bluuebunny/crossref_metadata_2025 huggingface dataset:
Differential Associations of Childhood Abuse and Neglect With Adult Autonomic Regulation and Mood-Related Pathology
Authors: Stevens Sarah K. , Williams DeWayne P. , Thayer Julian F. , Zalta Alyson K.
Published: July 2023

Objective

This study assessed whether different types of childhood maltreatment (i.e., abuse versus neglect) had differential relationships with heart rate variability (HRV) and baroreflex sensitivity. In addition, this study tested the indirect effect of maltreatment subtypes on adult mood-related psychopathology via HRV, and whether these relationships differed in those with HRV above and below established clinical cutoffs.

Methods

Secondary analysis was performed using the Midlife Development in the United States data set (N = 967; M
age = 55; 58.4% female; 75.9% White). In a single study visit, autonomic measurements were captured at rest, during two cognitive stressors (Stroop and MATH tasks), and during recovery after the tasks. Structural equation modeling was used to assess the relationships between key variables during all three measurement periods.

Results

Resting pathways from abuse and neglect to baroreflex sensitivity were nonsignificant, as was the pathway from HRV to mood-related pathology. Notably, greater abuse was significantly predictive of lower HRV (standardized β = −0.42, p = .009), whereas greater neglect was significantly predictive of higher HRV (standardized β = 0.32, p = .034). In addition, higher abuse was significantly predictive of greater adult symptoms (standardized β = 0.39, p < .001), but neglect was not found to be related to adult mood-related pathology. Significant relationships between variables were only found in those with low HRV.

Conclusions

Although cross-sectional, our findings provide further evidence that low HRV may be a transdiagnostic endophenotype for mood-related pathology and suggest that greater differentiation between abuse and neglect is appropriate when investigating the impact of childhood maltreatment on adult health outcomes.
Reaching HIV epidemic control in Nigeria using a lower HIV viral load suppression cut-off
Authors: Chun Helen M. , Milligan Kyle , Boyd Mary Adetinuke , Abutu Andrew , Bachanas Pamela , Dirlikov Emilio
Published: July 2023

Background:

Virologic suppression (VS) has been defined using an HIV viral load (VL) of <1,000 copies/mL. Low-level viremia (51-999 copies/mL) is associated with an increased risk of virologic failure and HIV drug resistance.

Methods:

Retrospective data from persons with HIV (PWH) who initiated ART between January 2016–September 2022 in Nigeria were analyzed for VS at cut-off values <1000 copies/mL.

Results:

In 2022, VS at <1000 copies/mL was 95.7%. Using cut-off values of <400, <200 and <50 copies/mL, VS was 94.2%, 92.5%, and 87.0%, respectively.

Discussion:

Monitoring VS using lower cut-off values, alongside differentiated management of low-level viremia, may help Nigeria achieve HIV epidemic control targets.
Vascular injury markers associated with cognitive impairment in people with HIV on suppressive antiretroviral therapy
Authors: Guha Debjani , Misra Vikas , Yin Jun , Horiguchi Miki , Uno Hajime , Gabuzda Dana
Published: July 2023

Objective:

Human immunodeficiency virus (HIV)-associated neurocognitive disorders (HAND) remain prevalent despite viral suppression on antiretroviral therapy (ART). Vascular disease contributes to HAND, but peripheral markers that distinguish vascular cognitive impairment (VCI) from HIV-related etiologies remain unclear.

Design:

Cross-sectional study of vascular injury, inflammation, and central nervous system (CNS) injury markers in relation to HAND.

Methods:

Vascular injury (VCAM-1, ICAM-1, CRP), inflammation (IFN-γ, IL-1β, IL-6, IL-8, IL-15, IP-10, MCP-1, VEGF-A), and CNS injury (NFL, total Tau, GFAP, YKL-40) markers were measured in plasma and CSF from 248 individuals (143 HIV+ on suppressive ART and 105 HIV- controls).

Results:

Median age was 53 years, median CD4 count, and duration of HIV infection were 505 cells/μl and 16 years, respectively. Vascular injury, inflammation, and CNS injury markers were increased in HIV+ compared with HIV- individuals (p<0.05). HAND was associated with increased plasma VCAM-1, ICAM-1, and YKL-40 (p < 0.01) and vascular disease (p = 0.004). In contrast, inflammation markers had no significant association with HAND. Vascular injury markers were associated with lower neurocognitive T scores in age-adjusted models (p < 0.01). Furthermore, plasma VCAM-1 correlated with NFL (r = 0.29, p = 0.003). Biomarker clustering separated HAND into three clusters: two clusters with high prevalence of vascular disease, elevated VCAM-1 and NFL, and distinctive inflammation profiles (CRP/ICAM-1/YKL-40 or IL-6/IL-8/IL-15/MCP-1), and one cluster with no distinctive biomarker elevations.

Conclusions:

Vascular injury markers are more closely related to HAND and CNS injury in PWH on suppressive ART than inflammation markers and may help to distinguish relative contributions of VCI to HAND.
Unequal Cerebral Magnetic Resonance Imaging Changes in Perinatal Hypoxic Ischemic Injury of Term Neonates
Authors: Venkatakrishna Shyam Sunder B. , Elsingergy Mohamed , Worede Fikadu , Curic Jelena , Andronikou Savvas
Published: July 2023

Background

Perinatal hypoxic ischemic injury (HII) has a higher prevalence in the developing world. One of the primary concepts for suggesting that an imaging pattern reflects a global insult to the brain is when the injury is noted to be bilateral and symmetric in distribution. In the context of HII in term neonates, this is either bilateral symmetric (a) peripheral/watershed (WS) injury or (b) bilateral symmetric basal-ganglia-thalamus (BGT) pattern, often with the peri-Rolandic and hippocampal injury. Unilateral, asymmetric, or unequal distribution of injury may therefore be misdiagnosed as perinatal arterial ischemic stroke.

Objectives

We aimed to determine the prevalence of unequal cerebral injury in HII, identify patterns, and determine their relationship with existing classification of HII.

Materials and Methods

Review of brain magnetic resonance imaging from a database of children with HII. Reports with any unequal pattern of injury were included and further classified as a unilateral, bilateral asymmetric, or symmetric but unequal degree pattern of HII.

Results

A total of 1213 MRI scans in patients with a diagnosis of HII revealed 156 (13%) with unequal involvement of the hemispheres: unilateral in 2 of 1213 (0.2%) (involvement only in the WS), asymmetric in 48 of 1213 (4%) (WS in 6 [0.5%], BGT in 4 [0.3%], and combined BGT and WS in 38 [3.1%]), and bilateral symmetric but unequal degree in 106 of 1213 (8.7%) (WS in 20 [1.6%], BGT in 17 [1.4%], and combined BGT and WS in 69 [5.7%]).

Conclusions

The majority of children with cerebral palsy due to HII demonstrate a characteristic bilateral symmetric pattern of injury. In our study, 13% demonstrated an unequal pattern. Differentiation from perinatal arterial ischemic stroke, which is mostly unilateral and distributed typically in the middle cerebral artery territory, should be possible and recognition of the typical BGT or WS magnetic resonance imaging patterns should add confidence to the diagnosis, in such scenarios.
Quantitative Relaxometry Assessment of Brain Microstructural Abnormality of Preschool Children With Autism Spectrum Disorder With Synthetic Magnetic Resonance Imaging
Authors: Li Shuang-Yu , Zhao Xin , Cheng Mei-Ying , Lu Lin , Guo Jin-Xia , Xuan De-Sheng , Sun Yong-Bing , Xing Qing-Na , Meng Ling-Song , Liao Jun-Jie , Cui Shu-Hong , Zhang Ling-Jie , Feng Zhan-Qi , Zhang Xiao-An
Published: July 2023

Objective

This study aimed to perform an assessment of brain microstructure in children with autism aged 2 to 5 years using relaxation times acquired by synthetic magnetic resonance imaging.

Materials and Methods

Thirty-four children with autism spectrum disorder (ASD) (ASD group) and 17 children with global developmental delay (GDD) (GDD group) were enrolled, and synthetic magnetic resonance imaging was performed to obtain T1 and T2 relaxation times. The differences in brain relaxation times between the 2 groups of children were compared, and the correlation between significantly changed T1/T2 and clinical neuropsychological scores in the ASD group was analyzed.

Results

Compared with the GDD group, shortened T1 relaxation times in the ASD group were distributed in the genu of corpus callosum (GCC) (P = 0.003), splenium of corpus callosum (P = 0.002), and right thalamus (TH) (P = 0.014), whereas shortened T2 relaxation times in the ASD group were distributed in GCC (P = 0.011), left parietal white matter (P = 0.035), and bilateral TH (right, P = 0.014; left, P = 0.016). In the ASD group, the T2 of the left parietal white matter is positively correlated with gross motor (developmental quotient [DQ] 2) and personal-social behavior (DQ5), respectively (r = 0.377, P = 0.028; r = 0.392, P = 0.022); the T2 of the GCC was positively correlated with DQ5 (r = 0.404, P = 0.018); and the T2 of the left TH is positively correlated with DQ2 and DQ5, respectively (r = 0.433, P = 0.009; r = 0.377, P = 0.028). All significantly changed relaxation values were not significantly correlated with Childhood Autism Rating Scale scores.

Conclusions

The shortened relaxometry times in the brain of children with ASD may be associated with the increased myelin content and decreased water content in the brain of children with ASD in comparison with GDD, contributing the understanding of the pathophysiology of ASD. Therefore, the T1 and T2 relaxometry may be used as promising imaging markers for ASD diagnosis.
Being Caught in a Vicious Circle
Authors: Wennström Berith , Lindberg Susan , Svensson Johanna , Larsson Elin , Stensby Helen , Larsson Per-Anders
Published: July 2023

Large paraesophageal hernias are related to life-threatening complications that warrant immediate surgery. Whether the long-standing chronic symptoms related to the disease in individuals without hernia incarceration motivate surgical treatment is still a subject for discussion. The aim of this study was to explore how individuals suffering from Grade II–IV hiatal hernia describe their symptoms and health, as well as how the disease affects their life. Semistructured interviews were performed with 22 individuals planning to undergo surgery for a large paraesophageal hernia. The data were analyzed using qualitative content analysis and resulted in one main theme “Being caught in a vicious circle” and six subthemes “Distressing and uncertain times,” “The symptoms have seized control over my health,” “Loss of energy and strength,” “Strategies for managing daily life,” “Loss of social life,” and “Moments of hope despite failing health.” Central to the participants' descriptions is their commitment to strategies for managing the ever-present and unpredictable symptoms that have seized control over their health. They were trapped in a hopeless and isolated existence, that is, a vicious circle, from which they were unable to escape. Despite the low incidence of volvulus and incarceration, the symptom burden and effect on general health motivate treatment in these individuals.
Heatstroke on the Rise
Authors: Tucker Lucy , Evans Emily
Published: July 2023

Heat-related illnesses, namely, heatstroke is on the rise and is a public health concern nationally and internationally. Heatstroke is generally considered to be a core body temperature greater than 40 °C (104 °F) with dry, hot skin, and central nervous system manifestations. Heatstroke is characterized by a systemic inflammatory response that leads to multiple-organ dysfunction and ultimately death if not treated in a timely manner. Rapid recognition and cooling are imperative, as mortality is high, especially in the elderly. There are many cooling methods that have been studied that include cold-water immersion, tarp-assisted cooling with oscillation (TACO), evaporative cooling (misting/fanning), commercial ice packs, cooling vests and jackets, cold showers, and ice sheets. Although cold-water immersion is the fastest method for cooling, it is not usually feasible in an emergency department (ED). TACO is the most feasible and effective cooling method for EDs. It is vital that EDs have a specific plan in place before implementing TACO, as it requires 30–40 gallons of ice water, a tarp or waterproof sheet, core temperature monitoring, and an ample number of ED staff members to oscillate the water over the patient. Further research is needed to study TACO in the ED setting. As the incidence of heatstroke is expected to increase in the coming years, EDs must have a plan in place to rapidly recognize and treat patients with heatstroke so that patients will have improved outcomes and reduced mortality.
Pediatric Optic Pathway Gliomas Resource Utilization and Prevalence in the OptumLabs Data Warehouse
Authors: Stoddard-Bennett Theo N. , Yu Fei , Spiegel Samuel J. , Perez Claudia F. , Coleman Anne L. , Repka Michael X. , Pineles Stacy L.
Published: July 2023

Background:

Although significant progress has been made in improving the rate of survival for pediatric optic pathway gliomas (OPGs), data describing the methods of diagnosis and treatment for OPGs are limited in the modern era. This retrospective study aims to provide an epidemiological overview in the pediatric population and an update on eye care resource utilization in OPG patients using big data analysis.

Methods:

Using the OptumLabs Data Warehouse, 9–11 million children from 2016 to 2021 assessed the presence of an OPG claim. This data set was analyzed for demographic distribution data and clinical data including average ages for computed tomography (CT), MRI, strabismus, and related treatment (surgery, chemotherapy, and radiation), as well as yearly rates for optical coherence tomography (OCT) and visual field (VF) examinations.

Results:

Five hundred fifty-one unique patients ranging in age from 0 to 17 years had an OPG claim, with an estimated prevalence of 4.6–6.1 per 100k. Among the 476 OPG patients with at least 6 months of follow-up, 88.9% had at least one MRI and 15.3% had at least one CT. Annual rates for OCT and VF testing were similar (1.26 vs 1.35 per year), although OCT was ordered for younger patients (mean age = 9.2 vs 11.7 years, respectively). During the study period, 14.1% of OPG patients had chemotherapy, 6.1% had either surgery or radiation, and 81.7% had no treatment.

Conclusions:

This study updates OPG demographics for the modern era and characterizes the burden of the treatment course for pediatric OPG patients using big data analysis of a commercial claims database. OPGs had a prevalence of about 0.005% occurring equally in boys and girls. Most did not receive treatment, and the average child had at least one claim for OCT or VF per year for clinical monitoring. This study is limited to only commercially insured children, who represent approximately half of the general child population.
Neurobeachin haploinsufficient mice display sex-independent alterations in cued and contextual fear conditioning
Authors: Budniok Samuel , Odent Paulien , Callaerts-Vegh Zsuzsanna , Bosmans Guy , D’Hooge Rudi
Published: July 2023

Neurobeachin (NBEA) is a cytoplasmic protein that regulates receptor trafficking, neurotransmitter and hormone secretion, as well as synaptic connectivity. Recently, hippocampus-dependent contextual extinction, the gradual decrease of a conditioned fear response to a context, was suggested to be specifically impaired in male mice with Nbea deficiency (Nbea
+/-). The current study examines the role of sex in this effect and whether Nbea also influences cued fear conditioning. We included both female and male mice and used a phased contextual and cued fear acquisition protocol that consists of different phases allowing us to assess fear acquisition, cued and contextual fear memory and within-phase extinction. Performance of Nbea
+/- mice during assessment of both contextual and cued fear memory was significantly altered compared to controls, independent of sex. Follow-up analyses revealed that this altered performance could be indicative of impaired within-phase extinction. Altered within-phase extinction was not exclusively attributable to hippocampus, and independent of sex. Our results rather suggest that Nbea influences complex learning more broadly across different brain structures.
NDUFC2 deficiency exacerbates endothelial mesenchymal transformation during ischemia-reperfusion via NLRP3
Authors: Chen Jianwei , Liu Xiaoyu , Bi Ran , Liu Pengtao , Gong Weidong
Published: July 2023

Ischemic stroke is the main type of cerebrovascular disease. Emergency thrombectomy combined with medication therapy is currently the primary treatment for stroke. Inflammation and oxidative stress induced by ischemia-reperfusion cause secondary damage to blood vessels, especially endothelial mesenchymal transformation (EndoMT). However, much is still unclear about the role of EndoMT in ischemia-reperfusion. In this study, an in vivo ischemia-reperfusion model was established by transient middle cerebral artery occlusion (tMCAO) in wild-type (WT) C57BL/6 mice and NLRP3 (NOD-like receptor thermal protein domain associated protein 3) knockout (KO) C57BL/6 mice. An in vitro ischemia-reperfusion model was established by oxygen glucose deprivation and reoxygenation (OGD/R) of human brain microvascular endothelial cells (HBMECs). α-SMA (alpha smooth muscle actin), CD31 (platelet endothelial cell adhesion molecule-1, PECAM-1/CD31), NDUFC2 (NADH: ubiquinone oxidoreductase subunit C2), and NLRP3 were used to evaluate EndoMT and inflammation. Real-time PCR measured superoxide dismutase 1 (SOD1) and catalase (CAT) mRNA expression to evaluate oxidative stress levels. NLRP3 was activated by ischemia-reperfusion injury and NLRP3 inactivation inhibited the EndoMT in tMCAO mice. Further experiments demonstrated that OGD/R treatment induced NLRP3 activation and EndoMT in HBMECs, which resulted in NDUFC2 deficiency. NDUFC2 overexpression suppressed NLRP3 activation and EndoMT in HBMECs induced by OGD/R. Moreover, NDUFC2 overexpression rescued SOD1 and CAT mRNA expression. These results demonstrated that NDUFC2 deficiency decreased the antioxidant levels, leading to NLRP3 activation and EndoMT during ischemia-reperfusion injury and suggesting that NDUFC2 is a potential drug target for the treatment of ischemic stroke.
The transport of mannitol in Sinorhizobium meliloti is carried out by a broad-substrate polyol transporter SmoEFGK and is affected by the ability to transport and metabolize fructose
Authors: Kohlmeier MacLean G. , Oresnik Ivan J.
Published: July 2023

The smo locus (sorbitol mannitol oxidation) is found on the chromosome of

S. meliloti

’s tripartite genome. Mutations at the smo locus reduce or abolish the ability of the bacterium to grow on several carbon sources, including sorbitol, mannitol, galactitol, d-arabitol and maltitol. The contribution of the smo locus to the metabolism of these compounds has not been previously investigated. Genetic complementation of mutant strains revealed that smoS is responsible for growth on sorbitol and galactitol, while mtlK restores growth on mannitol and d-arabitol. Dehydrogenase assays demonstrate that SmoS and MtlK are NAD+-dependent dehydrogenases catalysing the oxidation of their specific substrates. Transport experiments using a radiolabeled substrate indicate that sorbitol, mannitol and d-arabitol are primarily transported into the cell by the ABC transporter encoded by smoEFGK. Additionally, it was found that a mutation in either frcK, which is found in an operon that encodes the fructose ABC transporter, or a mutation in frk, which encodes fructose kinase, leads to the induction of mannitol transport.
Leukocytes carryingClonal Hematopoiesis of Indeterminate Potential(CHIP) Mutations invade Human Atherosclerotic Plaques
Authors: Scheidt Moritz von , Bauer Sabine , Ma Angela , Hao Ke , Kessler Thorsten , Vilne Baiba , Wang Ying , Hodonsky Chani J. , Ghosh Saikat K.B. , Mokry Michal , Gao Hua , Kawai Kenji , Sakamoto Atsushi , Kaiser Juliane , Bongiovanni Dario , Fleig Julia , Oldenbuettel Lilith , Chen Zhifen , Moggio Aldo , Sager Hendrik B. , Hecker Judith S. , Bassermann Florian , Maegdefessel Lars , Miller Clint L. , Koenig Wolfgang , Zeiher Andreas M. , Dimmeler Stefanie , Graw Matthias , Braun Christian , Ruusalepp Arno , Leeper Nicholas J. , Kovacic Jason C. , Björkegren Johan L.M. , Schunkert Heribert
Published: July 2023

Background

Leukocyte progenitors derived from clonal hematopoiesis of undetermined potential (CHIP) are associated with increased cardiovascular events. However, the prevalence and functional relevance of CHIP in coronary artery disease (CAD) are unclear, and cells affected by CHIP have not been detected in human atherosclerotic plaques.

Methods

CHIP mutations in blood and tissues were identified by targeted deep-DNA-sequencing (DNAseq: coverage >3,000) and whole-genome-sequencing (WGS: coverage >35). CHIP-mutated leukocytes were visualized in human atherosclerotic plaques by mutaFISHTM. Functional relevance of CHIP mutations was studied by RNAseq.

Results

DNAseq of whole blood from 540 deceased CAD patients of the Munich cardIovaScular StudIes biObaNk (MISSION) identified 253 (46.9%) CHIP mutation carriers (mean age 78.3 years). DNAseq on myocardium, atherosclerotic coronary and carotid arteries detected identical CHIP mutations in 18 out of 25 mutation carriers in tissue DNA. MutaFISHTMvisualized individual macrophages carryingDNMT3ACHIP mutations in human atherosclerotic plaques. Studying monocyte-derived macrophages from Stockholm-Tartu Atherosclerosis Reverse Networks Engineering Task (STARNET; n=941) by WGS revealed CHIP mutations in 14.2% (mean age 67.1 years). RNAseq of these macrophages revealed that expression patterns in CHIP mutation carriers differed substantially from those of non-carriers. Moreover, patterns were different depending on the underlying mutations, e.g. those carryingTET2mutations predominantly displayed upregulated inflammatory signaling whereasASXL1mutations showed stronger effects on metabolic pathways.

Conclusions

Deep-DNA-sequencing reveals a high prevalence of CHIP mutations in whole blood of CAD patients. CHIP-affected leukocytes invade plaques in human coronary arteries. RNAseq data obtained from macrophages of CHIP-affected patients suggest that pro-atherosclerotic signaling differs depending on the underlying mutations. Further studies are necessary to understand whether specific pathways affected by CHIP mutations may be targeted for personalized treatment.
From Tribal Polarization to Socio-Economic Disparities: Exploring the Landscape of Vaccine Hesitancy on Twitter
Authors: Ayaz Huzeyfe , Celik Muhammed Hasan , Koytak Huseyin Zeyd , Yanik Ibrahim Emre
Published: July 2023

This study analyzed Twitter posts related to vaccine hesitancy and its association with socio-economic variables in the US at the state level. The unique socio-economic characteristics of US states, such as education, race, or income, are significantly associated with attitudes toward vaccination. Our results indicate that vaccine hesitancy is a multifaceted phenomenon shaped by a complex interplay of factors. Furthermore, the research identifies two distinct sets of justifications for vaccine hesitancy. The first set pertains to political concerns, including constitutional rights and conspiracy theories. The second pertains to medical concerns about vaccine safety and efficacy. However, vaccine-hesitant Twitter users pragmatically use broad categories of justification for their beliefs. This behavior may suggest that vaccine hesitancy is influenced by political beliefs, unconscious emotions, and gut-level instinct. Our findings have further implications for the critical role of trust in shaping attitudes toward vaccination and the need for tailored communication strategies to restore faith in marginalized communities.
A nine-year investigation of industry payments to emergency physicians in the United States between 2013 and 2021
Authors: Murayama Anju
Published: July 2023

Objectives

To examine the characteristics and trends in the industry payments to emergency physicians since the inception of the Open Payments Database in 2013 and the COVID-19 pandemic in 2020.

Methods

Using the Open Payments Database between August 2013 and December 2021, this population-based cohort study examined all research and general payments made by the healthcare industry to emergency physicians registered in the National Plan and Provider Enumeration System in the United States. We performed descriptive analyses on payment data and generalized estimating equations for payment trends.

Results

Among 50,483 active emergency physicians, 28,678 (56.8%) accepted a total of $457,640,796.73 payments from the healthcare industry between 2013 and 2021. 56.6% and 1.3% of all emergency physicians received general and research payments, respectively. 20.8% ($94.98 millions) of overall industry payments were general payments. Median general and research payments per-physician (interquartile range) were $133.21 ($44.78–$355.77) and $62,842.97 ($10,320.00–$273,285.28), respectively. Top 1% of emergency physicians received 86.2% of overall general payments, respectively. The number of physicians receiving general payments decreased by 2.9% (95% CI: −3.2 to −2.5, p<0.001) annually between 2014 and 2019 and 47.8% (95% CI: −49.8 to −45.6, p<0.001) in 2020. Although there were no significant changes in research payments before COVID-19 pandemic, the research payments significantly increased by 69.4% (95% CI: 28.9–122.7, p<0.001) in 2021 than those in 2020.

Conclusions

Majority of emergency physicians accepted general payments from the healthcare industry, but the number of emergency physician accepting the general payments significantly decreased since the inception of Open Payments Database.
Tricuspid annulus remodelling after transcatheter edge-to-edge repair for reduction of tricuspid regurgitation
Authors: Widmann Maddalena , Castriota Fausto , Nerla Roberto , Ribichini Flavio , Pesarini Gabriele , Fisicaro Andrea , Squeri Angelo
Published: July 2023

Abstract

Background

In the last years multiple transcatheter devices for tricuspid valve interventions were developed. Aim of the study is to evaluate the acute tricuspid annulus remodelling after percutaneous leaflet repair, using a leaflet approximation device (TriClip Abbott Vascular, Santa Clara, CA, USA) for reduction of tricuspid regurgitation.

Methods and results

This is a retrospective dual-center cohort study that includes 26 consecutive patients, treated with TriClip in Maria Cecilia Hospital of Cotignola and in the University Hospital of Verona. Tricuspid annulus geometry was evaluated using three-dimensional transesophageal echocardiography examinations conducted during the procedure before and after TriClip implantation.

The mean age of the study cohort was 79,3 years, and 88,5% were female. Tricuspid regurgitation was graded severe or greater at pre-operative examination in all patients, mostly due to annular dilation. Procedure was successfully in all patients, with at least 1-grade reduction of tricuspid regurgitation before hospital dismissal. A significative reduction of mean septal-lateral diameter (4,09 ± 0,44 cm vs 3,54 ± 0,53 cm, p=< 0,0001), mean major diameter (4,65 ± 0,63 cm vs 4,28 ± 0,65 cm, p=0,0002), planimetric area (14,00 ± 2,91 cm2 vs 11,25 ± 2,91 cm2, p=<0,0001) and perimeter (13,62 ± 1,43 cm vs 12,42 ± 1,62 cm, p=<0,0001) of the tricuspid annulus was observed.

Conclusions

In this small real-world population, edge-to-edge repair using TriClip was found to be effective and safe. Tricuspid transcatheter repair with a leaflet approximation device lead also to reduction in the tricuspid annular dimensions. This is to date the first study that shows positive changes in tricuspid annular geometry, that could have potentially relevant therapeutic implications.
Multimorbidity and blood pressure control: a cross-sectional analysis among 67,385 adults with hypertension in Canada
Authors: Nguyen Tu N , Kalia Sumeet , Hanlon Peter , Jani Bhautesh D , Nicholl Barbara I , Christie Chelsea D. , Aliarzadeh Babak , Moineddin Rahim , Harrison Christopher , Chow Clara , Fortin Martin , Mair Frances S , Greiver Michelle
Published: July 2023

Background

There has been conflicting evidence on the association between multimorbidity and blood pressure (BP) control. This study aimed to investigate this associations in people with hypertension attending primary care in Canada, and to assess whether individual long-term conditions are associated with BP control.

Methods

A cross-sectional study in people with hypertension attending primary care in Toronto between January 01 2017 and December 31 2019. Uncontrolled BP was defined as systolic BP≥140 mmHg or diastolic BP≥90 mmHg. A list of 11 a priori selected chronic conditions was used to define multimorbidity. Multimorbidity was defined as having ≥1 long-term condition in addition to hypertension. Logistic regression models were used to estimate the association between multimorbidity (or individual long-term conditions) with uncontrolled BP.

Results

A total of 67,385 patients with hypertension were included. They had a mean age of 70, 53.1% were female, 80.6% had multimorbidity, and 35.7% had uncontrolled BP. Patients with multimorbidity had lower odds of uncontrolled BP than those without multimorbidity (adjusted OR 0.72, 95% CI 0.68-0.76). Among the long-term conditions, diabetes (aOR 0.73, 95%CI 0.70-0.77), heart failure (aOR 0.81, 95%CI 0.73-0.91), ischemic heart disease (aOR 0.74, 95%CI 0.69-0.79), schizophrenia (aOR 0.79, 95%CI 0.65-0.97), depression/anxiety (aOR 0.91, 95%CI 0.86-0.95), dementia (aOR 0.87, 95%CI 0.80-0.95), and osteoarthritis (aOR 0.89, 95%CI 0.85-0.93) were associated with a lower likelihood of uncontrolled BP.

Conclusion

We found that multimorbidity was associated with better BP control. Several conditions were associated with better control, including diabetes, heart failure, ischemic heart disease, schizophrenia, depression/anxiety, dementia, and osteoarthritis.
Molecular Basis of Kv1 Channel Downregulation and Its Epileptogenic Implications in Lgi1 Knock-out Mice
Authors: Ramirez-Franco Jorge , Debreux Kévin , Sangiardi Marion , Belghazi Maya , Kim Yujin , Lee Suk-Ho , Lévêque Christian , Seagar Michael , El Far Oussama
Published: July 2023

The Kv1members (KCNA, Shaker) of the voltage-gated potassium channels are implicated in determining key functional neuronal properties from spike generation at axonal initial segments to the control of synaptic strength at nerve terminals. In animal models of LGI1-dependent autosomal dominant lateral temporal lobe epilepsy (ADTLE), Kv1channels are downregulated, suggesting their crucial involvement in epileptogenesis. The molecular basis of Kv1channel-downregulation in LGI1 knock-out mice has not been elucidated and how the absence of this extracellular protein induces an important modification in the expression of Kv1remains unknown. In this study we analyse by immunofluorescence the detailed modifications in neuronal Kv1.1and Kv1.2distribution throughout the hippocampal formation of LGI1 knock-out mice. We show that Kv1downregulation is not restricted to the axonal compartment, but also takes place in the somatodendritic region and is accompanied by a drastic decrease in Kv2expression levels. Moreover, we find that the downregulation of these Kv channels is associated with an important increase in bursting patterns. Finally, mass spectrometry uncovered key important modifications in the Kv1interactome that highlight the epileptogenic implication of Kv1downregulation in LGI1 knock-out animals.
A step in the deep evolution of Alvinellidae (Annelida: Polychaeta): A phylogenomic comparative approach based on transcriptomes
Authors: Brun Pierre-Guillaume , Hourdez Stéphane , Ballenghien Marion , Zhou Yadong , Mary Jean , Jollivet Didier
Published: July 2023

The Alvinellidae are a family of worms that are endemic to deep-sea hydrothermal vents in the Pacific and Indian Oceans. These annelid worms, a sister group to the Ampharetidae, occupy a wide range of thermal habitats. The family includes the most thermotolerant marine animals described to date such as the Pompeii wormAlvinella pompejana, and other species living at much lower temperatures such asParalvinella grassleiorParalvinella pandorae. The phylogeny of this family has not been studied extensively. It is, however, a complex case where molecular phylogenies have given conflicting results, especially concerning the monophyletic or polyphyletic nature of the genusParalvinella.

We carried out a comprehensive study of the phylogeny of this family using the best molecular data currently available from RNAseq datasets, leading to several hundred orthologous transcripts for 11 of the 14 species currently described or in description. The results obtained by the two most popular phylogenetic inference models (using either gene concatenation with maximum likelihood, or a coalescent-based model from gene trees) were compared using a series of ampharetid and terebellid outgroups.

Our study shows that the global phylogenetic signal favors the hypothesis of paraphyly for theParalvinellagenus, withP. pandoraebeing sister species of the other Alvinellidae. However, a high number of gene trees also supports the hypothesis of alternative trees in which the monophyly of theParalvinellagenus, as initially proposed by Desbruyères and Laubier, is valid with the speciesP. pandoraeandParalvinella unidentatabeing sister species. According to molecular dating, the radiation of the Alvinellidae was rapid and took place in a short period of time between 80 and 110 million years ago. This is reflected at the genomic scale by gene trees equally separated between different phylogenetic hypothesis, showing high rates of incomplete lineage sorting between the first lineages of the Alvinellidae and probable gene transfers. Although different genomic regions seem to have different phylogenetic stories in the early step of the alvinellid radiation, our study supports the view that the twoP. pandoraespecies can be grouped into a separate genus (possiblyNautalvinella) and that theMiralvinellasubgenus, defined by Desbruyères and Laubier, is not valid anymore.
The CB1receptor interacts with cereblon and drives cereblon deficiency-associated memory shortfalls
Authors: Costas-Insua Carlos , Hermoso-López Alba , Moreno Estefanía , Montero-Fernández Carlos , Álvaro-Blázquez Alicia , Diez-Alarcia Rebeca , Maroto Irene B. , Morales Paula , Canela Enric I. , Casadó Vicent , Urigüen Leyre , Bellocchio Luigi , Rodríguez-Crespo Ignacio , Guzmán Manuel
Published: July 2023

Cereblon/CRBN is a substrate-recognition component of the Cullin4A-DDB1-Roc1 E3 ubiquitin ligase complex. Destabilizing mutations in the humanCRBNgene cause a form of autosomal recessive non-syndromic intellectual disability (ARNSID) that is modelled by knocking-out the mouseCrbngene. A reduction in excitatory neurotransmission has been proposed as an underlying mechanism of the disease, but the intimate factors eliciting this impairment remain mostly unknown. Here we report that CRBN molecules selectively located on glutamatergic neurons are necessary for proper memory function. Combining variousin vivoapproaches, we show that the cannabinoid CB1receptor (CB1R), a key suppressor of synaptic transmission, is overactivated in CRBN deficiency-linked ARNSID mouse models, and that the memory deficits observed in these animals can be rescued by acute CB1R-selective pharmacological antagonism. Molecular studies demonstrated that CRBN interacts physically with CB1R and impairs the CB1R-Gi/o-cAMP-PKA pathway in a ubiquitin ligase-independent manner. Taken together, these findings unveil that CB1R overactivation is a driving mechanism of CRBN deficiency-linked ARNSID and anticipate that the blockade of CB1R could constitute a new therapy for this orphan disease.
Mining drug-target interactions from biomedical literature using chemical and gene descriptions-based ensemble transformer model
Authors: Aldahdooh Jehad , Tanoli Ziaurrehman , Tang Jing
Published: July 2023

Drug-target interactions (DTIs) play a pivotal role in drug discovery, as it aims to identify potential drug targets and elucidate their mechanism of action. In recent years, the application of natural language processing (NLP), particularly when combined with pre-trained language models, has gained considerable momentum in the biomedical domain, with the potential to mine vast amounts of texts to facilitate the efficient extraction of DTIs from the literature. In this article, we approach the task of DTIs as an entity-relationship extraction problem, utilizing different pretrained transformer language models, such as BERT, to extract DTIs. Our results indicate that an ensemble approach, by combining gene descriptions from the Entrez Gene database with chemical descriptions from the Comparative Toxicogenomics Database (CTD), is critical for achieving optimal performance. The proposed model achieves an F1 score of80.6on the hidden DrugProt test set, which is the top-ranked performance among all the submitted models in the official evaluation. Furthermore, we conduct a comparative analysis to evaluate the effectiveness of various gene textual descriptions sourced from Entrez Gene and UniProt databases to gain insights into their impact on the performance. Our findings highlight the potential of NLP-based text mining using gene and chemical descriptions to improve drug-target extraction tasks. Datasets utilized in this study are accessible athttps://dtis.drugtargetcommons.org/.
Data-driven probabilistic definition of the low energy conformational states of protein residues
Authors: Gavalda-Garcia Jose , Bickel David , Roca-Martinez Joel , Raimondi Daniele , Orlando Gabriele , Vranken Wim
Published: July 2023

Protein dynamics and related conformational changes are essential for their function but difficult to characterise and interpret. Amino acids in a protein behave according to their local energy landscape, which is determined by their local structural context and environmental conditions. The lowest energy state for a given residue can correspond to sharply defined conformations,e.g., in a stable helix, or can cover a wide range of conformations,e.g., in intrinsically disordered regions. A good definition of such low energy states is therefore important to describe the behavior of a residue and how it changes with its environment. We propose a data-driven probabilistic definition of six low energy conformational states typically accessible for amino acid residues in proteins. This definition is based on solution NMR information of 1,322 proteins through a combined analysis of structure ensembles with interpreted chemical shifts. We further introduce a conformational state variability parameter that captures, based on an ensemble of protein structures from molecular dynamics or other methods, how often a residue moves between these conformational states. The approach enables a different perspective on the local conformational behavior of proteins that is complementary to their static interpretation from single structure models.
Immune Profiling among Colorectal Cancer Subtypes using Dependent Mixture Models
Authors: Duan Yunshan , Guo Shuai , Wang Wenyi , Mueller Peter
Published: July 2023

Comparison of transcriptomic data across different conditions is of interest in many biomedical studies. In this paper, we consider comparative immune cell profiling for early-onset (EO) versus late-onset (LO) colorectal cancer (CRC). EOCRC, diagnosed between ages 18-45, is a rising public health concern that needs to be urgently addressed. However, its etiology remains to be poorly understood. We work towards filling this gap by identifying homogeneous T cell subpopulations that show significantly distinct characteristics across the two tumor types, and to identify others that are shared between EOCRC and LOCRC. Such inference may reveal underlying determinants of clinically observed differences in the two disease subpopulations. We develop dependent finite mixture models where immune subtypes enriched under a specific condition are characterized by terms in the mixture model with common atoms but distinct weights across conditions, whereas common subtypes are characterized by sharing both atoms and relative weights. The proposed model defines a variation of mixtures of finite mixture models, facilitating the desired comparison by introducing highly structured multi-layer Dirichlet priors. The model allows us to explicitly compare features across conditions. We illustrate inference with simulation studies and data examples. Results identify EO-enriched and LO-enriched T cells subtypes whose biomarkers are found to be linked to mechanisms of tumor progression. The findings reveal distinct characteristics of the immune profiles in EOCRC and LOCRC, and potentially motivate insights into treatment and management of CRC.
Identification of novel pathogenic genes of childhood epileptic encephalopathies
Authors: Shi Yi-Wu , Zhang Jian-Guo , He Na , Ye Zi-Long , Li Wen-Bin , Liu Han-Kui , Liu Zhi-Gang , Shen Nan-Xiang , Qu Xiao-Chong , Fan Cui-Xia , Wang Jie , Luo Sheng , Lv Yu-Dan , Gao Li , Chen Jing , Huang Shao-Ping , Lu Xin-Guo , Yu Jing , Zhang Jie , Wang Xiu-Xia , Gao Qu-Wen , Jiang Li , Chen Yan-Hui , Qi Hui , Qiao Jing-Da , Chen Li-Zhi , Zeng Yuan-Jin , Yang Xiao-Xue , Yan Hong-Jun , Li Cheng-Yan , Zeng Tao , Min Fu-Li , Qin Bing , Xu Hai-Qing , Xu Lin , Li Bing-Mei , Yi Yong-Hong , Zhuo Zhi-Hong , Guo Qing-Hui , He Su-Li , Zhang Hong-Wei , Guan Li-Ping , Deng Wei-Yi , Ren Xiao-Fan , Zou Dong-Fang , Gu Wei-Yue , Su Tao , Liu Xiao-Rong , Qu Yi-Bo , Yang Xin-Ping , Liao Wei-Ping
Published: July 2023

Background

Epileptic encephalopathy is a devastating epilepsy with etiologies largely elusive, despite whole-gene/exon sequencing of large cohorts. This study targeted the genetic causes of childhood epileptic encephalopathy, typically Lennox-Gastaut syndrome (LGS) featured by age-dependent onset and characteristic clinical manifestations.

Methods

Trio-based whole-exome sequencing was performed in 235 LGS cases with individualized analyses on each trio by explainable inheritance origin with stratified frequency filtration and on each gene in four aspects, and specified statistical analyses including that on compound heterozygous variants with controls of 1942 asymptomatic parents. Animal models were used to validate the roles of novel candidate genes.

Results

We identified three novel causative genes, includingSBF1withde novo,CELSR2with recessive, andTENM1with X-linked recessive variants. Significantly higher excesses ofde novo SBF1variants and biallelicCELSR2variants, aggregated variant frequencies ofSBF1,CELSR2, andTENM1, and frequency of compound heterozygousCELSR2variants in the cases were detected. Phenotype severity/outcome was correlated with the genotype of the variants in these genes. InDrosophila, knockdown of these genes showed increased seizure-like behavior and increased firing of excitatory neurons.Sbf1knockout zebrafish showed seizure-like behavior, premature death, and increased firing of neurons.Celsr2knockout mice showed spontaneous seizures with epileptiform discharges. Additional 42 genes were identified as novel candidate pathogenic genes with evidence of the four genetic aspects/statistics.

Conclusions

This study suggestsSBF1,CELSR2, andTENM1are pathogenic genes of LGS and highlights the implications of phenotype subclassification and individualized analyses protocol in identifying genetic causes of human diseases.
Flexibility of brain dynamics is increased and predicts clinical impairment in Relapsing-Remitting but not in Secondary Progressive Multiple Sclerosis
Authors: Cipriano Lorenzo , Minino Roberta , Liparoti Marianna , Polverino Arianna , Romano Antonella , Bonavita Simona , Jirsa Viktor , Sorrentino Giuseppe , Sorrentino Pierpaolo , Lopez Emahnuel Troisi
Published: July 2023

Background

Large-scale brain activity has long been investigated under the erroneous assumption of stationarity. Nowadays, we know that resting state functional connectivity is characterised by aperiodic, scale-free bursts of activity (i.e. neuronal avalanches) that intermittently recruit different brain regions. These different patterns of activity represent a measure of brain flexibility, whose reduction has been found to predict clinical impairment in multiple neurodegenerative diseases such as Parkinson’s disease, Amyotrophic Lateral Sclerosis, and Alzheimer’s disease. Brain flexibility has been recently found increased in Multiple Sclerosis (MS) but its relationship with clinical disability remains elusive. Also, potential differences in brain dynamics according to the MS clinical phenotypes remain unexplored so far.

Methods

We studied brain flexibility through source-reconstruction of magnetoencephalography (MEG) signals in a cohort of 25 MS patients (10 RRMS and 15 SPMS) and 25 healthy controls (HC).

Results

RRMS patients showed greater brain flexibility than HC. On the contrary, no differences in brain dynamics were found in SPMS patients as compared to HC. Finally, brain dynamics showed a different predictive power on clinical disability according to the MS type.

Conclusion

For the first time, we investigated brain dynamics in MS patients through high temporal resolution techniques, unveiling differences in brain flexibility according to the MS phenotype and its relationship with clinical disability.
Modelling seasonality of Lassa fever in Nigeria
Authors: McKendrick James , Tennant Warren , Tildesley Michael J.
Published: July 2023

Lassa fever (Lf) is a viral haemorrhagic disease endemic to West Africa and is caused by theLassa mammarenavirus. The rodentMastomys natalensisserves as the primary reservoir and its ecology and behaviour have been linked to the distinct spatial and temporal patterns in the incidence of Lf. Nigeria has experienced an unprecedented epidemic that lasted from January until April of 2018, which has been followed by subsequent epidemics of Lf in the same period every year since. While previous research has modelled the case seasonality within Nigeria, this did not capture the seasonal variation in the reproduction of the zoonotic reservoir and its effect on case numbers. To this end, we introduce an approximate Bayesian computation scheme to fit our model to the case data from 2018–2020 supplied by the NCDC. In this study we used a periodically forced seasonal nonautonomous system of ordinary differential equations as a vector model to demonstrate that the population dynamics of the rodent reservoir may be responsible for the spikes in the number of observed cases in humans. The results show that in December through to March, spillover from the zoonotic reservoir drastically increases and spreads the virus to the people of Nigeria. Therefore to effectively combat Lf, attention and efforts should be concentrated during this period.

Author summary

Lassa fever is a viral disease prevalent in West Africa, withMastomys natalensisserving as the primary reservoir. In Nigeria, annual outbreaks occur from December to March. Using a novel model and data from 2018-2020, we demonstrate that the population dynamics of the reservoir contribute to spikes in human cases. Specifically, spillover transmission increases drastically during this period, highlighting the need for concentrated efforts and interventions. Understanding the seasonal dynamics of the reservoir is crucial for effective Lassa fever control and prevention strategies in Nigeria.