bluuebunny/crossref_metadata_2025 huggingface dataset:
Histopathology-validated lesion detection rates of clinically significant prostate cancer with mpMRI, [68Ga]PSMA-11-PET and [11C]Acetate-PET
Authors: Sandgren Kristina , Strandberg Sara N. , Jonsson Joakim H. , Grefve Josefine , Keeratijarut Lindberg Angsana , Nilsson Erik , Bergh Anders , Söderkvist Karin , Thellenberg Karlsson Camilla , Friedrich Bengt , Widmark Anders , Blomqvist Lennart , Berg Loegager Vibeke , Axelsson Jan , Ögren Mattias , Ögren Margareta , Nyholm Tufve , Riklund Katrine
Published: August 2023

Objective

PET/CT and multiparametric MRI (mpMRI) are important diagnostic tools in clinically significant prostate cancer (csPC). The aim of this study was to compare csPC detection rates with [68Ga]PSMA-11-PET (PSMA)-PET, [11C]Acetate (ACE)-PET, and mpMRI with histopathology as reference, to identify the most suitable imaging modalities for subsequent hybrid imaging. An additional aim was to compare inter-reader variability to assess reproducibility.

Methods

During 2016–2019, all study participants were examined with PSMA-PET/mpMRI and ACE-PET/CT prior to radical prostatectomy. PSMA-PET, ACE-PET and mpMRI were evaluated separately by two observers, and were compared with histopathology-defined csPC. Statistical analyses included two-sided McNemar test and index of specific agreement.

Results

Fifty-five study participants were included, with 130 histopathological intraprostatic lesions >0.05 cc. Of these, 32% (42/130) were classified as csPC with ISUP grade ≥2 and volume >0.5 cc. PSMA-PET and mpMRI showed no difference in performance (P = 0.48), with mean csPC detection rate of 70% (29.5/42) and 74% (31/42), respectively, while with ACE-PET the mean csPC detection rate was 37% (15.5/42). Interobserver agreement was higher with PSMA-PET compared to mpMRI [79% (26/33) vs 67% (24/38)]. Including all detected lesions from each pair of observers, the detection rate increased to 90% (38/42) with mpMRI, and 79% (33/42) with PSMA-PET.

Conclusion

PSMA-PET and mpMRI showed high csPC detection rates and superior performance compared to ACE-PET. The interobserver agreement indicates higher reproducibility with PSMA-PET. The combined result of all observers in both PSMA-PET and mpMRI showed the highest detection rate, suggesting an added value of a hybrid imaging approach.
The effect of exercise interventions on gait outcomes in subacute and chronic rehabilitation from lower-limb amputation: A systematic review and meta-analysis
Authors: Madou Edward , Sureshkumar Ashvene , Payne Michael W. , Viana Ricardo , Hunter Susan W.
Published: August 2023

Successful walking is a substantial contributor to quality of life in people with lower-limb amputation (PLLA), yet gait difficulties are common. Evidence-based exercise guidelines are necessary for PLLA with different clinical characteristics and at different phases of recovery. To systematically review the literature evaluating effects of exercise interventions on gait outcomes in PLLA at subacute and chronic stages of recovery. Databases MEDLINE, EMBASE, CINAHL, SPORTDiscus, Scopus, and the Cochrane Library were searched (inception to May 10, 2022). Inclusion criteria: randomized controlled trials assessing gait outcomes following exercise intervention; subjects were PLLA ≥18 years of age and used a prosthesis for walking. Meta-analysis using random effects with inverse variance to generate standardized mean differences (SMDs) was completed for primary gait outcomes. Subgroup analysis was conducted for the recovery phase (i.e., subacute and chronic) and level of amputation (e.g., transfemoral and transtibial). Of 16 included articles, 4 studies examined the subacute phase of recovery, whereas 12 examined the chronic phase. Subacute interventions were 30 minutes, 1–7 times/week, for 2–12 weeks. Chronic interventions were 15–60-minutes, 2–3 times/week, for 4–16 weeks. Low–moderate level evidence was shown for a small improvement in the subacute phase (SMD = 0.42, 95% confidence interval [0.06–0.79], I2 = 46.0%) and a moderate improvement in the chronic phase (SMD = 0.67, 95% confidence interval [0.40–0.94], I2 = 0.0%) in favor of exercise intervention groups. Multicomponent exercise programs consisting of gait, balance, and strength training are effective at improving gait outcomes in PLLA at subacute and chronic phases of recovery. The optimal duration and frequency of exercise is unclear because of variation between interventions, highlighting an area for future work.
The First Collective Examination of Immunosuppressive Practices Among American Intestinal Transplant Centers
Authors: Weiner Joshua , Llore Nathaly , Ormsby Dylan , Fujiki Masato , Segovia Maria Cristina , Obri Mark , Jafri Syed-Mohammed , Liggett Jedson , Kroemer Alexander H.K. , Matsumoto Cal , Moon Jang , Di Cocco Pierpaolo , Selvaggi Gennaro , Garcia Jennifer , Ganoza Armando , Khanna Ajai , Mazariegos George , Wendel Danielle , Reyes Jorge ,   for The American Intestinal Transplantation Working Group
Published: August 2023

Background.

Unlike other solid organs, no standardized treatment algorithms exist for intestinal transplantation (ITx). We established a consortium of American ITx centers to evaluate current practices.

Methods.

All American centers performing ITx during the past 3 y were invited to participate. As a consortium, we generated questions to evaluate and collect data from each institution. The data were compiled and analyzed.

Results.

Ten centers participated, performing 211 ITx during the past 3 y (range, 3–46; mean 21.1). Induction regimens varied widely. Thymoglobulin was the most common, used in the plurality of patients (85/211; 40.3%), but there was no consensus regimen. Similarly, regimens for the treatment of acute cellular rejection, antibody-mediated rejection, and graft-versus-host disease varied significantly between centers. We also evaluated differences in maintenance immunosuppression protocols, desensitization regimens, mammalian target of rapamycin use, antimetabolite use, and posttransplantation surveillance practices. Maintenance tacrolimus levels, stoma presence, and scoping frequency were not associated with differences in rejection events. Definitive association between treatments and outcomes, including graft and patient survival, was not the intention of this initial collaboration and is prevented by the lack of patient-level data and the presence of confounders. However, we identified trends regarding rejection episodes after various induction strategies that require further investigation in our subsequent collaborations.

Conclusions.

This initial collaboration reveals the extreme heterogeneity of practices among American ITx centers. Future collaboration will explore patient-level data, stratified by age and transplant type (isolated intestine versus multivisceral), to explore the association between treatment regimens and outcomes.
Mediation and Longitudinal Analysis to interpret the association between clozapine pharmacokinetics, pharmacogenomics, and absolute neutrophil count
Authors: Lock Siobhan K. , Legge Sophie E. , Kappel Djenifer B. , Willcocks Isabella R. , Helthuis Marinka , Jansen John , Walters James T. R. , Owen Michael J. , O’Donovan Michael C. , Pardiñas Antonio F.
Published: August 2023

Clozapine is effective at reducing symptoms of treatment-resistant schizophrenia, but it can also induce several adverse outcomes including neutropenia and agranulocytosis. We used linear mixed-effect models and structural equation modelling to determine whether pharmacokinetic and genetic variables influence absolute neutrophil count in a longitudinal UK-based sample of clozapine users not currently experiencing neutropenia (N = 811). Increased daily clozapine dose was associated with elevated neutrophil count, amounting to a 133 cells/mm3rise per standard deviation increase in clozapine dose. One-third of the total effect of clozapine dose was mediated by plasma clozapine and norclozapine levels, which themselves demonstrated opposing, independent associations with absolute neutrophil count. Finally, CYP1A2 pharmacogenomic activity score was associated with absolute neutrophil count, supporting lower neutrophil levels in CYP1A2 poor metabolisers during clozapine use. This information may facilitate identifying at-risk patients and then introducing preventative interventions or individualised pharmacovigilance procedures to help mitigate these adverse haematological reactions.
The interplay between air pollution, built environment, and physical activity: perceptions of children and youth in rural and urban India
Authors: Patel Jamin , Katapally Tarun Reddy , Khadilkar Anuradha , Bhawra Jasmin
Published: August 2023

The role of physical inactivity as a contributor to non-communicable diseases (NCDs) risk in children and youth is widely recognized. Air pollution and built environment can limit participation in physical activity and exacerbate NCD risk; however, the relationships between perceptions of air pollution, built environment, and health behaviors are not fully understood, particularly among children and youth in low and middle-income countries. Currently, there are no studies capturing how child and youth perceptions of air pollution and built environment influence physical activity in India, thus, this study investigates the association between perceived air pollution and built environmental factors on moderate-to-vigorous physical activity (MVPA) levels of children and youth in both rural and urban India. Online surveys captured MVPA, perception of air pollution and built environment factors, as well as relevant sociodemographic characteristics from parents and children aged 5 to 17 years in partnership with 41 schools across 28 urban and rural locations during the Coronavirus disease lockdowns in 2021. After adjusting for age, gender, and location, a significant association was found between the perception of air pollution and MVPA levels (β = −18.365, p < 0.001). Similarly, the perception of a high crime rate was associated with lower MVPA levels (β = −23.383, p = 0.002). Reporting the presence of zebra crossings and pedestrian signals or attractive natural sightings was associated with higher MVPA levels; however, this association varied across sociodemographic groups. These findings emphasize the importance of addressing air pollution and improving the built environment to facilitate outdoor active living, including active transportation – solutions that are particularly relevant not only for NCD risk mitigation, but also for climate change adaptation.
Pretreatment and interventional parameters predict excellent recanalization of large vessel occlusion in patients with acute ischemic stroke
Authors: Yedavalli Vivek , Koneru Manisha , Hoseinyazdi Meisam , Greene Cynthia , Copeland Karen , Xu Risheng , Luna Licia , Caplan Justin , Dmytriw Adam , Guenego Adrien , Heit Jeremy , Albers Gregory , Wintermark Max , Gonzalez Fernando , Urrutia Victor , Huang Judy , Leigh Richard , Marsh Elisabeth , Llinas Rafael , Hillis Argye , Nael Kambiz
Published: August 2023

Background

In patients with acute ischemic stroke secondary to large vessel occlusion (AIS-LVO), improved functional outcomes have been reported in patients who achieve Modified Thrombolysis In Cerebral Infarction (mTICI) 2c/3 (excellent recanalization) over mTICI 2b. We aimed to determine pretreatment and interventional variables that could predict achieving mTICI 2c/3 over 2b reperfusion in patients who underwent technically successful mechanical thrombectomy (MT).

Methods

In this retrospective study, consecutive AIS patients with anterior circulation LVO who underwent MT and achieved recanalization with mTICI 2b/2c/3 were included. We evaluated the association between pretreatment clinical and imaging variables and interventional parameters in patients who achieved mTICI 2c/3 vs. 2b using logistic regression and ROC analyses.

Results

From 5/11/2019 to 10/09/2022, 149 consecutive patients met our inclusion criteria (median 70 years old [IQR 65 - 78.5], 57.7% female). Adjusted multivariate regression analyses showed that patients with excellent recanalization had lower admission NIHSS (aOR 0.93, p = 0.036), were less likely to have a history of diabetes mellitus (DM) (aOR 0.42, p = 0.050) and prior stroke (aOR 0.27, p = 0.007), had a cerebral blood volume (CBV) index >= 0.7 (aOR 3.75, p = 0.007), and were more likely to achieve excellent recanalization with aspiration alone (aOR 2.89, p = 0.012). A multivariate logistic regression model comprising these independent factors predicted mTICI 2c/3 with an AUC 0.79 (95% CI: 0.68-0.86; p < 0.001), sensitivity of 94%; specificity of 41%.

Conclusion

Robust collateral status (CS) defined by CBV index >= 0.7, absence of DM and prior stroke, lower initial stroke severity, and direct aspiration are all predictive of excellent recanalization in successfully recanalized AIS-LVO patients. Our findings highlight the prognostic implications of robust CS, DM and stroke prevention, as well as use of aspiration alone in maximizing the likelihood of excellent recanalization.
Global Longitudinal Active Strain Energy Density (GLASED): Age and Sex Differences in young and Veteran Athletes
Authors: MacIver David H. , Zhang Henggui , Johnson Christopher , Papatheodorou Efstathios , Parry-Williams Gemma , Sharma Sanjay , Oxborough David
Published: August 2023

Abstract Figure

Graphic abstract

Clinical perspective

Global longitudinal active strain energy density (GLASED) is a recently introduced potential measure of ventricular function that combines myocardial stress and strain information. GLASED estimates the work performed per unit volume of myocardium during contraction. Recent studies with cardiac MRI have demonstrated that GLASED predicts prognosis more accurately than ejection fraction or strain alone. Our current study uses echocardiography and reveals previously unknown physiological differences in myocardial function between male and female athletes, as well as among young and veteran athletes. Our results suggest that GLASED could be a valuable tool in assessing cardiac diseases, particularly when the clinical phenotype is uncertain

Background

Global longitudinal active strain energy density (GLASED) is an innovative method for assessing myocardial function by quantifying the work performed by the left ventricular muscle. The use of GLASED holds promise for improving the diagnosis and management of cardiac diseases. This study aimed to evaluate the feasibility of measuring GLASED using echocardiography and investigate potential differences in GLASED values among athletes based on age and sex.

Methods and Results

An observational echocardiographic study was conducted, involving male controls, male and female young athletes, and male and female veteran athletes. GLASED was calculated from the myocardial stress and strain. The mean age (years) of young athletes was 21.6 for males and 21.4 for females, while the mean age of veteran athletes was 53.5 for males and 54.2 for females. GLASED was found to be highest in young male athletes (2.40 kJ/m3) and lowest in female veterans (1.96 kJ/m3). Veteran males exhibited lower values (1.96 kJ/m3) compared to young male athletes (P<0.001). Young females demonstrated greater GLASED (2.28 kJ/m3) than veteran females (P<0.01). However, no significant difference in GLASED was observed between male and female veterans.

Conclusions

Our findings demonstrate the feasibility of measuring GLASED using echocardiography. GLASED values were higher in young male athletes compared to female athletes, and it decreased with age. Importantly, the sex-related differences observed in GLASED values among young athletes were no longer present in veteran athletes. Estimating GLASED may serve as a valuable screening tool for cardiac diseases in athletes, particularly for those with borderline phenotypes of hypertrophic and dilated cardiomyopathies.
Caspase-2 protects against ferroptotic cell death
Authors: Dawar Swati , Benitez Mariana C. , Lim Yoon , Dite Toby A. , Yousef Jumana M. , Thio Niko , Garciaz Sylvain , Jackson Thomas D. , Milne Julia V. , Dagley Laura F. , Phillips Wayne A. , Kumar Sharad , Clemons Nicholas J.
Published: August 2023

Caspase-2, one of the most evolutionarily conserved member of the caspase family, is an important regulator of the cellular response to oxidative stress. Given that ferroptosis is suppressed by antioxidant defense pathways, such as that involving selenoenzyme glutathione peroxidase 4 (GPX4), we hypothesised that caspase-2 may play a role in regulating ferroptosis. This study provides the first demonstration of an important and unprecedented function of caspase-2 in protecting cancer cells from undergoing ferroptotic cell death. Specifically, we show that depletion of caspase-2 leads to downregulation of stress response genes includingSESN2, HMOX1, SLC7A11and sensitises mutant-p53 cancer cells to cell death induced by various ferroptosis inducing compounds. Importantly, the canonical catalytic activity of caspase-2 is not required for its role and suggests that caspase-2 regulates ferroptosis via non-proteolytic interaction with other proteins. Using an unbiased BioID proteomics screen, we identified novel caspase-2 interacting proteins (including heat shock proteins and co-chaperones) that regulate cellular responses to stress. Finally, we demonstrate that caspase-2 limits chaperone mediated autophagic degradation of GPX4 to promote survival of mutant-p53 cancer cells. In conclusion, we document a novel role for caspase-2 as a negative regulator of ferroptosis in cells with mutant-p53. Our results provide evidence for a novel function of caspase-2 functions in cell death regulation and open potential new avenues to exploit ferroptosis in cancer therapy.
Recurrent SARS-CoV-2 mutations at Spike D796 evade antibodies from pre-Omicron convalescent and vaccinated subjects
Authors: Elko Evan A , Mead Heather L , Nelson Georgia A , Zaia John A , Ladner Jason T , Altin John A
Published: August 2023

SARS-CoV-2 lineages of the Omicron variant rapidly became dominant in early 2022 and frequently cause human infections despite vaccination or prior infection with other variants. In addition to antibody-evading mutations in the Receptor Binding Domain, Omicron features amino acid mutations elsewhere in the Spike protein, however their effects generally remain ill-defined. The Spike D796Y substitution is present in all Omicron sub-variants and occurs at the same site as a mutation (D796H) selected during viral evolution in a chronically-infected patient. Here we map antibody reactivity to a linear epitope in the Spike protein overlapping position 796. We show that antibodies binding this region arise in pre-Omicron SARS-CoV-2 convalescent and vaccinated subjects, but that both D796Y and D796H abrogate their binding. These results suggest that D796Y contributes to the fitness of Omicron in hosts with pre-existing immunity to other variants of SARS-CoV-2 by evading antibodies targeting this site.
Migrant men and HIV care engagement in Johannesburg, South Africa
Authors: Nardell Maria F. , Govathson Caroline , Mngadi-Ncube Sithabile , Ngcobo Nkosinathi , Letswalo Daniel , Lurie Mark , Miot Jacqui , Long Lawrence , Katz Ingrid T. , Pascoe Sophie
Published: August 2023

Background

South Africa (SA) has one of the highest rates of migration on the continent, largely comprised of men seeking labor opportunities in urban centers. Migrant men are at risk for challenges engaging in HIV care. However, rates of HIV and patterns of healthcare engagement among migrant men in urban Johannesburg are poorly understood.

Methods

We analyzed data from 150 adult men (≥18 years) recruited in 10/2020-11/2020 at one of five sites in Johannesburg, Gauteng Province, SA where migrants typically gather for work, shelter, transit, or leisure: a factory, building materials store, homeless shelter, taxi rank, and public park. Participants were surveyed to assess migration factors (e.g., birth location, residency status), self-reported HIV status, and use and knowledge of HIV and general health services. Proportions were calculated with descriptive statistics. Associations between migration factors and health outcomes were examined with Fisher exact tests and logistic regression models. Internal migrants, who travel within the country, were defined as South African men born outside Gauteng Province. International migrants were defined as men born outside SA.

Results

Two fifths (60/150, 40%) of participants were internal migrants and one fifth (33/150, 22%) were international migrants. More internal migrants reported living with HIV than men born in Gauteng (20% vs 6%, p=0.042), though in a multi-variate analysis controlling for age, being an internal migrant was not a significant predictor of self-reported HIV positive status. Over 90% all participants had undergone an HIV test in their lifetime. Less than 20% of all participants had heard of pre-exposure prophylaxis (PrEP), with only 12% international migrants having familiarity with PrEP. Over twice as many individuals without permanent residency or citizenship reported “never visiting a health facility,” as compared to citizens/permanent residents (28.6% vs. 10.6%, p=0.076).

Conclusions

Our study revealed a high proportion of migrants within our community-based sample of men and demonstrated a need for bringing PrEP awareness and services to migrants in Johannesburg. Future research is warranted to further disaggregate this heterogenous population by different dimensions of mobility and to understand how to design HIV programs in ways that will address migrants’ challenges.
Risk Factors for Post-Traumatic Stress Disorder (PTSD) in COVID Survivors: A Cross-Sectional Study
Authors: Dhakal Surakshaya , Khatiwada Ram Prasad
Published: August 2023

The study aimed to investigate the impact of demographic, socio-economic, health, and lifestyle variables on the development of PTSD symptoms in COVID survivors. The study used a cross-sectional design, and data were collected via a standard set of questionnaires from 228 COVID survivors, who required oxygen support and were admitted to Damak COVID hospital from April to October 2021.

Descriptive statistics such as frequency and percentage were used to summarize the data and inferential statistics such as chi-square test, Fisher’s exact test, and Binary logistic regression were used to analyze the data and to infer the overall result from the taken sample. The study found that only three variables, i.e., gender, diabetes, and chronic obstructive pulmonary disorder (COPD), were significant factors that posed a higher threat of PTSD in COVID survivors. Additionally, the study uses model adequacy tests such as Pseudo R2 test, Reliability test and Hosmer and Lemeshow test to validate the model fitted.

The study found that only three variables had significant impact PTSD symptoms in COVID survivors. Male patients were more likely to have PTSD symptoms than female patients. The presence of diabetes before or after the infection increased the risk of PTSD. The patients with high blood pressure before COVID and those who developed chronic obstructive pulmonary disorder (COPD) after COVID were more likely to experience PTSD symptoms. The study provides valuable information on the risk factors for developing PTSD symptoms in COVID survivors. This study can contribute to the understanding and growing body of research on the psychological impact of COVID and help healthcare professionals identify patients who are at risk of developing PTSD and provide them with appropriate interventions to prevent or treat PTSD.
Mortality risk in infants receiving therapeutic care for malnutrition: A secondary analysis
Authors: Mahmud Imteaz , Guesdon Benjamin , Kerac Marko , Grijalva-Eternod Carlos S.
Published: August 2023

Background

Small and nutritionally at-risk infants aged <6 months are at high risk of death, but important evidence gaps exist on how to best identify them. We aimed to determine associations between anthropometric deficits and mortality among infants <6m admitted to inpatient therapeutic care.

Methods

A secondary analysis of 2002-2008 data included 5,034 infants aged <6m from 12 countries. The prevalence, concurrence, and severity of wasted, stunted, underweight, and the Composite Index of Anthropometric Failure (CIAF) were analysed. We used logistic regression to examine the association of different anthropometric deficits with in-programme mortality.

Results

Among 3,692 infants aged <6m with complete data, 3,539 (95.8%) were underweight, 3,058 (82.8%) were wasted, 2,875 (77.8%) were stunted, and 3,575 (96.8%) had CIAF. Infants with multiple anthropometric deficits were more severely wasted, stunted, and underweight. A total of 141 infants died during inpatient therapeutic care. Among these, severely wasted (116) and severely underweight (138) infants had higher odds of mortality than normal infants (OR=2.1, 95% CI: 1.2-2.7, p=0.009, and OR=3.3, 95% CI: 0.8-13.6, p=0.09, respectively). Boys had higher odds of inpatient mortality than girls (OR=1.40, 95% CI: 1.02-1.92, p=0.03).

Conclusion

Multiple anthropometric deficits (CIAF) is common among infants <6m. Future work needs to explore which are the most useful indicator for programme admission and in-programme prognosis: our data supports both WLZ and WAZ, but future work which better accounts for admission bias is urgently needed. Boys appear to be most at-risk. Programmes should ensure that all infants receive timely, evidence-based, effective care.
New Admissions and Asymptomatic TB Cases fuel TB Epidemic in Prisons, a Cross Sectional Survey in Tanzania
Authors: Mangu Chacha David , Clowes Petra , van den Hombergh Jan , Mwakabenga Clement , Mwanyonga Simeon , Ambindwile Jane , Kayombo Faith , Minja Monica , Kalluvya Samuel , Gerwing-Adima Lisa , Kasang Christa , Mueller Andreas , Chilolo Edward , Angolwisye Juma , Nsajigwa Dickson , Kachima Adili , Kamala Deus , Mutayobya Beatrice , Ntinginya Nyanda Elias , Hoelscher Michael , Saathoff Elmar , Rachow Andrea
Published: August 2023

Background

There is an increased risk for tuberculosis (TB) infection and disease progression in prison settings. TB prevalence in prisons of high and middle/low income countries have been measured to be between 5 and 50 -times higher than in the general population.

Methods

We performed TB active case finding in five central prisons, Keko, Segerea, Ukonga, Butimba and Ruanda prison in Tanzania, using the Xpert MTB/RIF®assay on early morning or spot sputum sample from inmates and new entries between April 2014 and July 2015.

Results

Out of 13,868 prisoners tested, 13,763 had valid results. TB prevalence was 1.55% (214/13,763); new admissions contributed to the majority (61.68%) of TB cases, but prevalence was higher among inmates (1.75%) compared to new admissions (1.45%). Ukonga, an urban prison which incarcerates long-term convicted inmates had the highest prevalence of 4.02%. Male gender (OR=2.51, p<0.001), repeated incarcerations (OR=2.85, p<0.001), history of TB treatment (OR=1.78, p =0.002), TB symptoms (OR=2.78, p=0.006) and HIV infection (OR=2.86, p=0.002) were associated with positive TB results.

Conclusion

New admissions could be the driving force of the TB epidemic in the penitentiary system. However, prison environments remain a major risk factor for developing active TB disease.
COVID-19 Symptoms and Immunotherapy in People with Multiple Sclerosis: An Analysis of the COVID-19 in MS Global Data Sharing Initiative Dataset
Authors: Garcia-Dominguez Maria A. , Srichawla Bahadar S. , Kipkorir Vincent
Published: August 2023

OBJECTIVES

To analyze the symptoms and severity of coronavirus disease 2019 (COVID-19) in people with multiple sclerosis (pwMS) on immunotherapy using data from the COVID-19 in multiple sclerosis (MS) Global Data Sharing Initiative dataset provided by PhysioNet.

METHODS

The open-access COVID-19 in MS Global Data Sharing Initiative dataset was obtained through credentialed access using PhysioNet. The variables analyzed included body mass index (BMI), symptoms of COVID-19, age, current use of disease-modifying therapy (DMT), efficacy of DMT, comorbidities, hospitalization status, and type of MS. A linear regression analysis was completed. Data analysis and visualization were completed using STATAv1.5, R-Studiov1.1.447, Pythonv3.8, and its associated libraries, including NumPy, Pandas, and Matplotlib.

RESULTS

A total of 1141 participants were included in the analysis. 904 women and 237 men were diagnosed with MS. Among the pwMS included in the study; 208 (19.54%) had a suspected infection with COVID-19 and only 49 (5.25%) were confirmed. Any COVID-19 symptom was present in 360 individuals. The commonly reported DMT agents included dimethyl fumarate (12.71%) and fingolimod (10.17%). 101 in total (8.85%) reported not using any DMT. Factors associated with hospitalization and/or admission to the ICU included having any comorbidity (p = 0.01), neuromuscular disorder (p = 0.046), hypertension (p = 0.005), chronic kidney disease (p < 0.001), and immunodeficiency (p = 0.003). The type of MS, the duration of the disease, and high-efficacy DMT therapy did not have a statistically significant influence on hospitalization.

CONCLUSION

This study underscores the importance of comorbidities, especially neuromuscular disorders, hypertension, chronic kidney disease (CKD), and immunodeficiencies, as possible prognostic indicators for worse outcomes of COVID-19 in pwMS. On the contrary, the type of MS, the duration of the disease, and the efficacy of disease-modifying therapy did not significantly affect the severity of the symptoms of COVID-19 in this cohort.
Cystic fibrosis systemic immune profile is associated with lung microbes and characterized by widespread alterations in the innate and adaptive immune compartments
Authors: Rossi Elio , Lausen Mads , Friesgård Øbro Nina , Colque Antonella , Nielsen Bibi Uhre , Møller Rikke , de Gier Camilla , Hald Annemette , Skov Marianne , Pressler Tacjana , Molin Søren , Ostrowski Sisse Rye , Marquart Hanne Vibeke , Johansen Helle Krogh
Published: August 2023

Polymicrobial airway infections and detrimental inflammation characterize patients with cystic fibrosis (CF), a disease with heterogeneous clinical outcomes. How the overall immune response is affected in CF, its relationships with the lung microbiome, and the source of clinical heterogeneity are unclear. Our work identifies a specific CF immune profile characterized by widespread hyperactivation, enrichment of CD35+/CD49d+neutrophils, and reduction in dendritic cells. Further, our data indicate signs of immune dysregulation due to alterations in Tregs homeostasis, which, together with an impaired B-cell immune function, are linked with patients’ lung function and are potentially the source of clinical heterogeneity. Indeed, clinical heterogeneity does not stem from a specific lung microbiome; yet, commensal bacteria correlate with higher concentrations of circulating immune cells and lower expression of leukocyte activation markers, a condition reversed by pathogenic microorganisms. Overall, our findings provide unique markers and immunomodulatory targets for improving the treatment of CF.
Antibodies Expand the Scope of Angiotensin Receptor Pharmacology
Authors: Skiba Meredith A. , Sterling Sarah M. , Rawson Shaun , Gilman Morgan S.A. , Xu Huixin , Nemeth Genevieve R. , Hurley Joseph D. , Shen Pengxiang , Staus Dean P. , Kim Jihee , McMahon Conor , Lehtinen Maria K. , Wingler Laura M. , Kruse Andrew C.
Published: August 2023

G protein-coupled receptors (GPCRs) are key regulators of human physiology and are the targets of many small molecule research compounds and therapeutic drugs. While most of these ligands bind to their target GPCR with high affinity, selectivity is often limited at the receptor, tissue, and cellular level. Antibodies have the potential to address these limitations but their properties as GPCR ligands remain poorly characterized. Here, using protein engineering, pharmacological assays, and structural studies, we develop maternally selective heavy chain-only antibody (“nanobody”) antagonists against the angiotensin II type I receptor (AT1R) and uncover the unusual molecular basis of their receptor antagonism. We further show that our nanobodies can simultaneously bind to AT1R with specific small-molecule antagonists and demonstrate that ligand selectivity can be readily tuned. Our work illustrates that antibody fragments can exhibit rich andevolvablepharmacology, attesting to their potential as next-generation GPCR modulators.
Caloric restriction promotes beta cell longevity and delays aging and senescence by enhancing cell identity and homeostasis mechanisms
Authors: dos Santos Cristiane , Shrestha Shristi , Cottam Matthew , Perkins Guy , Lev-Ram Varda , Roy Birbickram , Acree Christopher , Kim Keun-Young , Deerinck Thomas , Cutler Melanie , Dean Danielle , Cartailler Jean Philippe , MacDonald Patrick E. , Hetzer Martin , Ellisman Mark , Arrojo e Drigo Rafael
Published: August 2023

Caloric restriction (CR) extends organismal lifespan and health span by improving glucose homeostasis mechanisms. How CR affects organellar structure and function of pancreatic beta cells over the lifetime of the animal remains unknown. Here, we used single nucleus transcriptomics to show that CR increases the expression of genes for beta cell identity, protein processing, and organelle homeostasis. Gene regulatory network analysis link this transcriptional phenotype to transcription factors involved in beta cell identity (Mafa) and homeostasis (Atf6). Imaging metabolomics further demonstrates that CR beta cells are more energetically competent. In fact, high-resolution light and electron microscopy indicates that CR reduces beta cell mitophagy and increases mitochondria mass, increasing mitochondrial ATP generation. Finally, we show that long-term CR delays the onset of beta cell aging and senescence to promote longevity by reducing beta cell turnover. Therefore, CR could be a feasible approach to preserve compromised beta cells during aging and diabetes.
Diving Deep into Fish Bornaviruses: Uncovering Hidden Diversity and Transcriptional Strategies through Comprehensive Data Mining
Authors: Eshak Mirette , Rubbenstroth Dennis , Beer Martin , Pfaff Florian
Published: August 2023

Recently, we discovered two novel orthobornaviruses in colubrid and viperid snakes using anin silicodata mining approach. Here, we present the results of a screening of more than 100,000 nucleic acid sequence datasets of fish samples from the Sequence Read Archive (SRA) for potential bornaviral sequences. We discovered the potentially complete genomes of seven bornaviruses in datasets from osteichthyans and chondrichthyans. Four of these are likely to represent novel species within the genusCultervirus, and we propose that one genome represents a novel genus within the family ofBornaviridae. Specifically, we identified sequences of Wǔhàn sharpbelly bornavirus (WhSBV) in sequence data from the widely used grass carp liver and kidney cell lines L8824 and CIK, respectively. A complete genome of Murray-Darling carp bornavirus (MDCBV) was identified in sequence data from a goldfish (Carassius auratus). The newly discovered little skate bornavirus (LSBV), identified in the little skate (Leucoraja erinacea) dataset, contained a novel and unusual genomic architecture (N-Vp1-Vp2-X-P-G-M-L), as compared to other bornaviruses. Its genome is thought to encode two additional open reading frames (tentatively named Vp1 and Vp2), which appear to represent ancient duplications of the gene encoding for the viral glycoprotein (G). The datasets also provided insights into the possible transcriptional gradients of these bornaviruses and revealed previously unknown splicing mechanisms.
Homeostasis of mRNA concentrations through coupling transcription, exportation, and degradation
Authors: Wang Qirun , Lin Jie
Published: August 2023

Many experiments showed that eukaryotic cells maintain a constant mRNA concentration upon various perturbations by actively regulating mRNA production and degradation rates, known as mRNA buffering. However, the underlying mechanism is still unknown. Here, we propose a mechanistic model of mRNA buffering: the releasing-shuttling (RS) model. The model incorporates two crucial factors, X and Y, which play key roles in the transcription, exportation, and degradation processes. The model explains the constant mRNA concentration under genome-wide genetic perturbations and cell volume changes. Moreover, it quantitatively explains the slowed-down mRNA degradation after Pol II depletion and the temporal transcription dynamics after Xrn1 depletion. The RS model suggests that X and Y are likely composed of multiple molecules possessing redundant functions. We also present a list of X and Y candidates, and an experimental method to identify X. Our work uncovers a possible coupling mechanism between transcription, exportation, and degradation.
A comparison of the parasitoid wasp species richness of tropical forest sites in Peru and Uganda – subfamily Rhyssinae (Hymenoptera: Ichneumonidae)
Authors: Tapani Hopkins , Hanna Tuomisto , Gómez Isrrael C. , Sääksjärvi Ilari E.
Published: August 2023

The global distribution of parasitoid wasp species richness is poorly known. Past attempts to compare data from different sites have been hampered by small sample sizes and lack of standardisation. During the past decades, we have carried out long-term Malaise trapping using a standardised approach in the tropical forests of Peru (western Amazonia) and Uganda (eastern Africa). Here, we test how well such data can be used for global comparisons, by comparing the results for the subfamily Rhyssinae (Hymenoptera: Ichneumonidae). We found that more rhyssine species were caught in Peru than in Uganda, despite the Ugandan samples containing many more individuals both in absolute terms and per unit time. The difference in the number of individuals caught may largely be due to more rainfall in Peru, since rain reduces Malaise trap catches. Peruvian traps caught species at a faster rate (per individual caught) than Ugandan traps. We interpret this as a sign that the Peruvian sites have more species than the Ugandan site. Long-term, standardised Malaise trapping showed promise for global comparisons of species richness. Sampling more sites on both continents, and analysing all subfamilies, would give an estimate of which continent has more parasitoid wasp species. We suggest some refinements to the sampling design that would further improve sampling efficiency for future studies.
Spatial lipidomics of fresh-frozen spines
Authors: Bender Kayle J. , Wang Yongheng , Zhai Chuo Ying , Saenz Zoe , Wang Aijun , Neumann Elizabeth K.
Published: August 2023

Technologies assessing the lipidomics, genomics, epigenomics, transcriptomics, and proteomics of tissue samples at single-cell resolution have deepened our understanding of physiology and pathophysiology at an unprecedented level of detail. However, the study of single-cell spatial metabolomics in undecalcified bones faces several significant challenges, such as the fragility of bone which often requires decalcification or fixation leading to the degradation or removal of lipids and other molecules and. As such, we describe a method for performing mass spectrometry imaging on undecalcified spine that is compatible with other spatial omics measurements. In brief, we use fresh-freeze rat spines and a system of carboxyl methylcellulose embedding, cryofilm, and polytetrafluoroethylene rollers to maintain tissue integrity, while avoiding signal loss from variations in laser focus and artifacts from traditional tissue processing. This reveals various tissue types and lipidomic profiles of spinal regions at 10 μm spatial resolutions using matrix-assisted laser desorption/ionization mass spectrometry imaging. We expect this method to be adapted and applied to the analysis of spinal cord, shedding light on the mechanistic aspects of cellular heterogeneity, development, and disease pathogenesis underlying different bone-related conditions and diseases. This study furthers the methodology for high spatial metabolomics of spines, as well as adds to the collective efforts to achieve a holistic understanding of diseases via single-cell spatial multi-omics.
Off-targets of BRAF inhibitors disrupt endothelial signaling and differentially affect vascular barrier function
Authors: Bromberger Sophie , Zadorozhna Yuliia , Ressler Julia Maria , Holzner Silvio , Nawrocki Arkadiusz , Zila Nina , Springer Alexander , Larsen Martin Røssel , Schossleitner Klaudia
Published: August 2023

Targeted therapies against mutant BRAF are effectively used in combination with MEK inhibitors (MEKi) to treat advanced melanoma. However, treatment success is affected by resistance and adverse events (AEs). Approved BRAF inhibitors (BRAFi) show high levels of target promiscuity, which can contribute to these effects. Blood vessels are in direct contact with high plasma concentrations of BRAFi, but effects of the inhibitors in this cell type are unknown. Hence, we aimed to characterize responses to approved BRAFi for melanoma in the vascular endothelium. We showed that all clinically approved BRAFi induced a paradoxical activation of endothelial MAPK signaling. Moreover, phosphoproteomics revealed distinct sets of off-targets per inhibitor. Endothelial barrier function and junction integrity were impaired upon treatment with Vemurafenib and the next-generation dimerization inhibitor PLX8394, but not with Dabrafenib or Encorafenib. Together, these findings provide insights on the surprisingly distinct side effects of BRAFi on endothelial signaling and functionality. Better understanding of off-target effects could help to identify molecular mechanisms behind AEs and guide the continued development of therapies for BRAF-mutant melanoma.
Structural equation modeling (SEM) analysis: an innovative female entrepreneurship education ecosystem in China
Authors: Feng Lei , Sumettikoon Piyapong
Published: August 2023

Purpose

This study aims to add a gender perspective to the current ecosystem of entrepreneurship education whereby an innovative model of the female entrepreneurship education ecosystem (FEEE) consisting of five stakeholders (university, government, society, enterprise and the international community) is examined.

Design/methodology/approach

The study conducted an online questionnaire among 505 respondents from two universities and one higher vocational college in China. Confirmatory factor analysis (CFA) was used to test the correlation between factors and structural equation modeling (SEM) was applied to test the five hypotheses proposed in the study.

Findings

The results indicated that the five stakeholders (the university, government, society, enterprise and international community) positively affect FEEE. The study emphasizes the urgent demand to consider gender perspectives in the ecosystem of entrepreneurship education and provides plausible ways to conduct female-targeted education with the joint efforts of different stakeholders.

Practical implications

The study aims to increase the number of future female entrepreneurs, enhance the future skills of female students in the digital era and ultimately advance humankind. The study emphasizes the urgent demand to consider gender-perspective in the entrepreneurship education ecosystem and provides plausible ways to conduct female-targeted education with the joint efforts of different stakeholders.

Originality/value

This paper sheds light on evaluating FEEE through five stakeholders' dimensions, which explores the solutions to the current female entrepreneurship education (FEE) issues.
Views of African higher education scholars about effective leadership
Authors: Alemu Daniel S.
Published: August 2023

Purpose

The purpose of this study is to investigate the views of African higher education scholars about effective leadership and if those views reflect a unique, African meaning of leadership.

Design/methodology/approach

The study sought to explore the views of African higher education scholars about leadership in general and if those views reflect a unique, African meaning, that does not necessarily fit the widely accepted western theories. Using a researcher-designed questionnaire, higher education faculty and administrators were asked their understanding and beliefs about leadership. Data from quantitative responses were analyzed using descriptive statistics and t-test. In addition, qualitative answers, from one open ended question, were utilized to possibly triangulate with quantitative responses.

Findings

This study found that most research participants believe that the widely used western leadership theories are not fully applicable to Africa's context. However, the list of qualities of effective leadership, these participants suggest to be unique to Africa, included mixed attributes from Western, Non-Western and Culture-Neutral theories.

Research limitations/implications

This study has some limitations. First, the data for this study was collected electronically which might have affected the potential responses from those with limited Internet connection or who have not updated their current email addresses. Second, the participants of the study are higher education professionals whose insight about leadership may not necessarily reflect the views of others from different background.

Practical implications

By examining leadership effectiveness in Africa's context, this study adds to the body of literature on the ongoing discussion on the topic of culture and leadership. It is hoped that the findings of the study provide important insights regarding the debate on “western vs non-western” leadership theories.

Originality/value

The universal understanding of leadership and the application of leadership theories across cultures have been an issue of debate for leadership scholars and practitioners around the globe. Many authors argue that the widely used leadership theories are “too western” in value and character (Bass, 1990; Hofstede, 1993; House and Aditya, 1997). This study adds the perspectives of African scholars to the ongoing debate and expands the understanding about leadership across culture.
Does status demotion in hierarchical loyalty programs foster relationship fading?
Authors: Banik Shanta , Rabbanee Fazlul K.
Published: August 2023

Purpose

Status demotion in hierarchical loyalty programs (HLPs) has received considerable academic attention. However, existing research is relatively silent on whether HLP status demotion fosters service relationship fading by influencing demoted customers’ psychological disengagement and the likelihood of patronage reduction. Drawing on the relationship fading literature and the stimulus–organism–response framework, this study aims to examine these effects. It further investigates the moderating role of psychological ownership on the links of status demotion with psychological disengagement and the likelihood of patronage reduction.

Design/methodology/approach

Two studies (Studies 1 and 2) were conducted in the context of airline HLPs. Study 1 was a structured survey conducted among 213 demoted airline HLP customers in Australia, and Study 2 was an experiment conducted among 178 executive MBA students in Bangladesh. The PROCESS macro was used to test the moderated mediation model.

Findings

The results of both studies show that HLP status demotion significantly influences customers’ psychological disengagement and the likelihood of patronage reduction. The findings also reveal that psychological disengagement mediates the relationship between status demotion and the likelihood of patronage reduction. Further, customers with high (low) psychological ownership feel high (less) psychological disengagement and show high (less) likelihood of patronage reduction due to their HLP status demotion.

Originality/value

This study extends the existing literature on relationship marketing and HLPs by offering a better understanding of how and under what conditions status demotion elicits customers’ psychological disengagement and the likelihood of patronage reduction.