bluuebunny/crossref_metadata_2025 huggingface dataset:
The synergistic effect of the triglyceride-glucose index and serum uric acid on the prediction of major adverse cardiovascular events after coronary artery bypass grafting: a multicenter retrospective cohort study
Authors: Wu Zhenguo , Cheng Cheng , Sun Xiangfei , Wang Juan , Guo Dachuan , Chen Sha , Zhang Yerui , Liu Xiaoyu , Liu Li , Zhang Cheng , Yang Jianmin
Published: May 2023

Background

Elevated serum uric acid (SUA) is regarded as a risk factor for the development of cardiovascular diseases. Triglyceride-glucose (TyG) index, a novel surrogate for insulin resistance (IR), has been proven to be an independent predictor for adverse cardiac events. However, no study has specifically focused on the interaction between the two metabolic risk factors. Whether combining the TyG index and SUA could achieve more accurate prognostic prediction in patients undergoing coronary artery bypass grafting (CABG) remains unknown.

Methods

This was a multicenter, retrospective cohort study. A total of 1225 patients who underwent CABG were included in the final analysis. The patients were grouped based on the cut-off value of the TyG index and the sex-specific criteria of hyperuricemia (HUA). Cox regression analysis was conducted. The interaction between the TyG index and SUA was estimated using relative excess risk due to interaction (RERI), attributable proportion (AP), and synergy index (SI). The improvement of model performance yielded by the inclusion of the TyG index and SUA was examined by C-statistics, net reclassification improvement (NRI) and integrated discrimination improvement (IDI). The goodness-of-fit of models was evaluated using the Akaike information criterion (AIC), Bayesian information criterion (BIC) and χ2likelihood ratio test.

Results

During follow-up, 263 patients developed major adverse cardiovascular events (MACE). The independent and joint associations of the TyG index and SUA with adverse events were significant. Patients with higher TyG index and HUA were at higher risk of MACE (Kaplan–Meier analysis: log-rankP < 0.001; Cox regression: HR = 4.10; 95% CI 2.80–6.00,P < 0.001). A significant synergistic interaction was found between the TyG index and SUA [RERI (95% CI): 1.83 (0.32–3.34),P = 0.017; AP (95% CI): 0.41 (0.17–0.66),P = 0.001; SI (95% CI): 2.13 (1.13–4.00),P = 0.019]. The addition of the TyG index and SUA yielded a significant improvement in prognostic prediction and model fit [change in C-statistic: 0.038,P < 0.001; continuous NRI (95% CI): 0.336 (0.201–0.471),P < 0.001; IDI (95% CI): 0.031 (0.019–0.044),P < 0.001; AIC: 3534.29; BIC: 3616.45; likelihood ratio test:P < 0.001).

Conclusions

The TyG index interacts synergistically with SUA to increase the risk of MACE in patients undergoing CABG, which emphasizes the need to use both measures concurrently when assessing cardiovascular risk.
PKM2/STAT1-mediated PD-L1 upregulation on neutrophils during sepsis promotes neutrophil organ accumulation by serving an anti-apoptotic role
Authors: Li Yinjiaozhi , Tan Ruoming , Li Ranran , Tian Rui , Liu Zhaojun , Wang Xiaoli , Chen Erzhen , Pan Tingting , Qu Hongping
Published: May 2023

Background

Delayed neutrophil apoptosis during sepsis may impact neutrophil organ accumulation and tissue immune homeostasis. Elucidating the mechanisms underlying neutrophil apoptosis may help identify potential therapeutic targets. Glycolysis is critical to neutrophil activities during sepsis. However, the precise mechanisms through which glycolysis regulates neutrophil physiology remain under-explored, especially those involving the non-metabolic functions of glycolytic enzymes. In the present study, the impact of programmed death ligand-1 (PD-L1) on neutrophil apoptosis was explored. The regulatory effect of the glycolytic enzyme, pyruvate kinase M2 (PKM2), whose role in septic neutrophils remains unaddressed, on neutrophil PD-L1 expression was also explored.

Methods

Peripheral blood neutrophils were isolated from patients with sepsis and healthy controls. PD-L1 and PKM2 levels were determined by flow cytometry and Western blotting, respectively. Dimethyl sulfoxide (DMSO)-differentiated HL-60 cells were stimulated with lipopolysaccharide (LPS) as an in vitro simulation of septic neutrophils. Cell apoptosis was assessed by annexin V/propidium iodide (annexin V/PI) staining, as well as determination of protein levels of cleaved caspase-3 and myeloid cell leukemia-1 (Mcl-1) by Western blotting. An in vivo model of sepsis was constructed by intraperitoneal injection of LPS (5 mg/kg) for 16 h. Pulmonary and hepatic neutrophil infiltration was assessed by flow cytometry or immunohistochemistry.

Results

PD-L1 level was elevated on neutrophils under septic conditions. Administration of neutralizing antibodies against PD-L1 partially reversed the inhibitory effect of LPS on neutrophil apoptosis. Neutrophil infiltration into the lung and liver was also reduced in PD-L1−/− mice 16 h after sepsis induction. PKM2 was upregulated in septic neutrophils and promoted neutrophil PD-L1 expression both in vitro and in vivo. In addition, PKM2 nuclear translocation was increased after LPS stimulation, which promoted PD-L1 expression by directly interacting with and activating signal transducer and activator of transcription 1 (STAT1). Inhibition of PKM2 activity or STAT1 activation also led to increased neutrophil apoptosis.

Conclusion

In this study, a PKM2/STAT1-mediated upregulation of PD-L1 on neutrophils and the anti-apoptotic effect of upregulated PD-L1 on neutrophils during sepsis were identified, which may result in increased pulmonary and hepatic neutrophil accumulation. These findings suggest that PKM2 and PD-L1 could serve as potential therapeutic targets.
Preloading with drugs before entry to the nighttime entertainment district: presentation, intoxication rates, and effects of police presence during assessment
Authors: Hughes Lee R. J. , Allen Corey , Devilly Grant J.
Published: May 2023

Background

Past research has either focused on alcohol or drug preloading before a night out, but not on the interaction between them. With increased risks of harm through interaction effects, we wished to build upon previous research in this area. We sought to determine who drug preloads, why do people engage in this practice, what drug/s are people using, and how inebriated they are as they enter the NED. Additionally, we examined what impact varying levels of police presence has on the collections of sensitive data in this context.

Methods

We captured estimates of drug and alcohol preloading from 4723 people entering nighttime entertainment districts (NEDs) in Queensland, Australia. Data collection occurred under three varying conditions of police presence (i.e., no police present, police present but not engaging with participants, and police engaging with participants).

Results

People who admitted to preloading drugs were found to be younger in age than non-drug admitters, more likely to be male than female, use one type of drug (mostly stimulants) rather than multiple (if we exclude alcohol), significantly more intoxicated upon arrival, and more subjectively affected from their use of alcohol and drugs as Breath Approximated Alcohol Concertation levels increased. People were more likely to admit having used drugs in the absence of police, but this had only a small effect.

Conclusions

People who drug preload are a vulnerable subset of the youth population that is susceptible to experiencing harms in this context. As they drink more alcohol, they experience higher affects than those who do not report to also take drugs. Police engagement through service rather than force may mitigate some risks. Further enquiry is needed to better understand those who engage in this practice and to have quick, cheap, objective tests of what drugs these people are using.
Preventative effect of TSPO ligands on mixed antibody-mediated rejection through a Mitochondria-mediated metabolic disorder
Authors: Zhang Yannan , He Jiannan , Yang Zhe , Zheng Haofeng , Deng Haoxiang , Luo Zihuan , Sun Qipeng , Sun Qiquan
Published: May 2023

Background

Immune-mediated rejection was the major cause of graft dysfunction. Although the advances in immunosuppressive agents have markedly reduced the incidence of T-cell-mediated rejection after transplantation. However, the incidence of antibody-mediated rejection (AMR) remains high. Donor-specific antibodies (DSAs) were considered the major mediators of allograft loss. Previously, we showed that treatment with 18-kDa translocator protein (TSPO) ligands inhibited the differentiation and effector functions of T cells and reduced the rejection observed after allogeneic skin transplantation in mice. This study we further investigate the effect of TSPO ligands on B cells and DSAs production in the recipients of mixed-AMR model.

Methods

In vitro, we explored the effect of treatment with TSPO ligands on the activation, proliferation, and antibody production of B cells. Further, we established a heart-transplantation mixed-AMR model in rats. This model was treated with the TSPO ligands, FGIN1-27 or Ro5-4864, to investigate the role of ligands in preventing transplant rejection and DSAs production in vivo. As TSPO was the mitochondrial membrane transporters, we then investigated the TSPO ligands effect on mitochondrial-related metabolic ability of B cells as well as expression of downstream proteins.

Results

In vitro studies, treatment with TSPO ligands inhibited the differentiation of B cells into CD138+CD27+ plasma cells; reduced antibodies, IgG and IgM, secretion of B cells; and suppressed the B cell activation and proliferation. In the mixed-AMR rat model, treatment with FGIN1-27 or Ro5-4864 attenuated DSA-mediated cardiac-allograft injury, prolonged graft survival, and reduced the numbers of B cells, including IgG+ secreting B cells, T cells and macrophages infiltrating in grafts. For the further mechanism exploration, treatment with TSPO ligands inhibited the metabolic ability of B cells by downregulating expression of pyruvate dehydrogenase kinase 1 and proteins in complexes I, II, and IV of the electron transport chain.

Conclusions

We clarified the mechanism of action of TSPO ligands on B-cell functions and provided new ideas and drug targets for the clinical treatment of postoperative AMR.
The effect of metformin on influenza vaccine responses in nondiabetic older adults: a pilot trial
Authors: Martin Dominique E. , Cadar Andreia N. , Panier Hunter , Torrance Blake L. , Kuchel George A. , Bartley Jenna M.
Published: May 2023

Background

Aging is associated with progressive declines in immune responses leading to increased risk of severe infection and diminished vaccination responses. Influenza (flu) is a leading killer of older adults despite availability of seasonal vaccines. Geroscience-guided interventions targeting biological aging could offer transformational approaches to reverse broad declines in immune responses with aging. Here, we evaluated effects of metformin, an FDA approved diabetes drug and candidate anti-aging drug, on flu vaccination responses and markers of immunological resilience in a pilot and feasibility double-blinded placebo-controlled study.

Results

Healthy older adults (non-diabetic/non-prediabetic, age: 74.4 ± 1.7 years) were randomized to metformin (n = 8, 1500 mg extended release/daily) or placebo (n = 7) treatment for 20 weeks and were vaccinated with high-dose flu vaccine after 10 weeks of treatment. Peripheral blood mononuclear cells (PBMCs), serum, and plasma were collected prior to treatment, immediately prior to vaccination, and 1, 5, and 10 weeks post vaccination. Increased serum antibody titers were observed post vaccination with no significant differences between groups. Metformin treatment led to trending increases in circulating T follicular helper cells post-vaccination. Furthermore, 20 weeks of metformin treatment reduced expression of exhaustion marker CD57 in circulating CD4 T cells.

Conclusions

Pre-vaccination metformin treatment improved some components of flu vaccine responses and reduced some markers of T cell exhaustion without serious adverse events in nondiabetic older adults. Thus, our findings highlight the potential utility of metformin to improve flu vaccine responses and reduce age-related immune exhaustion in older adults, providing improved immunological resilience in nondiabetic older adults.
Uncovering neglected subtypes and zoonotic transmission of Hepatitis E virus (HEV) in Brazil
Authors: dos Santos Debora Regina Lopes , Durães-Carvalho Ricardo , Gardinali Noemi Rovaris , Machado Lais Ceschini , de Paula Vanessa Salete , da Luz Wallau Gabriel , de Oliveira Jaqueline Mendes , Pena Lindomar José , Pinto Marcelo Alves , Gil Laura Helena Vega Gonzalez , de Oliveira-Filho Edmilson Ferreira
Published: May 2023

Hepatitis E virus (HEV) circulation in humans and swine has been extensively studied in South America over the last two decades. Nevertheless, only 2.1% of reported HEV strains are available as complete genome sequences. Therefore, many clinical, epidemiological, and evolutionary aspects of circulating HEV in the continent still need to be clarified. Here, we conducted a retrospective evolutionary analysis of one human case and six swine HEV strains previously reported in northeastern, southern, and southeastern Brazil. We obtained two complete and four nearly complete genomic sequences. Evolutionary analysis comparing the whole genomic and capsid gene sequences revealed high genetic variability. This included the circulation of at least one unrecognized unique South American subtype. Our results corroborate that sequencing the whole capsid gene could be used as an alternative for HEV subtype assignment in the absence of complete genomic sequences. Moreover, our results substantiate the evidence for zoonotic transmission by comparing a larger genomic fragment recovered from the sample of the autochthonous human hepatitis E case. Further studies should continuously investigate HEV genetic diversity and zoonotic transmission of HEV in South America.
Newly arrived migrants did not represent an additional COVID-19 burden for Italy: data from the italian information flow
Authors: Sisti Leuconoe Grazia , Di Napoli Anteo , Petrelli Alessio , Diodati Alessandra , Cavani Andrea , Mirisola Concetta , Costanzo Gianfranco
Published: May 2023

Background

During the COVID-19 pandemic, migrants arriving in host countries irregularly have not infrequently been perceived as increasing the COVID-19 burden. Italy is a transit and destination country for migrants who cross the Central Mediterranean route and, during the pandemic, all migrants who landed on Italian shores were COVID-19 tested and quarantined. Our study aimed to investigate the impact of the SARS-CoV-2 infection among migrants who landed on the Italian coasts by analyzing both incidence and health outcomes.

Methods

A retrospective observational study has been designed. The population of interest was represented by 70,512 migrants (91% male, 99% <60 years old) who landed in Italy between January 2021 and 2022. SARS-CoV-2 incidence rate per 1,000 (with 95%CI) in migrants and the resident population in Italy of the corresponding age group was computed. The incidence rate ratio (IRR) was used to compare the incidence rates in migrants and the resident population.

Results

2,861 migrants out of those landed in Italy during the observation period tested positive, with an incidence rate of 40.6 (39.1–42.1) cases per 1,000. During the same period, 177.6 (177.5-177.8) cases per 1,000 were reported in the resident population, with an IRR of 0.23 (0.22–0.24). 89.7% of cases were male and 54.6% belonged to the 20–29 age group. 99% of cases reported no symptoms, no relevant comorbidities were reported and no cases were hospitalized.

Conclusions

Our study found a low rate of SARS-CoV-2 infection in migrants reaching Italy by sea with an incidence rate that is roughly a quarter of that of the resident population. Thus, irregular migrants who arrived in Italy during the observation period did not increase the COVID-19 burden. Further studies are needed to investigate possible reasons for the low incidence observed in this population.
Breastfeeding practices in Northeast China in 2008 and 2018: cross-sectional surveys to explore determinants over a decade
Authors: Zhou Qianling , Feng Xing Lin
Published: May 2023

Background

This study was conducted to investigate the prevalence and determinants of breastfeeding in 2008 and 2018, respectively, in Northeast China, where health service efficiency is at the lowest national level and regional data on breastfeeding are lacking. The influence of early initiation of breastfeeding on later feeding practices was specifically explored.

Methods

Data from the China National Health Service Survey in Jilin Province in 2008 (n = 490) and 2018 (n = 491) were analysed. Multistage stratified random cluster sampling procedures were used to recruit the participants. Data collection was conducted in the selected villages and communities in Jilin. Early initiation of breastfeeding was defined as the proportion of children born in the last 24 months who were put to the breast within one hour after birth in both the 2008 and 2018 surveys. Exclusive breastfeeding was defined as the proportion of infants 0–5 months of age who were fed exclusively with breast milk in the 2008 survey; while defined as the proportion of infants 6–60 months of age who had been fed exclusively with breast milk within the first six months of life in the 2018 survey.

Results

The prevalence of early initiation of breastfeeding (27.6% in 2008 and 26.1% in 2018) and exclusive breastfeeding during the first six months (< 50%) were low in two surveys. Logistic regression revealed that exclusively breastfeeding at six months was positively associated with early initiation of breastfeeding (OR 2.65; 95% confidence interval (CI) 1.65, 4.26) and negatively associated with caesarean section (OR 0.65; 95% CI 0.43, 0.98) in 2018. Continued breastfeeding at one year and timely introduction of complementary foods were associated with maternal residence and place of delivery, respectively, in 2018. Early initiation of breastfeeding was associated with mode and place of delivery in 2018 but residence in 2008.

Conclusion

Breastfeeding practices in Northeast China are far from optimal. The negative effect of caesarean section and positive effect of early initiation of breastfeeding on exclusive breastfeeding suggest that an institution-based approach should not be substituted by the community-based one in the formulation of breastfeeding strategies in China.
Mutations in α-synuclein, TDP-43 and tau prolong protein half-life through diminished degradation by lysosomal proteases
Authors: Sampognaro Paul J. , Arya Shruti , Knudsen Giselle M. , Gunderson Emma L. , Sandoval-Perez Angelica , Hodul Molly , Bowles Kathryn , Craik Charles S. , Jacobson Matthew P. , Kao Aimee W.
Published: May 2023

Background

Autosomal dominant mutations in α-synuclein, TDP-43 and tau are thought to predispose to neurodegeneration by enhancing protein aggregation. While a subset of α-synuclein, TDP-43 and tau mutations has been shown to increase the structural propensity of these proteins toward self-association, rates of aggregation are also highly dependent on protein steady state concentrations, which are in large part regulated by their rates of lysosomal degradation. Previous studies have shown that lysosomal proteases operate precisely and not indiscriminately, cleaving their substrates at very specific linear amino acid sequences. With this knowledge, we hypothesized that certain coding mutations in α-synuclein, TDP-43 and tau may lead to increased protein steady state concentrations and eventual aggregation by an alternative mechanism, that is, through disrupting lysosomal protease cleavage recognition motifs and subsequently conferring protease resistance to these proteins.

Results

To test this possibility, we first generated comprehensive proteolysis maps containing all of the potential lysosomal protease cleavage sites for α-synuclein, TDP-43 and tau. In silico analyses of these maps indicated that certain mutations would diminish cathepsin cleavage, a prediction we confirmed utilizing in vitro protease assays. We then validated these findings in cell models and induced neurons, demonstrating that mutant forms of α-synuclein, TDP-43 and tau are degraded less efficiently than wild type despite being imported into lysosomes at similar rates.

Conclusions

Together, this study provides evidence that pathogenic mutations in the N-terminal domain of α-synuclein (G51D, A53T), low complexity domain of TDP-43 (A315T, Q331K, M337V) and R1 and R2 domains of tau (K257T, N279K, S305N) directly impair their own lysosomal degradation, altering protein homeostasis and increasing cellular protein concentrations by extending the degradation half-lives of these proteins. These results also point to novel, shared, alternative mechanism by which different forms of neurodegeneration, including synucleinopathies, TDP-43 proteinopathies and tauopathies, may arise. Importantly, they also provide a roadmap for how the upregulation of particular lysosomal proteases could be targeted as potential therapeutics for human neurodegenerative disease.
The Notch signaling pathway: a potential target for cancer immunotherapy
Authors: Li Xinxin , Yan Xianchun , Wang Yufeng , Kaur Balveen , Han Hua , Yu Jianhua
Published: May 2023

Dysregulation of the Notch signaling pathway, which is highly conserved across species, can drive aberrant epigenetic modification, transcription, and translation. Defective gene regulation caused by dysregulated Notch signaling often affects networks controlling oncogenesis and tumor progression. Meanwhile, Notch signaling can modulate immune cells involved in anti- or pro-tumor responses and tumor immunogenicity. A comprehensive understanding of these processes can help with designing new drugs that target Notch signaling, thereby enhancing the effects of cancer immunotherapy. Here, we provide an up-to-date and comprehensive overview of how Notch signaling intrinsically regulates immune cells and how alterations in Notch signaling in tumor cells or stromal cells extrinsically regulate immune responses in the tumor microenvironment (TME). We also discuss the potential role of Notch signaling in tumor immunity mediated by gut microbiota. Finally, we propose strategies for targeting Notch signaling in cancer immunotherapy. These include oncolytic virotherapy combined with inhibition of Notch signaling, nanoparticles (NPs) loaded with Notch signaling regulators to specifically target tumor-associated macrophages (TAMs) to repolarize their functions and remodel the TME, combining specific and efficient inhibitors or activators of Notch signaling with immune checkpoint blockers (ICBs) for synergistic anti-tumor therapy, and implementing a customized and effective synNotch circuit system to enhance safety of chimeric antigen receptor (CAR) immune cells. Collectively, this review aims to summarize how Notch signaling intrinsically and extrinsically shapes immune responses to improve immunotherapy.
miR-92a-1-5p enriched prostate cancer extracellular vesicles regulate osteoclast function via MAPK1 and FoxO1
Authors: Yu Lijuan , Sui Bingdong , Zhang Xin , Liu Jiayun , Hao Xiaoke , Zheng Lei
Published: May 2023

Background

We have previously reported that extracellular vesicles (EVs) derived from osteoblastic, osteoclastic and mixed prostate cancer cells promote osteoclast differentiation and inhibit osteoblast differentiation via transferring miR-92a-1-5p. In the present study, we focused on engineering miR-92a-1-5p into EVs and determining any therapeutic roles and mechanisms of the engineered EVs.

Methods

A stable prostate cancer cell line (MDA PCa 2b) overexpressing miR-92a-1-5p was constructed by lentivirus, and EVs were isolated by ultracentrifugation. The overexpression of miR-92a-1-5p in both cells and EVs was tested using qPCR. Osteoclast function was evaluated by Trap staining, mRNA expression of osteoclastic markers ctsk and trap, immunolabeling of CTSK and TRAP and microCT using either in vitro and in vivo assays. Target gene of miR-92a-1-5p was proved by a dual-luciferase reporter assay system. siRNAs were designed and used for transient expression in order to determine the role of downstream genes on osteoclast differentiation.

Results

Stable overexpression cells of miRNA-92a-5p was associated with EVs upregulating this microRNA, as confirmed by qPCR. Further, miR-92a-1-5p enriched EVs promote osteoclast differentiation in vitro by reducing MAPK1 and FoxO1 expression, associated with increased osteoclast function as shown by TRAP staining and mRNA expression of osteoclast functional genes. siRNA targeting MAPK1 or FoxO1 resulted in similar increase in osteoclast function. In vivo, the miR-92a-1-5p enriched EVs given via i.v. injection promote osteolysis, which was associated with reduction of MAPK1 and FoxO1 expression in bone marrow.

Conclusion

These experiments suggest that miR-92a-1-5p enriched EVs regulate osteoclast function via reduction of MAPK1 and FoxO1.

Graphical Abstract
Cutaneous lesions in psoriatic arthritis are enriched in chemokine transcriptomic pathways
Authors: Johnsson Hanna , Cole John , Siebert Stefan , McInnes Iain B. , Graham Gerard
Published: May 2023

Objectives

Skin from people with psoriasis has been extensively studied and is assumed to be identical to skin from those with psoriatic arthritis (PsA). Chemokines and the CC chemokine scavenger receptor ACKR2 are upregulated in uninvolved psoriasis. ACKR2 has been proposed as a regulator of cutaneous inflammation in psoriasis. The aim of this study was to compare the transcriptome of PsA skin to healthy control (HC) skin and evaluate ACKR2 expression in PsA skin.

Methods

Full-thickness skin biopsies from HC, lesional and uninvolved skin from participants with PsA were sequenced on NovaSeq 6000. Findings were validated using qPCR and RNAscope.

Results

Nine HC and nine paired PsA skin samples were sequenced. PsA uninvolved skin was transcriptionally similar to HC skin, and lesional PsA skin was enriched in epidermal and inflammatory genes. Lesional PsA skin was enriched in chemokine-mediated signalling pathways, but uninvolved skin was not. ACKR2 was upregulated in lesional PsA skin but had unchanged expression in uninvolved compared with HC skin. The expression of ACKR2 was confirmed by qPCR, and RNAscope demonstrated strong expression of ACKR2 in the suprabasal layer of the epidermis in PsA lesions.

Conclusion

Chemokines and their receptors are upregulated in lesional PsA skin but relatively unchanged in uninvolved PsA skin. In contrast to previous psoriasis studies, ACKR2 was not upregulated in uninvolved PsA skin. Further understanding of the chemokine system in PsA may help to explain why inflammation spreads from the skin to the joints in some people with psoriasis.
A biomarker-validated time scale in years of disease progression has identified early- and late-onset subgroups in sporadic Alzheimer’s disease
Authors: Almkvist Ove , Nordberg Agneta
Published: May 2023

Background

It is possible to calculate the number of years to the expected clinical onset (YECO) of autosomal-dominant Alzheimer’s disease (adAD). A similar time scale is lacking for sporadic Alzheimer’s disease (sAD). The purpose was to design and validate a time scale in YECO for patients with sAD in relation to CSF and PET biomarkers.

Methods

Patients diagnosed with Alzheimer’s disease (AD, n = 48) or mild cognitive impairment (MCI, n = 46) participated in the study. They underwent a standardized clinical examination at the Memory clinic, Karolinska University Hospital, Stockholm, Sweden, which included present and previous medical history, laboratory screening, cognitive assessment, CSF biomarkers (Aβ42, total-tau, and p-tau), and an MRI of the brain. They were also assessed with two PET tracers, 11C-Pittsburgh compound B and 18F-fluorodeoxyglucose. Assuming concordance of cognitive decline in sAD and adAD, YECO for these patients was calculated using equations for the relationship between cognitive performance, YECO, and years of education in adAD (Almkvist et al. J Int Neuropsychol Soc 23:195-203, 2017).

Results

The mean current point of disease progression was 3.2 years after the estimated clinical onset in patients with sAD and 3.4 years prior to the estimated clinical onset in patients with MCI, as indicated by the median YECO from five cognitive tests. The associations between YECO and biomarkers were significant, while those between chronological age and biomarkers were nonsignificant. The estimated disease onset (chronological age minus YECO) followed a bimodal distribution with frequency maxima before (early-onset) and after (late-onset) 65 years of age. The early- and late-onset subgroups differed significantly in biomarkers and cognition, but after control for YECO, this difference disappeared for all except the APOE e4 gene (more frequent in early- than in late-onset).

Conclusions

A novel time scale in years of disease progression based on cognition was designed and validated in patients with AD using CSF and PET biomarkers. Two early- and late-disease onset subgroups were identified differing with respect to APOE e4.
Centralizing prescreening data collection to inform data-driven approaches to clinical trial recruitment
Authors: Kirn Dylan R. , Grill Joshua D. , Aisen Paul , Ernstrom Karin , Gale Seth , Heidebrink Judith , Jicha Gregory , Jimenez-Maggiora Gustavo , Johnson Leigh , Peskind Elaine , McCann Kelly , Shaffer Elizabeth , Sultzer David , Wang Shunran , Sperling Reisa , Raman Rema
Published: May 2023

Background

Recruiting to multi-site trials is challenging, particularly when striving to ensure the randomized sample is demographically representative of the larger disease-suffering population. While previous studies have reported disparities by race and ethnicity in enrollment and randomization, they have not typically investigated whether disparities exist in the recruitment process prior to consent. To identify participants most likely to be eligible for a trial, study sites frequently include a prescreening process, generally conducted by telephone, to conserve resources. Collection and analysis of such prescreening data across sites could provide valuable information to improve understanding of recruitment intervention effectiveness, including whether traditionally underrepresented participants are lost prior to screening.

Methods

We developed an infrastructure within the National Institute on Aging (NIA) Alzheimer’s Clinical Trials Consortium (ACTC) to centrally collect a subset of prescreening variables. Prior to study-wide implementation in the AHEAD 3–45 study (NCT NCT04468659), an ongoing ACTC trial recruiting older cognitively unimpaired participants, we completed a vanguard phase with seven study sites. Variables collected included age, self-reported sex, self-reported race, self-reported ethnicity, self-reported education, self-reported occupation, zip code, recruitment source, prescreening eligibility status, reason for prescreen ineligibility, and the AHEAD 3–45 participant ID for those who continued to an in-person screening visit after study enrollment.

Results

Each of the sites was able to submit prescreening data. Vanguard sites provided prescreening data on a total of 1029 participants. The total number of prescreened participants varied widely among sites (range 3–611), with the differences driven mainly by the time to receive site approval for the main study. Key learnings instructed design/informatic/procedural changes prior to study-wide launch.

Conclusion

Centralized capture of prescreening data in multi-site clinical trials is feasible. Identifying and quantifying the impact of central and site recruitment activities, prior to participants signing consent, has the potential to identify and address selection bias, instruct resource use, contribute to effective trial design, and accelerate trial enrollment timelines.
Rare and heterogeneous manifestations of leucocyte adhesion deficiency type 1: report of two cases with diagnostic dilemmas and novel ITGB2 mutation
Authors: Anis Sabiha , Abid Aiysha , Kodwavwala Sadaf Aba Umer , Sarfaraz Sabahat , Junejo Samina , Shahid Saba , Sultan Sajid , Rizvi Adibul Hasan
Published: May 2023

Background

Primary immunodeficiency disorders (PID) are rare disorders with heterogeneous manifestations, overlapping with other diseases such as autoimmunity, malignancy, and infections. This makes the diagnosis very challenging and delays management. Leucocyte adhesion defects (LAD) are a group of PIDs in which patients lack adhesion molecules on leukocytes needed for their emigration through blood vessels to the site of infection. Patients with LAD can present with diverse clinical features including severe and life-threatening infections, early in life, and the absence of pus formation around infection or inflammation. There is often delayed umbilical cord separation, omphalitis, late wound healing, and a high white blood cell count. If not recognized and managed early, can lead to life-threatening complications and death.

Case Presentation

LAD 1 is characterized by homozygous pathogenic variants in the integrin subunit beta 2 (ITGB2) gene. We report two cases of LAD1 with unusual presentations (post-circumcision excessive bleeding and chronic inflammation of the right eye) which were confirmed by flow cytometric analysis and genetic testing. We found two disease-causing ITGB2 pathogenic variants in both cases.

Conclusions

These cases highlight the importance of a multidisciplinary approach to recognizing clues in patients with uncommon manifestations of a rare disease. This approach initiates a proper diagnostic workup of primary immunodeficiency disorder leading to a better understanding of the disease, and appropriate patient counseling, and helps clinicians to be better equipped to deal with complications.
Peptide-based PET imaging agent of tumor TIGIT expression
Authors: Weng Dinghu , Guo Rong , Zhu Ziyang , Gao Yu , An Rui , Zhou Xiuman
Published: May 2023

Background

Accumulating studies have demonstrated that elevated TIGIT expression in tumor microenvironment correlates with better therapeutic response to TIGIT-based immunotherapy in pre-clinical studies. Therefore, a non-invasive method to detect tumor TIGIT expression is crucial to predict the therapeutic effect.

Methods

In this study, a peptide-based PET imaging agent, 68Ga-DOTA-DTBP-3, was developed to non-invasively detect TIGIT expression by micro-PET in tumor-bearing BALB/c mice. DTBP-3, a D-peptide comprising of 12 amino acids, was radiolabeled with 68Ga through a DOTA chelator. In vitro studies were performed to evaluate the affinity of 68Ga-DOTA-DTBP-3 to TIGIT and its stability in fetal bovine serum. In vivo studies were assessed by micro-PET, biodistribution, and immunohistochemistry on tumor-bearing BALB/c mice.

Results

The in vitro studies showed the equilibrium dissociation constant of 68Ga-DOTA-DTBP-3 for TIGIT was 84.21 nM and its radiochemistry purity was 89.24 ± 1.82% in FBS at 4 h in room temperature. The results of micro-PET, biodistribution and immunohistochemistry studies indicated that 68Ga-DOTA-DTBP-3 could be specifically targeted in 4T1 tumor-bearing mice, with a highest uptake at 0.5 h.

Conclusion

68Ga-DOTA-DTBP-3 holds potential for non-invasively detect tumor TIGIT expression and for timely assessment of the therapeutic effect of immune checkpoint blockade.
Resilience of swine nasal microbiota to influenza A virus challenge in a longitudinal study
Authors: Hau Samantha J. , Nielsen Daniel W. , Mou Kathy T. , Alt David P. , Kellner Steven , Brockmeier Susan L.
Published: May 2023

Influenza A virus (IAV) is an important contributing pathogen of porcine respiratory disease complex (PRDC) infections. Evidence in humans has shown that IAV can disturb the nasal microbiota and increase host susceptibility to bacterial secondary infections. Few, small-scale studies have examined the impact of IAV infection on the swine nasal microbiota. To better understand the effects of IAV infection on the nasal microbiota and its potential indirect impacts on the respiratory health of the host, a larger, longitudinal study was undertaken to characterize the diversity and community composition of the nasal microbiota of pigs challenged with an H3N2 IAV. The microbiome of challenged pigs was compared with non-challenged animals over a 6-week period using 16S rRNA gene sequencing and analysis workflows to characterize the microbiota. Minimal changes to microbial diversity and community structure were seen between the IAV infected and control animals the first 10 days post-IAV infection. However, on days 14 and 21, the microbial populations were significantly different between the two groups. Compared to the control, there were several genera showing significant increases in abundance in the IAV group during acute infection, such asActinobacillusandStreptococcus. The results here highlight areas for future investigation, including the implications of these changes post-infection on host susceptibility to secondary bacterial respiratory infections.
A high-accuracy and low-energy range-free localization algorithm for wireless sensor networks
Authors: Cui Huanqing , Wang Sen , Zhou Chuanai
Published: May 2023

As the backbone of the Internet of Things, wireless sensor networks are widely applied to perceive the physical world. Most applications need to associate perception information with a position to generate physical significance. This paper proposes WRCDV-Hop, which has quadruple improvements of the well-known DV-Hop. First, the hop count between a pair of sensor nodes is measured as a continuous value rather than a discrete value. Second, the unknown nodes calculate the average distance per hop by the weighted method. Third, each sensor node only records and relays limited but sufficient beacons of the anchors. Fourth, the unknown nodes apply the whale optimization algorithm to estimate positions. The first two improvements ensure that the distance estimation between a pair of sensor nodes is highly accurate, and the third improvement reduces the energy consumption. The last improvement makes the position estimation more precise. The simulation results show that WRCDV-Hop performs well in terms of localization accuracy and energy consumption.
Approximation of G-variational inequality problems and fixed-point problems of G-κ-strictly pseudocontractive mappings by an intermixed method endowed with a graph
Authors: Sripattanet Anchalee , Kangtunyakarn Atid
Published: May 2023

In this paper, we first study G-κ-strictly pseudocontractive mappings and we establish a strong convergence theorem for finding the fixed points of two G-κ-strictly pseudocontractive mappings, two G-nonexpansive mappings, and two G-variational inequality problems in a Hilbert space endowed with a directed graph without the Property G. Moreover, we prove an interesting result involving the set of fixed points of a G-κ-strictly pseudocontractive and G-variational inequality problem and if Λ is a G-κ-strictly pseudocontractive mapping, then $I-\Lambda $
I
−
Λ
is a $G-\frac{(1-\kappa )}{2}$
G
−

(
1
−
κ
)

2

-inverse strongly monotone mapping, shown in Lemma 3.3. In support of our main result, some examples are also presented.
Cecal microbiota transplantation: unique influence of cecal microbiota from divergently selected inbred donor lines on cecal microbial profile, serotonergic activity, and aggressive behavior of recipient chickens
Authors: Fu Yuechi , Hu Jiaying , Erasmus Marisa A. , Zhang Huanmin , Johnson Timothy A. , Cheng Hengwei
Published: May 2023

Background

Accumulating evidence from human trials and rodent studies has indicated that modulation of gut microbiota affects host physiological homeostasis and behavioral characteristics. Similarly, alterations in gut microbiota could be a feasible strategy for reducing aggressive behavior and improving health in chickens. The study was conducted to determine the effects of early-life cecal microbiota transplantation (CMT) on cecal microbial composition, brain serotonergic activity, and aggressive behavior of recipient chickens.

Methods

Chicken lines 63 and 72 with nonaggressive and aggressive behavior, respectively, were used as donors and a commercial strain Dekalb XL was used as recipients for CMT. Eighty-four 1-d-old male chicks were randomly assigned to 1 of 3 treatments with 7 cages per treatment and 4 chickens per cage (n = 7): saline (control, CTRL), cecal solution of line 63 (63-CMT), and cecal solution of line 72 (72-CMT). Transplantation was conducted via oral gavage once daily from d 1 to 10, and then boosted once weekly from week 3 to 5. At weeks 5 and 16, home-cage behavior was recorded, and chickens with similar body weights were assigned to paired aggression tests between the treatments. Samples of blood, brain, and cecal content were collected from the post-tested chickens to detect CMT-induced biological and microbiota changes.

Results

63-CMT chickens displayed less aggressive behavior with a higher hypothalamic serotonergic activity at week 5. Correspondingly, two amplicon sequence variants (ASVs) belonging to Lachnospiraceae and one Ruminococcaceae UCG-005 ASV were positively correlated with the levels of brain tryptophan and serotonin, respectively. 72-CMT chickens had lower levels of brain norepinephrine and dopamine at week 5 with higher levels of plasma serotonin and tryptophan at week 16. ASVs belonging to Mollicutes RF39 and GCA-900066225 in 72-CMT chickens were negatively correlated with the brain 5-hydroxyindoleacetic acid (5-HIAA) at week 5, and one Bacteroides ASV was negatively correlated with plasma serotonin at week 16.

Conclusion

Results indicate that CMT at an early age could regulate aggressive behavior via modulating the cecal microbial composition, together with central serotonergic and catecholaminergic systems in recipient chickens. The selected CMT could be a novel strategy for reducing aggressive behavior through regulating signaling along the microbiota-gut-brain axis.
Maternal Western diet mediates susceptibility of offspring to Crohn’s-like colitis by deoxycholate generation
Authors: Huang Chongyang , Tan Huishi , Song Mengyao , Liu Ke , Liu Hongbin , Wang Jun , Shi Yanqiang , Hou Fengyi , Zhou Qian , Huang Ruo , Shen Binghai , Lin Xinlong , Qin Xiaoming , Zhi Fachao
Published: May 2023

Background

The Western dietary pattern, characterized by high consumption of fats and sugars, has been strongly associated with an increased risk of developing Crohn’s disease (CD). However, the potential impact of maternal obesity or prenatal exposure to a Western diet on offspring’s susceptibility to CD remains unclear. Herein, we investigated the effects and underlying mechanisms of a maternal high-fat/high-sugar Western-style diet (WD) on offspring’s susceptibility to 2,4,6-Trinitrobenzenesulfonic acid (TNBS)-induced Crohn’s-like colitis.

Methods

Maternal dams were fed either a WD or a normal control diet (ND) for eight weeks prior to mating and continued throughout gestation and lactation. Post-weaning, the offspring were subjected to WD and ND to create four groups: ND-born offspring fed a normal diet (N–N) or Western diet (N-W), and WD-born offspring fed a normal (W–N) or Western diet (W-W). At eight weeks of age, they were administered TNBS to induce a CD model.

Results

Our findings revealed that the W–N group exhibited more severe intestinal inflammation than the N–N group, as demonstrated by a lower survival rate, increased weight loss, and a shorter colon length. The W–N group displayed a significant increase in Bacteroidetes, which was accompanied by an accumulation of deoxycholic acid (DCA). Further experimentation confirmed an increased generation of DCA in mice colonized with gut microbes from the W–N group. Moreover, DCA administration aggravated TNBS-induced colitis by promoting Gasdermin D (GSDMD)-mediated pyroptosis and IL-1beta (IL-1β) production in macrophages. Importantly, the deletion of GSDMD effectively restrains the effect of DCA on TNBS-induced colitis.

Conclusions

Our study demonstrates that a maternal Western-style diet can alter gut microbiota composition and bile acid metabolism in mouse offspring, leading to an increased susceptibility to CD-like colitis. These findings highlight the importance of understanding the long-term consequences of maternal diet on offspring health and may have implications for the prevention and management of Crohn’s disease.
Three-dimensional analysis of human pancreatic cancer specimens by phase-contrast based X-ray tomography – the next dimension of diagnosis
Authors: Pinkert-Leetsch Diana , Frohn Jasper , Ströbel Philipp , Alves Frauke , Salditt Tim , Missbach-Guentner Jeannine
Published: May 2023

Background

The worldwide increase of pancreatic ductal adenocarcinoma (PDAC), which still has one of the lowest survival rates, requires novel imaging tools to improve early detection and to refine diagnosis. Therefore, the aim of this study was to assess the feasibility of propagation-based phase-contrast X-ray computed tomography of already paraffin-embedded and unlabeled human pancreatic tumor tissue to achieve a detailed three-dimensional (3D) view of the tumor sample in its entirety.

Methods

Punch biopsies of areas of particular interest were taken from paraffin blocks after initial histological analysis of hematoxylin and eosin stained tumor sections. To cover the entire 3.5 mm diameter of the punch biopsy, nine individual tomograms with overlapping regions were acquired in a synchrotron parallel beam configuration and stitched together after data reconstruction. Due to the intrinsic contrast based on electron density differences of tissue components and a voxel size of 1.3 μm achieved PDAC and its precursors were clearly identified.

Results

Characteristic tissue structures for PDAC and its precursors, such as dilated pancreatic ducts, altered ductal epithelium, diffuse immune cell infiltrations, increased occurrence of tumor stroma and perineural invasion were clearly identified. Certain structures of interest were visualized in three dimensions throughout the tissue punch. Pancreatic duct ectasia of different caliber and atypical shape as well as perineural infiltration could be contiguously traced by viewing serial tomographic slices and by applying semi-automatic segmentation. Histological validation of corresponding sections confirmed the former identified PDAC features.

Conclusion

In conclusion, virtual 3D histology via phase-contrast X-ray tomography visualizes diagnostically relevant tissue structures of PDAC in their entirety, preserving tissue integrity in label-free, paraffin embedded tissue biopsies. In the future, this will not only enable a more comprehensive diagnosis but also a possible identification of new 3D imaging tumor markers.