bluuebunny/crossref_metadata_2025 huggingface dataset:
Diminished humoral and cellular responses to SARS-CoV-2 vaccines in patients with chronic lymphocytic leukemia
Authors: Ujjani Chaitra , Gooley Ted A. , Spurgeon Stephen E. , Stephens Deborah M. , Lai Catherine , Broome Catherine M. , O’Brien Susan , Zhu Haiying , Laing Kerry J. , Winter Allison M. , Pongas Georgios , Greninger Alexander L , Koelle David M. , Siddiqi Tanya , Davids Matthew S. , Rogers Kerry A. , Danilov Alexey V. , Sperling Amy , Tu Brian , Sorensen Tyler , Launchbury Kelsey , Burrow Carlissa J. , Quezada Genesis , Hill Joshua A. , Shadman Mazyar , Thompson Philip A.
Published: December 2022

Previous studies have demonstrated low rates of seroconversion to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) messenger RNA (mRNA) vaccines in patients with chronic lymphocytic leukemia (CLL). In this national collaboration of 11 cancer centers in the United States, we aimed to further characterize and understand vaccine-induced immune responses, including T-cell responses, and the impact of CLL therapeutics (#NCT04852822). Eligible patients were enrolled in 2 cohorts (1) at the time of initial vaccination and (2) at the time of booster vaccination. The serologic response rates (anti-S) from 210 patients in the initial vaccination cohort and 117 in the booster vaccination cohort were 56% (95% confidence interval [CI], 50-63) and 68% (95% CI, 60-77), respectively. Compared with patients not on therapy, those receiving B-cell-directed therapy were less likely to seroconvert (odds ratio [OR], 0.27; 95% CI, 0.15-0.49). Persistence of response was observed at 6 months; anti-S titers increased with the administration of booster vaccinations. In the initial vaccination cohort, positive correlations were observed between the quantitative serologic response and CD4 T-cell response for the Wuhan variant and, to a lesser degree, for the Omicron variant (Spearman P = 0.45 Wuhan; P = 0.25 Omicron). In the booster vaccination cohort, positive correlations were observed between serologic responses and CD4 T-cell responses for both variants (P = 0.58 Wuhan; P = 0.57 Omicron) and to a lesser degree for CD8 T-cell responses (P = 0.33 Wuhan; P = 0.22 Omicron). Although no deaths from coronavirus disease 2019 (COVID-19) have been reported after booster vaccinations, patients should use caution as newer variants emerge and escape vaccine-induced immunity. This trial was registered at www.clinicaltrials.gov as #NCT04852822.
Development of a tool to detect small airways dysfunction in asthma clinical practice
Authors: Kocks Janwillem , van der Molen Thys , Voorham Jaco , Baldi Simonetta , van den Berge Maarten , Brightling Chris , Fabbri Leonardo M. , Kraft Monica , Nicolini Gabriele , Papi Alberto , Rabe Klaus F. , Siddiqui Salman , Singh Dave , Vonk Judith , Leving Marika , Flokstra-de Blok Bertine
Published: December 2022

Background

Small airways dysfunction (SAD) in asthma is difficult to measure and a gold standard is lacking. The aim of this study was to develop a simple tool including items of the Small Airways Dysfunction Tool (SADT) questionnaire, basic patient characteristics and respiratory tests available depending on the clinical setting to predict SAD in asthma.

Methods

This study was based on the data of the multinational ATLANTIS (Assessment of Small Airways Involvement in Asthma) study including the earlier developed SADT questionnaire. Key SADT items together with clinical information were now used to build logistic regression models to predict SAD group (less likely or more likely to have SAD). Diagnostic ability of the models was expressed as area under the receiver operating characteristic curve (AUC) and positive likelihood ratio (LR+).

Results

SADT item 8, “I sometimes wheeze when I am sitting or lying quietly”, and the patient characteristics age, age at asthma diagnosis and body mass index could reasonably well detect SAD (AUC 0.74, LR+ 2.3). The diagnostic ability increased by adding spirometry (percentage predicted forced expiratory volume in 1 s: AUC 0.87, LR+ 5.0) and oscillometry (resistance difference between 5 and 20 Hz and reactance area: AUC 0.96, LR+ 12.8).

Conclusions

If access to respiratory tests is limited (e.g.primary care in many countries), patients with SAD could reasonably well be identified by asking about wheezing at rest and a few patient characteristics. In (advanced) hospital settings patients with SAD could be identified with considerably higher accuracy using spirometry and oscillometry.
Mycobacterium aviumcomplex genomics and transmission in a London hospital
Authors: van Tonder Andries J. , Ellis Huw C. , Churchward Colin P. , Kumar Kartik , Ramadan Newara , Benson Susan , Parkhill Julian , Moffatt Miriam F. , Loebinger Michael R. , Cookson William O.C.
Published: December 2022

Background

Non-tuberculous mycobacteria (NTM) are environmental microorganisms and opportunistic pathogens in individuals with pre-existing lung conditions such as cystic fibrosis (CF) and non-CF bronchiectasis. While recent studies ofMycobacterium abscessushave identified transmission within single CF centres as well as nationally and globally, transmission of other NTM species is less well studied.

Methods

To investigate the potential for transmission of theMycobacterium aviumcomplex (MAC) we sequenced 996 isolates from 354 CF and non-CF patients at the Royal Brompton Hospital (London, UK; collected 2013–2016) and analysed them in a global context. Epidemiological links were identified from patient records. Previously published genomes were used to characterise global population structures.

Results

We identified putative transmission clusters in three MAC species, although few epidemiological links could be identified. ForM. avium, lineages were largely limited to single countries, while forMycobacterium chimaera, global transmission clusters previously associated with heater-cooler units (HCUs) were found. However, the immediate ancestor of the lineage causing the major HCU-associated outbreak was a lineage already circulating in patients.

Conclusions

CF and non-CF patients shared transmission chains, although the lack of epidemiological links suggested that most transmission is indirect and may involve environmental intermediates or asymptomatic carriage in the wider population.
Inflammasome activation mediated by oxidised low-density lipoprotein in patients with sleep apnoea and early subclinical atherosclerosis
Authors: Díaz-García Elena , Sanz-Rubio David , García-Tovar Sara , Alfaro Enrique , Cubero Pablo , Gil Ana V. , Marin José M. , Cubillos-Zapata Carolina , García-Río Francisco
Published: December 2022

Background

Atherosclerosis is a common comorbidity of obstructive sleep apnoea (OSA) patients, caused by the interaction of dyslipidaemia and systemic inflammation. The OSA pro-inflammatory response is mediated by NLRP3 inflammasome activation, which requires a priming signal mediated by intermittent hypoxia (IH) and an activation signal provided by soluble stimulus present in plasma. Our objectives were to study oxidised low-density lipoprotein (oxLDL) expression in OSA patients with or without early subclinical atherosclerosis (eSA) as well as its contribution to NLRP3 activation and tissue factor (TF) release.

Methods

We analysed oxLDL, key components of the NLRP3 inflammasome cascade and TF in plasma and monocytes from OSA patients and non-apnoeic subjects, with or without eSA as determined by increased carotid intima–media thickness without the appearance of atherosclerotic plaques. The oxLDL contribution to NLRP3 inflammasome activation was assessed usingin vitromodels.

Results

High levels of oxLDL were identified in plasma from OSA patients, particularly in those with eSA, as well as an overexpression of NLRP3 cascade components and TF. Furthermore,in vitromodels showed that both oxLDL and plasma from OSA patients with eSA act synergistically with IH as a priming and activation signal of NLRP3 that enhances the inflammatory response, pyroptosis and TF release.

Conclusions

OSA patients with eSA exhibit NLRP3 activation by IH and the presence of oxLDL capable of releasing TF, constituting a pathway for the interaction between dyslipidaemia and systemic inflammation in the development of atherosclerotic lesions.
MicroRNA composition of plasma extracellular vesicles: a harbinger of late cardiotoxicity of doxorubicin
Authors: Totoń-Żurańska Justyna , Sulicka-Grodzicka Joanna , Seweryn Michał T. , Pitera Ewelina , Kapusta Przemysław , Konieczny Paweł , Drabik Leszek , Kołton-Wróż Maria , Chyrchel Bernadeta , Nowak Ewelina , Surdacki Andrzej , Grodzicki Tomasz , Wołkow Paweł P.
Published: December 2022

Background

The use of doxorubicin is associated with an increased risk of acute and long-term cardiomyopathy. Despite the constantly growing number of cancer survivors, little is known about the transcriptional mechanisms which progress in the time leading to a severe cardiac outcome. It is also unclear whether long-term transcriptomic alterations related to doxorubicin use are similar to transcriptomic patterns present in patients suffering from other cardiomyopathies.

Methods

We have sequenced miRNA from total plasma and extracellular vesicles (EVs) from 66 acute lymphoblastic leukemia (ALL) survivors and 61 healthy controls (254 samples in total). We then analyzed processes regulated by differentially expressed circulating miRNAs and cross-validated results with the data of patients with clinically manifested cardiomyopathies.

Results

We found that especially miRNAs contained within EVs may be informative in terms of cardiomyopathy development and may regulate pathways related to neurotrophin signaling, transforming growth factor beta (TGFβ) or epidermal growth factor receptors (ErbB). We identified vesicular miR-144-3p and miR-423-3p as the most variable between groups and significantly correlated with echocardiographic parameters and, respectively, for plasma: let-7g-5p and miR-16-2-3p. Moreover, vesicular miR-144-3p correlates with the highest number of echocardiographic parameters and is differentially expressed in the circulation of patients with dilated cardiomyopathy. We also found that distribution of particular miRNAs between of plasma and EVs (proportion between compartments) e.g., miR-184 in ALL, is altered, suggesting changes within secretory and miRNA sorting mechanisms.

Conclusions

Our results show that transcriptomic changes resulting from doxorubicin induced myocardial injury are reflected in circulating miRNA levels and precede development of the late onset cardiomyopathy phenotype. Among miRNAs related to cardiac function, we found vesicular miR-144-3p and miR-423-3p, as well as let-7g-5p and miR-16-2-3p contained in the total plasma. Selection of source for such studies (plasma or EVs) is of critical importance, as distribution of some miRNA between plasma and EVs is altered in ALL survivors, in comparison to healthy people, which suggests that doxorubicin-induced changes include miRNA sorting and export to extracellular space.
Active Compliance Control of a Position-Controlled Industrial Robot for Simulating Space Operations
Authors: He Jun , Shen Mingjin , Gao Feng , Zhang Haibo
Published: December 2022

An industrial robot with a six-axis force/torque sensor is usually used to produce a zero-gravity environment for testing space robotic operations. However, using traditional force control methods, such as admittance control, causes position-controlled industrial robots to undergo from force divergence owing to intrinsic time delay. In this paper, a new force control method is proposed to eliminate the force divergence. A hardware-in-the-loop (HIL) simulator with an industrial robot is first presented. The free-floating satellite dynamics and the motion mapping from the satellites to simulator are both established. Thus, the effects of measurement delay and dynamic response delay on contact velocity and force are investigated. After that, a real-time estimation method for contact stiffness and damping is proposed based on the adaptive Kalman filter. The measurement delay is compensated by a phase lead model. Moreover, the identified contact parameters are adopted to modify contact forces, and thus the dynamics response delay can be compensated for. Finally, a co-simulation and experiments were conducted to verify the force control method. The results show that contact stiffness and damping could be identified exactly and that the simulation divergence could be prevented. This paper proposes an active compliance control method that can deal with force constrained tasks of a position-controlled robot in unknown environments.
Longitudinal changes in functional connectivity and pain-induced brain activations in patients with migraine: a functional MRI study pre- and post- treatment with Erenumab
Authors: Schwedt Todd J. , Nikolova Simona , Dumkrieger Gina , Li Jing , Wu Teresa , Chong Catherine D.
Published: December 2022

Background

Migraine involves central and peripheral nervous system mechanisms. Erenumab, an anti-calcitonin gene-related peptide (CGRP) receptor monoclonal antibody with little central nervous system penetrance, is effective for migraine prevention. The objective of this study was to determine if response to erenumab is associated with alterations in brain functional connectivity and pain-induced brain activations.

Methods

Adults with 6–25 migraine days per month during a 4-week headache diary run-in phase underwent pre-treatment brain functional MRI (fMRI) that included resting-state functional connectivity and BOLD measurements in response to moderately painful heat stimulation to the forearm. This was followed by two treatments with 140 mg erenumab, at baseline and 4 weeks later. Post-treatment fMRI was performed 2 weeks and 8 weeks following the first erenumab treatment. A longitudinal Sandwich estimator analysis was used to identify pre- to post-treatment changes in resting-state functional connectivity and brain activations in response to thermal pain. fMRI findings were compared between erenumab treatment-responders vs. erenumab non-responders.

Results

Pre- and post-treatment longitudinal imaging data were available from 32 participants. Average age was 40.3 (+/− 13) years and 29 were female. Pre-treatment average migraine day frequency was 13.8 (+/− 4.7) / 28 days and average headache day frequency was 15.8 (+/− 4.4) / 28 days. Eighteen of 32 (56%) were erenumab responders. Compared to erenumab non-responders, erenumab responders had post-treatment differences in 1) network functional connectivity amongst pain-processing regions, including higher global efficiency, clustering coefficient, node degree, regional efficiency, and modularity, 2) region-to-region functional connectivity between several regions including temporal pole, supramarginal gyrus, and hypothalamus, and 3) pain-induced activations in the middle cingulate, posterior cingulate, and periaqueductal gray matter.

Conclusions

Reductions in migraine day frequency accompanying erenumab treatment are associated with changes in resting state functional connectivity and central processing of extracranial painful stimuli that differ from erenumab non-responders.

Trial registration

clinicaltrials.gov
(NCT03773562).
Appropriateness of drug prescriptions in patients with chronic kidney disease in primary care: a double-center retrospective study
Authors: Ruiz-Boy Sonia , Rodriguez-Reyes Montserrat , Clos-Soldevila Joan , Rovira-Illamola Marina
Published: December 2022

Background

Chronic kidney disease (CKD) is a highly prevalent disease worldwide. A basic pillar for the management of a patient with CKD is the safe use of drugs. Inadequate dosing of medication or contraindicated drugs in renal impairment can lead to negative outcomes. The primary objective was to analyse the drug prescriptions of patients with CKD from two primary care centres to see if they were optimally adapted to the patient's estimated glomerular filtration rate (eGFR).

Methods

A retrospective observational study was conducted in two urban primary care centres. The study period was between September–October 2019. Patients over 18 years of age, with established CKD and with an eGFR less than 60 mL/min/1.73m2 for at least three months were included. Their demographic data (age and sex) and clinical variables such as associated comorbidities, eGFR value were retrospectively registered. Finally, their medication plans were reviewed in order to detect: inappropriate prescribing (IP), defined as an incorrect dose/frequency or contraindicated drug according to the renal function of the patient; nephrotoxic drugs and drugs with a high sodium content.

Results

A total of 273 patients were included. The most common patient profile was an elderly woman, polymedicated, with other concomitant diseases and with mild CKD. Two hundred and one IPs were detected, 13.9% of which were contraindicated drugs. Of all patients, 49.1% had been prescribed at least one IP on their medication plan, 93.8% had some potentially nephrotoxic drug and 8.4% had drugs with a high sodium content prescribed.

Conclusions

Patients with CKD are at increased risk of medication-related problems. It is necessary to implement measures to improve the safety in the prescription of drugs in patients with CKD.
Identifying airway obstruction in primary care: is there a role for physiotherapists?
Authors: Pagano Lisa , Dennis Sarah , Wootton Sally , Mahadev Sriram , Chan Andrew S. L. , Zwar Nicholas , Pallavicini Deborah , McKeough Zoe
Published: December 2022

Aims

To examine the implementation of a physiotherapist-driven spirometry case finding service in primary care to identify new cases of COPD and confirm diagnosis of existing cases of COPD.

Methods

Four general practices were recruited. ‘At risk’ participants (aged ≥ 40 years, current/ex-smoker) and people with ‘existing’ COPD were identified from practice databases and invited to attend an assessment with a cardiorespiratory physiotherapist in each general practice. The physiotherapist performed pre/post-bronchodilator spirometry to identify or confirm a diagnosis of COPD (FEV1/FVC < 0.7). Outcome measures included number (%) of new cases of COPD, number (%) confirmed diagnosis of COPD and number (%) of high quality spirometry assessments with accurate interpretation.

Results

One hundred forty eight participants (mean age 70 years (SD 11.1), 57% female) attended a baseline assessment (117 ‘at risk’, 31’existing’ COPD) from 748 people invited. Physiotherapists performed 145 pre/post bronchodilator spirometry assessments. Obstruction on post-bronchodilator spirometry was confirmed in 17% (19/114) of ‘at risk’ and 77% (24/31) of ‘existing’ COPD. Majority of cases were classified as GOLD Stage II (63%, n = 27). Quality of pre/post bronchodilator spirometries for FEV1 were classified as A (68%), B (19%) and C (5%).

Conclusion

Physiotherapists integrated into primary care performed high quality spirometry testing, successfully case finding ‘at risk’ patients and identifying potential misdiagnosis of obstruction in some ‘existing’ COPD cases.

Trial registration

ANZCTR, ACTRN12619001127190. Registered 12 August 2019 – Retrospectively registered, http://www.ANZCTR.org.au/ACTRN12619001127190.aspx
Diagnostic performance of fecal Helicobacter pylori antigen test in Uganda
Authors: Owot Jacob Canwat , Tuhumwire Caleb , Tumuhimbise Christine , Tusiime Florence , Emmanuel Byaruhanga , Lumori Boniface A. E. , Okello Samson
Published: December 2022

We evaluated the diagnostic performance of a qualitative stool antigen test (SAT) in individuals with dyspepsia in rural Uganda using the polymerase chain reaction-based 16S ribosomal RNA assay (16S rRNA) for nucleotide sequences for two common H. pylori-associated genes as the reference standard. We enrolled 150 adults with dyspepsia with no self-reported use of antibiotic and/or antiacid medication medications within a fortnight. We performed blinded SAT on fecal specimens and 16S rRNA tests on gastric specimens. Using nonlinear mixed models, SAT had a sensitivity of 85⋅1% (95%CI 76⋅54%, 93⋅6%), and specificity of 97⋅6% (95%CI 94⋅3, 100). Twelve individuals with dyspepsia need to be tested to correctly diagnose 10 with H. pylori infection using SAT. The SAT is a robust diagnostic test to improve the diagnosis of H. pylori infection in people with dyspepsia in resource-limited settings.
Impact of atherosclerosis on the postoperative complications of colorectal surgery in older patients with colorectal cancer
Authors: Gunji Takahiro , Tomita Koichi , Koganezawa Itsuki , Nakagawa Masashi , Yokozuka Kei , Ochiai Shigeto , Kobayashi Toshimichi , Sano Toru , Tabuchi Satoshi , Chiba Naokazu , Hidaka Eiji , Kawachi Shigeyuki
Published: December 2022

Background

Atherosclerosis is associated with various comorbidities; nonetheless, its effect on the postoperative complications of colorectal surgery in older patients with colorectal cancer (CRC) remains unclear. This study aimed to evaluate the impact of atherosclerosis on the postoperative complications of colorectal surgery in older adults with CRC.

Methods

Patients aged ≥ 65 years who underwent surgery for CRC between April 2017 and October 2020 were enrolled. To evaluate atherosclerosis, we prospectively calculated the cardio-ankle vascular index (CAVI) measured by the blood pressure/pulse wave test and abdominal aortic calcification (AAC) score from computed tomography. Risk factors for Clavien–Dindo grade ≥ III postoperative complications were evaluated by univariate and logistic regression analyses.

Results

Overall, 124 patients were included. The mean CAVI value and AAC score were 9.5 ± 1.8 and 7.0 ± 8.0, respectively. Clavien–Dindo grade ≥ III postoperative complications were observed in 14 patients (11.3%). CAVI (odds ratio, 1.522 [95% confidence interval, 1.073–2.160], p = 0.019), AAC score (1.083 [1.009–1.163], p = 0.026); and operative time (1.007 [1.003–1.012], p = 0.001) were identified as risk factors for postoperative complications. Based on the optimal cut-off values of CAVI and AAC score, the probability of postoperative complications was 27.8% in patients with abnormal values for both parameters, which was 17.4 times higher than the 1.6% probability of postoperative complications in patients with normal values.

Conclusions

Atherosclerosis, particularly that assessed using CAVI and AAC score, could be a significant predictor of postoperative complications of colorectal surgery in older adults with CRC.
Comparison of two different types of hybrid Tibial fixations for anterior cruciate ligament reconstruction: a prospective comparative cohort study
Authors: Lai Po-Jen , Wong Chin-Chean , Chang Wen-Pei , Liaw Chen-Kun , Chen Chih-Hwa , Weng Pei-Wei
Published: December 2022

Background

Previous studies have compared different kinds of fixations for anterior cruciate ligament reconstruction. Nevertheless, there is no optimal method to date. To the best of authors’ knowledge, there is no article discussing the combination of adjustable suspensory device and interference screw for hybrid tibial fixation.

Methods

In total, 66 patients (n = 34, adjustable suspensory device and interference screw; n = 32, cortical screw and interference screw) were analyzed. Their International Knee Documentation Committee score and Tegner activity level scale were evaluated before and after a 2-year follow-up. The Single Assessment Numeric Evaluation score was evaluated after a 2-year follow-up. Physical exams such as range of motion, anterior knee pain (VAS > = 3) and Lachman test were assessed before and at least 12 months after surgery. To evaluate tunnel widening, anteroposterior and lateral view radiography was conducted 1 day and at least 12 months after surgery. A more than 10% change was considered tibial tunnel widening. Mann–Whitney U test, independent t test, paired t test, Fisher’s exact test and chi-squared test were used to compare the variables. Linear and logistic regression models were applied to adjust for potential confounders.

Results

No variable except gender (P = 0.006) showed significant difference with regard to demographic data. After adjustment, there was no statistically significant difference between the groups regarding post-operative physical exams. Patients who used adjustable suspensory device and interference screw had lower post-operative Single Assessment Numeric Evaluation score (adjusted β − 8.194; P = 0.017), Tegner activity level scale (adjusted β − 1.295; P = 0.001) and pre-operative degrees of knee flexion (adjusted β − 2.825; P = 0.026). Less percentage of tunnel widening in the lateral view of radiographs was seen in patients in group of adjustable suspensory device and interference screw (adjusted β − 1.733; P = 0.038). No significant difference was observed in the anteroposterior view of radiographs (adjusted β − 0.667; P = 0.26).

Conclusion

In these 66 patients, we observed less tibial tunnel widening and lower post-operative functional scores in the group of adjustable suspensory device and interference screw. Both groups displayed similar outcomes of physical exams as well as improvement after operation. The proposed method may become an alternative option. Nonetheless, the quality of our study is still limited, and thus further studies are warranted to determine the efficacy and further application.

Trial registration

Joint Institutional Review Board of Taipei Medical University, Taipei, Taiwan (No: N201805094).

Study design

Prospective comparative cohort study; Level of evidence, II.
Combination of IL-17A/F and TNF-α uniquely alters the bronchial epithelial cell proteome to enhance proteins that augment neutrophil migration
Authors: Altieri Anthony , Piyadasa Hadeesha , Hemshekhar Mahadevappa , Osawa Natasha , Recksiedler Breann , Spicer Victor , Hiemstra Pieter S , Halayko Andrew J , Mookherjee Neeloffer
Published: December 2022

Background

The heterodimer interleukin (IL)-17A/F is elevated in the lungs in chronic respiratory disease such as severe asthma, along with the pro-inflammatory cytokine tumor necrosis factor-α (TNF-α). Although IL-17A/F and TNF-α are known to functionally cooperate to exacerbate airway inflammation, proteins altered by their interaction in the lungs are not fully elucidated.

Results

We used Slow Off-rate Modified Aptamer-based proteomic array to identify proteins that are uniquely and/or synergistically enhanced by concurrent stimulation with IL-17A/F and TNF-α in human bronchial epithelial cells (HBEC). The abundance of 38 proteins was significantly enhanced by the combination of IL-17A/F and TNF-α, compared to either cytokine alone. Four out of seven proteins that were increased > 2-fold were those that promote neutrophil migration; host defence peptides (HDP; Lipocalin-2 (LCN-2) and Elafin) and chemokines (IL-8, GROα). We independently confirmed the synergistic increase of these four proteins by western blots and ELISA. We also functionally confirmed that factors secreted by HBEC stimulated with the combination of IL-17A/F and TNF-α uniquely enhances neutrophil migration. We further showed that PI3K and PKC pathways selectively control IL-17A/F + TNF-α-mediated synergistic production of HDPs LCN-2 and Elafin, but not chemokines IL-8 and GROα. Using a murine model of airway inflammation, we demonstrated enhancement of IL-17A/F, TNF-α, LCN-2 and neutrophil chemokine KC in the lungs, thus corroborating our findings in-vivo.

Conclusion

This study identifies proteins and signaling mediated by concurrent IL-17A/F and TNF-α exposure in the lungs, relevant to respiratory diseases characterized by chronic inflammation, especially neutrophilic airway inflammation such as severe asthma.
TMT-based quantitative proteomics analysis of the effects of Jiawei Danshen decoction myocardial ischemia-reperfusion injury
Authors: Zhu Xiang-Mei , Tan Yang , Shi Yu-He , Li Qing , Zhu Jue , Liu Xiang-Dan , Tong Qiao-Zhen
Published: December 2022

Background

Every year, approximately 17 million people worldwide die due to coronary heart disease, with China ranking second in terms of the death toll. Myocardial ischemia-reperfusion injury (MIRI) significantly influences cardiac function and prognosis in cardiac surgery patients. Jiawei Danshen Decoction (JWDSD) is a traditional Chinese herbal prescription that has been used clinically for many years in China to treat MIRI. The underlying molecular mechanisms, however, remain unknown. To investigate the proteomic changes in myocardial tissue of rats given JWDSD for MIRI therapy-based proteomics.

Methods

MIRI rat model was created by ligating/releasing the left anterior descending coronary artery. For seven days, the drugs were administered twice daily. The model was created following the last drug administration. JWDSD's efficacy in improving MIRI was evaluated using biochemical markers and cardiac histology. Tandem mass tag-based quantitative proteomics (TMT) technology was also used to detect proteins in the extracted heart tissue. To analyze differentially expressed proteins (DEPs), bioinformatics analysis, including gene ontology (GO) and Kyoto encyclopedia of genes and genomes (KEGG) pathways, were employed. Furthermore, western blotting confirmed the potential targets regulated by JWDSD.

Results

The histopathologic characteristics and biochemical data showed JWDSD's protective effects on MIRI rats. A total of 4549 proteins were identified with FDR (false discovery rate) ≤1%. Twenty overlapping were identified (162 DEPs and 45 DEPs in Model/Control or JWDSD/Model group, respectively). Of these DEPs, 16 were regulated by JWDSD. GO analysis provided a summary of the deregulated protein expression in the categories of biological process (BP), cell component (CC), and molecular function (MF). KEGG enrichment analysis revealed that the signaling pathways of neutrophil extracellular trap formation, RNA polymerase, serotonergic synapse, and linoleic acid metabolism are all closely related to JWDSD effects in MIRI rats. Furthermore, T-cell lymphoma invasion and metastasis 1 (TIAM1) was validated using western blotting, and the results were consistent with proteomics data.

Conclusions

Our study suggests that JWDSD may exert therapeutic effects through multi-pathways regulation in MIRI treatment. This work may provide proteomics clues for continuing research on JWDSD in treating MIRI.
Exploring substance use disorder discussions in Native American communities: a retrospective Twitter infodemiology study
Authors: Calac Alec J. , McMann Tiana , Cai Mingxiang , Li Jiawei , Cuomo Raphael , Mackey Tim K.
Published: December 2022

Background

The opioid epidemic has had a devastating impact on youth from American Indian and Alaska Native (AI/AN) Tribes and Villages, which also experience disparate suicide rates. The use of publicly available social media data originating from AI/AN communities may enhance public health response time to substance use disorder (SUD)-related overdose and augment Tribal public health surveillance systems, but these concepts have yet to be adequately explored. The goal of this exploratory analysis was to identify primary and secondary accounts of overdose and characterize relevant contextual factors in the AI/AN population on social media.

Methods

The Twitter application programming interface was queried for all Tweets containing geocoded data between March 2014 and June 2020 and filtered for the keyword [‘overdose’]. This sample of Tweets (n = 146,236) was then restricted to those geolocated from US Tribal lands (n = 619). Tweets were manually annotated for primary or secondary accounts of overdose as well as suicidal ideation, substance(s) used, stigma of drug use, and community-wide incidents.

Results

We collected a total of 146,235 tweets that were geocoded and contained the word ‘overdose,’ of which 9.5% were posted on Tribal lands (n = 619). 9.4% of these tweets (n = 58) met our study inclusion criteria and were mainly posted from Oklahoma (n = 26, 45%) and North Carolina (n = 13, 22.4%). Most Tweets (n = 41, 71%) described a primary account of an overdose and were mostly posted from 2014 to 2015. Less than half of the Tweets (n = 27, 46.5%) referenced a specific substance. Those substances mentioned included alcohol, marijuana, methamphetamine, heroin, laundry softener, cocaine, K2-Spice (synthetic cannabinoid), codeine, morphine, Nyquil, and Xanax.

Discussion

Though exploratory, our study identified SUD-related content self-reported by AI/AN communities on Twitter, especially in Oklahoma and North Carolina. These results may assist in the future design and detection of infodemiology trends and early warning signs that can better facilitate intervention specific to the ongoing Tribal opioid epidemic. While all data were collected from the public domain, additional care should be given to individual and community privacy.
Offering a lifestyle intervention to women of premenopausal age as primary prevention for cardiovascular disease? – assessing its cost-effectiveness
Authors: Gao Lan , Moodie Marj
Published: December 2022

Background

There is limited evidence of cost-effective primary prevention interventions for cardiovascular disease (CVD) in young women. This study aimed to assess the value for money of primary prevention of CVD in this population.

Methods

A Markov microsimulation model consisting of both first-ever and recurrent CVD events was developed to simulate the lifetime intervention impact on cost and health outcomes in women of premenopausal age (30 to 54 years) from the Australian healthcare system perspective. The latest wave of the Australian National Health Survey defined the modelled population’s characteristics. The intervention effectiveness of a lifestyle modification program involving changes in diet and physical activity demonstrated to be effective in this population was sourced from a systematic review and meta-analysis. The first-ever and recurrent CVD probabilities were derived from the CVD risk calculators accounting for socio-demographic and clinical characteristics. Costs and utility weights associated with CVD events and long-term management post-CVD were informed by national statistics/published literature. Sensitivity analyses were undertaken to examine the robustness of base case results.

Results

The lifestyle modification program was associated with both higher costs and benefits (in terms of quality-adjusted life years, QALYs) as a primary prevention measure of CVD in premenopausal women, with an ICER of $96,377/QALY or $130,469/LY. The intervention led to fewer first-ever (N = −19) and recurrent CVD events (N = -23) per 10,000 women over the modelled life horizon. The avoided cost due to reduced hospitalisations (−$24) and management (−$164) of CVD could partially offset the cost associated with the intervention ($1560). Sensitivity analysis indicated that time horizon, starting age of the intervention, discount rate, and intervention effectiveness were the key drivers of the results. If the intervention was scaled up to the national level (N = 502,095 at-risk premenopausal women), the total intervention cost would be $794 million with $95 million in healthcare cost-savings.

Conclusion

Offering a lifestyle modification program to premenopausal women in Australia as primary prevention of CVD is not cost-effective from a healthcare system perspective. We should continue to search for new or adapt/optimise existing effective and cost-effective primary prevention measures of CVD for women.
Multi-scale pathology image texture signature is a prognostic factor for resectable lung adenocarcinoma: a multi-center, retrospective study
Authors: Wang Yumeng , Pan Xipeng , Lin Huan , Han Chu , An Yajun , Qiu Bingjiang , Feng Zhengyun , Huang Xiaomei , Xu Zeyan , Shi Zhenwei , Chen Xin , Li Bingbing , Yan Lixu , Lu Cheng , Li Zhenhui , Cui Yanfen , Liu Zaiyi , Liu Zhenbing
Published: December 2022

Background

Tumor histomorphology analysis plays a crucial role in predicting the prognosis of resectable lung adenocarcinoma (LUAD). Computer-extracted image texture features have been previously shown to be correlated with outcome. However, a comprehensive, quantitative, and interpretable predictor remains to be developed.

Methods

In this multi-center study, we included patients with resectable LUAD from four independent cohorts. An automated pipeline was designed for extracting texture features from the tumor region in hematoxylin and eosin (H&E)-stained whole slide images (WSIs) at multiple magnifications. A multi-scale pathology image texture signature (MPIS) was constructed with the discriminative texture features in terms of overall survival (OS) selected by the LASSO method. The prognostic value of MPIS for OS was evaluated through univariable and multivariable analysis in the discovery set (n = 111) and the three external validation sets (V1, n = 115; V2, n = 116; and V3, n = 246). We constructed a Cox proportional hazards model incorporating clinicopathological variables and MPIS to assess whether MPIS could improve prognostic stratification. We also performed histo-genomics analysis to explore the associations between texture features and biological pathways.

Results

A set of eight texture features was selected to construct MPIS. In multivariable analysis, a higher MPIS was associated with significantly worse OS in the discovery set (HR 5.32, 95%CI 1.72–16.44; P = 0.0037) and the three external validation sets (V1: HR 2.63, 95%CI 1.10–6.29, P = 0.0292; V2: HR 2.99, 95%CI 1.34–6.66, P = 0.0075; V3: HR 1.93, 95%CI 1.15–3.23, P = 0.0125). The model that integrated clinicopathological variables and MPIS had better discrimination for OS compared to the clinicopathological variables-based model in the discovery set (C-index, 0.837 vs. 0.798) and the three external validation sets (V1: 0.704 vs. 0.679; V2: 0.728 vs. 0.666; V3: 0.696 vs. 0.669). Furthermore, the identified texture features were associated with biological pathways, such as cytokine activity, structural constituent of cytoskeleton, and extracellular matrix structural constituent.

Conclusions

MPIS was an independent prognostic biomarker that was robust and interpretable. Integration of MPIS with clinicopathological variables improved prognostic stratification in resectable LUAD and might help enhance the quality of individualized postoperative care.
Naturally selected CD7 CAR-T therapy without genetic editing demonstrates significant antitumour efficacy against relapsed and refractory acute myeloid leukaemia (R/R-AML)
Authors: Lu Yu , Liu Ying , Wen Shupeng , Kuang Na , Zhang Xuejun , Li Jianqiang , Wang Fuxu
Published: December 2022

Background

The survival rate for patients with relapsed and refractory acute myeloid leukaemia (R/R-AML) remains poor, and treatment is challenging. Chimeric antigen receptor T cells (CAR-T cells) have been widely used for haematologic malignancies. Current CAR-T therapies for acute myeloid leukaemia mostly target myeloid-lineage antigens, such as CD123 and CD33, which may be associated with potential haematopoietic toxicity. As a lineage-specific receptor, CD7 is expressed in acute myeloid leukaemia cells and T cells but is not expressed in myeloid cells. Therefore, the use of CD7 CAR-T cells for R/R-AML needs to be further explored.

Methods

In this report, immunohistochemistry and flow cytometry were used to analyse CD7 expression in clinical samples from R/R-AML patients and healthy donors (HDs). We designed naturally selected CD7 CAR-T cells to analyse various functions and in vitro antileukaemic efficacy based on flow cytometry, and xenograft models were used to validate in vivo tumour dynamics.

Results

We calculated the percentage of cells with CD7 expression in R/R-AML patients with minimal residual disease (MRD) (5/16, 31.25%) from our institution and assessed CD7 expression in myeloid and lymphoid lineage cells of R/R-AML patients, concluding that CD7 is expressed in T cells but not in myeloid cells. Subsequently, we designed and constructed naturally selected CD7 CAR-T cells (CD7 CAR). We did not perform CD7 antigen knockdown on CD7 CAR-T cells because CD7 molecule expression is naturally eliminated at Day 12 post transduction. We then evaluated the ability to target and kill CD7+acute myeloid leukaemia cells in vitro and in vivo. Naturally selected CD7 CAR-T cells efficiently killed CD7+acute myeloid leukaemia cells and CD7+primary blasts of R/R-AML patients in vitro and significantly inhibited leukaemia cell growth in a xenograft mouse model.

Conclusion

Naturally selected CD7 CAR-T cells represent an effective treatment strategy for relapsed and refractory acute myeloid leukaemia patients in preclinical studies.
The prebiotic effects of soluble dietary fiber mixture on renal anemia and the gut microbiota in end-stage renal disease patients on maintenance hemodialysis: a prospective, randomized, placebo-controlled study
Authors: Li Yang , Han Min , Song Jia , Liu Shijin , Wang Yongjun , Su Xinhuan , Wei Kai , Xu Zhen , Li Hui , Wang Zunsong
Published: December 2022

Background

Renal anemia is caused by end-stage renal disease (ESRD) but has a complex etiology. The application of dietary fiber (DF) to regulate the gut microbiota has shown effective therapeutic effects in some diseases, but its role in renal anemia is not clear. The aim of this study was to explore the effect of DF on renal anemia by regulating the gut microbiota and its metabolite, short-chain fatty acids (SCFAs).

Methods

A total of 162 ESRD patients were enrolled and randomly distributed into a DF or a control group (received oral DF or potato starch, 10 g/day for 8 weeks). Hemoglobin (Hb), serum iron (Fe2+), serum ferritin (SF), soluble transferrin receptor (sTfR), hepcidin and the dosage of recombinant human erythropoietin (rhEPO) before and after intervention in patients were analyzed. The gut microbiota and SCFAs in both groups were analyzed by 16S rDNA sequencing and gas chromatography–mass spectrometry, respectively. Spearman’s correlation test was used to analyze the correlation between the gut microbiota, SCFAs and the hematological indicators.

Results

Compared with the control group, (1) the patients in the DF group had higher Hb [117.0 (12.5) g/L vs. 94.0 (14.5) g/L, p < 0.001], Fe2+ [13.23 (4.83) μmol/L vs. 10.26 (5.55) μmol/L, p < 0.001], and SF levels [54.15 (86.66) ng/ml vs. 41.48 (36.60) ng/ml, p = 0.003]. (2) The rhEPO dosage in the DF group was not significantly decreased (p = 0.12). (3) Bifidobacterium adolescentis, Lactobacillus and Lactobacillaceae were increased in the DF group, and Lactobacillus and Lactobacillaceae were positively correlated with Hb (r = 0.44, p < 0.001; r = 0.44, p < 0.001) and Fe2+ levels (r = 0.26, p = 0.016; r = 0.26, p = 0.016) and negatively correlated with rhEPO dosage (r = − 0.45, p < 0.001; r = − 0.45, p < 0.001). (4) Patients in the DF group had elevated serum butyric acid (BA) levels [0.80 (1.65) vs. 0.05 (0.04), p < 0.001] and BA levels were positively correlated with Hb (r = 0.26, p = 0.019) and Fe2+ (r = 0.31, p = 0.005) and negatively correlated with rhEPO dosage (r = − 0.36, p = 0.001). Lactobacillus and Lactobacillaceae were positively correlated with BA levels (r = 0.78, p < 0.001; r = 0.78, p < 0.001).

Conclusion

DF may improve renal anemia in ESRD patients by regulating the gut microbiota and SCFAs.

Trial registration This study was registered in the China Clinical Trial Registry (www.chictr.org.cn) on December 20, 2018 (ChiCTR1800020232).
Genetic risk factors for ME/CFS identified using combinatorial analysis
Authors: Das Sayoni , Taylor Krystyna , Kozubek James , Sardell Jason , Gardner Steve
Published: December 2022

Background

Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a debilitating chronic disease that lacks known pathogenesis, distinctive diagnostic criteria, and effective treatment options. Understanding the genetic (and other) risk factors associated with the disease would begin to help to alleviate some of these issues for patients.

Methods

We applied both GWAS and the PrecisionLife combinatorial analytics platform to analyze ME/CFS cohorts from UK Biobank, including the Pain Questionnaire cohort, in a case–control design with 1000 cycles of fully random permutation. Results from this study were supported by a series of replication and cohort comparison experiments, including use of disjoint Verbal Interview CFS, post-viral fatigue syndrome and fibromyalgia cohorts also derived from UK Biobank, and compared results for overlap and reproducibility.

Results

Combinatorial analysis revealed 199 SNPs mapping to 14 genes that were significantly associated with 91% of the cases in the ME/CFS population. These SNPs were found to stratify by shared cases into 15 clusters (communities) made up of 84 high-order combinations of between 3 and 5 SNPs.p-values for these communities range from 2.3 × 10–10to 1.6 × 10–72. Many of the genes identified are linked to the key cellular mechanisms hypothesized to underpin ME/CFS, including vulnerabilities to stress and/or infection, mitochondrial dysfunction, sleep disturbance and autoimmune development. We identified 3 of the critical SNPs replicated in the post-viral fatigue syndrome cohort and 2 SNPs replicated in the fibromyalgia cohort. We also noted similarities with genes associated with multiple sclerosis and long COVID, which share some symptoms and potentially a viral infection trigger with ME/CFS.

Conclusions

This study provides the first detailed genetic insights into the pathophysiological mechanisms underpinning ME/CFS and offers new approaches for better diagnosis and treatment of patients.
Sirtuin 5 aggravates microglia-induced neuroinflammation following ischaemic stroke by modulating the desuccinylation of Annexin-A1
Authors: Xia Qian , Gao Shuai , Han Tangrui , Mao Meng , Zhan Gaofeng , Wang Yonghong , Li Xing
Published: December 2022

Background

Microglia-induced excessive neuroinflammation plays a crucial role in the pathophysiology of multiple neurological diseases, such as ischaemic stroke. Controlling inflammatory responses is considered a promising therapeutic approach. Sirtuin 5 (SIRT5) mediates lysine desuccinylation, which is involved in various critical biological processes, but its role in ischaemic stroke remains poorly understood. This research systematically explored the function and potential mechanism of SIRT5 in microglia-induced neuroinflammation in ischaemic stroke.

Methods

Mice subjected to middle cerebral artery occlusion were established as the animal model, and primary cultured microglia treated with oxygen–glucose deprivation and reperfusion were established as the cell model of ischaemic stroke. SIRT5 short hairpin RNA, adenovirus and adeno-associated virus techniques were employed to modulate SIRT5 expression in microglia both in vitro and in vivo. Coimmunoprecipitation, western blot and quantitative real-time PCR assays were performed to reveal the molecular mechanism.

Results

In the current study, we showed that SIRT5 expression in microglia was increased in the early phase of ischaemic stroke. SIRT5 interacts with and desuccinylates Annexin A1 (ANXA1) at K166, which in turn decreases its SUMOylation level. Notably, the desuccinylation of ANXA1 blocks its membrane recruitment and extracellular secretion, resulting in the hyperactivation of microglia and excessive expression of proinflammatory cytokines and chemokines, ultimately leading to neuronal cell damage after ischaemic stroke. Further investigation showed that microglia-specific forced overexpression of SIRT5 worsened ischaemic brain injury, whereas downregulation of SIRT5 exhibited neuroprotective and cognitive-preserving effects against ischaemic brain injury, as proven by the decreased infarct area, reduced neurological deficit scores, and improved cognitive function.

Conclusions

Collectively, these data identify SIRT5 as a novel regulator of microglia-induced neuroinflammation and neuronal damage after cerebral ischaemia. Interventions targeting SIRT5 expression may represent a potential therapeutic target for ischaemic stroke.