bluuebunny/crossref_metadata_2025 huggingface dataset:
Virtual Subinternships in the COVID Era: Lessons Learned from Three Institutional Experiences
Authors: Reghunathan Meera , Dekker Paige K. , Belza Caitlyn C. , Kim Kevin G. , Phillips Brett T. , Fan Kenneth L. , Brown David A. , Gosman Amanda A. , Lance Samuel H.
Published: March 2023

After the cessation of all in-person visiting rotations during the coronavirus 2019 pandemic, many programs developed virtual rotations as an alternative for the recruitment and education of prospective applicants. In this study, we developed a consortium of three institutions each with a unique virtual subinternship and prospectively surveyed participating students in order to reflect and improve upon future rotations. All students participating in virtual subinternships at three institutions were administered the same pre subinternship and post subinternship electronic surveys. Subinternship curricula were developed independently at each respective institution. Fifty-two students completed both surveys, for an overall response rate of 77.6%. Students’ primary objectives were to evaluate their fit with the program (94.2%), interact with residents (94.2%), gain faculty mentorship (88.5%), and improve didactic knowledge (82.7%). Postrotation surveys revealed that over 73% of students reported having met all of these objectives over the course of the rotation. On average, students ranked programs 5% higher overall after the rotation (P = 0.024). Postrotation results showed that the majority (71.2%) of students perceived the virtual subinternship as slightly less valuable than in-person subinternships but that all students would participate in a virtual subinternship again. Student objectives can be successfully met using the virtual format for subinternships. The virtual format is also effective in enhancing the overall perception of a program and its residents. Although students still prefer in-person subinternships, our results suggest that virtual rotations are more accessible and very capable of meeting student goals.
The association between soluble CD163, disease severity, and ursodiol treatment in patients with primary biliary cholangitis
Authors: Bossen Lars , Lau Tobias Stemann , Nielsen Mette Bak , Nielsen Marlene Christina , Andersen Astrid Højmark , Ott Peter , Becker Sabine , Glerup Henning , Svenningsen Lise , Eivindson Martin , Kornerup Linda , Kjeldsen Niels Bjørndal , Neumann Anders , Møller Holger Jon , Jepsen Peter , Grønbæk Henning
Published: March 2023

Introduction:

The macrophage activation marker soluble (s)CD163 is associated with disease severity and prognosis in patients with primary biliary cholangitis (PBC). Ursodeoxycholic acid (UDCA) treatment attenuates fibrosis progression in PBC patients, but its effect on macrophage activation is unclear. We examined the effect of UDCA on macrophage activation, as determined by sCD163 levels.

Methods:

We included 2 cohorts of PBC patients; 1 cohort with prevalent PBC patients, and 1 cohort of incident PBC patients before start of UDCA treatment and with follow-up after 4 weeks and 6 months. We measured sCD163 and liver stiffness in both cohorts. Further, we measured sCD163 and TNF-α shedding in vitro in monocyte-derived macrophages after UDCA and lipopolysaccharide incubation.

Results:

We included 100 patients with prevalent PBC [93% women, median age 63 y (interquartile range: 51–70)] and 47 patients with incident PBC [77% women, median age 60 y (49–67)]. Prevalent PBC patients had a lower median sCD163 of 3.54 mg/L (2.77–4.72) than incident PBC patients with a median sCD163 of 4.33 mg/L (2.83–5.99) at inclusion. Patients with an incomplete response to UDCA and patients with cirrhosis had higher sCD163 than responders to UDCA and noncirrhosis patients. After 4 weeks and 6 months of UDCA treatment median sCD163 decreased by 4.6% and 9.0%, respectively. In in vitro experiments, UDCA attenuated shedding of TNF-α, but not sCD163, from monocyte-derived macrophages.

Conclusion:

In PBC patients, sCD163 levels correlated with liver disease severity and treatment response to UDCA. Further, after 6 months of UDCA treatment, we observed a decrease in sCD163, which may be related to the treatment.
Disparities in presentation and management of chronic hepatitis B among Hispanics in a diverse safety net system
Authors: Wang Allison E. , Terrault Norah A. , Fong Tse-Ling , Zhou Kali
Published: March 2023

Background:

Chronic hepatitis B (HBV) prevalence is highest in foreign-born Asian and African individuals in the US, though Hispanics make up the largest proportion of the immigrant population. Differences in the diagnosis and management of chronic HBV in Hispanics might exist due to the lower awareness of risk. We aim to examine racial/ethnic disparities in the diagnosis, presentation, and immediate management of chronic HBV in a diverse safety net system enriched for Hispanics.

Methods:

In a large urban safety-net hospital system, we retrospectively identified patients with chronic HBV by serological data and categorized them into mutually exclusive self-identified racial/ethnic groups: Hispanics, Asians, Blacks, and Whites. We then examined differences in screening, disease phenotype and severity, follow-up testing, and referral by race/ethnicity.

Results:

Among 1063 patients, 302 (28%) were Hispanics, 569 (54%) Asians, 161 (15%) Blacks, and 31 (3%) Whites. More Hispanics (30%) were screened in the acute setting (defined as inpatient or emergency department encounters) than Asians (13%), Blacks (17%), or Whites (23%) (p<0.01). Hispanics also had lower rates of follow-up testing after HBV diagnosis than Asians including HBeAg status (43% vs. 60%, p<0.01) and HBV DNA levels (42% vs. 58%, p<0.01) and lower rates of linkage to specialty care (32% vs. 55%, p<0.01). Among those with available testing, however, the presence of immune-active chronic HBV was infrequent and similar across racial/ethnic groups. 25% of Hispanics had cirrhosis at initial presentation, proportionally higher than other groups (p<0.01).

Conclusion:

Our results underscore the importance of raising chronic HBV awareness and increasing both screening and linkage to care among Hispanic immigrants in addition to the existing risk groups, with the goal of mitigating downstream liver-related complications.
Implementing a Sedentary Behavior Change Smartphone App in Cardiac Rehabilitation
Authors: Patterson Kacie , Keegan Richard , Davey Rachel , Freene Nicole
Published: March 2023

Background

Smartphone apps used in research offer a variety of capabilities to track and influence behavior; however, they often do not translate well into real-world use. Implementation strategies for using apps to reduce sedentary behavior in cardiac rehabilitation are currently unknown.

Objective

The aim of this study was to explore (1) barriers and enablers for use of a behavioral smartphone app (Vire and ToDo-CR program) for reducing sedentary behavior in cardiac rehabilitation participants and (2) implementation strategies for future smartphone apps aimed at reducing sedentary behavior in this population.

Methods

In-depth semistructured interviews were conducted with cardiac rehabilitation participants in the ToDo-CR randomized controlled trial. Participants had used the Vire app and a wearable activity tracker for 6 months. Interviews were audio recorded and transcribed. The researchers used thematic analysis and deductive mapping of themes to the Theoretical Domains Framework and the Capability, Opportunity, and Motivation-Behavior model. Sociodemographic and clinical variables were recorded.

Results

Fifteen participants aged 59 ± 14 years were interviewed. Most were male, tertiary educated, and employed, and had varying experiences with smartphone apps and wearable activity trackers. Five core themes explaining the user experiences of cardiac rehabilitation participants with the Vire app were identified: (1) being tech savvy can be both an enabler and a barrier, (2) app messaging needs to be clear—set expectations from the beginning, (3) get to know me—personalization is important, (4) curious to know more instant feedback, and (5) first impression is key. The themes and subthemes mapped to 12 of the 14 Theoretical Domains Framework domains. Improving engagement and implementation of future smartphone apps for sedentary behavior may be aided by building psychological capability, physical opportunity, and reflective motivation.

Conclusions

Shifting to in-the-moment behavioral nudges, setting clear expectations, assisting participants to monitor their sitting time, increasing the frequency of tailoring, and understanding more about the participant as well as their experiences and needs for reducing sedentary behavior in cardiac rehabilitation are important future directions.
Expression, clinicopathologic, and prognostic significance of MMP15 in operable pancreatic ductal adenocarcinoma
Authors: Liu Wen-Jing , Liu Jian-Zhou , Zhou Wei-Xun , Zhou Li , Guo Jun-Chao
Published: March 2023

Objective:

Matrix metalloproteinase 15 (MMP15) has been previously reported to be involved in many cancers. However, its expression pattern in pancreatic ductal adenocarcinoma (PDAC) remains contradictory. In addition, its clinicopathologic and prognostic significance in this malignancy has not been elucidated.

Methods:

Expression of MMP15 was immunohistochemically detected in a tissue microarray of formalin-fixed paraffin-embedded samples from 95 patients of PDAC after surgery. Its expression pattern and relations with clinicopathologic factors and disease-specific survival (DSS) were then evaluated. Finally, its expression and prognostic value were measured in the on-line publically available database, GEPIA, using TCGA data.

Results:

In comparison of all samples and 75 paired ones, MMP15 expression in tumor tissues was all significantly higher than that in para-tumor ones (P = .037 and .016). Furthermore, tumoral MMP15 expression was associated with peri-neural invasion. Survival analysis showed that patients with high tumoral MMP15 expression had significantly poorer DSS than those with low MMP15 expression (P = .0059). In univariate and multivariate Cox regression tests, tumoral MMP15 expression was all significantly predictive for DSS. In the on-line publically available GEPIA database, MMP15 was also overexpressed in PDAC, but was not found to be prognostic.

Conclusion:

Our results indicated that MMP15 expression was elevated in operable PDAC and might have a prognostic impact.
Association of hemostasis and inflammation biomarkers with outcomes in acute coronary syndromes
Authors: Matsudo Maia , Aladio Jose M. , Costa Diego , Scazziota Alejandra S. , Swieszkowski Sandra , Perez de la Hoz Ricardo
Published: March 2023

Plaque rupture triggers a prothrombotic response that is counterbalanced by a fibrinolytic response. d-dimer serves as a marker of both processes. Inflammatory mediators are also released, evidenced with the rise of high-sensitive C reactive protein (hsCRP). Current evidence with these biomarkers has shown conflicting results. Determine an association between d-dimer and hsCRP within hospital and 1-year mortality in patients with acute coronary syndromes. In total, 127 patients were included. In-hospital mortality was 5.7%, and 1-year all-cause and cardiovascular mortality were 14.6 and 9.7%, respectively. The median of admission d-dimer for patients who died during hospital stay was higher than those who survived [4.59 (interquartile ranges (IQR) 1.94–6.05 μg/ml fibrinogen equivalent units (FEU)) vs. 0.56 (IQR 0.31–1.12 μg/ml FEU), P = 0.001]. At 1-year follow-up, the median of admission d-dimer for patients who died was significantly higher than those who survived: 1.55 (IQR 0.91–5.08 μg/ml FEU) vs. 0.53 (IQR 0.29–0.90 μg/ml FEU), P < 0.001. Positive d-dimer vs. negative d-dimer at admission analysis evidenced that almost 25% of the positive patients were dead at 1-year follow-up (22.4 vs. 2.4% negative d-dimer, P = 0.011). Multivariate logistic regression analysis showed that d-dimer has an independent association with 1-year mortality [odds ratio 1.06 (95% confidence interval 1.02–1.10), P = 0.006]. Positive significative correlations between d-dimer and hsCRP levels (R = 0.56, P < 0.001) were found. High levels of admission d-dimer were strongly associated with in-hospital and 1-year mortality. Significant correlations with hsCRP could explain the inflammatory nature that led to poorer outcomes. d-dimer could be useful in risk stratification in acute coronary syndromes; however, a specific threshold should be defined for this type of patient.
Attachment Style and Self-Experience
Authors: de With Justine , de Haan Lieuwe , Schirmbeck Frederike
Published: March 2023

The present study aimed to examine the cross-sectional association between attachment style and self-reported disturbed self-awareness (disturbed sense of mineness of experiences) and depersonalization (disturbed sense of first-person perspective) in patients with psychotic disorders, unaffected siblings, and healthy controls. Data pertain to a subsample of the GROUP (Genetic Risk and Outcome of Psychosis) study. We found positive associations between anxious attachment and disturbed self-awareness and depersonalization across participants with different psychosis vulnerability. We also found a positive association between avoidant attachment and depersonalization, although on a trend level. Findings indicate that attachment style is associated with self-reported disturbed self-awareness and depersonalization over and above the influence of psychotic or depressive experiences in people across the vulnerability spectrum of psychosis. This supports the importance of attachment style, self-awareness, and depersonalization as potential targets in prevention and treatment interventions in patients with psychotic disorders or those with increased vulnerability.
Surgical Management of Presacral Tumors: Report of 5 Cases With Video Vignette of Laparoscopic Removal
Authors: Körfer Daniel , Jentschura Dirk
Published: March 2023

Background:

Cystic tumors in the presacral space represent a rare pathology. In case of symptoms, but particularly due to the danger of malignant degeneration, surgical removal is indicated. Due to the complex position in the pelvis with its proximity to important anatomic structures, the choice of the surgical approach is decisive.

Methods:

To present an overview of the recent knowledge of presacral tumors, a PubMed-based literature review was performed. Subsequently, we present 5 cases where different surgical strategies were evaluated including a video of a laparoscopic removal.

Results:

Presacral tumors can be of different histopathologic origins. Complete surgical excision is the treatment of choice, with open abdominal, open abdominoperineal, and posterior accesses available, as well as minimally invasive techniques.

Conclusion:

Laparoscopic resection of presacral tumors is a well-suitable option, but the decision must always be made individually.
Up and over: Consequences of raising the United States-Mexico border wall height
Authors: Marshall William A. , Bansal Vishal , Krzyzaniak Andrea , Haines Laura N. , Berndtson Allison E. , Ignacio Romeo , Keller Benjamin A. , Doucet Jay J. , Costantini Todd W.
Published: March 2023

OBJECTIVES

San Diego County’s geographic location lends a unique demographic of migrant patients injured by falls at the United States-Mexico border. To prevent migrant crossings, a 2017 Executive Order allocated funds to increase the southern California border wall height from 10 ft to 30 ft, which was completed in December 2019. We hypothesized that the elevated border wall height is associated with increased major trauma, resource utilization, and health care costs.

METHODS

Retrospective trauma registry review of border wall falls was performed by the two Level I trauma centers that admit border fall patients from the southern California border from January 2016 to June 2022. Patients were assigned to either “pre-2020” or “post-2020” subgroups based upon timing of completion of the heightened border wall. Total number of admissions, operating room utilization, hospital charges, and hospital costs were compared.

RESULTS

Injuries from border wall falls grew 967% from 2016 to 2021 (39 vs. 377 admissions); this percentage is expected to be supplanted in 2022. When comparing the two subgroups, operating room utilization (175 vs. 734 total operations) and median hospital charges per patient ($95,229 vs. $168,795) have risen dramatically over the same time period. Hospital costs increased 636% in the post-2020 subgroup ($11,351,216 versus $72,172,123). The majority (97%) of these patients are uninsured at admission, with costs largely subsidized by federal government entities (57%) or through state Medicaid enrollment postadmission (31%).

CONCLUSION

The increased height of the United States-Mexico border wall has resulted in record numbers of injured migrant patients, placing novel financial and resource burdens on already stressed trauma systems. To address this public health crisis, legislators and health care providers must conduct collaborative, apolitical discussions regarding the border wall's efficacy as a means of deterrence and its impact on traumatic injury and disability.

LEVEL OF EVIDENCE

Prognostic and Epidemiological; Level IV.
Altered functional connectivity between the default mode network in diabetic retinopathy patients
Authors: Chen Wan Yun , Zhong Yu Lin , Jin Han , Huang Xin
Published: March 2023

Objectives

Previous studies have demonstrated that diabetic retinopathy is associated with cognitive impairment. This study aimed to investigate the intrinsic functional connectivity pattern within the default mode network (DMN) and its associations with cognitive impairment in diabetic retinopathy patients using resting-state functional MRI (rs-fMRI).

Methods

A total of 34 diabetic retinopathy patients and 37 healthy controls were recruited for rs-fMRI scanning. Both groups were age, gender, and education level matched. The posterior cingulate cortex (PCC) was chosen as the region of interest for detecting functional connectivity changes.

Results

Compared with the healthy control group, diabetic retinopathy patients showed increased functional connectivity between PCC and left medial superior frontal gyrus and increased functional connectivity between PCC and right precuneus.

Conclusion

Our study highlights that diabetic retinopathy patients show enhanced functional connectivity within DMN, suggesting that a compensatory increase of neural activity might occur in DMN, which offers new insight into the potential neural mechanism of cognitive impairment in diabetic retinopathy patients.
Long non-coding RNA MEG3 alleviates postoperative cognitive dysfunction by suppressing inflammatory response and oxidative stress via has-miR-106a-5p/SIRT3
Authors: Ye Lingling , Cheng Xiaoe , Shi Yinqi , Liu Ziye , Xiong Yingfen , Huang Yuanlu
Published: March 2023

Postoperative cognitive dysfunction (POCD), a neurological complication after surgery, is common among the elderly in particular. Maternal expression gene 3 (MEG3) is a novel long non-coding RNA (lncRNA) that contributes to glial cell activation and inflammation. We aim to further explore its role in POCD. Mice were induced with sevoflurane anesthesia and underwent orthopedic surgery to establish a POCD model. BV-2 microglia activation was induced by lipopolysaccharide. The overexpressed lentiviral plasmid lv-MEG3 and its control were injected into mice. pcDNA3.1-MEG3, has-miR-106a-5p mimic, and its negative control were transfected into BV-2 cells. The expressions of has-miR-106a-5p MEG3 and Sirtuin 3 (SIRT3) in rat hippocampus and BV-2 cells were quantitatively detected. Levels of SIRT3, TNF-α, and IL-1β were detected by western blot, levels of TNF-α and IL-1β by ELISA, and expression of GSH-Px, SOD, and MDA by kits. The targeting relationship between MEG3 and has-miR-106a-5p was confirmed using bioinformatics and dual-luciferase reporter assay. LncRNA MEG3 was down-regulated in POCD mice, whereas has-miR-106a-5 levels were up-regulated. Overexpression of MEG3 could attenuate cognitive dysfunction and inflammatory response in POCD mice, inhibit lipopolysaccharide-induced inflammatory response and oxidative stress in BV-2 cells, and promote has-miR-106a through competitive binding with has-miR-106a-5-5 expression of target gene SIRT3. Overexpression of has-miR-106a-5p had a reverse effect on overexpression of MEG3 functioning on lipopolysaccharide-induced BV-2 cells. LncRNA MEG3 could inhibit the inflammatory response and oxidative stress via has-miR-106a-5p/SIRT3, thereby reducing POCD, which might be a potential biological target for the diagnosis and treatment of clinical POCD.
Bayesian causal inference: a critical review
Authors: Li Fan , Ding Peng , Mealli Fabrizia
Published: March 2023

This paper provides a critical review of the Bayesian perspective of causal inference based on the potential outcomes framework. We review the causal estimands, assignment mechanism, the general structure of Bayesian inference of causal effects and sensitivity analysis. We highlight issues that are unique to Bayesian causal inference, including the role of the propensity score, the definition of identifiability, the choice of priors in both low- and high-dimensional regimes. We point out the central role of covariate overlap and more generally the design stage in Bayesian causal inference. We extend the discussion to two complex assignment mechanisms: instrumental variable and time-varying treatments. We identify the strengths and weaknesses of the Bayesian approach to causal inference. Throughout, we illustrate the key concepts via examples.

This article is part of the theme issue ‘Bayesian inference: challenges, perspectives, and prospects’.
Regulation of phosphate starvation-specific responses in Escherichia coli
Authors: Moreau Patrice L.
Published: March 2023

Toxic agents added into the medium of rapidly growing

Escherichia coli

induce specific stress responses through the activation of specialized transcription factors. Each transcription factor and downstream regulon (e.g. SoxR) are linked to a unique stress (e.g. superoxide stress). Cells starved of phosphate induce several specific stress regulons during the transition to stationary phase when the growth rate is steadily declining. Whereas the regulatory cascades leading to the expression of specific stress regulons are well known in rapidly growing cells stressed by toxic products, they are poorly understood in cells starved of phosphate. The intent of this review is to both describe the unique mechanisms of activation of specialized transcription factors and discuss signalling cascades leading to the induction of specific stress regulons in phosphate-starved cells. Finally, I discuss unique defence mechanisms that could be induced in cells starved of ammonium and glucose.
Development and validation of a novelin-vivovascular injury score for prediction of in-stent restenosis
Authors: Cornelissen Anne , Florescu Roberta Andreea , Reese Stefanie , Behr Marek , Ranno Anna , Manjunatha Kiran , Schaaps Nicole , Böhm Christian , Liehn Elisa Anamaria , Zhao Liguo , Nilcham Pakhwan , Milzi Andrea , Schröder Jörg , Vogt Felix Jan
Published: March 2023

Background

Despite optimizations of coronary stenting technology, a residual risk of in-stent restenosis (ISR) remains. Vessel wall injury has important impact on the development of ISR. While injury can be assessed in histology, there is no injury score available to be used in clinical practice.

Methods

Seven rats underwent abdominal aorta stent implantation. At 4 weeks after implantation, animals were euthanized, and strut indentation, defined as the impression of the strut into the vessel wall, as well as neointimal growth were assessed. Established histological injury scores were assessed to confirm associations between indentation and vessel wall injury. In addition, stent strut indentation was assessed by optical coherence tomography (OCT) in an exemplary clinical case.

Results

Stent strut indentation was associated with vessel wall injury in histology. Furthermore, indentation was positively correlated with neointimal thickness, both in the per-strut analysis (r=0.5579) and in the per-section analysis (r=0.8620; both p ≤0.001). In a clinical case, indentation quantification in OCT was feasible, enabling assessment of injuryin vivo.

Conclusion

Assessing stent strut indentation enables periprocedural assessment of stent-induced damagein vivoand therefore allows for optimization of stent implantation. The assessment of stent strut indentation might become a valuable tool in clinical practice.
Factors affecting the quality of life of acne-suffering adolescents in Honduras, Central America, and its repercussions
Authors: Espinoza-Turcios Eleonora , Chinchilla-Castañeda Kathya , Sosa-Mendoza Carlos , Zambrano Lysien Ivania , Castro Ramos Henry Noel , Armada José , Mejia Cristian R.
Published: March 2023

Introduction

Adolescence is a stage of physical, psychological, and social changes, which determine the personality of the individual, which can be influenced by physical appearance because of alterations in the skin texture of adolescents. Patients with dermatosis have a higher risk of developing depression, anxiety and suicidal ideas. Acne is an important factor for quality of life and affects adolescents both physically and psychosocially.

Objective

To determine the factors associated with the repercussions of acne in adolescents in Honduras.

Methodology

Analytical cross-sectional study. The Cardiff Acne Disability Index (CADI) scale was used through a questionnaire in Google Forms. Descriptive and analytical statistics were obtained.

Results

Of the 3,272 young participants, with respect to quality of life, 25.8% (845) had medium or high repercussions, 5.3% were very depressed by the appearance of their skin in the month prior to filling out the questionnaire. When multivariate analysis was performed, it was found that those who had medium or high repercussions due to acne were women (RPa: 1.33; 95%CI: 1.20-1.48; p-value<0.001), those of indigenous ethnicity (RPa: 1.36; 95%CI: 1.05-1.75; p-value=0.019), those who had scars on the face (RPa: 13.08; 95%CI: 10.02-17.05; p-value<0.001) or those who had the father (RPa: 1.13; 95%CI: 1.01-1.25; p-value=0.031) or siblings with acne (RPa: 1.16; 95%CI: 1.04-1.28; p-value=0.005).

Conclusion

It was found that gender, belonging to an indigenous ethnicity, having scars on the face or that having a close relative who had suffered from acne were associated with medium or high repercussions on the quality of life; it is important to take care of acne in this stage of life to avoid repercussions in adulthood.
Impact of Providing Future Cardiovascular Risk Based on Genetic Testing on Low-Density Lipoprotein Cholesterol in Patients with Familial Hypercholesterolemia (GenTLe-FH): A Randomized Wait-list Controlled Open-Label Trial
Authors: Nomura Akihiro , Okada Hirofumi , Nohara Atsushi , Kawashiri Masaaki , Takamura Masayuki , Tada Hayato
Published: March 2023

Background and Aims

Familial hypercholesterolemia (FH) is an autosomal dominant monogenic disease characterized by high low-density lipoprotein cholesterol (LDL-C) levels. Although carrying causative FH variants is associated with coronary heart disease (CHD), it remains unclear whether disclosing its associated cardiovascular risk affects outcomes in patients with FH. Here, we evaluated the efficacy of providing future cardiovascular risk based on genetic testing in addition to a standard FH education program.

Methods

We conducted a randomized, wait-list controlled, open-label, single-center trial. In the intervention group, we reported a future cardiovascular risk based on the genetic testing adding to standard FH education at week 0. In the wait-list control group, we only disseminated standard FH education according to the guidelines at week 0; they later received a genetic testing-based cardiovascular risk assessment at week 24. The primary endpoint of this study was the plasma LDL-C level at week 24.

Results

Fifty eligible patients with clinically diagnosed FH, without a history of CHD, were allocated to the intervention group (n=24) or the wait-list control group (n=26). At week 24, the intervention group had a significantly greater reduction in LDL-C levels than the wait-list control group (mean changes, -13.1 mg/dL vs. 6.6 mg/dL; difference, -19.7 mg/dL; 95% confidence interval, -34 to -5.6; p=0.009). This interventional effect was consistent with FH causative variant carriers but not with non-carriers.

Conclusions

In addition to standard FH care, providing future cardiovascular risk based on genetic testing can further reduce plasma LDL-C levels, particularly among FH causal variant carriers.

Registration

Japan Registry of Clinical Trials (jRCTs04218002). URL:https://jrct.niph.go.jp/latest-detail/jRCTs042180027
Lipoarabinomannan regulates septation inMycobacterium smegmatis
Authors: Sparks Ian L. , Nijjer Japinder , Yan Jing , Morita Yasu S.
Published: March 2023

The growth and division of mycobacteria, which include several clinically relevant pathogens, deviate significantly from that of canonical bacterial models. Despite their Gram-positive ancestry, mycobacteria synthesize and elongate a diderm envelope asymmetrically from the poles, with the old pole elongating more robustly than the new pole. In addition to being structurally distinct, the molecular components of the mycobacterial envelope are also evolutionarily unique, including the phosphatidylinositol-anchored lipoglycans lipomannan (LM) and lipoarabinomannan (LAM). LM and LAM modulate host immunity during infection, but their role outside of intracellular survival remains poorly understood, despite their widespread conservation among non-pathogenic and opportunistically pathogenic mycobacteria. Previously,Mycobacterium smegmatisandMycobacterium tuberculosismutants producing structurally altered LM and LAM were shown to grow slowly under certain conditions and to be more sensitive to antibiotics, suggesting that mycobacterial lipoglycans may support cellular integrity or growth. To test this, we constructed multiple biosynthetic lipoglycan mutants ofM. smegmatisand determined the effect of each mutation on cell wall biosynthesis, envelope integrity, and division. We found that mutants deficient in LAM, but not LM, fail to maintain cell wall integrity in a medium-dependent manner, with envelope deformations specifically associated with septa and new poles. Conversely, a mutant producing abnormally large LAM formed multiseptated cells in way distinct from that observed in a septal hydrolase mutant. These results show that LAM plays critical and distinct roles at subcellular locations associated with division in mycobacteria, including maintenance of local cell envelope integrity and septal placement.

Significance

Mycobacteria cause many diseases including tuberculosis (TB). Lipoarabinomannan (LAM) is a lipoglycan of mycobacteria and related bacteria, playing important roles as a surface-exposed pathogen-associated molecular pattern during host-pathogen interactions. Its importance is highlighted by the facts that anti-LAM antibody appears to be protective against TB disease progression, and urine LAM serves as a diagnostic marker for active TB. Given the clinical and immunological relevance of the molecule, it was a striking gap in knowledge that we did not know the cellular function of this lipoglycan in mycobacteria. In this study, we demonstrated that LAM regulates septation, a principle potentially generalizable to other lipoglycans widely found in a group of Gram-positive bacteria that lack lipoteichoic acids.
Probing metazoan polyphosphate biology usingDrosophilareveals novel and conserved polyP functions
Authors: Sarkar Sunayana , Sharma Harsha , Hosen SK Yasir , Ladke Jayashree S , Balasubramanian Deepa , Raran-Kurussi Sreejith , Bhandari Rashna , Jaiswal Manish
Published: March 2023

Polyphosphate exists in all life forms; however, its biological functions in metazoans are understudied. Here, we exploredDrosophilaas the first genetic model to explore polyP biology in metazoans. We first established biochemical and in situ methods to detect, quantify, and visualise polyP inDrosophila.We then engineered a FLYX system to deplete polyP in subcellular compartments in a tissue-specific manner. Using these tools, we demonstrated a spatiotemporal and subcellular compartment-specific regulation of polyP levels in various developmental stages and tissue types. We then uncovered that polyP is crucial for hemolymph clotting and developmental timing. These results indicate the evolutionarily conserved role of polyP as theex vivoaddition of polyP accelerates mammalian blood clotting. Further, the transcriptomics analysis of polyP-depleted larvae demonstrates the impact of polyP on several cellular processes including translation. These observations underscore the utility of the toolkit we developed to discover previously unknown polyP functions in metazoans.
Long-term psychological outcomes following stroke: The OX-CHRONIC study
Authors: Kusec Andrea , Milosevich Elise , Williams Owen A. , Chiu Evangeline G. , Watson Pippa , Carrick Chloe , Drozdowska Bogna A. , Dillon Avril , Jennings Trevor , Anderson Bloo , Dawes Helen , Thomas Shirley , Kuppuswamy Annapoorna , Pendlebury Sarah T. , Quinn Terence J. , Demeyere Nele
Published: March 2023

Background

Stroke survivors rate longer-term (>2 years) psychological recovery as their top priority, but data on how frequently psychological consequences occur is lacking. Prevalence of cognitive impairment, depression/anxiety, fatigue, apathy and related psychological outcomes, and whether rates are stable in long-term stroke, is unknown.

Methods

N= 105 long-term stroke survivors (M[SD] age = 72.92 [13.01];M[SD] acute NIH Stroke Severity Score = 7.39 [6.25]; 59.0% Male;M[SD] years post-stroke = 4.57 [2.12]) were recruited (potentialN= 208). Participants completed 3 remote assessments, including a comprehensive neuropsychological battery, and questionnaires on emotional distress, fatigue, apathy and other psychological outcomes. Ninety participants were re-assessed one year later. Stability of outcomes was assessed by Cohen’sdeffect size estimates and percent Minimal Clinically Important Difference changes between time points.

Results

On the Montreal Cognitive Assessment 65.3% scored <26. On the Oxford Cognitive Screen 45.9% had at least one cognitive impairment. Attention (27.1%) and executive function (40%) were most frequently impaired. 23.5% and 22.5% had elevated depression/anxiety respectively. Fatigue (51.4%) and apathy (40.5%) rates were high. Attention (d= −0.12; 85.8% stable) and depression (d= 0.09, 77.1% stable) were the most stable outcomes. Following alpha-adjustments, only perceptuomotor abilities (d= 0.69; 40.4% decline) and fatigue (d= −0.33; 37.2% decline) worsened over one year. Cognitive impairment, depression/anxiety, fatigue and apathy all correlated with worse quality of life.

Conclusion

Nearly half of participants >2 years post-event exhibited psychological difficulties, which impact long-term quality of life. Stroke is a chronic condition requiring long-term psychological support.
Lower vaccination coverage against COVID-19 in school-aged children is associated with low socioeconomic status in the Metropolitan Area of Santiago, Chile
Authors: Guerrero-Araya Enzo , Ravello Cesar , Rosemblatt Mario , Perez-Acle Tomas
Published: March 2023

Background

The burden of COVID-19 has been heterogeneous, indicating that the effects of this disease are synergistic with both other non-communicable diseases and socioeconomic status (SES), high-lighting its syndemic character. While the appearance of vaccines has moderated the pandemic effects, their coverage has also been heterogeneous, both when comparing different countries, and when comparing different populations within countries. Of note, once again SES appears to be a correlated factor.

Methods

To examine the relationship between SES and vaccination coverage, we analyzed publicly available data detailing the percentage of school-aged vaccinated children in different municipalities belonging to the Metropolitan Area (MA) of Santiago, Chile, one of the most largely vaccinated countries in the world. Vaccination data was compiled per school type, either public, state-subsidized and private, at three different dates along the COVID-19 pandemic so to cover the dispersion ofDelta, andOmicron, includingOmicronsubvariants BA.4 and BA.5. We computed the median vaccination ratio for each municipality and school type and calculated their Spearman’s rank correlation coefficient with each one of nine SES indices.

Findings

In the MA of Santiago, Chile, the percentage of school-age children who have received vaccinations against COVID-19 correlates with SES. Vulnerable municipalities with low SES exhibit low levels of vaccination coverage. Of note, this strong correlation is observed in both public and state-subsidized schools, but to a meaningless extent in private schools. Although inequity in vaccination coverage decreases over time, it remains higher among students enrolled either in public and state-subsidized schools compared to those of private schools.

Interpretation

Available data is insufficient to explore plausible causes behind lower vaccination coverage in vulnerable municipalities in the MA of Santiago, Chile. However, considering the available literature, it is likely that a combination of factors including the lack of proper information about the importance of vaccination, the lack of incentives for children’s vaccination, low trust in the government, and/or limited access to vaccines for lower-income people, may all have contributed to this low vaccination coverage. Importantly, unless corrected, the inequity in vaccination coverage will exacerbate the syndemic nature of COVID-19.

Funding

This material is based upon work supported by the U.S. Air Force Office of Scientific Research under award number FA9550-20-1-0196. Financial support is also acknowledged to Centro Ciencia & Vida, FB210008, Financiamiento Basal para Centros Científicos y Tecnológicos de Excelencia de ANID.
Distinct role of TGN-resident clathrin adaptors for Rab5 activation in the TGN-endosome trafficking pathway
Authors: Nagano Makoto , Aoshima Kaito , Shimamura Hiroki , Siekhaus Daria Elisabeth , Toshima Junko Y. , Toshima Jiro
Published: March 2023

Clathrin-mediated vesicle trafficking plays central roles in the post-Golgi transport pathways from thetrans-Golgi network (TGN) to endosomes. In yeast, two clathrin adaptors – AP-1 complex and GGA proteins (GGAs) – are predicted to generate distinct transport vesicles at the TGN, and epsin-related Ent3p/Ent5p act as accessories for these adaptors. Recently, we showed that vesicle transport from the TGN, rather than from the plasma membrane, is crucial for Rab5-mediated endosome formation, and that Ent3p/5p are crucial for this process, whereas AP-1 and GGAs are dispensable. However, these observations were incompatible with previous studies showing that these adaptors are required for Ent3p/5p recruitment to the TGN, and thus the overall mechanism responsible for regulation of Rab5 activity remains ambiguous. Here we investigated the functional relationships between clathrin adaptors in post-Golgi-mediated Rab5 activation. We were able to show that AP-1 disruption inent3Δ/5Δ mutant impairs Rab5-GEF Vps9p transport to the Rab5 compartment, and severely reduces Rab5 activity. Additionally, GGAs, Golgi-resident PI4 kinase Pik1p and Rab11 GTPases Ypt31p/32p were found to have partially overlapping functions for recruitment of AP-1 and Ent3p/5p to the TGN. These findings suggest a distinct role of clathrin adaptors for Rab5 activation in the TGN-endosome trafficking pathway.
Temporal perturbation of STAT1/2 activity reveals dynamic ligand discrimination of type I interferon signaling
Authors: Yang Haowen , van de Kreeke Thomas , Van Eyndhoven Laura C. , Tel Jurjen
Published: March 2023

Type-I interferon (IFN-I) subtypes signal through the same IFNα receptor (IFNAR), and initiate temporal STAT1/2 activation to orchestrate innate and adaptive immunity. It remains unknown how IFNAR discriminates between subtypes (e.g., IFNα and IFNβ), and how STAT1/2 signaling is affected by time-varying inputs. Here, we utilize our microfluidic system and live-cell imaging to quantify STAT1/2 activation dynamics in a reporter fibroblast model. Population-averaged and single-cell analyses reveal distinct STAT1/2 responses to various IFNα and IFNβ inputs. Upon continuous stimulation, cells show less sensitivity but more sustained responses to IFNα over IFNβ. A short IFNα pulse induces nearly homogeneous STAT1/2 dynamics, in contrast to heterogeneous responses in IFNβ-pulsed cells. Distinct STAT1/2 refractory states emerge upon exposure to repeated IFN-I pulses, while alternating pulse stimulation reveals that IFNβ can revoke STAT1/2 refractoriness caused by IFNα, but not vice versa. These findings highlight the differences between IFNα and IFNβ signaling and how they can elicit distinct temporal cellular behaviors during viral infection.
β-actin is essential for structural integrity and physiological function of the retina
Authors: Vedula Pavan , Fina Marie E. , Bell Brent A. , Nikonov Sergei S. , Kashina Anna , Dong Dawei W.
Published: March 2023

Lack of non-muscleβ-actin gene (Actb) leads to early embryonic lethality in mice, however mice withβ- toγ-actin replacement develop normally and show no detectable phenotypes at young age. Here we investigated the effect of this replacement in the retina. During aging, these mice have accelerated de-generation of retinal structure and function, including elongated microvilli and defective mitochondria of retinal pigment epithelium (RPE), abnormally bulging photoreceptor outer segments (OS) accompanied by reduced transducin concentration and light sensitivity, and accumulation of autofluorescent microglia cells in the subretinal space between RPE and OS. These defects are accompanied by changes in the F-actin binding of several key actin interacting partners, including ezrin, myosin, talin, and vinculin known to play central roles in modulating actin cytoskeleton and cell adhesion and mediating the phagocytosis of OS. Our data show thatβ-actin protein is essential for maintaining normal retinal structure and function.
Quantitative proteomics and phosphoproteomics of PPP2R5D variants reveal deregulation of RPS6 phosphorylation through converging signaling cascades
Authors: Smolen KA , Papke CM , Swingle MR , Musiyenko A , Li C , Camp AD , Honkanen RE , Kettenbach AN
Published: March 2023

Variants in the phosphoprotein phosphatase-2 regulatory protein-5D gene (PPP2R5D) cause the clinical phenotype of Jordan’s Syndrome (PPP2R5D-related disorder), which includes intellectual disability, hypotonia, seizures, macrocephaly, autism spectrum disorder and delayed motor skill development. The disorder originates fromde novosingle nucleotide mutations, generating missense variants that act in a dominant manner. Pathogenic mutations altering 13 different amino acids have been identified, with the E198K variant accounting for ∼40% of reported cases. Here, we use CRISPR-PRIME genomic editing to introduce a transition (c.592G>A) in thePPP2R5Dallele in a heterozygous manner in HEK293 cells, generating E198K-heterozygous lines to complement existing E420K variant lines. We generate global protein and phosphorylation profiles of wild-type, E198K, and E420K cell lines and find unique and shared changes between variants and wild-type cells in kinase- and phosphatase-controlled signaling cascades. As shared signaling alterations, we observed ribosomal protein S6 (RPS6) hyperphosphorylation, indicative of increased ribosomal protein S6-kinase activity. Rapamycin treatment suppressed RPS6 phosphorylation in both, suggesting activation of mTORC1. Intriguingly, our data suggest AKT-dependent (E420K) and -independent (E198K) activation of mTORC1. Thus, although upstream activation of mTORC1 differs between PPP2R5D-related disorder genotypes, treatment with rapamycin or a p70S6K inhibitor warrants further investigation as potential therapeutic strategies for patients.
Perceptions of equity in leader peer learning groups
Authors: Loeffler Kurstyn , Wittmer Jenell Lynn-Senter
Published: March 2023

Purpose

Peer groups have been established as one of the best tools for leadership learning for family business leaders. However, these groups remain underutilized because business leaders disengage and voluntarily create turnover from these groups. This study explores the perceptions of family business leaders concerning the usefulness, growth opportunities, and equity within peer learning groups to determine what factors impact retention in these groups.

Design/methodology/approach

Two surveys were administered to 321 family business owners and leaders through three large family business centers in different regions of the United States. Leaders were grouped into those who left versus those who remained in a peer learning group. Data were collected about their learning experiences and why they remained or voluntarily left a group.

Findings

Lack of equity was found to be the main determinant of turnover in peer learning groups. Peer learning groups need to consist of business owners along the same trajectory, career stage, and in similar stages of growing a family business in order to equally contribute to the group’s learning. Business leaders who are in peer learning groups they report as being equal also report that their groups are more helpful, trustworthy and create better-quality learning experiences.

Originality/value

Peer groups are important for peer-to-peer learning and continued education for family business leaders. Having a group of peers whom have dealt with similar issues can help business leaders overcome problems successfully. However, little research exists that examines what factors make these peer groups successful.
Managing common resources in Gilgit-Baltistan: a case of Markhor trophy hunt
Authors: Mazhar Ummad
Published: March 2023

Learning outcomes

1. What are public goods? What are the defining characteristics of public goods?2. What is special about managing common resources like Markhors/Ibex (and other rare species)? What is the free rider problem?3. How the incentives-based system works?4. What are the consequences of Community Trophy Hunt Program (CTHP) in Pakistan?

Learning objectives

Learning objectives are as follows:1. applying new approaches to manage common resources;2. understanding the various types of goods that society needs for its material progress;3. understanding the challenges associated with the management of common resources because of their particular nature; and4. understanding the need for incentive-based engagement in the management of public policies at the community level.

Case overview/synopsis

Management of shared resources is challenging. This case uses the problem of a forest officer who was given the task of managing the animal population of the region. The primary focus of the case is common resources and how it can be managed through incentive-based system. The case demonstrates how individual actions have external effects. These external effects are sometimes good for the community, but sometimes, they are bad. Many desirable outcomes require social cooperation, but they cannot be achieved because individual self-interest dominates collective well-being, the issue called Prisoners' Dilemma. Gulnar (the fictional forest officer) was convinced about the potential of managing common resources by means of a CTHP in the Gilgit–Baltistan region (in Pakistan). The CTHP provided not just environmental benefits but also substantial social and economic benefits to the local community. The financial gains from the initiative can be used in community projects that help locals become less reliant on their natural environment, create more space for wildlife and enhance the quality of life for people.

Complexity academic level

BS (Hons.) Economics, MS Economics (Public Policy), MBA (Business Economics)

Supplementary materials

Supplementary materials teaching notes are available for educators only.

Subject code

CSS 4: Environmental Management