bluuebunny/crossref_metadata_2025 huggingface dataset:
Aging measures and cancer: Findings from the Health and Retirement Study
Authors: Wang Shuo , Prizment Anne , Moshele Puleng , Vivek Sithara , Blaes Anne H. , Nelson Heather H. , Thyagarajan Bharat
Published: September 2023

Background

Compared to cancer-free persons, cancer survivors of the same chronological age (CA) have increased physiological dysfunction, i.e., higher biological age (BA), which may lead to higher morbidity and mortality. We estimated BA using eight aging metrics: BA computed by Klemera Doubal method (KDM-BA), phenotypic age (PhenoAge), five epigenetic clocks (ECs, Horvath, Hannum, Levine, GrimAge, and pace of aging (POA)), and subjective age (SA). We tested if aging constructs were associated with total cancer prevalence and all-cause mortality in cancer survivors and controls, i.e., cancer-free persons, in the Health and Retirement Study (HRS), a large population-based study.

Methods

In 2016, data on BA-KDM, PhenoAge, and SA were available for 946 cancer survivors and 4,555 controls; data for the five ECs were available for 582 cancer survivors and 2,805 controls. Weighted logistic regression was used to estimate the association between each aging construct and cancer prevalence (odds ratio, OR, 95%CI). Weighted Cox proportional hazards regression was used to estimate the associations between each aging construct and cancer incidence as well as all-cause mortality (hazard ratio, HR, 95%CI). To study all BA metrics (except for POA) independent of CA, we estimated age acceleration as residuals of BA regressed on CA.

Results

Age acceleration for each aging construct and POA were higher in cancer survivors than controls. In a multivariable-adjusted model, five aging constructs (age acceleration for Hannum, Horvath, Levine, GrimAge, and SA) were associated with cancer prevalence. Among all cancer survivors, age acceleration for PhenoAge and four ECs (Hannum, Horvath, Levine, and GrimAge), was associated with higher all-cause mortality over 4 years of follow-up. PhenoAge, Hannum, and GrimAge were also associated with all-cause mortality in controls. The highest HR was observed for GrimAge acceleration in cancer survivors: 2.03 (95% CI, 1.58-2.60). In contrast, acceleration for KDM-BA and POA was significantly associated with mortality in controls but not in cancer survivors. When all eight aging constructs were included in the same model, two of them (Levine and GrimAge) were significantly associated with mortality among cancers survivors. None of the aging constructs were associated with cancer incidence.

Conclusion

Variations in the associations between aging constructs and mortality in cancer survivors and controls suggests that aging constructs may capture different aspects of aging and that cancer survivors may be experiencing age-related physiologic dysfunctions differently than controls. Future work should evaluate how these aging constructs predict mortality for specific cancer types.
PSYCHIATRIC COMORBIDITY & STRUCTURAL BRAIN FEATURES IN THE ADOLESCENT BRAIN AND COGNITIVE DEVELOPMENT STUDY COHORT: A CROSS-SECTIONAL US POPULATION-BASED STUDY
Authors: Luna Alex , Wu Qihang , Zhu Xi , Ryu Hyunnam , Marsh Rachel , Lee Seonjoo
Published: September 2023

Abstract

Background

Children who develop a psychiatric disorder often also develop additional comorbid psychiatric conditions, ultimately impacting prognosis, outcomes, and treatment planning. In this cross-sectional study using the ABCD dataset, the authors set out to identify distinct comorbidity profiles using comorbidity network analysis and any associated clinical correlates of behavior and structural neuroimaging markers.

Methods

Structural magnetic resonance imaging and psychometric testing were obtained from 7077 eligible children between the ages of 9-10 in the ABCD dataset. Children were separated into the typically developing group and the psychiatric group based on the presence of a DSM-V diagnosis.

Results

Three comorbidity profiles across gender emerged using comorbidity network analysis. Girls with the ADHD – ODD (AO) comorbidity profile and sparse comorbidity profile had thicker left superior frontal gyri compared to typically developing children. Boys and girls with the ADHD – ODD comorbidity profile had significantly higher externalizing scores compared to typically developing children. The ADHD-OCD-Specific Phobia (AOS) profile among boys had significantly higher internalizing scores, while the AO profile had significantly higher internalizing scores for girls. The AOS profile for boys and the AO profile for girls had significantly higher total problem scores compared to typically developing children.

Conclusion

Comorbidity network analysis successfully identified comorbidity profiles associated with unique neurobiological markers and behavioral correlates and is a feasible technique for the investigation of comorbid psychiatric conditions.
Association between lipoprotein(a),LPAgenetic risk score, aortic valve disease, and subsequent major adverse cardiovascular events
Authors: Moore Matthew K , Jones Gregory T , McCormick Sally , Williams Michael JA , Coffey Sean
Published: September 2023

Background

Cohort studies have demonstrated associations between calcific aortic valve disease (CAVD) and Lp(a). As Lp(a) is almost entirely genetically determined, with the increasing clinical availability of genetic information, we aimed to determine if Lp(a), when predicted from genetic data, is associated with CAVD and major adverse cardiovascular events (MACE).

Methods

Patients undergoing coronary angiography were invited to participate in the study. Of 752 analysable participants, 446 had Lp(a) measured, and 703 had a calculableLPAgenetic risk score (GRS). CAVD was categorized as absent/present and by severity. The primary outcomes were presence of CAVD at baseline, and MACE over seven years follow-up.

Results

The GRS explained 45% of the variation in Lp(a). After adjustment for cardiac risk factors and coronary artery disease, the odds of CAVD increased with Lp(a) (OR 1.039 per 10 unit increase, 95% C.I. 1.022 – 1.057, p<0.001) and GRS (OR 1.054 per 10-unit increase, 95% C.I. 1.024 – 1.086; p <0.001). Lp(a) and the GRS as continuous variables were not associated with subsequent MACE. Dichotomised GRS (>54) was associated with MACE, but this relationship became non-significant when coronary artery disease classification was added into the model (OR 1.333, 95% C.I. 0.927 – 1.912; p = 0.12).

Conclusion

AnLPAGRS can explain 45% of the variation in Lp(a) levels, and both Lp(a) and the GRS are associated with CAVD. An elevated GRS is associated with future cardiac events in a secondary risk setting, but, if coronary artery disease status is known, it does not provide additional prognostic information.
Prehospital scale to differentiate intracerebral hemorrhage from large-vessel occlusion patients: A prospective cohort study
Authors: Freixa-Cruz A , Jimenez-Jimenez G , Mauri-Capdevila G , Gallego-Sánchez Y , García-Díaz A , Mitjana Penella R , Paul-Arias M , Pereira-Priego C , Ruiz-Fernández E , Salvany-Montserrat S , Sancho-Saldaña A , San-Pedro-Murillo E , Saureu E , Vázquez-Justes D , Purroy F
Published: September 2023

Background and rationale

Evaluating scales to detect large vessel occlusion (LVO) could aid in considering early referrals to a thrombectomy-capable center in the prehospital stroke code setting. Nevertheless, they entail a significant number of false positives, corresponding to intracranial hemorrhages (ICH), which could result in a delay in medical attention and potential harm. Our study aims to identify easily collectible variables for the development of a scale to differentiate patients with ICH from LVO in a prehospital context.

Methods

We conducted a prospective cohort study of stroke code patients between May 2021 and January 2023. Patients were evaluated with CT/CT-Angiography at arrival. We compared clinical variables and vascular risk factors between ICH and LVO patients to design a prehospital ICH screening scale (PreICH).

Results

Out of 989 stroke code patients, we included 190 (66.7%) LVO cases and 95 (33.3) ICH cases. In the multivariate analysis, headache (odds ratio [OR] 3.56; 1.50-8.43), GCS<8 (OR 8.19; 3.17-21.13), SBP>160mmHg (OR 6.43; 3.37-12.26) and male sex (OR 2.07; 1.13-3.80) were associated with ICH, while previous hypercholesterolemia (HCL) (OR 0.35; 0.19-0.65) with LVO. The scale design was conducted, assigning a score to each significant variable based on its specific weight: +2 points for SBP > 160, +1 points for headache, +1 points for male sex, +2 points for GCS<8, and -1 points for HCL. The area under the curve (AUC) was 0.82 (0.77-0.87). A score ≥4 exhibited a sensitivity of 0.10, a specificity of 0.99, a positive predictive value of 0.21, and a negative predictive value of 0.98.

Conclusion

We present the development of a prehospital scale to discriminate between ICH and LVO patients, utilizing easily detectable variables in the prehospital setting.
Unlocking Efficient Hospital Operations: Discrete Event Simulation in R
Authors: Kamal Mohamed , Hassanain Omneya
Published: September 2023

In healthcare systems, optimizing resource allocation without compromising patient care is paramount. This study employs a simulation-based approach to evaluate the efficiency of bed allocation within a hospital setting. Utilizing a patient arrival model with an exponential distribution, we simulated patient trajectories to examine system bottlenecks, particularly focusing on waiting times. Initial simulations painted a scenario of an “unstable” system, where waiting times and queue lengths surged due to the limited number of available beds. Through iterative simulations, we explored the operational research question: “What is the minimum number of beds required to stabilize the system?” Our results, visualized in a series of detailed metrics plots, suggest that the addition of a specific number of beds can significantly reduce patient waiting time and stabilize the system. This research offers insights for hospital management on resource optimization, potentially leading to improved patient care and reduced operational costs.
Simulation-based validation of a method to detect changes in SARS-CoV-2 reinfection risk
Authors: Lombard Belinda , Moultrie Harry , Pulliam Juliet R.C. , van Schalkwyk Cari
Published: September 2023

Background

Given the high global seroprevalence of SARS-CoV-2, understanding the risk of reinfection becomes increasingly important. Models developed to track trends in reinfection risk should be robust against possible biases arising from imperfect data observation processes.

Objectives

We performed simulation-based validation of an existing catalytic model designed to detect changes in the risk of reinfection by SARS-CoV-2.

Methods

The catalytic model assumes the risk of reinfection is proportional to observed infections. Validation involved using simulated primary infections, consistent with the number of observed infections in South Africa. We then simulated reinfection datasets that incorporated different processes that may bias inference, including imperfect observation and mortality, to assess the performance of the catalytic model. A Bayesian approach was used to fit the model to simulated data, assuming a negative binomial distribution around the expected number of reinfections, and model projections were compared to the simulated data generated using different magnitudes of change in reinfection risk. We assessed the approach’s ability to accurately detect changes in reinfection risk when included in the simulations, as well as the occurrence of false positives when reinfection risk remained constant.

Key Findings

The model parameters converged in most scenarios leading to model outputs aligning with anticipated outcomes. The model successfully detected changes in the risk of reinfection when such a change was introduced to the data. Low observation probabilities (10%) of both primary- and re-infections resulted in low numbers of observed cases from the simulated data and poor convergence.

Limitations

The model’s performance was assessed on simulated data representative of the South African SARS-CoV-2 epidemic, reflecting its timing of waves and outbreak magnitude. Model performance under similar scenarios may be different in settings with smaller epidemics (and therefore smaller numbers of reinfections).

Conclusions

Ensuring model parameter convergence is essential to avoid false-positive detection of shifts in reinfection risk. While the model is robust in most scenarios of imperfect observation and mortality, further simulation-based validation for regions experiencing smaller outbreaks is recommended. Caution must be exercised in directly extrapolating results across different epidemiological contexts without additional validation efforts.
Impact of bivalent BA.4/5 BNT162b2 COVID-19 vaccine on acute symptoms, quality of life, work productivity and activity levels among symptomatic US adults testing positive for SARS-CoV-2 at a national retail pharmacy
Authors: Fusco Manuela Di , Sun Xiaowu , Anatale-Tardiff Laura , Yehoshua Alon , Coetzer Henriette , Alvarez Mary B. , Allen Kristen E. , Porter Thomas M. , Puzniak Laura , Lopez Santiago M.C , Cappelleri Joseph C.
Published: September 2023

Background

Evidence on the impact of COVID-19 vaccination on symptoms, Health-Related Quality of Life (HRQoL), Work Productivity and Activity Impairment (WPAI) is scarce. We analyzed associations between bivalent BA.4/5 BNT162b2 and these patient-reported outcomes (PROs).

Methods

Symptomatic US adults who tested positive for SARS-CoV-2 were recruited between 03/02-05/18/2023. PROs were assessed using a CDC-based symptom questionnaire, EQ-5D-5L, WPAI-GH, and PROMIS Fatigue, from pre-COVID to Week 4 following infection. Multivariable analysis using mixed models for repeated measures was conducted, adjusting for several covariates.

Results

The study included 641 participants: 314 vaccinated with bivalent BA.4/5 BNT162b2 and 327 unvaccinated/not up-to-date. Mean (SD) age was 46.5 years (15.9), 71.2% were female, 44.2% reported prior infection, 25.7% had ≥1 comorbidity. The BA.4/5 BNT162b2 cohort reported fewer acute symptoms through Week 4, especially systemic and respiratory symptoms. All PROs were adversely affected, especially at Week 1; however, at that time point, the bivalent BA.4/5 BNT162b2 cohort reported better work performance, driven by less absenteeism, and fewer work hours lost. No significant differences were observed for HRQoL.

Conclusions

COVID-19 negatively impacted patient outcomes. Compared with unvaccinated/not up-to-date participants, those vaccinated with bivalent BA.4/5 BNT162b2 reported fewer and less persistent symptoms and improved work performance.

Clinicaltrials.govNCT05160636
Within-host models unravelling the dynamics of dengue reinfections
Authors: Anam Vizda , Guerrero Bruno V. , Srivastav Akhil Kumar , Stollenwerk Nico , Aguiar Maíra
Published: September 2023

Dengue fever is a major public health concern in tropical regions, caused by four distinct serotypes. Sequential infection with a different serotype increases the risks of severe disease through antibody-dependent enhancement (ADE). Huge modeling efforts have focused on primary and heterologous secondary infections, while the dynamics of homologous secondary infections were overlooked due to the assumption of lifelong immunity preventing reinfections by the same serotype.

Recent findings challenge the current understanding of dengue immunity. To explore immunological responses in various dengue infection scenarios, we use a within-host modeling framework that considers individual immunological variations. These models are validated using empirical data. In addition to successfully capturing primary and heterologous secondary infection dynamics facilitated by ADE, this framework provides, for the first time, insights into homotypic reinfection dynamics and discusses its relevance in dengue transmission at the population level, with potential implications for disease prevention and control strategies.
Methylenetetrahydrofolate reductase polymorphic variants in rectal cancer: significance for cancer risk and response to chemoradiotherapy
Authors: Stanojevic Aleksandra , Spasic Jelena , Marinkovic Mladen , Stojanovic-Rundic Suzana , Jankovic Radmila , Djuric Ana , Zoidakis Jerome , Fijneman Remond J.A. , Castellvi-Bel Sergi , Cavic Milena
Published: September 2023

Background

Methylenetetrahydrofolate reductase (MTHFR) small nucleotide polymorphisms (SNPs) have been suggested as risk, prognostic, and predictive factors for colorectal cancer in various populations, but have not been validated so far. The aim of this study was to analyze the association ofMTHFRC677T (rs1801133) and A1298C (rs1801131) small nucleotide polymorphisms with the risk of rectal cancer as well as the response to neoadjuvant chemoradiotherapy (nCRT) based on 5-Fluorouracil (5- FU)/leucovorin (LV) in the locally advanced setting.

Patients and methods

A total of 102 patients with locally advanced rectal cancer (LARC) and 119 healthy controls were included in this case-control study. Restriction fragment length polymorphism analysis (PCR-RFLP) was used forMTHFRgenotyping

Results

Using dominant and recessive models, it was found that theMTHFR667C allele and the 1298A allele were significantly associated with rectal cancer as low-penetrant factors. Combined genotype analysis highlighted the protective role of the 677CT/1298AC genotype and increased risk for rectal cancer development for carriers of 677CC/1298AA. Haplotype analysis indicated that carriers of haplotype 677C/1298A have an increased risk for rectal cancer development while the haplotype 677T/1298A has a protective role. No significant association with response to chemoradiotherapy was found

Conclusion

Our data point toMTHFR667C allele and 1298A alleles as low-penetrant risk factors for rectal cancer in our population. To the best of our knowledge, this is the first study of this type performed on the Slavic population in the Western Balkan area which might be useful for future meta-analyses and the construction of genetic cancer risk prediction panels, as various population-based factors might also be significant in this setting.
Sleep and circadian biomarkers of postoperative delirium: protocol for a prospective, observational cohort study
Authors: Sugg Elizabeth , Gleeson Elizabeth , Baker Sarah N. , Li Peng , Gao Chenlu , Mueller Ariel , Deng Hao , Shen Shiqian , Franco Garcia Esteban , Saxena Richa , Musiek Erik , Akeju Oluwaseun , Xie Zhongcong , Hu Kun , Gao Lei
Published: September 2023

Surgical patients over 70 experience postoperative delirium (POD) complications in up to 50% of procedures. Sleep/circadian disruption has emerged as a potential risk factor for POD in epidemiological studies. However, the relationship remains unclear in a clinical setting. This protocol presents a single-site, prospective, noninvasive observational study designed to examine the relationship between sleep/circadian regulation and POD and how this association is influenced by AD pathology and genetic risk for AD. This novel approach for understanding modifiable risk factors of POD and cognitive decline after surgery could assist with establishing treatments and preventative measures for POD in the future.
Remnant cholesterol associated with all-cause mortality in oldest-old acute coronary syndrome patients: a cohort study
Authors: Zhou Boning , Gao Ling , Zhang Xin , Shen Jian , Li Ying , Jiao Yang , Wang Jian , Hou Xiaoling , Su Yongkang , Fu Zhenhong
Published: September 2023

Background

Previous studies showed that remnant cholesterol(RC) partially explained the residual risk of cardiovascular disease. We tried to test the hypothesis that remnant cholesterol is a risk factor for all-cause mortality in oldest-old(>80 years old) patients with acute coronary syndrome(ACS).

Methods

662 oldest-old patients with acute coronary syndrome and undergoing coronary angiography were finally included in our study. Remnant cholesterol(RC) was calculated by fasting total cholesterol(TC) minus low-density lipoprotein cholesterol(LDL-C) and high-density lipoprotein cholesterol(HDL-C). Multivariable Cox regression analysis was used to identify the association between RC and all-cause mortality. Receiver operating characteristic(ROC) curve was used to compare the discrimination capacity of RC, TC, HDL-C and LDL-C to predict all-cause mortality.

Results

Among the 662 oldest-old patients enrolled, 92.90% accepted statin therapy. The average age was 81.87 ± 2.14 years old. In the fully-adjusted Cox regression model, the Hazard ratio(HR) [95% confidence interval (CI)] of all-cause mortality was 1.17 (1.01, 1.36) for each standard deviation(SD) increase in RC. Compared to tertile 1, tertile 3 was associated with a 130% increased risk of all-cause mortality (HR:2.30;95%CI:1.45, 3.63). The increased risk of death from tertile 1 to tertile 3 was statistically significant (P for trend<0.001). The subgroup analysis confirmed the significant association between RC and all-cause mortality. ROC curve showed that RC had a better discrimination capacity at predicting all-cause mortality and improved the prognostic value of the Gensini score combined with left ventricular ejection fraction(LVEF).

Conclusion

Remnant cholesterol was associated with all-cause mortality in oldest-old patients with ACS in a long-term follow-up.

Key learning points

What is already known

(1) Remnant cholesterol was a risk factor for atherosclerotic cardiovascular disease(ASCVD);

(2) Emerging studies reported that RC was associated with all-cause mortality in general population, patients with disease status including ischemic heart disease(IHD), heart failure(HF) and metabolic dysfunction-associated fatty liver disease(MAFLD) or patients receiving special treatment such as peritoneal dialysis(PD) and kidney transplantation;

(3) However, some studies found that there was no correlation between RC and all-cause mortality.

What this study adds

(1) We focused on oldest-old ACS patients who underwent angiography and found that RC was associated with all-cause mortality in this special population;

(2) The correlation between RC and all-cause mortality was dose–response;

(3) RC had a better discrimination capacity at predicting all-cause mortality and improved the prognostic value of the Gensini score combined with LVEF.
Pulse pressure modifies the association between diastolic blood pressure and decrease in kidney function: The Japan Specific Health Checkups (J-SHC) Study
Authors: Tamaki Hiroyuki , Eriguchi Masahiro , Yoshida Hisako , Uemura Takayuki , Tasaki Hikari , Furuyama Riri , Fukata Fumihiro , Nishimoto Masatoshi , Kosugi Takaaki , Matsui Masaru , Samejima Ken-ichi , Iseki Kunitoshi , Fujimoto Shouichi , Konta Tsuneo , Moriyama Toshiki , Yamagata Kunihiro , Narita Ichiei , Kasahara Masato , Shibagaki Yugo , Kondo Masahide , Asahi Koichi , Watanabe Tsuyoshi , Tsuruya Kazuhiko
Published: September 2023

Background

Unlike systolic blood pressure (SBP), the prognostic value of diastolic blood pressure (DBP) in kidney function has not been established. We hypothesized that pulse pressure (PP), which is associated with arteriosclerosis, would affect the prognostic value of DBP.

Methods

This longitudinal study used data from the Japan Specific Health Checkups Study conducted between 2008 and 2014. The participants were stratified into 3 PP subgroups (low-PP ≤39, normal-PP 40–59, and high-PP ≥60 mmHg). The exposures of interest were SBP and DBP, and the association between SBP/DBP and kidney outcomes (30% decline in the estimated glomerular filtration rate from baseline) was examined in each PP subgroup using a Cox proportional hazards model.

Results

Among 725,022 participants, 20,414 (2.8%) developed kidney outcomes during a median follow-up period of 34.6 months. Higher SBP was consistently associated with a higher incidence of kidney outcome in all PP subgroups. Although DBP had a positive linear association with the incidence of kidney outcome in low-and normal-PP subgroups, both lower (≤60 mmHg) and higher (≥101 mmHg) DBP were associated with a higher incidence of kidney outcome in high-PP subgroup with U-shaped curve. Hazard ratios (95% confidence intervals) of ≤60 mmHg (reference: 61-80 mmHg in normal-PP subgroup) and ≥101 mmHg were 1.26 (1.15–1.38) and 1.86 (1.62–2.14), respectively.

Conclusion

In this large population-based cohort, DBP was differently associated with kidney outcome by PP levels; lower DBP was significantly associated with a higher incidence of kidney outcome in high-PP subgroup but not in low-and normal-PP subgroups.
Cardiac complications following cerebrovascular disease
Authors: Rohner Marco Heinrich , Gebhard Catherine , Luft Andreas , Hänsel Martin , Wegener Susanne
Published: September 2023

Background

Accumulating evidence suggest that cardiac complications after stroke are an important yet understudied manifestation of brain-heart interactions. Our aim was to investigate and compare cardiac findings after different cerebrovascular events (acute ischemic stroke, transient ischemic attack, and hemorrhagic stroke).

Methods

7113 patients treated between December 2013 and December 2020 at the University Hospital Zurich for ischemic stroke, transient ischemic attack, and hemorrhagic stroke were screened. 721 patients without evidence of previous cardiac disease or presumed cardioembolic origin of their cerebrovascular disease and with at least one cardiac check-up were included. Clinical reports from the year following disease onset were screened for new cardiac findings, which were categorized as arrhythmia/electrocardiographic (ECG) changes, myocardial alterations, valvular abnormalities, coronary perfusion insufficiency, and hypotensive/hypertensive blood pressure abnormalities. Differences in proportions of findings between groups were analyzed using Pearson’s Chi-Square Test or Fisher’s exact Test.

Results

ECG changes were observed in 81.7% of patients with ischemic stroke, 71.4% with transient ischemic attack, and 55.8% with hemorrhagic stroke (p<0.001). Myocardial alterations occurred often in all three groups (60.9% ischemic stroke, 59.2% transient ischemic attack, 44.2% hemorrhage, p=0.1). Hypotensive/hypertensive blood pressure abnormalities were most frequent (48.8%) in hemorrhagic stroke patients (p<0.001).

Conclusions

Cardiac complications are frequent in patients with cerebrovascular disease, even without prior cardiac problems or suspected cardiac etiology. While findings were different in the three event types, our data suggest that all patients with acute cerebrovascular events should receive thorough workup searching for cardiac complications.
Both brain network topology and striatal dopamine depletion mediate the effects of autonomic dysfunction on disease burden of Parkinson’s disease
Authors: Chen Zhichun , Li Guanglu , Zhou Liche , Zhang Lina , Liu Jun
Published: September 2023

Background

Autonomic dysfunction is one of the most common non-motor symptoms in Parkinson’s disease (PD). Whether autonomic dysfunction contributes to disease progression and brain network abnormalities in PD remain largely unknown. The objective of this study is to evaluate how autonomic dysfunction affects clinical features and brain networks of PD patients.

Methods

PD patients from Parkinson’s Progression Markers Initiative (PPMI) database were included if they received magnetic resonance imaging. According to the scores of Scale for Outcomes in Parkinson’s Disease-Autonomic (SCOPA-AUT), PD patients were classified into lower quartile group (SCOPA-AUT score rank: 0%~25%), interquartile group (SCOPA-AUT score rank: 26%~75%), and upper quartile group (SCOPA-AUT score rank: 76%~100%) based on their SCOPA-AUT score quartiles to examine how autonomic dysfunction shapes clinical manifestations and brain networks.

Results

PD patients in the upper quartile group showed more severe motor and non-motor symptoms, as well as more deficits in dopamine transporter binding compared to lower quartile group. Additionally, they also showed statistically different topological properties in structural and functional network compared to lower quartile group. Both structural and functional network metrics mediated the effects of autonomic dysfunction on clinical symptoms of PD patients. Reduced dopamine transporter binding also contributed to the effects of autonomic dysfunction on disease burden of PD patients.

Conclusions

PD patients with more severe autonomic dysfunction exhibit worse disease and impairment of brain network topology. Both network topology and striatal dopamine depletion mediate the effects of autonomic dysfunction on clinical symptoms of PD patients.
Incorporating prior knowledge to seeds of adaptive sampling molecular dynamics simulations of ligand transport in enzymes with buried active sites
Authors: Sarkar Dheeraj Kumar , Surpeta Bartlomiej , Brezovsky Jan
Published: September 2023

Given that most proteins have buried active sites, protein tunnels or channels play a crucial role in mitigating the transport of small molecules to the buried cavity for enzymatic catalysis. Tunnels can critically modulate the biological process of protein-ligand recognition. Various molecular dynamics methods have been developed for exploring and exploiting the protein-ligand conformational space to extract high-resolution details of the binding processes, one of the most recent represented by energetically unbiased high-throughput adaptive sampling simulations. The current study systematically contrasts the role of integrating prior knowledge while generating useful initial protein-ligand configurations, called seeds, for these simulations. Using a non-trivial system of haloalkane dehalogenase mutant with multiple transport tunnels leading to a deeply buried active site, these simulations were employed to derive kinetic models describing the process of association and dissociation of the substrate molecule. The more knowledge-based seed generation enabled high-throughput simulations that could more consistently capture the entire transport process, effectively explore the complex network of transport tunnels, and predict equilibrium dissociation constants,koff/kon, on the same order of magnitude as experimental measurements. Overall, the infusion of more knowledge into the initial seeds of adaptive sampling simulations could render analyses of transport mechanisms in enzymes more consistent even for very complex biomolecular systems, thereby promoting the rational design of enzymes with buried active sites and drug development efforts.
Quantitative monitoring of neuronal regeneration by functional assay and wireless neural recording
Authors: Liang Min-Zong , Yang Jenq-Wei , Chen Hsin , Cheng Mei-Yuan , Chen Linyi
Published: September 2023

Brain injury is heterozygous in nature and no single scheme is ideal for diagnosis and prognosis. Assessing proteins in cerebrospinal fluid is limited or not applicable after surgery whereas plasma biomarkers can only report occurrence of injury. The lack of regeneration markers renders the difficulty during drug discovery. This study aims to establish a potential reporter that correlates the regeneration progress of injured brain neurons. According to our recent publication, treatment of mitochondrial uncoupler carbonyl cyanide 4-(trifluoromethoxy) phenylhydrazone (FCCP) could rescue motor function deficit of mice after traumatic brain injury. We thus measured the local field potential (LFP) at sites proximal to the injury region. The recorded neuronal activity reported stimulation of right forelimb of mice. Our experimental results indicate that the recovery of evoked LFP correlates with FCCP treatment and could potentially be used as a regeneration biomarker. These promising findings suggest future application of a wireless, non-invasive recording system as a potential companion diagnosis device during drug development.
A model for collagen secretion by intercompartmental continuities
Authors: Bunel Louis , Pincet Lancelot , Malhotra Vivek , Raote Ishier , Pincet Frédéric
Published: September 2023

Newly synthesized secretory proteins are exported from endoplasmic reticulum (ER) at specialized subcompartments called exit sites (ERES). Cargoes like procollagen are too large for export by the standard COPII-coated vesicle of 60 nm average diameter. We have previously suggested that procollagen is transported from the ER to the next secretory organelle, the ERGIC, in TANGO1-dependent inter-organelle tunnels. Here, we show that intrinsically disordered domains of TANGO1 in the ER lumen generate an entropic contraction that pulls procollagen towards the ERES. Molecular gradients of pH and HSP47 between the ER and ERGIC generate a force in the range of tens of femtoNewtons (fN), which is sufficient to propel procollagen from the ER at a speed of ∼1 nm.s-1. This calculated speed and the quantities of collagen secreted are similar to its observed physiological secretion rate in fibroblasts, consistent with the proposal that ER export is the rate limiting step for procollagen secretion. Our theoretical model explains how cells can utilize molecular gradients to export procollagens at a rate commensurate with physiological needs.

Significance Statement

Procollagen cannot be exported from the endoplasmic reticulum (ER) by standard COPII-coated vesicle of 60 nm average diameter. We have previously suggested that collagen is transported from the ER to the next secretory organelle, the ERGIC, in TANGO1-dependent inter-organelle tunnels. ER and ERGIC differ in molecular composition including their pH and protein composition. We propose a mechanical/entropic ratchet model whereby molecular gradients of pH and the collagen chaperone HSP47, provide the energy to propel procollagen from the ER at a speed that matches the physiological rate of collagen secretion.
Trem2 Agonist Reprograms Foamy Macrophages to Promote Atherosclerotic Plaque Stability
Authors: Patterson Michael T. , Xu Yingzheng , Hillman Hannah , Osinski Victoria , Schrank Patricia R. , Kennedy Ainsley E. , Zhu Alisha , Tollison Samuel , Shekhar Sia , Stromnes Ingunn M. , Tassi Ilaria , Wu Dick , Binstadt Bryce A. , Williams Jesse W.
Published: September 2023

Objective

Trem2, a surface lipid receptor, is expressed on foamy macrophages within atherosclerotic lesions and regulates cell survival, proliferation, and anti-inflammatory responses. Studies examining the role of Trem2 in atherosclerosis have shown that deletion of Trem2 leads to impaired foamy macrophage lipid uptake, proliferation, survival, and cholesterol efflux. Thus, we tested the hypothesis that administration of a validated Trem2 agonist antibody (AL002a) to atherogenic mice could drive macrophage survival and decrease necrotic core formation to improve plaque stability.

Approach and Results

To model a therapeutic intervention approach, atherosclerosis-prone mice (Ldlr-/-) were fed a high fat diet (HFD) for 8 weeks, then transitioned to treatment with AL002a or isotype control for an additional 8 weeks while continuing on an HFD. AL002a-treated mice had increased lesion size in both the aortic sinus and whole mount aorta, which correlated with an expansion of plaque macrophage area. This expansion was due to increased macrophage survival and proliferation in plaques. Importantly, plaques from AL002a-treated mice showed improved features of plaque stability, including smaller necrotic cores, increased fibrous caps, and greater collagen deposition. Single cell RNA sequencing of whole aorta suspensions from isotype and AL002a-treated atherosclerotic mice revealed that Trem2 agonism dramatically altered foamy macrophage transcriptome. This included upregulation of oxidative phosphorylation and increased expression of collagen genes. In vitro studies validated that Trem2-agonism with AL002a promoted foamy macrophage oxLDL uptake, survival, and cholesterol efflux in culture.

Conclusions

Trem2 agonist expands plaque macrophages by promoting cell survival and proliferation but improves features of plaque stability by rewiring foamy macrophage function to enhance collagen deposition.
Comparative analysis of the RNA-chromatin interactions data. Completeness and accuracy
Authors: Ryabykh Grigory , Vasilyev Artem , Garkul Lidia , Shatskiy Vladimir , Mironov Andrey
Published: September 2023

Non-coding RNAs play an essential role in a wide variety of biological processes. We have previously developed RNA-Chrom, an analytical database containing uniformly processed RNA-chromatin interactions data. Here, we analyzed the consistency of these data with each other and performed a comparative analysis of human and mouse datasets from “all-to-all” experiments (interactome of all possible RNAs in a cell) and “one-to-all” experiments (individual RNA interactome). We analyzed the dependence of RNA cis-contacts density as a function of distance to the RNA source gene and found that in all experiments, density of cis-contacts decreases with distance. We tested whether the most contacting RNAs of one “all-to-all” experiment (“RNA-leaders”) are the same for the other “all-to-all” experiments. Our analysis shows that “all-to-all” experiments are not complete and require substantially deeper sequencing, and conclusions can only be drawn for highly contacting RNAs. We noted that for “all-to-all” experiments, sequencing depth and the type of cell treatment give a significant impact on the contact map, while the cell line does not have as much of an impact.
The predictive value of microfilariae-based stop-MDA thresholds after triple drug therapy with IDA in treatment-naive Indian settings
Authors: James Ananthu , Coffeng Luc E. , Blok David J. , King Jonathan D. , de Vlas Sake J. , Stolk Wilma A.
Published: September 2023

Mass drug administration (MDA) of antifilarial drugs is the main strategy towards the elimination of lymphatic filariasis (LF). Recent clinical trials indicated that the triple drug therapy with ivermectin, diethylcarbamazine and albendazole (IDA) is much more effective against LF than the widely used two-drug combinations (albendazole plus either ivermectin or diethylcarbamazine). For IDA-based MDA, the stop-MDA decision is taken based on microfilariae (mf) prevalence in adults. In this study, we assess how the probability of eventually reaching elimination of transmission depends on the critical threshold used in transmission assessment surveys (TAS-es) to define whether transmission was successfully suppressed and triple-drug MDA can be stopped. This analysis focuses on treatment-naive Indian settings. We do this for a range of epidemiological and programmatic contexts, using the established LYMFASIM model for transmission and control of LF. Based on our simulations, a single TAS one year after the last MDA round provides limited predictive value of having achieved suppressed transmission, while a higher MDA coverage increases elimination probability, thus leading to a higher predictive value. Every additional TAS, conditional on previous TAS-es being passed with the same threshold, further improves predictive value for low values of stop-MDA thresholds. An mf prevalence threshold of 0.5% corresponding to TAS-3 results in ≥95% predictive value even when the MDA coverage is relatively low.
A combined risk model shows viability for personalized breast cancer risk assessment in the Indonesian population
Authors: Rabbani Bijak , Tanu Sabrina Gabriel , Ramanto Kevin Nathanael , Audrienna Jessica , Aldila Fatma , Fernandez Eric Aria , Gonzalez-Porta Mar , Valeska Margareta Deidre , Haruman Jessline , Ulag Lorina Handayani , Maulana Yusuf , Junusmin Kathleen Irena , Amelia Margareta , Gabriella Gabriella , Soetyono Feilicia , Fajarrahman Aulian , Hasan Salma Syahfani Maudina , Agatha Faustina Audrey , Wijaya Marco , Sormin Stevany Tiurma Br , Sani Levana , Ali Soegianto , Irwanto Astrid , Haryono Samuel J
Published: September 2023

Breast cancer remains a significant concern worldwide, with a rising incidence in Indonesia. This study aims to evaluate the applicability of risk-based screening approaches in the Indonesian demographic through a case-control study involving 305 women. We developed a personalized breast cancer risk assessment workflow that integrates multiple risk factors, including clinical (Gail) and polygenic (Mavaddat) risk predictions, into a consolidated risk category. By evaluating the area under the receiver operating characteristic curve (AUC) of each single-factor risk model, we demonstrate that they retain their predictive accuracy in the Indonesian context (AUC for clinical risk: 0.67 [0.61,0.74]; AUC for genetic risk: 0.67 [0.61,0.73]). Notably, our combined risk approach enhanced the AUC to 0.70 [0.64,0.76], highlighting the advantages of a multifaceted model. Our findings demonstrate for the first time the applicability of the Mavaddat and Gail models to Indonesian populations, and show that within this demographic, combined risk models provide a superior predictive framework compared to single-factor approaches.
Total-body Dynamic Imaging and Kinetic Modeling of18F-AraG in Healthy Individuals and a Non-Small Cell Lung Cancer Patient Undergoing Anti-PD-1 Immunotherapy
Authors: Omidvari Negar , Levi Jelena , Abdelhafez Yasser G , Wang Yiran , Nardo Lorenzo , Daly Megan E , Wang Guobao , Cherry Simon R
Published: September 2023

Immunotherapies, especially the checkpoint inhibitors such as anti-PD-1 antibodies, have transformed cancer treatment by enhancing immune system’s capability to target and kill cancer cells. However, predicting immunotherapy response remains challenging.18F-AraG is a molecular imaging tracer targeting activated T cells, which may facilitate therapy response assessment by non-invasive quantification of immune cell activity within tumor microenvironment and elsewhere in the body. The aim of this study was to obtain preliminary data on total-body pharmacokinetics of18F-AraG, as a potential quantitative biomarker for immune response evaluation.

Methods

The study consisted of 90-min total-body dynamic scans of four healthy subjects and one non-small cell lung cancer (NSCLC) patient, scanned before and after anti-PD-1 immunotherapy. Compartmental modeling with Akaike information criterion model selection were employed to analyze tracer kinetics in various organs. Additionally, seven sub-regions of the primary lung tumor and four mediastinal lymph nodes were analyzed. Practical identifiability analysis was performed to assess reliability of kinetic parameter estimation. Correlations of SUVmean, SUVR (tissue-to-blood ratio), and Logan plot slope (KLogan) with total volume-of-distribution (VT) were calculated to identify potential surrogates for kinetic modeling.

Results

Strong correlations were observed betweenKLoganand SUVR values withVT, suggesting that they can be used as promising surrogates forVT, especially in organs with low blood-volume fraction. Moreover, the practical identifiability analysis suggests that the dynamic18F-AraG PET scans could potentially be shortened to 60 minutes, while maintaining quantification accuracy for all organs-of-interest. The study suggests that although18F-AraG SUV images can provide insights on immune cell distribution, kinetic modeling or graphical analysis methods may be required for accurate quantification of immune response post-therapy. While SUVmean showed variable changes in different sub-regions of the tumor post-therapy, the SUVR,KLogan, andVTshowed consistent increasing trends in all analyzed sub-regions of the tumor with high practical identifiability.

Conclusion

Our findings highlight the promise of18F-AraG dynamic imaging as a non-invasive biomarker for quantifying the immune response to immunotherapy in cancer patients. The promising total-body kinetic modeling results also suggest potentially wider applications of the tracer in investigating the role of T cells in the immunopathogenesis of diseases.
TRENDS IN CLINICAL STAGE AT PRESENTATION FOR FOUR COMMON ADULT CANCERS IN IBADAN, NIGERIA
Authors: Omigbodun Akinyinka O. , Agboola Adebayo D. , Fayehun Olufunke A , Ajisola Motunrayo , Oladejo Abiola , Popoola Omolara , Lilford Richard
Published: September 2023

Introduction

Cancer outcome is largely determined by stage at diagnosis. We hypothesised that people living in Low- and Middle-Income Countries may be reaching diagnosis at an early stage, reflecting growth in awareness of the disease and its symptoms. We examined stage at diagnosis for four common cancers presenting at a referral centre in Nigeria.

Methods

A retrospective review of case-records from cases treated for four common cancers (colorectal, uterine cervix, breast and prostate) at University College Hospital, Ibadan over two epochs: 2012-2013 and 2017-2018.

Results

There is no evidence that cases were diagnosed at an earlier stage in the later epoch. Seventy-five percent of cases were diagnosed at late stage (III or IV) in the second epoch, vs seventy percent in the first epoch.

Conclusion

There is no evidence in the data that the problem of late presentation of common cancers is reducing in Oyo State, Nigeria.
Investigation of singlet oxygen sensitive genes in the cyanobacteriumSynechocystisPCC 6803
Authors: Patyi Gábor , Hódi Barbara , Mallick Ivy , Maróti Gergely , Kós Péter B. , Vass Imre
Published: September 2023

Singlet oxygen (1O2) is an important reactive oxygen species whose formation by the type-II, light-dependent, photodynamic reaction is inevitable during photosynthetic processes. In the last decades, the recognition that1O2is not only a damaging agent, but can also affect gene expression and participates in signal transduction pathways has received increasing attention. However, contrary to several other taxa,1O2-specific genes have not been identified in the important cyanobacterial model organismSynechocystisPCC 6803. By using global transcript analysis we have identified a large set of1O2-responsiveSynechocystisgenes, whose transcript levels were either enhanced or repressed in the presence of1O2. Characteristic1O2responses were observed in several light-inducible genes ofSynechocystis, especially in thehli(orscp) family encoding HLIP/SCP proteins involved in photoprotection. Other important1O2-induced genes include components of the Photosystem II repair machinery (psbA2andftsH2,ftsH3), iron homeostasis genesisiAandidiA, the Group-2 sigma factorsigD, some components of the transcriptomes induced by salt-, hyperosmotic and cold-stress, as well as several genes of unknown function. One of the most pronounced1O2-induced upregulation was observed for thehliBgene, whose deletion provided tolerance against1O2-mediated light damage. A bioreporterSynechocystisstrain was created by fusing thehliBpromoter to the bacterial luciferase (lux), which showed its utility for continuous monitoring of1O2concentrations inside the cell.