transition to differentiation. In the proliferative stage, immature SEPs and cells in the niche increased expression of inducible nitric oxide synthase (Nos2oriNOS) to generate NO. Increased NO rewires SEP metabolism to increase anabolic pathways, which drive the biosynthesis of nucleotides, amino acids and other intermediates needed for cell division. This NO-dependent metabolism promotes cell proliferation while also inhibiting erythroid differentiation leading to the amplification of a large population of non-committed progenitors. The transition of these progenitors to differentiation is mediated by the activation of nuclear factor erythroid 2-related factor 2 (Nfe2l2 or Nrf2). Nrf2 acts as an anti-inflammatory regulator that decreases NO production, which removes the NO-dependent erythroid inhibition and allows for differentiation. These data provide a paradigm for how alterations in metabolism allow inflammatory signals to amplify immature progenitors prior to differentiation.

Key points

Nitric-oxide (NO) dependent signaling favors an anabolic metabolism that promotes proliferation and inhibits differentiation.

Activation of Nfe2l2 (Nrf2) decreases NO production allowing erythroid differentiation.
Developmental Characterization of Neuronal Migration Anomalies and Axon Proliferation in mTOR pathway-associated Malformations of Cortical Development
Authors: Hoffman Paige , Svalina Matthew N. , Flores Chiara , Brzezinski Christine , Kushner J. Keenan , Staple Brandon , Franco Santos , Alexander Allyson L.
Published: March 2023

Drug-resistant epilepsy (DRE) is a prevalent problem in children that can lead to abnormal development and various psychiatric comorbidities. Malformations of cortical development (MCD) include focal cortical dysplasia, tuberous sclerosis complex and hemimegalencephaly, which are the most common pathologies among children who undergo surgical resection for treatment of DRE. These disorders share many histopathological features, including dyslamination of the cerebral cortex and enlarged neuronal somata. Recently, genetic mutations in the mammalian target of rapamycin (mTOR) signaling cascade have been shown to underpin most MCDs. Rodent models, including the RhebCAmodel, recapitulate histologic and physiologic aspects of human DRE. However, there have been few studies characterizing the developmental time point of the histological changes seen in MCDs. In this study, we usein uteroelectroporation to upregulate the Rheb protein (directly upstream of mTOR) in a focal area of the neocortex. We demonstrate that mTOR dysregulation leads to focal dyslamination and increased neuronal size that is histologically similar to MCD, which correlates to spontaneous recurrent seizures. We used immunohistochemistry to investigate neuronal lamination at several time points during development between E18 and P21 and show early differences in lamination that persisted through development. Furthermore, the increased axonal length associated with mTOR upregulation occurs early in development. Our study provides a time frame for the initial development of abnormal neuronal migration and cellular growth that occurs in MCDs, and our data supports that these anatomical changes may contribute to the formation of epileptic networks.
Volumetric analysis of the terminal ductal lobular unit architecture and cell phenotypes in the human breast
Authors: Paavolainen Oona , Peurla Markus , Koskinen Leena M. , Pohjankukka Jonna , Saberi Kamyab , Tammelin Ella , Sulander Suvi-Riitta , Valkonen Masi , Mourao Larissa , Boström Pia , Brück Nina , Ruusuvuori Pekka , Scheele Colinda LGJ , Hartiala Pauliina , Peuhu Emilia
Published: March 2023

Abstract

The major lactiferous ducts of the human breast branch out and ultimately end at terminal ductal lobular units (TDLUs). These glandular structures are the source of milk upon lactation, and also the most common origin of breast cancer. Despite their functional and clinical importance, the three dimensional (3D) architecture of TDLUs has remained undetermined, largely due to their absence in rodent animal models. By utilizing recent technological advances in optical tissue clearing, 3D reconstruction histology and microscopy, we imaged the 3D structure of healthy human breast tissue to determine whether general branching patterns or cell type specific niches exist in the TDLU. Our data demonstrate that highly branched TDLUs, also exhibiting elevated proliferation, are uncommon in the breast tissue regardless of donor age, parity or hormonal contraception. Overall, TDLUs have a consistent shape and their branch parameters are largely comparable between different TDLUs and individuals irrespective of donor age or parity. Simulation of TDLU branching morphogenesis in 3D by mathematical modelling suggests that evolutionarily conserved mechanisms regulate mammary gland branching in humans and mice, despite their anatomical differences. The data also demonstrate a new level of organization within the TDLU structure identifying a main subtree that dominates in bifurcation events and exhibits a more duct-like keratin expression pattern. In all, our data provide the first structural insights into 3D human breast anatomy and branching, and exemplify the power of volumetric imaging in deeper understanding of human breast biology.

Graphical Abstract
ipsecr: An R package for awkward spatial capture–recapture data
Authors: Efford Murray G.
Published: March 2023

Some capture–recapture models for population estimation cannot easily be fitted by the usual methods (maximum likelihood and Markov‐chain Monte Carlo). For example, there is no straightforward probability model for the capture of animals in traps that hold a maximum of one individual (‘single‐catch traps’), yet such data are commonly collected. It is usual to ignore the limit on individuals per trap and analyse with a competing‐risk ‘multi‐catch’ model that gives unbiased estimates of average density. However, that approach breaks down for models with varying density.

Simulation and inverse prediction was suggested by Efford (2004) for estimating population density with data from single‐catch traps, but the method has been little used, in part because the existing software allows only a narrow range of models. I describe a new R package that refines the method and extends it to include models with varying density, trap interference and other sources of non‐independence among detection histories.

The method depends on (i) a function of the data that generates a proxy for each parameter of interest and (ii) functions to simulate new datasets given values of the parameters. By simulating many datasets, it is possible to infer the relationship between proxies and parameters and, by inverting that relationship, to estimate the parameters from the observed data.

The method is applied to data from a trapping study of brushtail possumsTrichosurus vulpeculain New Zealand. A feature of these data is the high frequency of non‐capture events that disabled traps (interference). Allowing for a time‐varying interference process in a model fitted by simulation and inverse prediction increased the steepness of inferred year‐on‐year population decline. Drawbacks and possible extensions of the method are discussed.
Generating continuous maps of genetic diversity using moving windows
Authors: Bishop Anusha P. , Chambers E. Anne , Wang Ian J.
Published: March 2023

Genetic diversity plays a key role in maintaining population viability by preventing inbreeding depression and providing the building blocks for adaptation. Understanding how genetic diversity varies across space is, therefore, of key interest in conservation and population genetics.

Here, we introduce wingen, an r package for calculating continuous maps of genetic diversity, including nucleotide diversity, allelic richness, and heterozygosity, from standard genotypic and spatial data using a spatial moving window approach. We provide functions to account for variation in sample size across space using rarefaction, to create kriging‐interpolated maps of genetic diversity, and to mask any areas that are outside the area of interest.

Tests with simulated and empirical datasets demonstrate that wingen can successfully capture variation in genetic diversity across landscapes from both reduced‐representation and whole genome sequencing datasets. For reduced‐representation datasets, wingen's functions can be run easily on a standard laptop computer, and we provide options for parallelization to increase the efficiency of running larger whole genome datasets.

wingen provides novel and computationally tractable tools for creating informative maps of genetic diversity with applications for conservation prioritization as well as population and landscape genetic analyses.
Superinfections in COVID‐19 patients receiving extracorporeal membrane oxygenation support
Authors: Andersen Harald V. , Jørgensen Vibeke R. L. , Steensen Morten , Pedersen Finn M. , Helleberg Marie
Published: March 2023

Background

The risk of superinfections and associations with mortality among patients with corona virus disease 2019 (COVID‐19) receiving veno‐venous extracorporeal membrane oxygenation (VV‐ECMO) is poorly elucidated.

Method

We identified all patients with COVID‐19 treated with VV‐ECMO >24 h at Rigshospitalet, Denmark from March 2020 to December 2021. Data were obtained by review of medical files. Associations between superinfections and mortality were assessed by logistic regression analyses adjusted for sex and age.

Results

Fifty patients, median age 53 years (interquartile range [IQR] 45–59), 66% male, were included. Median time on VV‐ECMO was 14.5 days (IQR 6.3–23.5), 42% were discharged from hospital alive. Bacteremia, ventilator associated pneumonia (VAP), invasive candidiasis, pulmonary aspergillosis, herpes simplex virus, and cytomegalovirus (CMV) were detected in 38%, 42%, 12%, 12%, 14%, and 20% of patients, respectively. No patients with pulmonary aspergillosis survived. CMV was associated with increased risk of death, odds ratio 12.6 (95% confidence interval 1.9–257, p = .05), whereas we found no associations between other superinfections and risk of death.

Conclusion

Bacteremia and VAP are common but does not seem to affect mortality, whereas pulmonary aspergillosis and CMV are associated with poor prognosis among COVID‐19 patients treated with VV‐ECMO.
A first‐level customization study of SAPS II with Norwegian Intensive Care and Pandemic Registry (NIPaR) data
Authors: Bruserud Øyvind , Haaland Øystein Ariansen , Kvåle Reidar , Buanes Eirik Alnes
Published: March 2023

Background

Severity scores and mortality prediction models (MPMs) are important tools for benchmarking and stratification in the intensive care unit (ICU) and need to be regularly updated using data from a local and contextual cohort. Simplified acute physiology score II (SAPS II) is widely used in European ICUs.

Methods

A first‐level customization was performed on the SAPS II model using data from the Norwegian Intensive Care and Pandemic Registry (NIPaR). Two previous SAPS II models (Model A: the original SAPS II model and Model B: a SAPS II model based on NIPaR data from 2008 to 2010) were compared to the new Model C. Model C was based on patients from 2018 to 2020 (corona virus disease 2019 patients omitted; n = 43,891), and its performances (calibration, discrimination, and uniformity of fit) compared to the previous models (Model A and Model B).

Results

Model C was better calibrated than Model A with a Brier score 0.132 (95% confidence interval 0.130–0.135) versus 0.143 (95% confidence interval 0.141–0.146). The Brier score for Model B was 0.133 (95% confidence interval 0.130–0.135). In the Cox's calibration regression and for both Model C and Model B but not for Model A. Uniformity of fit was similar for Model B and for Model C, both better than for Model A, across age groups, sex, length of stay, type of admission, hospital category, and days on respirator. The area under the receiver operating characteristic curve was 0.79 (95% confidence interval 0.79–0.80), showing acceptable discrimination.

Conclusions

The observed mortality and corresponding SAPS II scores have significantly changed during the last decades and an updated MPM is superior to the original SAPS II. However, proper external validation is required to confirm our findings. Prediction models need to be regularly customized using local datasets in order to optimize their performances.
Complicating College Access: Understanding Compliance and Resistance for Latinx Youth in Suburbia
Authors: Rodriguez Gabriel
Published: March 2023

This qualitative study examines the experiences of Latinx youth and mainly white staff of the Academic Scholars Program, a college access program that operated in an affluent suburban high school. Guided by Critical Race Theory and Critical Whiteness Studies, the findings highlight the constraints Latinx youth and staff faced and how they resisted assimilative practices.
Haemoglobin drift in patients following Whipple's procedure
Authors: Luo Yuchen , Tacey Mark , Hodgson Russell , Houli Nezor , Yong Tuck
Published: March 2023

Backgrounds

This study aims to identify the objective findings of haemoglobin (Hb) drift in patients that had a Whipple's procedure in the last 10 years, their transfusion status intraoperatively and post‐operatively, the potential factors affecting Hb drift, and the outcomes following Hb drift.

Methods

A retrospective study was conducted at Northern Health, Melbourne. All adult patients who were admitted for a Whipple's procedure from 2010 to 2020 were included and information collected retrospectively for demographics, pre‐operative, operative and post‐operative details.

Results

A total of 103 patients were identified. The median Hb drift calculated from a Hb level at the end of operation was 27.0 g/L (IQR 18.0–34.0), and 21.4% of patients received a packed red blood cell (PRBC) transfusion during the post‐operative period. Patients received a large amount of intraoperative fluid with a median of 4500 mL (IQR 3400‐5600). Hb drift was statistically associated with intraoperative and post‐operative fluid infusion leading to concurrent issues with electrolyte imbalance and diuresis.

Conclusion

Hb drift is a phenomenon that does happen in major operations such as a Whipple's procedure, likely secondary to fluid over‐resuscitation. Considering the risk of fluid overload and blood transfusion, Hb drift in the setting of fluid over‐resuscitation needs to be kept in mind prior to blood transfusion to avoid unnecessary complications and wasting of other precious resources.
Reference values for interleukin‐6 in the amniotic fluid of asymptomatic pregnant women
Authors: del Barco Ester , Franco‐Jarava Clara , Vargas Mireia , Maíz Nerea , Arevalo Silvia , Sánchez Maria Ángeles , Avilés Maria Teresa , Rodó Carlota , Mendoza Manel , Goya Maria , Hernández‐González Manuel , Carreras Elena
Published: March 2023

Introduction

Nowadays, proinflammatory factors are considered to play an important role in the pathophysiology of threatened preterm labor or chorioamnionitis. The aim of this study was to establish the normal reference range for interleukin‐6 (IL‐6) levels in the amniotic fluid and to identify factors which may alter this value.

Material and methods

Prospective study in a tertiary‐level center including asymptomatic pregnant women undergoing amniocentesis for genetic studies from October 2016 to September 2019. IL‐6 measurements in amniotic fluid were performed using a fluorescence immunoassay with microfluidic technology (ELLA Proteinsimple, Bio Techne). Maternal history and pregnancy data were also recorded.

Results

This study included 140 pregnant women. Of those, women who underwent termination of pregnancy were excluded. Therefore, a total of 98 pregnancies were included in the final statistical analysis. The mean gestational age was 21.86 weeks (range: 15–38.7) at the time of amniocentesis, and 38.6 weeks (range: 30.9–41.4) at delivery. No cases of chorioamnionitis were reported. The log10 IL‐6 values follow a normal distribution (W = 0.990, p = 0.692).

The median, and the 5th, 10th, 90th, and 95th percentiles for IL‐6 levels were 573, 105, 130, 1645, and 2260 pg/mL, respectively. The log10 IL‐6 values were not affected by gestational age (p = 0.395), maternal age (p = 0.376), body mass index (p = 0.551), ethnicity (p = 0.467), smoking status (p = 0.933), parity (p = 0.557), method of conception (p = 0.322), or diabetes mellitus (p = 0.381).

Conclusions

The log10 IL‐6 values follow a normal distribution. IL‐6 values are independent of gestational age, maternal age, body mass index, ethnicity, smoking status, parity and method of conception. Our study provides a normal reference range for IL‐6 levels in the amniotic fluid that can be used in future studies. We also observed that normal IL‐6 values were higher in the amniotic fluid than in serum.
mTORsignaling in renal ion transport
Authors: Adella Anastasia , de Baaij Jeroen H. F.
Published: March 2023

The mammalian target of rapamycin (mTOR) signaling pathway is crucial in maintaining cell growth and metabolism. The mTOR protein kinase constitutes the catalytic subunit of two multimeric protein complexes called mTOR complex 1 (mTORC1) and mTOR complex 2 (mTORC2). As such, this pathway is indispensable for many organs, including the kidney. Since its discovery, mTOR has been associated with major renal disorders such as acute kidney injury, chronic kidney disease, and polycystic kidney disease. On top of that, emerging studies using pharmacological interventions and genetic disease models have unveiled mTOR role in renal tubular ion handling. Along the tubule, mTORC1 and mTORC2 subunits are ubiquitously expressed at mRNA level. Nevertheless, at the protein level, current studies suggest that a tubular segment‐specific balance between mTORC1 and mTORC2 exists. In the proximal tubule, mTORC1 regulates nutrients transports through various transporters located in this segment. On the other hand, in the thick ascending limb of the loop of Henle, both complexes play a role in regulating NKCC2 expression and activity. Lastly, in the principal cells of the collecting duct, mTORC2 determines Na+reabsorption and K+excretion by regulating of SGK1 activation. Altogether, these studies establish the relevance of the mTOR signaling pathway in the pathophysiology of tubular solute transport. Despite extensive studies on the effectors of mTOR, the upstream activators of mTOR signaling remain elusive in most nephron segments. Further understanding of the role of growth factor signaling and nutrient sensing is essential to establish the exact role of mTOR in kidney physiology.
HbA1c trajectories over 3 years in people with type 2 diabetes starting second‐line glucose‐lowering therapy: The prospective global DISCOVER study
Authors: Bongaerts Brenda , Kuss Oliver , Bonnet Fabrice , Chen Hungta , Cooper Andrew , Fenici Peter , Gomes Marilia B. , Hammar Niklas , Ji Linong , Khunti Kamlesh , Medina Jesús , Nicolucci Antonio , Shestakova Marina V. , Watada Hirotaka , Rathmann Wolfgang
Published: March 2023

Aim

To identify distinct HbA1c trajectories in people with type 2 diabetes (T2D) starting second‐line glucose‐lowering therapy.

Materials and Methods

DISCOVER was a 3‐year observational study of individuals with T2D beginning second‐line glucose‐lowering therapy. Data were collected at initiation of second‐line treatment (baseline) and at 6, 12, 24 and 36 months. Latent class growth modelling was used to identify groups with distinct HbA1c trajectories.

Results

After exclusions, 9295 participants were assessed. Four distinct HbA1c trajectories were identified. Mean HbA1c levels decreased between baseline and 6 months in all groups; 72.4% of participants showed stable good levels of glycaemic control over the remainder of follow‐up, 18.0% showed stable moderate levels of glycaemic control and 2.9% showed stable poor levels of glycaemic control. Only 6.7% of participants showed highly improved glycaemic control at month 6 and stable control over the rest of follow‐up. For all groups, dual oral therapy use decreased over time, compensated for by the increasing use of other treatment regimens. Use of injectable agents increased over time in groups with moderate and poor glycaemic control. Logistic regression models suggested that participants from high‐income countries were more probable to be in the stable good trajectory group.

Conclusions

Most people receiving second‐line glucose‐lowering treatment in this global cohort achieved stable good or highly improved long‐term glycaemic control. One‐fifth of participants showed moderate or poor glycaemic control during follow‐up. Further large‐scale studies are required to characterize possible factors associated with patterns of glycaemic control to inform personalized diabetes treatment.
Evaluation of arterial blood gas parameters as prognostic markers in amyotrophic lateral sclerosis
Authors: Alarcan Hugo , Cotet Camille , Lépine Nadège , Morel Julie , Vourc'h Patrick , Andres Christian , Corcia Philippe , Blasco Hélène
Published: March 2023

Background

Forced vital capacity (FVC) remains difficult to determine for some patients suffering from amyotrophic lateral sclerosis (ALS) due to the rapid progression of the disease. Arterial blood gas (ABG) parameters could represent a valuable alternative. The aim of this study was therefore to evaluate the correlation between ABG parameters and FVC, along with the prognostic ability of ABG parameters, in a large cohort of ALS patients.

Methods

ALS patients (n=302) with FVC and ABG parameters available at diagnosis were included. Correlations between ABG parameters and FVC were evaluated. Cox regression was then carried out to determine the association of each parameter (ABG and clinical data) with survival. Finally, receiver operating characteristic (ROC) curves were built to predict the survival of ALS.

Results

Bicarbonates (HCO3−), oxygen partial pressure (pO2), carbon dioxide partial pressure (pCO2), base excess (BE), oxygen saturation and oxyhemoglobin were significantly correlated with FVC both in patients with spinal or bulbar onset. Univariate Cox regression showed that HCO3− and BE were associated with survival but only in spinal forms. ABG parameters predicted the survival of ALS with a similar performance to FVC, HCO3− being the parameter with the highest area under the curve.

Conclusions

Our results suggest that there is an interest in conducting a longitudinal evaluation throughout disease progression to confirm the equal performances of FVC and ABG. This study highlights the benefits of performing ABG analysis that could be used as an interesting alternative to FVC when spirometry cannot be performed.
Palmitic acid‐induced ferroptosis via CD36 activates ER stress to break calcium‐iron balance in colon cancer cells
Authors: Kuang Hao , Sun Xuehua , Liu Ying , Tang Meng , Wei Yan , Shi Yingying , Li Ruibin , Xiao Guohui , Kang Jinlin , Wang Fen , Peng Jin , Xu Hui , Zhou Fuxiang
Published: March 2023

Ferroptosis, featuring an iron‐dependent peroxidation of lipids, is a novel form of programmed cell death that may hold great potential in cancer therapy. Our study found that palmitic acid (PA) inhibited colon cancer cell viability in vitro and in vivo, in conjunction with an accumulation of reactive oxygen species and lipid peroxidation. The ferroptosis inhibitor Ferrostatin‐1 but not Z‐VAD‐FMK (a pan‐caspase inhibitor), Necrostatin‐1 (a potent necroptosis inhibitor), or CQ (a potent inhibitor of autophagy), rescued the cell death phenotype induced by PA. Subsequently, we verified that PA induces ferroptotic cell death through excess iron as cell death was inhibited by iron chelator deferiprone (DFP), while it was exacerbated by a supplement of ferric ammonium citrate. Mechanistically, PA affects intracellular iron content by inducing endoplasmic reticulum (ER) stress leading to ER calcium release and regulating transferrin (TF) transport through increasing cytosolic calcium levels. Furthermore, we observed that cells with high expression of CD36 were more vulnerable to PA‐induced ferroptosis. Altogether, our findings reveal that PA engages in anti‐cancer properties by activating ER stress/ER calcium release/TF‐dependent ferroptosis, and PA might serve as a compound to activate ferroptosis in colon cancer cells with high CD36 expression.
Service performance assurance for small charities: Experiences from New Zealand
Authors: Xu Gina , Yang Cherrie
Published: March 2023

Small charities in New Zealand are leading the way in service performance reporting and assurance, providing a unique context for exploring the existing practices and challenges. This study investigates small charities' assurance practices based on a content analysis of the performance reports of 120 small registered charities. We found that many small charities have complied with the assurance and reporting requirements of service performance information. However, their reported outcomes and outputs may not be significant, understandable, or sufficient. Auditors exhibit high tolerance towards these issues because of the subjectivity, auditability and materiality related to service performance information. Our study provides preliminary insights on service performance assurance for small charities, which presumably will continue evolving and hopefully improving. However, there is a concern that some charities and assurance practitioners view service performance assurance as a compliance exercise, which does little to improve accountability and transparency in the charity sector.
Evaluation of RETRO‐Mapping for electrophysiological features including direction of plane activity during atrial fibrillation using multipolar catheters in humans
Authors: Smith Sabrina , Coyle Clare , Dhutia Niti , Kanagaratnam Prapa , Linton Nick W. F.
Published: March 2023

Introduction

A quantifiable, automated standard of analyzing heart rhythm has long eluded cardiologists due, in part, to the limitations in technology and the ability to analyze large electrogram datasets. In this proof‐of‐concept study, we propose new measures to quantify plane activity in atrial fibrillation (AF) using our Representation of Electrical Tracking of Origin (RETRO)‐Mapping software.

Methods

We recorded 30 s segments of electrograms at the lower posterior wall of the left atrium using a 20‐pole double loop catheter (AFocusII). The data were analyzed with the custom RETRO‐Mapping algorithm in MATLAB. Thirty second segments were analyzed for number of activation edges, conduction velocity (CV), cycle length (CL), activation edge direction, and wavefront direction. These features were compared across 34 613 plane edges in three types of AF: persistent AF treated with amiodarone (11 906 wavefronts), persistent AF without amiodarone (14 959 wavefronts), and paroxysmal AF (7748 wavefronts). Change in activation edge direction between subsequent frames and change in overall wavefront direction between subsequent wavefronts were analyzed.

Results

All activation edge directions were represented across the lower posterior wall. The median change in activation edge direction followed a linear pattern for all three types of AF with R2 = 0.932 for persistent AF treated without amiodarone, R2 = 0.942 for paroxysmal AF, and R2 = 0.958 for persistent AF treated with amiodarone. All medians and the standard deviation error bars remained below 45° (suggesting all activation edges were traveling within a 90° sector, a criterion for plane activity). The directions of approximately half of all wavefronts (56.1% for persistent without amiodarone, 51.8% for paroxysmal, 48.8% for persistent with amiodarone) were predictive of the directions of the subsequent wavefront.

Conclusion

RETRO‐Mapping can measure electrophysiological features of activation activity and this proof‐of‐concept study suggests that this can be extended to the detection of plane activity in three types of AF. Wavefront direction may have a role in future work for predicting plane activity. For this study, we focused more on the ability of the algorithm to detect plane activity and less the differences between the types of AF. Future work should be in validating these results with a larger data set and comparing with other types of activation such as rotational, collision, and focal. Ultimately, this work can be implemented in real‐time for prediction of wavefronts during ablation procedures.
Conduction system versus biventricular pacing in heart failure with non‐left bundle branch block
Authors: Tan Eugene S. J. , Soh Rodney , Lee Jie‐Ying , Boey Elaine , de Leon Jhobeleen , Chan Siew Pang , Yeo Wee Tiong , Lim Toon Wei , Seow Swee‐Chong , Kojodjojo Pipin
Published: March 2023

Introduction

The benefits of cardiac resynchronization therapy (CRT) with biventricular pacing (BiV) is significantly lower when applied to heart failure (HF) patients with non‐left bundle branch block (LBBB) conduction delay. We investigated clinical outcomes of conduction system pacing (CSP) for CRT in non‐LBBB HF.

Methods

Consecutive HF patients with non‐LBBB conduction delay undergoing CSP were propensity matched for age, sex, HF‐etiology, and atrial fibrillation (AF) in a 1:1 ratio to BiV from a prospective registry of CRT recipients. Echocardiographic response was defined as an increase in left ventricular ejection fraction (LVEF) by ≥10%. The primary outcome was the composite of HF‐hospitalizations or all‐cause mortality.

Results

A total of 96 patients were recruited (mean age 70 ± 11years, 22% female, 68% ischemic HF and 49% AF). Significant reductions in QRS duration and LV dimensions were seen only after CSP, while LVEF improved significantly in both groups (p < 0.05). Echocardiographic response occurred more frequently in CSP than BiV (51% vs. 21%, p < 0.01), with CSP independently associated with four‐fold increased odds (adjusted odds ratio 4.08, 95% confidence interval [CI] 1.34–12.41). The primary outcome occurred more frequently in BiV than CSP (69% vs. 27%, p < 0.001), with CSP independently associated with 58% risk reduction (adjusted hazard ratio [AHR] 0.42, 95% CI 0.21–0.84, p = 0.01), driven by reduced all‐cause mortality (AHR 0.22, 95% CI 0.07–0.68, p < 0.01), and a trend toward reduced HF‐hospitalization (AHR 0.51, 95% CI 0.21–1.21, p = 0.12).

Conclusions

CSP provided greater electrical synchrony, reverse remodeling, improved cardiac function and survival compared to BiV in non‐LBBB, and may be the preferred CRT strategy for non‐LBBB HF.
Comparison of lesion characteristics using temperature‐flow‐controlled versus conventional power‐controlled ablation with fixed ablation index
Authors: Ikenouchi Takashi , Takigawa Masateru , Goya Masahiko , Martin Claire A. , Yamamoto Tasuku , Yamaguchi Junji , Goto Kentaro , Shigeta Takatoshi , Nishimura Takuro , Tao Susumu , Miyazaki Shinsuke , Sasano Tetsuo ,   and other members of the Study Group
Published: March 2023

Introduction

The QDOT‐MicroTM catheter is a novel irrigated contact force (CF) sensing catheter which benefits from thermocouples for temperature monitoring, allowing temperature‐flow‐controlled (TFC) ablation. We compared lesion metrics at fixed ablation index (AI) value during TFC‐ablation and conventional power‐controlled (PC)‐ablation.

Methods

A total of 480 RF‐applications were performed on ex‐vivo swine myocardium with predefined AI targets (400/550) or until steam‐pop occurred, using the QDOT‐MicroTM (TFC‐ablation) and Thermocool SmartTouch SFTM (PC‐ablation).

Results

Both TFC‐ablation and PC‐ablation produced similar lesions in volume (218 ± 116 vs. 212 ± 107 mm3, p = .65); however, lesions using TFC‐ablation were larger in surface area (41.3 ± 8.8 vs. 34.8 ± 8.0  mm2, p < .001) and shallower in depth (4.0 ± 1.0 vs. 4.2 ± 1.1 mm, p = .044). Average power tended to be lower in TFC‐alation (34.2 ± 8.6 vs. 36.9 ± 9.2, p = .005) compared to PC‐ablation due to automatic regulation of temperature and irrigation‐flow. Although steam‐pops were less frequent in TFC‐ablation (24% vs. 15%, p = .021), they were particularly observed in low‐CF (10 g) and high‐power ablation (50 W) in both PC‐ablation (n = 24/240, 10.0%) and TFC‐ablation (n = 23/240, 9.6%). Multivariate analysis revealed that high‐power, low‐CF, long application time, perpendicular catheter orientation, and PC‐ablation were risk factors for steam‐pops. Furthermore, activation of automatic regulation of temperature and irrigation‐flow was independently associated with high‐CF and long application time while ablation power had no significant relationship.

Conclusions

With a fixed target AI, TFC‐ablation reduced the risk of steam‐pops, producing similar lesions in volume, but with different metrics in this ex‐vivo study. However, lower CF and higher power in fixed‐AI ablation may increase the risk of steam‐pops.
Fasting and prolonged food restriction differentially affect GH secretion independently of GH receptor signaling in AgRP neurons
Authors: de Sousa Maria E. , Gusmao Daniela O. , dos Santos Willian O. , Moriya Henrique T. , de Lima Felipe F. , List Edward O. , Kopchick John J. , Donato Jose
Published: March 2023

Growth hormone (GH) receptor (GHR) is abundantly expressed in neurons that co‐release the agouti‐related protein (AgRP) and neuropeptide Y (NPY) in the arcuate nucleus of the hypothalamus (ARH). Since ARHAgRP/NPY neurons regulate several hypothalamic–pituitary‐endocrine axes, this neuronal population possibly modulates GH secretion via a negative feedback loop, particularly during food restriction, when ARHAgRP/NPY neurons are highly active. The present study aims to determine the importance of GHR signaling in ARHAgRP/NPY neurons on the pattern of GH secretion in fed and food‐deprived male mice. Additionally, we compared the effect of two distinct situations of food deprivation: 16 h of fasting or four days of food restriction (40% of usual food intake). Overnight fasting strongly suppressed both basal and pulsatile GH secretion. Animals lacking GHR in ARHAgRP/NPY neurons (AgRP∆GHR mice) did not exhibit differences in GH secretion either in the fed or fasted state, compared to control mice. In contrast, four days of food restriction increased GH pulse frequency, basal GH secretion, and pulse irregularity/complexity (measured by sample entropy), whereas pulsatile GH secretion was not affected in both control and AgRP∆GHR mice. Hypothalamic Ghrh mRNA levels were unaffected by fasting or food restriction, but Sst expression increased in acutely fasted mice, but decreased after prolonged food restriction in both control and AgRP∆GHR mice. Our findings indicate that short‐term fasting and prolonged food restriction differentially affect the pattern of GH secretion, independently of GHR signaling in ARHAgRP/NPY neurons.
Phospholipase C‐ε defines a PACAP‐stimulated pathway for secretion in the chromaffin cell
Authors: Chen Xiaohuan , Coffman Breanna L. , Brindley Rebecca L. , Galpin Jason D. , Ahern Christopher A. , Currie Kevin P. M. , Smrcka Alan V. , Axelrod Daniel , Anantharam Arun
Published: March 2023

Adrenomedullary chromaffin cells respond to splanchnic (sympathetic) nerve stimulation by releasing stress hormones into the circulation. The signal for hormone secretion is encoded in the neurotransmitters – especially acetylcholine (ACh) and pituitary adenylate cyclase activating polypeptide (PACAP) – that are released into the splanchnic‐chromaffin cell synapse. However, functional differences in the effects of ACh and PACAP on the chromaffin cell secretory response are not well defined. Here, selective agonists of PACAP receptors or nicotinic and muscarinic acetylcholine receptors were applied to chromaffin cells. The major differences in the effects of these agents were not on exocytosis, per se, but rather on the steps upstream of exocytosis. In almost every respect, the properties of individual fusion events triggered by PACAP and cholinergic agonists were similar. On the other hand, the properties of the Ca2+ transients evoked by PACAP differed in several ways from those evoked by muscarinic and nicotinic receptor stimulation. A defining feature of the PACAP‐stimulated secretory pathway was its dependence on signaling through exchange protein directly activated by cAMP (Epac) and PLCε. However, the absence of PLCε did not disrupt Ca2+ transients evoked by cholinergic agonists. Accordingly, inhibition of Epac activity did not disrupt secretion triggered by acetylcholine or specific agonists of muscarinic and nicotinic receptors. Thus, PACAP and acetylcholine stimulate chromaffin cell secretion via separate and independent pathways. This feature of stimulus‐secretion coupling may be important for sustaining hormone release from the adrenal medulla under conditions associated with the sympathetic stress response.