bluuebunny/crossref_metadata_2025 huggingface dataset:
Acquired mutations in BAX confer resistance to BH3-mimetic therapy in acute myeloid leukemia
Authors: Moujalled Donia M. , Brown Fiona C. , Chua Chong Chyn , Dengler Michael A. , Pomilio Giovanna , Anstee Natasha S. , Litalien Veronique , Thompson Ella , Morley Thomas , MacRaild Sarah , Tiong Ing S. , Morris Rhiannon , Dun Karen , Zordan Adrian , Shah Jaynish , Banquet Sebastien , Halilovic Ensar , Morris Erick , Herold Marco J. , Lessene Guillaume , Adams Jerry M. , Huang David C. S. , Roberts Andrew W. , Blombery Piers , Wei Andrew H.
Published: October 2022

Randomized trials in acute myeloid leukemia (AML) have demonstrated improved survival by the BCL-2 inhibitor venetoclax combined with azacitidine in older patients, and clinical trials are actively exploring the role of venetoclax in combination with intensive chemotherapy in fitter patients with AML. As most patients still develop recurrent disease, improved understanding of relapse mechanisms is needed. We find that 17% of patients relapsing after venetoclax-based therapy for AML have acquired inactivating missense or frameshift/nonsense mutations in the apoptosis effector gene BAX. In contrast, such variants were rare after genotoxic chemotherapy. BAX variants arose within either leukemic or preleukemic compartments, with multiple mutations observed in some patients. In vitro, AML cells with mutated BAX were competitively selected during prolonged exposure to BCL-2 antagonists. In model systems, AML cells rendered deficient for BAX, but not its close relative BAK, displayed resistance to BCL-2 targeting, whereas sensitivity to conventional chemotherapy was variable. Acquired mutations in BAX during venetoclax-based therapy represent a novel mechanism of resistance to BH3-mimetics and a potential barrier to the long-term efficacy of drugs targeting BCL-2 in AML.
Effect of antiplatelet agents and tyrosine kinase inhibitors on oxLDL-mediated procoagulant platelet activity
Authors: Zheng Tony J. , Kohs Tia C. L. , Mueller Paul A. , Pang Jiaqing , Reitsma Stéphanie E. , Parra-Izquierdo Iván , Melrose Alexander R. , Yang Liping , Choi Jaewoo , Zientek Keith D. , Sviridov Denis O. , Larson Mark K. , Williams Craig D. , Pamir Nathalie , Shatzel Joseph J. , Reddy Ashok P. , Kievit Paul , Remaley Alan T. , Stevens Jan F. , Hinds Monica T. , McCarty Owen J. T. , Aslan Joseph E.
Published: October 2022

Low-density lipoprotein (LDL) contributes to atherogenesis and cardiovascular disease through interactions with peripheral blood cells, especially platelets. However, mechanisms by which LDL affects platelet activation and atherothrombosis, and how to best therapeutically target and safely prevent such responses remain unclear. Here, we investigate how oxidized low-density lipoprotein (oxLDL) enhances glycoprotein VI (GPVI)-mediated platelet hemostatic and procoagulant responses, and how traditional and emerging antiplatelet therapies affect oxLDL-enhanced platelet procoagulant activity ex vivo. Human platelets were treated with oxLDL and the GPVI-specific agonist, crosslinked collagen-related peptide, and assayed for hemostatic and procoagulant responses in the presence of inhibitors of purinergic receptors (P2YR), cyclooxygenase (COX), and tyrosine kinases. Ex vivo, oxLDL enhanced GPVI-mediated platelet dense granule secretion, α-granule secretion, integrin activation, thromboxane generation and aggregation, as well as procoagulant phosphatidylserine exposure and fibrin generation. Studies of washed human platelets, as well as platelets from mouse and nonhuman primate models of hyperlipidemia, further determined that P2YR antagonists (eg, ticagrelor) and Bruton tyrosine kinase inhibitors (eg, ibrutinib) reduced oxLDL-mediated platelet responses and procoagulant activity, whereas COX inhibitors (eg, aspirin) had no significant effect. Together, our results demonstrate that oxLDL enhances GPVI-mediated platelet procoagulant activity in a manner that may be more effectively reduced by P2YR antagonists and tyrosine kinase inhibitors compared with COX inhibitors.
LARRPM restricts lung adenocarcinoma progression and M2 macrophage polarization through epigenetically regulating LINC00240 and CSF1
Authors: Li Yue , Chen Chen , Liu Hai-lin , Zhang Zhen-fa , Wang Chang-li
Published: October 2022

Background

Long non-coding RNAs (lncRNAs) are critical regulators in lung adenocarcinoma (LUAD). M2-type tumor-associated macrophages (TAMs) also play oncogenic roles in LUAD. However, the involvement of lncRNAs in TAM activation is still largely unknown.

Methods

The expressions of LARRPM, LINC00240 and CSF1 were determined by RT-qPCR. The regulation of LINC00240 and CSF1 by LARRPM was investigated by RNA–protein pull-down, RNA immunoprecipitation, chromatin immunoprecipitation and bisulfite DNA sequencing. In vitro and in vivo gain- and loss-of-function assays were performed to investigate the roles of LARRPM.

Results

The lncRNA LARRPM was expressed at low levels in LUAD tissues and cells. The low expression of LARRPM was correlated with advanced stage and poor survival of patients with LUAD. Functional experiments revealed that LARRPM suppressed LUAD cell proliferation, migration and invasion, and promoted apoptosis. LARRPM also repressed macrophage M2 polarization and infiltration. Taken together, LARRPM significantly restricted LUAD progression in vivo. Mechanistically, LARRPM bound and recruited DNA demethylase TET1 to the promoter of its anti-sense strand gene LINC00240, leading to a decrease in DNA methylation level of the LINC00240 promoter and transcriptional activation of LINC00240. Functional rescue assays suggested that the lncRNA LINC00240 was responsible for the roles of LARRPM in the malignant behavior of LUAD cells. LARRPM decreased the binding of TET1 to the CSF1 promoter, resulting in increased DNA methylation of the CSF1 promoter and transcriptional repression of CSF1, which is responsible for the roles of LARRPM in macrophage M2 polarization and infiltration. The TAMs educated by LUAD cells exerted oncogenic roles, which was negatively regulated by LARRPM expressed in LUAD cells.

Conclusions

LARRPM restricts LUAD progression through repressing both LUAD cell and macrophages. These data shed new insights into the regulation of LUAD progression by lncRNAs and provide data on the potential utility of LARRPM as a target for LUAD treatment.
Comparative analysis of the endophytic bacteria inhabiting the phyllosphere of aquatic fern Azolla species by high-throughput sequencing
Authors: Yang Yan-Qiu , Deng Su-Fang , Yang You-Quan , Ying Zhao-Yang
Published: October 2022

Background

Azolla is a small floating fern living in symbiosis with nitrogen-fixing cyanobacteria and provides a variety of important ecosystem benefits. Previous studies have presented that Azolla harbors diverse bacteria that may play a key role in host fitness and productivity. However, the characteristics of endophytic bacteria inhabiting the phyllosphere of different species of Azolla have not yet been fully understood.

Results

In this study, the 16S ribosomal DNA (rDNA) V5-V7 region of bacteria was determined by Illumina high-throughput sequencing platform to study the diversity and richness of endophytic bacterial communities in the phyllosphere of five Azolla species collected from different countries. A total of 1150 operational taxonomic units (OTUs) were detected for the endophytic bacteria community. According to the α diversity indices, the diversity of bacteria was ordered as Azolla imbricata > A. pinnata > A. filiculoides > A. mexicana > A. caroliniana. The PCoA results displayed that the bacterial communities of A. mexicana and A. caroliniana shared the highest similarity, followed by the similarity between A. pinnata and A. imbricata, and they were significantly distinct from the community of A. filiculoides. The dominant bacteria of Azolla mainly belonged to the phylum of Proteobacteria, followed by Actinobacteria, Chlorobillobacteria, and Firmicutes. In detail, the relative abundance of Proteobacteria in A. imbricata was 52.23%, whereas it was more than 80.00% in the other four species of Azolla. Notably, Herbaspirillum (45.91%, 44.08%) and Methylophilus (29.97%, 37.96%) were the main genera inhabiting A. mexicana and A. caroliniana respectively. Ferrovibrio (18.54%) and Rhizobium (16.68%) were the dominant genera inhabiting A. filiculoides. The group of unidentified genera (41.63%, 44.92%) consisted most of the bacteria in A. imbricata and A. pinnata respectively. Further analysis suggested that the significant different bacteria identified in LDA Effect Size analysis existed Azolla species-specific patterns.

Conclusions

In summary, all results suggested that the diversity and composition of the endophytic bacterial communities were different in Azolla species.
Zinc oxide nanoparticles reduce biofilm formation, synergize antibiotics action and attenuate Staphylococcus aureus virulence in host; an important message to clinicians
Authors: Abdelghafar Aliaa , Yousef Nehal , Askoura Momen
Published: October 2022

Background

Biofilm-related infections are difficult to be treated because of higher resistance to antimicrobial agents. Current study aims to characterize the influence of zinc oxide nanoparticles (ZnO-NPs) on bothS. aureussusceptibility to antibiotics and pathogenesis.

Methods

The influence of ZnO-NPs on biofilm formation byS. aureuswas characterized by the crystal violet and tube assay. The synergistic effect of ZnO-NPs in combination with antibiotics onS. aureuswas characterized using the checkerboard method. The effect of ZnO-NPs onS. aureuscell surface hydrophobicity and blood hemolysis was investigated. RT-qPCR was used to investigate the effect of ZnO-NPs on the expression of biofilm related genes (icaA, icaRandsarA),katAandsigB. The impact of ZnO-NPs onS. aureuspathogenesis was evaluated using mice infection model.

Results

ZnO-NPs exhibited a good antibiofilm activity againstS. aureus. The findings indicate a synergistic antibiofilm effect of combination between ZnO-NPs and tested antibiotics. ZnO-NPs were capable of decreasingS. aureuscell surface hydrophobicity which could account for observed decrease in bacterial biofilm forming capacity. Moreover, ZnO-NPs-treated bacteria exhibited a significant decrease in blood hemolysis relative to control untreatedS. aureus. The expression of biofilm related genes was significantly repressed in ZnO-NPs treated bacteria as compared to untreated cells. Finally, the effect of ZnO-NPs onS. aureuspathogenesis was investigated using mice infection model where ZnO-NPs accelerated healing of wounds in mice as compared to control untreated mice.

Conclusions

Present data support the efficiency of ZnO-NPs as antibiofilm agent in treatment ofS. aureusinfections. This study recommends the incorporation of ZnO-NPs as adjuvant with other antibiotics targetingS. aureusbased on the promising findings obtained herein in order to control infection with this pathogen.
Prevalence of extended-spectrum β-lactamases, AmpC, and carbapenemases in Proteus mirabilis clinical isolates
Authors: Shaaban Mona , Elshaer Soha Lotfy , Abd El-Rahman Ola A.
Published: October 2022

Background

Proteus mirabilisis an opportunistic pathogen, causing a variety of community-acquired and nosocomial illnesses. It poses a potential threat to patients via the production of β-lactamases, which decrease the efficacy of antimicrobial treatment and impair the management of its pathogenicity. Hence, this study was established to determine the prevalence of extended-spectrum β-lactamases (ESBLs), AmpC, and carbapenemases ofP. mirabilisisolated from various clinical specimens.

Results

Proteus mirabiliswas identified in 20.7% (58/280) of specimens. ESBL producers were present at a rate of 51.7% (30/58). All AmpC-positive isolates (n = 20) produced ESBLs as well, so 66.7% of ESBL-producing isolates coproduced AmpC enzymes. The modified Hodge test confirmed carbapenemase production in six out of seven imipenem nonsusceptible isolates. Of these, only two (5.7%) isolates were also ESBL-and AmpC-positive. Antibiotic resistance reached the highest level for cotrimoxazole (62.1%,n = 36/58 isolates) and the lowest for imipenem (12.1%,n = 7/58 isolates). The levels of multidrug-resistant (MDR) was 41.4% among the tested isolates. TheblaSHV(83.3%),blaAmpC(80%), andblaVIM-1(50%) were the most detected genes in phenotypically confirmed ESBL-, AmpC-, and carbapenemase-producing isolates, respectively. Besides, more than a half of the testedP. mirabilisstrains (53%) coproduced ESBLs and AmpC. Moreover, two isolates coproduced ESBLs and AmpC together with carbapenemases. Furthermore, dendrogram analysis showed great genetic divergence based on the 21 different enterobacterial repetitive intergenic consensus (ERIC) patterns (P1–P21) through the 34 β-lactamase producers. ERIC analysis distinguished clonal similarities between isolates 21 and 22 in P2 and 9 and 10 in P4, which were isolated from the same clinical source and possessed similar patterns of β-lactamase-encoding genes.

Conclusion

Hence, there is an urgent need to monitor hospitalized patients and improve healthcare in order to reduce the incidence of infection and outbreaks of infection with antibiotic-resistantProteus.
Association between serum klotho levels and cardiovascular disease risk factors in older adults
Authors: Lee Jaeho , Kim Donghoon , Lee Hyo-jung , Choi Ju-Young , Min Jin-Young , Min Kyoung-Bok
Published: October 2022

Background

Klotho deficiency is a significant predictor of cardiovascular disease (CVD)-related mortality and morbidity. However, research assessing the association between klotho and individual risk factors of CVD is limited. This study aimed to explore the association between circulating serum klotho levels and risk factors for CVD in adults.

Methods

We used the 2007–2016 National Health and Nutrition Examination Survey and included 13,154 participants for whom serum klotho levels were available. Body mass index (BMI), exercise, smoking status, alcohol consumption, hypertension, dyslipidemia, serum lipid parameters, and blood pressure were considered as CVD risk factors.

Results

Circulating klotho levels were negatively associated with being overweight (beta coefficient: − 22.609, p = 0.0025), obesity (beta coefficient: − 23.716, p = 0.0011), current smoking (beta coefficient: − 46.412, p < 0.0001), and alcohol consumption (beta coefficient: − 51.194, p < 0.0001). There was a positive association between serum klotho levels and no history of dyslipidemia (beta coefficient: 15.474, p = 0.0053). Serum klotho levels were significantly decreased by a unit increase in triglycerides (beta coefficient: − 0.117, p = 0.0006) and total cholesterol (beta coefficient: − 0.249, p = 0.0002). There was a significant non-linear relationship between serum klotho levels, triglycerides, and total cholesterol.

Conclusions

Lower serum klotho levels are associated with certain CVD risk factors, including high BMI, smoking, alcohol consumption, and lipid parameters (triglycerides and total cholesterol). This study suggests that the soluble klotho level may be a potential marker for CVD risk.
A multidimensional approach to the resilience in older adults despite COVID-19
Authors: Perez-Rojo G. , López J. , Noriega C. , Velasco C. , Carretero I. , López-Frutos P. , Galarraga L.
Published: October 2022

Researchers have mainly focused on aging risk factors and COVID-19 consequences. However, older adults have proved their ability to overcome adversities along their life. Resilience is a protective variable that dampens the impact of stress. Based on MacLeod’s et al. (2016) approach, we aimed to analyze the relationship between older adults’ resilience and COVID-19 related-stressors as well as their physical, mental, and social characteristics. Eight hundred eighty-nine people aged 60 and over participated in this study. Older participants, women, having better perceived health and not losing a loved one because of the virus were associated with more resilience. Moreover, higher levels of gratitude, personal growth, life purpose and lower levels of depression were associated with greater scores in resilience. This study offers a change of perspective in which aging is perceived from a positive viewpoint by focusing on easily accessible resources that may help older adults to cope with adverse situations.
DNA ligase IV dificiency with elevated serum IgG levels suspected to have myelodysplastic syndrome: a case report
Authors: Huang Miao , Dong Guoqing , Lu Xiyan , Xiao Fei , Zhou Qixin , Zhang Shaoyi
Published: October 2022

Background

Ligase IV (LIG4) dificiency is a very rare clinical syndrome with around 50 cases reported to date. This syndrome is caused by biallelic pathogenic variants in the LIG4 gene, which cause DNA damage repair disorders, mainly manifesting as severe immunodeficiency.

Case presentation

We report the case of a 15-month-old male child with pancytopenia, growth retardation, microcephaly, history of vaccine-related rubella, elevated immunoglobulin G, and decreased T- and B lymphocytes. Next-generation sequencing revealed LIG4 pathogenic genes and compound heterozygous mutations, namely the missense mutation c.833G > T (p.Arg278Leu) and deletion mutation c.1271_1275del (p.Lys424Argfs*20).

Conclusion

This case suggests that LIG4 dificiency can manifest not only as immunodeficiency but also with increased serum IgG levels and pancytopenia, which constitutes an additional clinical phenotype. Furthermore, this case suggests that LIG4 deficiency should be considered upon differential diagnosis of myelodysplastic syndrome in children.
Investigation of neomycin biodegradation conditions using ericoid mycorrhizal and white rot fungal species
Authors: Stenholm Åke , Hedeland Mikael , Pettersson Curt E.
Published: October 2022

Background

In the search for methods to biodegrade recalcitrant compounds, the use of saprotrophic fungi and white rot fungi, in particular belonging to the phylum Basidiomycota, has gained interest. This group of fungi possesses a battery of unspecific extracellular enzymes that can be utilized in the biodegradation of preferably phenolic compounds. In this work, it was investigated under which conditions the white rot fungus Trametes versicolor and the ericoid mycorrhizal fungus Rhizoscyphus ericae (belonging to the phylum Ascomycota) could be used to biodegrade the antibiotic aminoglycoside neomycin at co-metabolic conditions in which external nutrients were supplied. Furthermore, it was also investigated whether a biodegradation could be accomplished using neomycin as the sole nutrient.

Results

The results show that both species can biodegrade neomycin 70% under co-metabolic conditions during a one-week time course and that Rhizoscyphus ericae is able to use neomycin as sole nutrient and to approximatively biodegrade it 60% under chosen non co-metabolic conditions.

At selected conditions, the biodegradation of neomycin using Rhizoscyphus ericae was monitored by oxidation products of D-ribose which is a hydrolysis product of neomycin.

Conclusion

The results are of general interest in the search for fungal species that can biodegrade recalcitrant compounds without the need of external nutrients. The key future application area that will be investigated is purification of waste from recombinant protein production in which neomycin, nutrients and E. coli with neomycin resistance genes are present.
Self-referrals and associated factors among laboring mothers at Dilla University Referral Hospital, Dilla, Gedeo Zone, Ethiopia: a cross-sectional study
Authors: Eritero Aneleay Cherinet , Gebreslasie Kahsay Zenebe , Asgedom Alem Tadesse , Areba Abriham Shiferaw , Wudneh Aregahegn , Bayisa Yesuneh , Molla Wondwosen
Published: October 2022

Background

When medical cases are difficult to manage at the level of primary health care units (PHCU), formal referral assists patients transferring to a higher level of care. In contrast, self-referral and bypassing are synonymously used in literature to describe the phenomenon of patients skipping their units to get basic medical services, even though they are close to their residence. Though proper and timely referral prevents the majority of deaths from obstetric complications in developing countries, more than 50% of referrals are self-referral trends. Such patient practice is increasingly becoming a concern for many health-care systems.

Objective

To assess the magnitude of self-referrals and associated factors among laboring mothers at Gedeo Zone, Ethiopia.

Methods

Facility-based cross-sectional study was conducted from August 1-September 30/2021 among laboring mothers at Dilla University Referral Hospital. A systematic random sampling technique was used to select 375 laboring mothers. Data were collected using a face-to-face interview with a structured questionnaire. Data were entered into a computer using Epi-Data 4.6 statistical program and then exported to STATA version 16 for analysis. In bivariate analysis variables with a p-value ≤ 0.25 were selected as a candidate variable for the multivariable analysis. P-value < 0.05 at 95% confidence interval considered as a statistically significant associations in the multivariable analysis.

Result

375 eligible mothers participated in the study, with a response rate of 98.16%. The magnitude of self-referrals among laboring mothers was 246 (65.6%) with 95% CI (0.60–0.70). Time ≥ 30 min to reach nearby facilities (AOR = 1.74, 95% CI, 1.08, 2.81), having no medicine supplies at nearby facilities (AOR = 1.75, 95% CI, 1.08, 2.82), having no equipment and supplies at nearby facilities (AOR = 1.70, 95% CI, 1.03, 2.78), having ANC visits ˃ 3 times (AOR = 0.29, 95% CI, 0.15, 0.55) and having poor perception of health provider technical competence at nearby facilities (AOR = 2.97, 95% CI, 1.83, 4.79) were found as significant factors for self-referral.

Conclusion

The magnitude of self-referral was high. Frequent Antenatal visits were protective, however time to reach the nearest facilities, perception towards health care providers, medicine, equipment and supplies at the nearest facilities were positive influencing factors. Government stakeholders should keep working on improving the quality of health service, especially at primary health care units(PHCU).
Pheromone sensing in Drosophila requires support cell-expressed Osiris 8
Authors: Scalzotto Marta , Ng Renny , Cruchet Steeve , Saina Michael , Armida Jan , Su Chih-Ying , Benton Richard
Published: October 2022

Background

The nose of most animals comprises multiple sensory subsystems, which are defined by the expression of different olfactory receptor families. Drosophila melanogaster antennae contain two morphologically and functionally distinct subsystems that express odorant receptors (Ors) or ionotropic receptors (Irs). Although these receptors have been thoroughly characterized in this species, the subsystem-specific expression and roles of other genes are much less well-understood.

Results

Here we generate subsystem-specific transcriptomic datasets to identify hundreds of genes, encoding diverse protein classes, that are selectively enriched in either Or or Ir subsystems. Using single-cell antennal transcriptomic data and RNA in situ hybridization, we find that most neuronal genes—other than sensory receptor genes—are broadly expressed within the subsystems. By contrast, we identify many non-neuronal genes that exhibit highly selective expression, revealing substantial molecular heterogeneity in the non-neuronal cellular components of the olfactory subsystems. We characterize one Or subsystem-specific non-neuronal molecule, Osiris 8 (Osi8), a conserved member of a large, insect-specific family of transmembrane proteins. Osi8 is expressed in the membranes of tormogen support cells of pheromone-sensing trichoid sensilla. Loss of Osi8 does not have obvious impact on trichoid sensillar development or basal neuronal activity, but abolishes high sensitivity responses to pheromone ligands.

Conclusions

This work identifies a new protein required for insect pheromone detection, emphasizes the importance of support cells in neuronal sensory functions, and provides a resource for future characterization of other olfactory subsystem-specific genes.
Empirical evidence of study design biases in nutrition randomised controlled trials: a meta-epidemiological study
Authors: Stadelmaier Julia , Roux Isabelle , Petropoulou Maria , Schwingshackl Lukas
Published: October 2022

Background

Instruments to critically appraise randomised controlled trials (RCTs) are based on evidence from meta-epidemiological studies. We aim to conduct a meta-epidemiological study on the average bias associated with reported methodological trial characteristics such as random sequence generation, allocation concealment, blinding, incomplete outcome data, selective reporting, and compliance of RCTs in nutrition research.

Methods

We searched the Cochrane Database of Systematic Reviews, for systematic reviews of RCTs, published between 01 January 2010 and 31 December 2019. We combined the estimates of the average bias (e.g. ratio of risk ratios [RRR] or differences in standardised mean differences) in meta-analyses using the random-effects model. Subgroup analyses were conducted to investigate the potential differences among the RCTs with low versus high/unclear risk of bias with respect to the different types of interventions (e.g. micronutrients, fatty acids, dietary approach), outcomes (e.g. mortality, pregnancy outcomes), and type of outcome (objective, subjective). Heterogeneity was assessed through I2 and τ2, and prediction intervals were calculated.

Results

We included 27 Cochrane nutrition reviews with 77 meta-analyses (n = 927 RCTs). The available evidence suggests that intervention effect estimates may not be exaggerated in RCTs with high/unclear risk of bias (versus low) judgement for sequence generation (RRR 0.97, 95% CI 0.93 to 1.02; I2 = 28%; τ2 = 0.002), allocation concealment (RRR 1.00, 95% CI 0.96 to 1.04; I2 = 27%; τ2 = 0.001), blinding of participants and personnel (RRR 0.95, 95% CI 0.91 to 1.00; I2 = 23%; τ2 = 0), selective reporting (RRR 0.97, 95% CI 0.92 to 1.02; I2 = 24%; τ2 = 0), and compliance (RRR 0.95, 95% CI 0.89 to 1.02; I2 = 0%; τ2 = 0). Intervention effect estimates seemed to be exaggerated in RCTs with a high/unclear risk of bias judgement for blinding of outcome assessment (RRR 0.81, 95% CI 0.70 to 0.94; I2 = 26%; τ2 = 0.03), which was predominately driven by subjective outcomes, and incomplete outcome data (RRR 0.92, 95% CI 0.88 to 0.97; I2 = 22%; τ2 = 0.001). For continuous outcomes, no differences were observed, except for selective reporting.

Conclusions

On average, most characteristics of nutrition RCTs may not exaggerate intervention effect estimates, but the average bias appears to be greatest in trials of subjective outcomes. Replication of this study is suggested in this field to keep this conclusion updated.
Early prediction of hemodialysis complications employing ensemble techniques
Authors: Othman Mai , Elbasha Ahmed Mustafa , Naga Yasmine Salah , Moussa Nancy Diaa
Published: October 2022

Background and objectives

Hemodialysis complications remain a critical threat among dialysis patients. They result in sudden termination of the session which impacts the efficiency of dialysis. As intra-dialytic complications are the result of the interplay of multiple factors, artificial intelligence can aid in their early prediction. This research aims to compare different machine learning tools for the early prediction of the most frequent hemodialysis complications with high performance, using the fewest predictors for easier practical implementation.

Methods

Fifty different variables were recorded during 6000 hemodialysis sessions performed in a regional dialysis unit in Egypt. The filter technique was used to extract the most relevant features. Then, five individual classifiers and three ensemble approaches were implemented to predict the occurrence of intra-dialytic complications. Different subsets of 25, 12 and 6 from the 50 collected features were tested.

Results

Random forest yielded the highest accuracy of 98% with the least training time using 12 features in a balanced dataset, while the gradient boosting allowed obtaining the highest F1-score of 94%, 92%, and 78% in the prediction of hypotension, hypertension, and dyspnea, respectively, in imbalanced datasets.

Conclusion

Applying different machine learning algorithms to big datasets can improve accuracy, reduce training time and model complexity allowing simple implementation in clinical practice. Our models can help nephrologists predict and possibly prevent dialysis complications.
Systematic review of associations of polychlorinated biphenyl (PCB) exposure with declining semen quality in support of the derivation of reference doses for mixture risk assessments
Authors: Ermler Sibylle , Kortenkamp Andreas
Published: October 2022

Background

Mixture risk assessments require reference doses for common health endpoints of all the chemicals to be considered together. In support of a mixture risk assessment for male reproductive health, we conducted a systematic review of the literature on associations between exposures to Polychlorinated Biphenyls (PCBs) and declines in semen quality. PCBs can act as Aryl-hydrocarbon Receptor (AhR)-agonists and Androgen Receptor (AR)-antagonists, both mechanisms which can affect sperm parameters. PCBs and other AR-antagonists can produce additive combination effects. Based on these observations our objective was to systematically gather data from animal and human studies to derive a reference dose for declines in semen quality for individual PCB.

Methods

We systematically reviewed and evaluated the evidence in human epidemiological and experimental animal studies on associations between PCBs and deteriorations in semen quality. Human data and findings from animal studies with PCB mixtures were considered as supporting evidence. Information for individual congeners from animal studies was required for inclusion in mixture risk assessment. Using a robust confidence rating approach, we identified suitable studies to derive reference doses for individual PCB congeners.

Results

Evaluation of human epidemiological studies revealed several reports of adverse effects on sperm parameters linked to PCB exposures, although some studies reported improved semen quality. Our review of experimental animal studies found that treatments with PCBs affected semen quality, in most cases adversely. We found robust evidence that PCB-118 and -169 were linked to declines in semen quality. Evidence for adverse effects of PCB-126, -132, -149, and -153 was moderate, whereas for PCB-77 it was slight and for PCB-180 indeterminate. Using widely accepted risk assessment procedures, we estimated reference dose values of 0.0029 µg/kg/day for PCB-118 and 0.00533 µg/kg/day for PCB-169. In addition, we derived values for PCB-126: 0.000073 µg/kg/day, PCB-132: 0.0228 µg/kg/day, PCB-149: 0.656 µg/kg/day, and PCB-153: 0.0058 µg/kg/day.

Conclusions

We found robust evidence for links between PCB exposure and deteriorations in semen quality, and derived reference doses for a set of congeners. We intend to use these values in combination with congener-specific exposure data in a mixture risk assessment for declines in semen quality, involving several other antiandrogenic chemicals.
Associations between long-term exposures to airborne PM2.5 components and mortality in Massachusetts: mixture analysis exploration
Authors: Jin Tingfan , Amini Heresh , Kosheleva Anna , Danesh Yazdi Mahdieh , Wei Yaguang , Castro Edgar , Di Qian , Shi Liuhua , Schwartz Joel
Published: October 2022

Background:

Numerous studies have documented PM2.5’s links with adverse health outcomes. Comparatively fewer studies have evaluated specific PM2.5components. The lack of exposure measurements and high correlation among different PM2.5components are two limitations.

Methods:

We applied a novel exposure prediction model to obtain annual Census tract-level concentrations of 15 PM2.5components (Zn, V, Si, Pb, Ni, K, Fe, Cu, Ca, Br, SO42−, NO3−, NH4+, OC, EC) in Massachusetts from 2000 to 2015, to which we matched geocoded deaths. All non-accidental mortality, cardiovascular mortality, and respiratory mortality were examined for the population aged 18 or over. Weighted quantile sum (WQS) regression models were used to examine the cumulative associations between PM2.5components mixture and outcomes and each component’s contributions to the cumulative associations. We have fit WQS models on 15 PM2.5components and a priori identified source groups (heavy fuel oil combustion, biomass burning, crustal matter, non-tailpipe traffic source, tailpipe traffic source, secondary particles from power plants, secondary particles from agriculture, unclear source) for the 15 PM2.5components. Total PM2.5mass analysis and single component associations were also conducted through quasi-Poisson regression models.

Results:

Positive cumulative associations between the components mixture and all three outcomes were observed from the WQS models. Components with large contribution to the cumulative associations included K, OC, and Fe. Biomass burning, traffic emissions, and secondary particles from power plants were identified as important source contributing to the cumulative associations. Mortality rate ratios for cardiovascular mortality were of greater magnitude than all non-accidental mortality and respiratory mortality, which is also observed in cumulative associations estimated from WQS, total PM2.5mass analysis, and single component associations.

Conclusion:

We have found positive associations between the mixture of 15 PM2.5components and all non-accidental mortality, cardiovascular mortality, and respiratory mortality. Among these components, Fe, K, and OC have been identified as having important contribution to the cumulative associations. The WQS results also suggests potential source effects from biomass burning, traffic emissions, and secondary particles from power plants.
Single-cell transcriptomics reveals the role of Macrophage-Naïve CD4 + T cell interaction in the immunosuppressive microenvironment of primary liver carcinoma
Authors: Mo Zhuomao , Liu Daiyuan , Chen Yihan , Luo Jin , Li Wenjing , Liu Jiahui , Yu Ling , Huang Bijun , Zhang Shijun
Published: October 2022

Background

Liver carcinoma generally presents as an immunosuppressive microenvironment that promotes tumor evasion. The intercellular crosstalk of immune cells significantly influences the construction of an immunosuppressive microenvironment. This study aimed to investigate the important interactions between immune cells and their targeting drugs in liver carcinoma, by using single-cell and bulk transcriptomic data.

Methods

Single-cell and bulk transcriptomic data were retrieved from Gene Expression Omnibus (GSE159977, GSE136103, and GSE125449) and The Cancer Genome Atlas (TGCA-LIHC), respectively. Quality control, dimension reduction, clustering, and annotation were performed according to the Scanpy workflow based on Python. Cell–cell interactions were explored using the CellPhone database and CellChat. Trajectory analysis was executed using a partition-based graph abstraction method. The transcriptomic factors (TFs) were predicted using single-cell regulatory network inference and clustering (SCENIC). The target genes from TFs were used to establish a related score based on the TCGA cohort; this score was subsequently validated by survival, gene set enrichment, and immune cell infiltration analyses. Drug prediction was performed based on the Cancer Therapeutics Response Portal and PRISM Repurposing datasets.

Results

Thirty-one patients at four different states, including health, hepatitis, cirrhosis, and cancer, were enrolled in this study. After dimension reduction and clustering, twenty-two clusters were identified. Cell–cell interaction analyses indicated that macrophage-naive CD4 + T cell interaction significantly affect cancerous state. In brief, macrophages interact with naive CD4 + T cells via different pathways in different states. The results of SCENIC indicated that macrophages present in cancer cells were similar to those present during cirrhosis. A macrophage-naive CD4 + T cell (MNT) score was generated by the SCENIC-derived target genes. Based on the MNT score, five relevant drugs (inhibitor of polo-like kinase 1, inhibitor of kinesin family member 11, dabrafenib, ispinesib, and epothilone-b) were predicted.

Conclusions

This study reveals the crucial role of macrophage-naive CD4 + T cell interaction in the immunosuppressive microenvironment of liver carcinoma. Tumor-associated macrophages may be derived from cirrhosis and can initiate liver carcinoma. Predictive drugs that target the macrophage-naive CD4 + T cell interaction may help to improve the immunosuppressive microenvironment and prevent immune evasion. The relevant mechanisms need to be further validated in experiments and cohort studies.

Graphical Abstract
The efficacy of azithromycin to prevent exacerbation of non-cystic fibrosis bronchiectasis: a meta-analysis of randomized controlled studies
Authors: Li Kui , Liu Li , Ou Yan
Published: October 2022

Introduction

The efficacy of azithromycin to prevent exacerbation for non-cystic fibrosis bronchiectasis remains controversial. We conduct this meta-analysis to explore the influence of azithromycin versus placebo for the treatment of non-cystic fibrosis bronchiectasis.

Methods

We have searched PubMed, EMbase, Web of science, EBSCO, and Cochrane library databases through July 2019 for randomized controlled trials (RCTs) assessing the efficacy of azithromycin versus placebo for non-cystic fibrosis bronchiectasis. This meta-analysis was performed using the random-effect model.

Results

Four RCTs were included in the meta-analysis. Overall, compared with control group for non-cystic-fibrosis bronchiectasis, azithromycin treatment was associated with improved free of exacerbation (odd ratios [OR] = 3.66; 95% confidence interval [CI] = 1.69–7.93;P = 0.001), reduced pulmonary exacerbations (OR = 0.27; 95% CI 0.13–0.59;P = 0.001) and number of pulmonary exacerbations (standard mean difference [SMD] =  − 0.87; 95% CI − 1.21 to − 0.54;P < 0.00001), but demonstrate no obvious impact on forced expiratory volume in 1 s (FEV1), score on St George’s respiratory questionnaire, nausea or vomiting, adverse events.

Conclusions

Azithromycin is effective to prevent exacerbation of non-cystic fibrosis bronchiectasis.
Long-term methylphenidate use for children and adolescents with attention deficit hyperactivity disorder and risk for depression, conduct disorder, and psychotic disorder: a nationwide longitudinal cohort study in South Korea
Authors: Park Jimyung , Lee Dong Yun , Kim Chungsoo , Lee Yo Han , Yang Su-Jin , Lee Sangha , Kim Seong-Ju , Lee Jeewon , Park Rae Woong , Shin Yunmi
Published: October 2022

Background

Methylphenidate (MPH) is the most frequently prescribed medication for the treatment of attention deficit hyperactivity disorder (ADHD). However, the safety of its long-term use remain unclear. In particular, real-world evidence of long-term MPH treatment regarding the risk of depression, conduct disorders, and psychotic disorders in children and adolescents is needed. This study aimed to compare the risks of depression, conduct disorder, and psychotic disorder between long- and short-term MPH treatments in children and adolescents.

Methods

This population-based cohort study used a nationwide claims database of all patients with ADHD in South Korea. Patients aged less than 18 years who were prescribed MPH were included in the study. Long- and short-term MPH were defined as > 1 year, and < 1 year, respectively. Overall, the risk of developing depressive disorder, conduct disorder and oppositional defiant disorder (ODD), and psychotic disorder were investigated. A 1:2 propensity score matching was used to balance the cohorts, and the Cox proportional hazards model was used to evaluate the safety of MPH.

Results

We identified 1309 long-term and 2199 short-term MPH users. Long-term MPH use was associated with a significantly lower risk of depressive (hazard ratio [HR], 0.70 [95% confidence interval [CI] 0.55–0.88]) and conduct disorders and ODD (HR, 0.52 [95% CI 0.38–0.73]) than short-term MPH use. Psychotic disorder was not significantly associated with long-term MPH use (hazard ratio [HR], 0.83 [95% confidence interval [CI] 0.52–1.32]).

Conclusions

Our findings suggest that long-term MPH use may be associated with a decreased risk of depression, conduct disorders and ODD. Moreover, the long-term use of MPH does not increase the risk of psychotic disorders. Long-term MPH administration may be considered as a favourable treatment strategy for children and adolescents with ADHD regarding depressive, conduct, and psychotic disorders.
Quantitative imaging of magnetic nanoparticles in an unshielded environment using a large AC susceptibility array
Authors: Soares Guilherme , Pinto Leonardo , Liebl Maik , Biasotti Gabriel , Prospero Andre , Stoppa Erick , Bakuzis Andris , Baffa Oswaldo , Wiekhorst Frank , Miranda José Ricardo Arruda
Published: October 2022

Background

Non-invasive magnetic imaging techniques are necessary to assist magnetic nanoparticles in biomedical applications, mainly detecting their distribution inside the body. In Alternating Current Biosusceptometry (ACB), the magnetic nanoparticle's magnetization response under an oscillating magnetic field, which is applied through an excitation coil, is detected with a balanced detection coil system.

Results

We built a Multi-Channel ACB system (MC-ACB) containing nineteen pick-up coils and obtained 2D quantitative images of magnetic nanoparticle distributions by solving an inverse problem. We reconstructed the magnetic nanoparticles spatial distributions in a field of view of 14 × 14 cm2 with a spatial resolution of 2.0 cm and sensitivity in the milligram scale. A correlation coefficient between quantitative reconstructed and nominal magnetic nanoparticle distributions above 0.6 was found for all measurements.

Conclusion

Besides other interesting features such as sufficient large field of view dimension for mice and rat studies, portability, and the ability to assess the quantitative magnetic nanoparticles distributions in real-time, the MC-ACB system is a promising tool for quantitative imaging of magnetic nanoparticles distributions in real-time, offering an affordable setup for easy access in clinical or laboratory environments.
The world’s first digital cell twin in cancer electrophysiology: a digital revolution in cancer research?
Authors: Baumgartner Christian
Published: October 2022

Background

The introduction of functional in-silico models, in addition to in-vivo tumor models, opens up new and unlimited possibilities in cancer research and drug development. The world's first digital twin of the A549 cell's electrophysiology in the human lung adenocarcinoma, unveiled in 2021, enables the investigation and evaluation of new research hypotheses about modulating the function of ion channels in the cell membrane, which are important for better understanding cancer development and progression, as well as for developing new drugs and predicting treatments.

Main body

The developed A549 in-silico model allows virtual simulations of the cell’s rhythmic oscillation of the membrane potential, which can trigger the transition between cell cycle phases. It is able to predict the promotion or interruption of cell cycle progression provoked by targeted activation and inactivation of ion channels, resulting in abnormal hyper- or depolarization of the membrane potential, a potential key signal for the known cancer hallmarks. For example, model simulations of blockade of transient receptor potential cation channels (TRPC6), which are highly expressed during S-G2/M transition, result in a strong hyperpolarization of the cell’s membrane potential that can suppress or bypass the depolarization required for the S-G2/M transition, allowing for possible cell cycle arrest and inhibition of mitosis. All simulated research hypotheses could be verified by experimental studies.

Short conclusion

Functional, non-phenomenological digital twins, ranging from single cells to cell–cell interactions to 3D tissue models, open new avenues for modern cancer research through "dry lab" approaches that optimally complement established in-vivo and in-vitro methods.
A PMM2-CDG caused by an A108V mutation associated with a heterozygous 70 kilobases deletion case report
Authors: Lebredonchel E. , Riquet A. , Neut D. , Broly F. , Matthijs G. , Klein A. , Foulquier F.
Published: October 2022

Background

Congenital Disorders of Glycosylation (CDG) are a large group of inborn errors of metabolism with more than 140 different CDG types reported to date (1). The first characterized, PMM2-CDG, with an autosomal recessive transmission, is also the most frequent. The PMM2 gene encodes a phosphomannomutase. Here, a novel genetic variation causing PMM2-CDG is reported. 

Case presentation

We report the case of a French child, from healthy and unrelated parents, presenting congenital ataxia with hypotonia, hyperlaxity, inverted nipples, as well as altered coagulation parameters and liver function. Transferrin isoelectrofocusing revealed a typical type I CDG profile. Direct Sanger sequencing and quantitative PCR of PMM2 revealed a unique and novel genotype. On one allele, the patient was heterozygote with a known missense variant NM_000303.3(PMM2):c.323C > T, p.Ala108Val in exon 4. On the second allele, whole genome sequencing (WGS) indicated the presence of a novel heterozygous 70 kb deletion.

Conclusion

We report in the present paper the largest known heterozygous deletion of a PMM2 gene. The observation reveals the impact of a precise diagnostic on genetic counselling: by using WGS, an erroneous conclusion of homozygosity in the case of a relatively rare variant could be avoided, and an index patient with healthy and unrelated parents correctly identified.
PCA outperforms popular hidden variable inference methods for molecular QTL mapping
Authors: Zhou Heather J. , Li Lei , Li Yumei , Li Wei , Li Jingyi Jessica
Published: October 2022

Background

Estimating and accounting for hidden variables is widely practiced as an important step in molecular quantitative trait locus (molecular QTL, henceforth “QTL”) analysis for improving the power of QTL identification. However, few benchmark studies have been performed to evaluate the efficacy of the various methods developed for this purpose.

Results

Here we benchmark popular hidden variable inference methods including surrogate variable analysis (SVA), probabilistic estimation of expression residuals (PEER), and hidden covariates with prior (HCP) against principal component analysis (PCA)—a well-established dimension reduction and factor discovery method—via 362 synthetic and 110 real data sets. We show that PCA not only underlies the statistical methodology behind the popular methods but is also orders of magnitude faster, better-performing, and much easier to interpret and use.

Conclusions

To help researchers use PCA in their QTL analysis, we provide an R package along with a detailed guide, both of which are freely available athttps://github.com/heatherjzhou/PCAForQTL. We believe that using PCA rather than SVA, PEER, or HCP will substantially improve and simplify hidden variable inference in QTL mapping as well as increase the transparency and reproducibility of QTL research.