bluuebunny/crossref_metadata_2025 huggingface dataset:
Prevalence of familial hypercholesterolemia and coronary heart disease in a tertiary referral hospital in Lithuania
Authors: Zubieliene K , Cereskevicius D , Tatarunas V , Zaliaduonyte D , Kabosis T , Zukaite G , Valteryte G , Jonaitiene N , Zebrauskaite G , Zabiela V
Published: June 2024

Introduction

Cascade screening and genetic testing have become one of the most effective methods for early detection of familial hypercholesterolemia (FH) identification and early prevention of coronary artery disease (CAD) [1]. FH is usually caused by variants in the genes coding for the low-density lipoprotein receptor (LDLR). Variants in the genes for apolipoprotein B (APOB) and proprotein convertase subtilisin/kexin type 9 (PCSK9) have also been associated with FH [2]. The results of our pilot study showed that APOB was widespread in our population.

Purpose

To estimate the prevalence of APOB variants in FH patient’s cohort.

Methods

This is a retrospective cohort study of patients with a suspected diagnosis of FH who were treated at a tertiary center between February 2022 and June 2023. Patients were included in the study according to the criteria of the Dutch Lipid Clinic (DLC). Patients were divided into three groups according to the results of the genetic tests: 1. patients with APOB variant; 2. patients without previously described variants causing FH; 3. patients with the LDLR variant. Next generation sequencing was used to sequence the coding regions. Statistical analysis was performed using SPSS 29.0.1. statistical software.

Results

A total of 45 patients were enrolled in this study, including 27 (60%) men and 18 (40%) women, with a mean age of 47.93 years (SD=9.391). After genetic sequencing evaluation, 7 (16%) patients were diagnosed with APOB rs5742904 variant causing FH. In addition, 2 (4%) patients were found to have an LDLR rs879254754 variant. As the patients with an LDLR variant had no CHD symptoms, no further screening was performed.

No statistically significant demographic and clinical differences were found between the groups. The distribution of DLC network scores is shown in Figure 1. The only significant difference between the groups was found in the patients with the APOB rs5742904 variant, where more patients had the highest DLC score.

The most frequently affected segments in both groups were: S1, S6 and S7. Conversely, the least affected segments were: S10, S14, S15 (Figure 2). A remarkable result was seen in the S2 segment, where complete occlusion occurred significantly more frequently in patients with an APOB rs5742904 variant than in patients without this variant.

Conclusion

Contrary to what is mentioned in the literature, there were more people with APOB rs5742904 mutation than with LDLR in our study. We also found that patients with the APOB rs5742904 mutation had statistically significantly more occlusions in the right coronary artery.
Association between oxidative balance score and diabetes among PURE Poland study participants
Authors: Rozanska D , Szuba A , Zatonska K , Regulska-Ilow B
Published: June 2024

Introduction

Oxidative stress is caused by an imbalance between free radicals production and antioxidants activity. It plays an important role in the pathogenesis of diabetes mellitus (DM).

The purpose of the study was to assess the relationship between oxidative balance score (OBS) and diabetes prevalence among PURE Poland study participants.

Methods

Study group included 1889 participants of the Polish arm of the Prospective Urban Rural Epidemiological (PURE) study (1185 women, 704 men), aged 35-70 years, from urban and rural area. The study was conducted in the first stage of the PURE Poland study. The study was approved by the Ethics Committee. Diabetes diagnosis was made based on fasting glucose level ≥ 126 mg/dl or declaration about DM occurrence in the medical interview. Impaired fasting glucose (IFG) was diagnosed when fasting glucose level was between 100-125 mg/dl with no statement about DM in the interview. Finally three analysis have been done: diabetes in the interview (DM_int), diabetes in the interview + diagnosis based on fasting glucose (DM_all) and DM_all + IFG (DM+IFG). Food intake was assessed using the Food Frequency Questionnaire (FFQ), which was developed and validated for this population within the PURE study. OBS was calculated taking into account prooxidant factors: smoking, BMI value, fats and iron intake with diet, and antioxidants intake with diet: zinc, copper, selenium, vitamin E and C, carotenoids, lycopene and flavonoids. The value of OBS was calculated by summing the points (from 0 to 2 for tertiles) for individual components. The maximum value of OBS could be 24 points, and higher number of points indicated better oxidative balance.

Results

Among women the prevalence of DM_int was 9.2%, 8.0% and 5.4% in the tertiles of OBS (T1, T2, T3, respectively). When comparing T3 vs T1 the odds ratio for DM_int prevalence was 0.56 (95% CI 0.33-0.96) for crude data, in model 2 with adjusting for energy intake 0.48 (95% CI 0.25-0.93) and in model 3 with adjusting for energy intake, age and place of residence 0.78 (95% CI 0.39-1.56). Taking into account DM_all among women there were no significant differences between OBS tertiles. The risk of DM+IFG prevalence among women was 34% lower (model 2; OR 0.66, 95% CI 0.47-0.94) in T3 vs T1 (31.9% vs 34.6%). Among men there were no significant differences between DM_int prevalence between OBS tertiles. DM_all prevalence was 14.6%, 12.3% and 8.5% in the tertiles of OBS, respectively. When comparing T3 vs T1 the OR for DM_all prevalence was 0.54 (95% CI 0.30-0.98) for crude data, 0.44 (95% CI 0.21-0.94) in model 2 and 0.59 (95% CI 0.27-1.29) in model 3. The risk of DM+IFG prevalence in the group of men was 63% lower (model 2; OR 0.47, 95% CI 0.29-0.77) in T3 vs T1 (31.0% vs 38.1%).

Conclusions

Higher value of the OBS meaning better oxidative balance, was associated with a lower risk of diabetes prevalence in the study group.
Inter-individual responses to a hybrid walking program in patients with peripheral arterial disease - an exploratory analysis of the PROSECO study
Authors: Tekerlek H , Claes J , Cornelis N , Marcal I R , Colle A , Fourneau I , Cornelissen V
Published: June 2024

Background/Introduction

Walking programs are recommended to enhance walking capacity and alleviate symptoms in peripheral arterial disease (PAD). However, not every individual experiences the same benefits following walking therapy. Therefore, early identification of good and poor responders is essential for better personalizing treatments, optimizing resource allocation and improving patient outcomes.

Purpose

To compare inter-individual variation in patient and clinical characteristics associated with clinically meaningful improvement in a 6-minute walk test following a walking intervention.

Methods

This is an exploratory analysis of the PROSECO-study including 41 patients with PAD [32 men, mean age=70.3±9.2 yrs, ankle-brachial index=0.66±0.26]who completed a 12 week progressive hybrid walking program. The intervention included one in-hospital supervised exercise session and two home-based walking sessions per week, aiming for 150 minutes of walking at moderate pain intensity. Patient and clinical characteristics, including cardiac autonomic function via heart rate variability, pain free walking distance (PFWD) and maximal walking distance (MWD) by means of a progressive treadmill test and functional capacity by means of a 6-minute walk test (6MWT), were assessed at baseline and following completion of the intervention. Based on an established minimally clinically relevant change in 6MWD, patients were divided into two groups: poor responders (∆6MWT<24 m) and good responders (∆6MWT≥24 m).

Results

Twenty three patients (56%) were identified as poor responders (median age 75 years, 73.9% male), while 18 patients (44%) were classified as good responders (median age 67.5 years, 83.3% male). 6MWD remained unchanged in the poor responders (median 6MWD pre 391 meters vs. post 389.50 m) and increased in the good responders (median 6MWD pre 478 vs post 501 m (Figure 1D). As shown in Table 1, good responders were younger and presented with a better PFWD at baseline. Good responders showed also a better improvement in PFWD (m), MWD (m) (Figure 1C-D-E) and an improvement in autonomic function (Figure 1A-B).

Conclusions

Our findings suggest that a significant proportion of patients do not show a significant improvement in functional capacity after walking therapy only. Further investigation is needed to better characterize patients that are more likely to respond favorably to walking therapy thereby enhancing personalisation of effective PAD treatment.
Effect of exercise training and potential moderating variables in patients with atrial fibrillation: a systematic review and meta-analysis
Authors: Manresa-Rocamora A , Fuertes-Kenneally L , Garcia-Cano L , Ibanez-Criado A , Blasco-Peris C , Baladzhaeva S , Sempere-Ruiz N , Hernandez-Perez I , Sanz-Rocher A , Garcia-Alvarez M , Climent-Paya V , Sarabia J
Published: June 2024

Background

While a substantial body of evidence supports the positive impact of exercise in patients with atrial fibrillation (AF), the specific influence of moderating variables on the effectiveness of exercise-based cardiac rehabilitation (CR) remains unclear.

Purpose

The aim of the current systematic review and meta-analysis was to determine the effect of exercise-based CR, either alone or combined with other interventions, in patients with AF. We also examined the influence of exercise variables in this context.

Methods

Electronic searches were carried out in Pubmed, Embase, and Web of Science up to September 2023. Studies comparing the effect of exercise-based CR against usual care intervention, and those investigating the influence of exercise variables, on quality of life, exercise capacity (i.e., peak oxygen uptake [VO2 peak] and distance covered in the 6-minute walk test [6MWT]), resting heart rate (HR) and AF burden, in patients with AF were selected. The mean difference (MD) or standardised mean difference (SMD) were calculated for each outcome. Additionally, meta-analyses were conducted if the number of studies for the specific endpoint was greater than two.

Results

Eleven randomised studies published from 2011 to 2022 fulfilled the inclusion criteria and were finally included. Intervention duration ranged from eight to 24 weeks. Eight studies (73%) were controlled studies and three (27%) were multi-intervention studies (i.e., two parallel groups), of which, one investigated the influence of the exercise mode and two the influence of the exercise intensity. From the 14 intervention groups, 12 (86%) performed aerobic exercise alone and 2 (14%) combined aerobic and resistance exercise. Nine studies (64%) performed moderate intensity aerobic exercise, while only two (14%) conducted high-intensity interval exercise. Compared to usual care, exercise-based CR increased VO2 peak (4 studies; MD = 2.68 [0.77; 4.59] ml/kg/min) and reduced resting HR (4 studies; MD = –7.05 [–12.83; –1.27] beats per minute) in patients with AF. In contrast, no differences were found between the two groups for enhancing quality of life (7 studies; SMD = 1.12 [–0.25; 2.50]) and 6MWT (4 studies; MD = 22.63 [–17.16; 62.43] m). Pooled analyses were not conducted due to the low number of studies investigating the influence of exercise variables.

Conclusions

Few studies have explored the impact of exercise variables on exercise-induced effects in patients with AF, highlighting the need for further exploration. CR, based mainly on aerobic exercise, has shown superior efficacy compared to usual care in improving VO2 peak and resting HR, both recognised as independent mortality predictors.
Association of cardiorespiratory fitness measured by cardiopulmonary exercise testing with covid-19 positivity: a prospective register-based cohort study
Authors: Espen Alexander Eriksen E A E , Dorthe Stensvold D S , Javaid Nauman J N , Ulrik Wisloeff U W , Torbjoern Omland T O
Published: June 2024

Background

It has been suggested that high cardiorespiratory fitness (CRF) may reduce the risk of infection and severe health outcomes for COVID-19. However, there is a need of studies to examine the association between objectively measured CRF and risk of COVID-19 infection.

Purpose

The objective of this study was to investigate if CRF measured by cardiopulmonary exercise testing is associated with risk of COVID-19 infection.

Methods

In this prospective register-based cohort study, we linked collected data from the Trøndelag Health Study (HUNT) (n = 2,408, 48,3% women) in Norway with the Norwegian Surveillance System for Communicable diseases (MSIS) registry. Included participants were tested for CRF as peak oxygen uptake (VO2peak) during cardiopulmonary exercise testing between 2017-2019. The individual data were matched with MSIS indicative of having COVID-19 by reporting a positive PCR-test between 26th of February 2020 and 1st of October 2022. Participants were classified into age- and sex-specific quintiles, and modified Poisson regression with log link was used to estimate adjusted relative risk (aRR) and 95% confidence intervals (CI) for the association of CRF with testing positive for COVID-19.

Results

During a median follow up of 2.6 years, 249 participants tested positive for COVID-19. After adjustment for confounders, participants in the highest quintile of CRF had a significantly lower risk (aRR = 0.59, 95% CI: 0.40 to 0.88) of testing positive for COVID-19, compared with those in the lowest quintile of CRF. Each MET higher CRF was associated with lower risk of COVID-19 infection (aRR = 0.92, 95% CI: 0.87 to 0.98).

Conclusions

This is the first study to assess the association between objectively measured CRF and risk of COVID-19 infection in a general population of healthy adults. The findings suggest a protective effect of high CRF on COVID-19 infection and highlight the importance of improving CRF to lower the burden of COVID-19 in the general population.
Muscle oxygenation kinetics in Long COVID-19: Illness severity and clinical implications
Authors: Luz Goulart C , Robson Fernando Borgesa R F B , Claudia Cristina Conde Holanda Sobral C C C H S , Thomas Beltrame T B , Mauricio Milani M M , Gerson Cipriano Junior G C J , Ana Cleides Pereira Dos Santos A C P S , Ricardo Stein R S , Fabricio Braga F B , Luiz Eduardo Fonteles Ritt L E F R
Published: June 2024

Introduction

Several mechanistic hypotheses for exercise limitations in post-acute sequelae of COVID-19 (PASC) have been formulated, but the issue is not yet resolved. It is believed that the limit to exercise performance is not central but rather peripheral. The latest findings raise the hypothesis of impairments in the utilization of oxygen by skeletal muscles, as initially observed in patients infected with SARS-CoV-2. Therefore, our study was designed to characterize and identify the main factors responsible for changes in the kinetic responses of muscle oxygenation and deoxygenation during constant-load exercise in the vastus lateralis muscle according to COVID-19 severity. This may help understand the phenotype of individuals with PASC.

Objective

The present study aimed to assess the muscle kinetics of oxyhemoglobin (oxy-[Hb/Mb]) and deoxyhemoglobin (deoxy-[Hb/Mb]) and the key clinical factors that may impact this response during constant-load exercise in individuals with PASC.

Methods and Results

Thirty individuals with PASC underwent constant load tests to assess the kinetics of oxy-[Hb/Mb] and deoxy-[Hb/Mb] of the vastus lateralis muscle utilizing near-infrared spectroscopy (NIRS). With a mean age of 52 years and 57% male, the most frequent comorbidities were hypertension (70%), obesity (43%), and diabetes (20%). Individuals were assessed on average 115 days after COVID-19, with a mean hospitalization length of stay of 22 days. We found an increased mean response time (MRT, s) for both oxy-[Hb/Mb] 141.8 (112.3-171.3) and deoxy-[Hb/Mb] 166.1 (135-196). Multivariate regression analysis showed that only body mass index (BMI, kg/m²) influenced the response of the decay time constant (τ) (β = 5.8; 95% CI: 1.3 to 10.3; p = 0.012) and MRT (β = 7.6; 95% CI: 1.1 to 14.1; p = 0.023) of oxy-[Hb/Mb] in the vastus lateralis muscle during constant load testing, even after adjusting for potential confounders such as sex and COVID-19 severity. Body adiposity was correlated with oxy-[Hb/Mb] τ (s) (r=0.488) and oxy-[Hb/Mb] MRT (s) (r = 0.431) in the vastus lateralis muscle during constant load testing. Additionally, when stratifying patients with Long COVID into obese and non-obese, obese patients showed a slower τ (s) and MRT (s) response compared to non-obese (p < 0.001).

Conclusion

We found that, along with the impairment (slowing) of peripheral muscle oxy-[Hb/Mb] kinetics during exercise in Long COVID, which was also associated with the prevalence of obesity. Peripheral oxygen muscle limitation may be related to exercise limitation in this population.
Evaluating the cardiovascular benefits of stair climbing: a systematic review and meta-analysis
Authors: Paddock S , Veerni R , Bhalraam U , Meng J , Dawson-Plincke E , Vassiliou V , Tsampasian V
Published: June 2024

Background

Physical inactivity causes a significant burden from cardiovascular disease worldwide. As sedentary behaviours and associated health risks become increasingly prevalent, there is a growing imperative to explore accessible and practical strategies to mitigate cardiovascular risk. This systematic review and meta-analysis aims to evaluate the association between physical activity in the form of stair climbing and cardiovascular risk.

Methods

A systematic literature search of the PubMed database was conducted from inception until the 9th October 2023. The search criteria used were: ["((Stairs) OR (Stair climbing)) AND ((Cardiac) OR (Heart) OR (Cardiovascular))"]. Randomised controlled trials or observational studies including stair climbing as a variable were included. The outcomes of interest were cardiovascular mortality and incidence of cardiovascular disease including myocardial infarction, ischaemic stroke and heart failure. Statistical analyses were conducted using the Review Manager (RevMan) software.

Results

The database search yielded 725 studies, out of which, 8 studies with 473 197 patients were included in the analysis. The pooled analysis of 5 studies and 455 578 patients revealed that stair climbing was associated with a significant reduction in cardiovascular mortality (RR 0.65, 95% confidence interval [CI] 0.50-0.83, p=0.0008) [figure 1]. Further analysis of these 5 studies revealed that stair climbing was also associated with a significant reduction in all-cause mortality (RR 0.70, 95% CI 0.56-0.87, p=0.002) [figure 2].

Conclusions

Physical activity in the form of stair climbing is associated with a reduced risk of cardiovascular and all-cause mortality. These findings highlight the importance of promoting everyday activities, even within the workplace and home, to foster healthier lifestyles and mitigate the risks associated with cardiovascular diseases.
Hostility and related psychometric profiling in coronary artery disease patients participating in cardiac rehabilitation: a matched cross-sectional study
Authors: Lin C , Hsu Y H , Weng C Y , Hsu B C , Hsieh L , Yao H , Chang C L
Published: June 2024

Background and aim

Cardiac rehabilitation is essential for coronary heart disease patients. Past studies show psychosocial factors like depression, anxiety, hostility, and Type D personality traits may affect rehabilitation outcomes. However, psychometric profiling in Taiwanese cardiac rehabilitation is limited. This study examines the psychosocial profiling of coronary artery disease patients in outpatient cardiac rehabilitation.

Method

From December 2022 to May 2023, patients diagnosed with myocardial infarction or coronary artery disease underwent screening and were enrolled in an outpatient cardiac rehabilitation program at a tertiary hospital in central Taiwan. Each patient was matched for age and gender with normal participants. Demographic and clinical data were collected from all participants. All subjects were assessed using the self-administered psychoneurological measures, including the Neuropsychiatric Inventory, Center for Epidemiologic Studies Depression Scale, General Anxiety Disorder-7 questionnaire, Type D personality questionnaire, and Chinese Hostility Inventory-Short Form.

Result

A total of 61 patients and 45 normal controls were included in the study, with 93% of patients participating in outpatient cardiac rehabilitation. Among the patient cohort, 27.9% presented with depression, 8.2% showed moderate to severe anxiety, and 16.4% manifested Type D personality traits. In the control group, 20% displayed depression, 8.9% exhibited moderate to severe anxiety, and 17.8% exhibited Type D personality traits. Hostility Inventory total scores were lower in the patient group compared to the control group, with a statistically significant difference noted in the Hostility Cognition domain (11.85+4.92 vs 13.80+4.83, p= 0.05).

Conclusion

In patients enrolled in outpatient cardiac rehabilitation, depression and anxiety are prevalent, underscoring the need for psychosocial risk factor-specific management within cardiac rehabilitation program. The potential effect of cardiac rehabilitation on improving patients' psychosocial health through the reduction of hostility merits additional investigation. Result-Psychometric profiling.
What Makes a Mimic? Orange, Red, and Black Color Production in the Mimic Poison Frog (Ranitomeya imitator)
Authors: Rubio Andrew O , Stuckert Adam M M , Geralds BreAnn , Nielsen Rasmus , MacManes Matthew D , Summers Kyle
Published: June 2024

Aposematic organisms rely on their conspicuous appearance to signal that they are defended and unpalatable. Such phenotypes are strongly tied to survival and reproduction. Aposematic colors and patterns are highly variable; however, the genetic, biochemical, and physiological mechanisms producing this conspicuous coloration remain largely unidentified. Here, we identify genes potentially affecting color variation in two color morphs of Ranitomeya imitator: the orange-banded Sauce and the redheaded Varadero morphs. We examine gene expression in black and orange skin patches from the Sauce morph and black and red skin patches from the Varadero morph. We identified genes differentially expressed between skin patches, including those that are involved in melanin synthesis (e.g. mlana, pmel, tyrp1), iridophore development (e.g. paics, ppat, ak1), pteridine synthesis (e.g. gch1, pax3-a, xdh), and carotenoid metabolism (e.g. dgat2, rbp1, scarb2). In addition, using weighted correlation network analysis, we identified the top 50 genes with high connectivity from the most significant network associated with gene expression differences between color morphs. Of these 50 genes, 13 were known to be related to color production (gch1, gmps, gpr143, impdh1, mc1r, pax3-a, pax7, ppat, rab27a, rlbp1, tfec, trpm1, xdh).
Higher Number of Children Is Associated With Increased Risk of Generalization Deficits in Older African American Women
Authors: Abedullah Salma M , Fausto Bernadette A , Osiecka Zuzanna , Gluck Mark A
Published: June 2024

Objectives

The objectives of this project were to: (1) examine the relationship between the number of biological children and hippocampal-dependent cognitive performance among older African American women and (2) determine the influence of socioeconomic status (i.e., age, education, marital status, median household income), if any, on this relationship.

Methods

A total of 146 cognitively unimpaired African American women aged 60 and older were recruited from the greater Newark area and reported their number of biological children, marital status, educational level, and age. We retrieved median household income from census tract data based on the participants’ addresses. Participants’ cognitive performance was assessed using the Rey Auditory Verbal Learning Test (RAVLT) long delay recall and a Rutgers generalization task (Concurrent Discrimination and Transfer Task).

Results

As the number of biological children a woman has had increases, the number of generalization errors also increased, indicating poorer hippocampal-dependent cognitive performance when controlling for age, education, marital status, and median household income. There was no significant relationship between the number of children and performance on a standardized neuropsychological measure of episodic memory (RAVLT), although education was a significant covariate.

Discussion

Generalization tasks may better capture early changes in cognitive performance in older African American women who have had children than standardized neuropsychological assessments. This finding may be explained by the fluctuations in estrogen associated with having children. Future studies should explore how these findings can be applied to protecting cognitive function and preventing Alzheimer’s disease in older African American women who have had children.
Persons With Cognitive Impairment and Care Partner Motivations and Experiences of Undergoing an Amyloid Scan: A Systematic Review of Qualitative Studies
Authors: Couch Elyse , Ashford Miriam T , Prina Matthew
Published: June 2024

Background and Objectives

Amyloid positron emission tomography scans can enhance the accuracy of dementia diagnoses. However, the perspectives and experiences of people with cognitive impairment and their care partners undergoing an amyloid scan are less well understood. Therefore, this review aimed to identify and summarize qualitative studies exploring patient and care partner experiences of undergoing an amyloid scan.

Research Design and Methods

We searched Embase, MEDLINE, and PsychInfo in March 2024. Articles were screened for inclusion by 2 reviewers and critically appraised using the Joanna Briggs Institute Critical Appraisal Tool for Qualitative Studies. Data from the included studies were synthesized using thematic synthesis.

Results

We identified 10 papers from 6 studies. We identified 4 themes: (1) motivations for undergoing an amyloid scan, (2) experiences of receiving the result, (3) emotional responses to the result, and (4) actions in light of the scan result. Participants reported undergoing the scan to determine the cause of cognitive impairment. They described the information gained from the scan as helpful but struggled to recall the correct terminology or implications of the scan. Emotional responses to the scan varied depending on the scan result. In light of the scan result, the most common action was making advanced plans; however, this was mainly discussed among participants with elevated amyloid.

Discussions and Implications

Amyloid scans can provide useful and actionable information. However, learning the scan result could be distressing. Future research is needed to balance the potential benefits and harms of amyloid scans.
Novel genetically glycoengineered human dendritic cell model reveals regulatory roles of α2,6-linked sialic acids in DC activation of CD4+ T cells and response to TNFα
Authors: Tian Weihua , Blomberg Anne Louise , Steinberg Kaylin Elisabeth , Henriksen Betina Lyngfeldt , Jørgensen Josefine Søborg , Skovgaard Kerstin , Skovbakke Sarah Line , Goletz Steffen
Published: June 2024

Dendritic cells (DCs) are central for the initiation and regulation of appropriate immune responses. While several studies suggest important regulatory roles of sialoglycans in DC biology, our understanding is still inadequate primarily due to a lack of appropriate models. Previous approaches based on enzymatic- or metabolic-glycoengineering and primary cell isolation from genetically modified mice have limitations related to specificity, stability, and species differences. This study addresses these challenges by introducing a workflow to genetically glycoengineer the human DC precursor cell line MUTZ-3, described to differentiate and maturate into fully functional dendritic cells, using CRISPR-Cas9, thereby providing and validating the first isogenic cell model for investigating glycan alteration on human DC differentiation, maturation, and activity. By knocking out (KO) the ST6GAL1 gene, we generated isogenic cells devoid of ST6GAL1-mediated α(2,6)-linked sialylation, allowing for a comprehensive investigation into its impact on DC function. Glycan profiling using lectin binding assay and functional studies revealed that ST6GAL1 KO increased the expression of important antigen presenting and co-stimulatory surface receptors and a specifically increased activation of allogenic human CD4 + T cells. Additionally, ST6GAL1 KO induces significant changes in surface marker expression and cytokine response to TNFα-induced maturation, and it affects migration and the endocytic capacity. These results indicate that genetic glycoengineering of the isogenic MUTZ-3 cellular model offers a valuable tool to study how specific glycan structures influence human DC biology, contributing to our understanding of glycoimmunology.
Interleukin-1 Receptor Antagonist Gene (IL1RN) Variants Modulate the Cytokine Release Syndrome and Mortality of COVID-19
Authors: Attur Mukundan , Petrilli Christopher , Adhikari Samrachana , Iturrate Eduardo , Li Xiyue , Tuminello Stephanie , Hu Nan , Chakravarti Aravinda , Beck David , Abramson Steven B
Published: June 2024

Background

We examined effects of single-nucleotide variants (SNVs) of IL1RN, the gene encoding the anti-inflammatory interleukin 1 receptor antagonist (IL-1Ra), on the cytokine release syndrome (CRS) and mortality in patients with acute severe respiratory syndrome coronavirus 2 (SARS-CoV-2) infection.

Methods

IL1RN CTA haplotypes formed from 3 SNVs (rs419598, rs315952, rs9005) and the individual SNVs were assessed for association with laboratory markers of inflammation and mortality. We studied 2589 patients hospitalized with SARS-CoV-2 between March 2020 and March 2021.

Results

Mortality was 15.3% and lower in women than men (13.1% vs 17.3%, P = .0003). Carriers of the CTA-1/2 IL1RN haplotypes exhibited decreased inflammatory markers and increased plasma IL-1Ra. Evaluation of the individual SNVs of the IL1RN, carriers of the rs419598 C/C SNV exhibited significantly reduced inflammatory biomarker levels and numerically lower mortality compared to the C/T-T/T genotype (10.0% vs 17.8%, P = .052) in men, with the most pronounced association observed in male patients ≤74 years old, whose mortality was reduced by 80% (3.1% vs 14.0%, P = .030).

Conclusions

The IL1RN haplotype CTA and C/C variant of rs419598 are associated with attenuation of the CRS and decreased mortality in men with acute SARS-CoV-2 infection. The data suggest that the IL1RN pathway modulates the severity of coronavirus disease 2019 (COVID-19) via endogenous anti-inflammatory mechanisms.
Plasma From Older Children in Malawi Inhibits Plasmodium falciparum Binding in 3-Dimensional Brain Microvessels
Authors: Joof Fatou , Hu Ruoqian , Saidi Alex , Seydel Karl B , Cohee Lauren M , Zheng Ying , Smith Joseph D
Published: June 2024

A hallmark of cerebral malaria is sequestration of Plasmodium falciparum-infected erythrocytes (IEs) in the brain microcirculation. Antibodies contribute to malaria immunity, but it remains unclear whether functional antibodies targeting parasite-expressed ligand can block cytoadhesion in the brain. Here, we screened the plasma of older children and young adults in Malawi to characterize the antibody response against the P. falciparum-IE surface and used a bioengineered 3-dimensional (3D) human brain microvessel model incorporating variable flow dynamics to measure adhesion-blocking responses. We found a strong correlation between surface antibody reactivity by flow cytometry and reduced P. falciparum-IE binding in 3D microvessels. Moreover, there was a threshold of surface antibody reactivity necessary to achieve robust inhibitory activity. Our findings provide evidence of the acquisition of adhesion-blocking antibodies against cerebral binding variants in people exposed to stable P. falciparum transmission and suggest the quality of the inhibitory response can be influenced by flow dynamics.
Adverse events reporting during the COVID-19 pandemic in a Danish region: a retrospective analysis
Authors: Uggerby Christian , Knudsen Søren Valgreen , Grøntved Simon , Sørensen Agnete Lund , Larsen Karen Lyng , Schmidt Charlotte Kaae , Jensen Tilde , Pedersen Jens Ravnholt , Mainz Jan
Published: June 2024

The 2020 onset of the COVID-19 pandemic globally strained healthcare. Healthcare systems worldwide had to rapidly reorganize, impacting service delivery, patient care, and care-seeking behaviors. This left little time to assess the pandemic’s effects on patient safety. This paper investigates COVID-19’s influence on patient safety in a Danish region, using data from the national reporting system for adverse events during the initial COVID-19 surge in early 2020. This retrospective analysis investigated how the early phase of the COVID-19 pandemic (January–September 2020) affected the incidence of adverse events in a Danish Region, comparing it to the same period in 2019. Data were sourced from the Danish Patient Safety Database and regional systems. Adverse events were reported numerically. Descriptive statistics were employed to describe the percentage difference in adverse events and hospital activity, as well as the rate of adverse events per 1000 activities. Additionally, COVID-19-specific adverse events from April 2020 to March 2021 were identified and analyzed, categorizing them into seven risk areas across various healthcare sectors. During Denmark’s initial COVID-19 surge in early 2020, the North Denmark Region’s hospitals reported a significant decrease in adverse events, with a 42.5% drop in March 2020 compared to March 2019. From January to September 2020, the number of adverse events dropped 8.5% compared to the same period in 2019. In the same period, hospital activity declined by 10.2%. The ratio of reported adverse events per 1000 hospital activities thus decreased in early 2020 but showed only a minor difference overall for January–September compared to 2019. Between April 2020 and March 2021, out of 5703 total adverse events, 324 (5.7%) were COVID-19 related. COVID-19-related events were categorized into seven distinct risk areas, reflecting diverse impacts across healthcare sectors including hospitals, general practices, pre-hospital care, and specialized services. The initial decline in reporting of adverse events likely resulted from rapid healthcare changes and under-prioritization of the reporting system during the acute phase. However, a near return to pre-pandemic reporting levels suggests a resilient reporting system despite the crisis. The study’s strength lies in the comprehensive data from Danish reporting systems, though it acknowledges potential underreporting and doesn’t measure the pandemic’s overall impact on patient safety.
An IR Textbook in the Interwar Period: Reflections on the Contents of a Quincy Wright “Time Capsule”
Authors: Beck Robert J
Published: June 2024

A recently opened “time capsule” from the 1930’s reveals how the marketing of a prominent textbook on International Relations (IR) was done then and how one opinion-leading scholar responded to that textbook’s marketing, but especially, to its overall approach. The textbook was Simonds and Emeny’s The Great Powers in World Politics (1935), putatively the “most widely sold book in its field.” The scholar was Quincy Wright, one of IR’s founders and most distinguished interwar figures. This essay shares the time capsule’s background, then assesses its fascinating contents, focusing particularly on Professor Wright’s scholarly response, which until now has remained undocumented. In the interwar period, higher education was a much smaller domain than it is today, and the IR field was in its nascency. Even so, IR textbooks were being written and their publishers were already manifesting aggressive and sophisticated advocacy. In that environment, Quincy Wright proved an engaged but critical audience, having by then developed quite robust views on his subject and how it should be studied. A review of this textbook episode offers compelling vignettes of both interwar IR’s milieu and one of its most intriguing personalities. More specifically, an examination of this incident underscores the importance of a discipline’s textbooks, enriches our understanding of Quincy Wright as intellectual, scholar, and teacher, and powerfully reminds us that the questions with which Wright and the IR discipline engaged almost a century ago remain salient and their answers highly contested. Moreover, revisionist accounts of Quincy Wright’s scholarship and IR’s early stages find strong support.
Active prokaryotic and eukaryotic viral ecology across spatial scale in a deep-sea brine pool
Authors: Minch Benjamin , Chakraborty Morgan , Purkis Sam , Rodrigue Mattie , Moniruzzaman Mohammad
Published: June 2024

Deep-sea brine pools represent rare, extreme environments, providing unique insight into the limits of life on Earth, and by analogy, the plausibility of life beyond it. A distinguishing feature of many brine pools is presence of thick microbial mats that develop at the brine–seawater interface. While these bacterial and archaeal communities have received moderate attention, viruses and their host interactions in these environments remain underexplored. To bridge this knowledge gap, we leveraged metagenomic and metatranscriptomic data from three distinct zones within the NEOM brine pool system (Gulf of Aqaba) to reveal the active viral ecology around the pools. We report a remarkable diversity and activity of viruses infecting microbial hosts in this environment, including giant viruses, RNA viruses, jumbo phages, and Polinton-like viruses. Many of these form distinct clades—suggesting presence of untapped viral diversity in this ecosystem. Brine pool viral communities exhibit zone-specific differences in infection strategy—with lysogeny dominating the bacterial mat further away from the pool’s center. We linked viruses to metabolically important prokaryotes—including association between a jumbo phage and a key manganese-oxidizing and arsenic-metabolizing bacterium. These foundational results illuminate the role of viruses in modulating brine pool microbial communities and biogeochemistry through revealing novel viral diversity, host associations, and spatial heterogeneity in viral dynamics.
Therapeutic drug monitoring of polymyxin B cerebrospinal fluid concentrations in patients with carbapenem-resistant Gram-negative bacteria-induced central nervous system infection
Authors: Wang Peile , Liu Shaohua , He Xia , Miao Wang , Sun Tongwen , Yang Jing
Published: June 2024

Objectives

Central nervous system (CNS) infections caused by carbapenem-resistant Gram-negative bacteria (CR-GNB) present a major health and economic burden worldwide. This multicentre prospective study aimed to assess the feasibility and usefulness of CSF therapeutic drug monitoring (TDM) after intrathecal/intraventricular administration of polymyxin B in patients with CNS infections.

Methods

Forty-two patients treated with intrathecal/intraventricular administration of polymyxin B against CR-GNB-induced CNS infections were enrolled. CSF trough level (Cmin) was collected beginning on Day 2 post-polymyxin B initiation and thereafter. The primary outcomes were clinical cure and 28-day all-cause mortality.

Results

All patients started with intrathecal/intraventricular administration of polymyxin B at a dose of 5 g/day, corresponding to a median CSF Cmin of 2.93 mg/L (range, 0.21–25.74 mg/L). Clinical cure was 71.4%, and the median CSF Cmin of this group was higher than that of clinical failure group [3.31 (IQR, 1.73–5.62) mg/L versus 2.25 (IQR, 1.09–4.12) mg/L; P = 0.011]. In addition, with MICs ≤ 0.5 mg/L, maintaining polymyxin B CSF Cmin above 2.0 mg/L showed a higher clinical cure rate (P = 0.041). The 28-day all-cause mortality rate was 31.0% and had no association with CSF Cmin.

Conclusions

After intrathecal/intraventricular administration of polymyxin B, CSF concentrations fluctuated considerably inter- and intra-individual. Polymyxin B CSF Cmin above 2.0 mg/L was associated with clinical cure when MICs were ≤ 0.5 mg/L, and the feasibility of TDM warrants additional clinical studies.
A detection of quarantine scale pest Icerya seychellarum (Hemiptera: Monophlebidae) in South Korea
Authors: Kim Hyeongsu , Lee Sang-Bin , Lee Wonhoon
Published: June 2024

Icerya seychellarum (Westwood, 1855) (Hemiptera: Monophlebidae) is found in most tropical and subtropical regions worldwide and is a highly polyphagous pest that affects more than 140 genera of host plants. In 2023, I. seychellarum was discovered for the first time in Seogwipo-si, Jeju Island, South Korea. The specimen was found in heavily infested Cycas revoluta. Here, we provide information regarding the associated host damage, a description of the species, and details of sampling locations. The discovery of I. seychellarum is of agricultural and quarantine importance in South Korea; therefore, this study presents an opportunity to investigate new strategies geared toward advancing efforts to detect and eliminate threats in the future.
β-Amyloid species production and tau phosphorylation in iPSC-neurons with reference to neuropathologically characterized matched donor brains
Authors: Oakley Derek H , Chung Mirra , Abrha Sara , Hyman Bradley T , Frosch Matthew P
Published: June 2024

A basic assumption underlying induced pluripotent stem cell (iPSC) models of neurodegeneration is that disease-relevant pathologies present in brain tissue are also represented in donor-matched cells differentiated from iPSCs. However, few studies have tested this hypothesis in matched iPSCs and neuropathologically characterized donated brain tissues. To address this, we assessed iPSC-neuron production of β-amyloid (Aβ) Aβ40, Aβ42, and Aβ43 in 24 iPSC lines matched to donor brains with primary neuropathologic diagnoses of sporadic AD (sAD), familial AD (fAD), control, and other neurodegenerative disorders. Our results demonstrate a positive correlation between Aβ43 production by fAD iPSC-neurons and Aβ43 accumulation in matched brain tissues but do not reveal a substantial correlation in soluble Aβ species between control or sAD iPSC-neurons and matched brains. However, we found that the ApoE4 genotype is associated with increased Aβ production by AD iPSC-neurons. Pathologic tau phosphorylation was found to be increased in AD and fAD iPSC-neurons compared to controls and positively correlated with the relative abundance of longer-length Aβ species produced by these cells. Taken together, our results demonstrate that sAD-predisposing genetic factors influence iPSC-neuron phenotypes and that these cells are capturing disease-relevant and patient-specific components of the amyloid cascade.
Polymicrobial brain abscesses: A complex condition with diagnostic and therapeutic challenges
Authors: Eichorn Frances-Claire , Kameda-Smith Michelle , Fong Crystal , Graham Alice K , Main Cheryl , Lu Jian-Qiang
Published: June 2024

Brain abscesses (BA) are focal parenchymal infections that remain life-threatening conditions. Polymicrobial BAs (PBAs) are complex coinfections of bacteria or bacterial and nonbacterial pathogens such as fungi or parasites, with diagnostic and therapeutic challenges. In this article, we comprehensively review the prevalence, pathogenesis, clinical manifestations, and microbiological, histopathological, and radiological features of PBAs, as well as treatment and prognosis. While PBAs and monomicrobial BAs have some similarities such as nonspecific clinical presentations, PBAs are more complex in their pathogenesis, pathological, and imaging presentations. The diagnostic challenges of PBAs include nonspecific imaging features at early stages and difficulties in identification of some pathogens by routine techniques without the use of molecular analysis. Imaging of late-stage PBAs demonstrates increased heterogeneity within lesions, which corresponds to variable histopathological features depending on the dominant pathogen-induced changes in different areas. This heterogeneity is particularly marked in cases of coinfections with nonbacterial pathogens such as Toxoplasma gondii. Therapeutic challenges in the management of PBAs include initial medical therapy for possibly underrecognized coinfections prior to identification of multiple pathogens and subsequent broad-spectrum antimicrobial therapy to eradicate identified pathogens. PBAs deserve more awareness to facilitate prompt and appropriate treatment.
Phase-separated super-enhancers confer an innate radioresistance on genomic DNA
Authors: Matsumoto Koki , Ikliptikawati Dini Kurnia , Makiyama Kei , Mochizuki Kako , Tobita Maho , Kobayashi Isao , Voon Dominic Chih-Cheng , Lim Keesiang , Ogawa Kazuma , Kashiwakura Ikuo , Suzuki Hiroshi I , Yoshino Hironori , Wong Richard W , Hazawa Masaharu
Published: June 2024

Recently, biomolecular condensates formed through liquid–liquid phase separation have been widely reported to regulate key intracellular processes involved in cell biology and pathogenesis. BRD4 is a nuclear protein instrumental to the establishment of phase-separated super-enhancers (SEs) to direct the transcription of important genes. We previously observed that protein droplets of BRD4 became hydrophobic as their size increase, implying an ability of SEs to limit the ionization of water molecules by irradiation. Here, we aim to establish if SEs confer radiation resistance in cancer cells. We established an in vitro DNA damage assay that measures the effect of radicals provoked by the Fenton reaction on DNA integrity. This revealed that DNA damage was markedly reduced when BRD4 underwent phase separation with DNA. Accordingly, co-focal imaging analyses revealed that SE foci and DNA damage foci are mutually exclusive in irradiated cells. Lastly, we observed that the radioresistance of cancer cells was significantly reduced when irradiation was combined with ARV-771, a BRD4 de-stabilizer. Our data revealed the existence of innately radioresistant genomic regions driven by phase separation in cancer cells. The disruption of these phase-separated components enfolding genomic DNA may represent a novel strategy to augment the effects of radiotherapy.
Appreciating animal induced pluripotent stem cells to shape plant cell reprogramming strategies
Authors: Wittmer Jana , Heidstra Renze
Published: June 2024

Animals and plants have developed resilience mechanisms to effectively endure and overcome physical damage and environmental challenges throughout their life span. To sustain their vitality, both animals and plants employ mechanisms to replenish damaged cells, either directly, involving the activity of adult stem cells, or indirectly, via dedifferentiation of somatic cells that are induced to revert to a stem cell state and subsequently redifferentiate. Stem cell research has been a rapidly advancing field in animal studies for many years, driven by its promising potential in human therapeutics, including tissue regeneration and drug development. A major breakthrough was the discovery of induced pluripotent stem cells (iPSCs), which are reprogrammed from somatic cells by expressing a limited set of transcription factors. This discovery enabled the generation of an unlimited supply of cells that can be differentiated into specific cell types and tissues. Equally, a keen interest in the connection between plant stem cells and regeneration has been developed in the last decade, driven by the demand to enhance plant traits such as yield, resistance to pathogens, and the opportunities provided by CRISPR/Cas-mediated gene editing. Here we discuss how knowledge of stem cell biology benefits regeneration technology, and we speculate on the creation of a universal genotype-independent iPSC system for plants to overcome regenerative recalcitrance.