bluuebunny/crossref_metadata_2025_split huggingface dataset:
Subcutaneous versus intravenous infliximab therapy – a real-world study: toward higher drug concentrations
Authors: Ferreira Ana Isabel , Lima Capela Tiago , Arieira Cátia , Xavier Sofia , Cotter José 
Published: August 2024

Background
Recently, a formula of subcutaneous infliximab (SC-IFX) has been approved for inflammatory bowel disease (IBD), demonstrating a better pharmacokinetic and immunogenic profiles, compared to intravenous infliximab (IV-IFX), with similar efficacy and safety.

Aim
The aim of this study is to evaluate the clinical, biochemical, and pharmacological outcomes of IBD patients in clinical remission, who switched from IV-IFX to SC-IFX, with a follow-up period of 6 months.

Methods
Retrospective cohort study, including IBD patients in clinical remission, previously medicated with IV-IFX, who switched to SC-IFX 120 mg every other week. Biochemical parameters were evaluated before the switch and 6 months after, namely infliximab serum concentrations, erythrocyte sedimentation rate (ESR), C-reactive protein (CRP), and fecal calprotectin.

Results
Included 41 patients in clinical remission, 32 with Crohn’s disease (78.0%) and 9 with ulcerative colitis (22.0%). All patients maintained clinical remission during the 6 months after the switch, with a treatment persistence rate of 100%, and no patients requiring corticosteroid therapy, switching back to IV-IFX, or IBD-related hospitalization. The mean infliximab serum concentrations were significantly higher after 6 months of SC-IFX (17.3 ± 6.6 vs. 9.1 ± 5.5 µg/ml, P < 0.001). However, there were no differences between values of ESR, CRP, and fecal calprotectin, before and after the switch (P = 0.791, P = 0.246, and P = 0.639). Additionally, none of the patients developed antibodies to infliximab.

Conclusion
Switching from IV-IFX to SC-IFX in IBD patients in clinical remission is effective and leads to higher infliximab serum concentrations, regardless of the combination with immunomodulatory therapy.
Comparative Evaluation Between Cutting of the Intersphincteric Space vs Cutting Seton in High Anal Fistula: A Randomized Controlled Trial
Authors: Qin Jiawei , Wu Yanlan , Zheng Xueping , Wu Kunlan , Dai Gongjian , Tan Yanyan , Yang Xu , Sun Yuqing 
Published: August 2024

BACKGROUND:
This study compared the efficacy of cutting of the intersphincteric space (COIS) with cutting seton (CS) procedure in treating high anal fistula.

STUDY DESIGN:
Patients diagnosed with high anal fistula were allocated into groups, who randomly received COIS and CS procedures. The primary outcome was wound healing time. Secondary outcomes included surgical parameters (operation time, hospital stay, and hospitalization expense), anal sphincter function, wound pain, wound size, clinical efficacy, recurrence after 12 months of follow-up, and complications.

RESULTS:
A total of 72 patients participated (36 in each group). The wound healing time was notably shorter in the COIS group than that in the CS group (35.75 ± 11.15 vs 55.69 ± 13. 42 days; p < 0.001). The COIS group also demonstrated superior basic surgical parameters compared with the CS group (p < 0.001). Postoperatively, the COIS group exhibited significantly higher anal resting pressure and anal maximum contractile pressure than the CS group at 3 months postoperatively (58.39 ± 6.72 vs 51.25 ± 4.33 mmHg; p < 0.001 and 143.72 ± 8.25 vs 126.75 ± 11.49 mmHg; p < 0.001). The Wexner incontinence score at 3 months postoperation in the COIS group was significantly lower than in the CS group (0.50; 0.00, 1.00 vs 3.00; 3.00, 4.00; p < 0.001). The recurrence rate was 2.78% in the COIS group and 8.33% in the CS group without statistically difference (p = 0.607).

CONCLUSIONS:
In comparison to the CS procedure, COIS appears to be an effective treatment option for high anal fistulas, offering quicker wound healing time, enhanced sphincter function, less pain, minimal invasiveness, and cost-efficiency while maintaining a high healing rate and low recurrence rate.
Distribution of paramagnetic and diamagnetic cortical substrates following mild Traumatic Brain Injury: A depth- and curvature-based quantitative susceptibility mapping study
Authors: Essex Christi A. , Merenstein Jenna L. , Overson Devon K. , Truong Trong-Kha , Madden David J. , Bedggood Mayan J. , Murray Helen , Holdsworth Samantha J. , Stewart Ashley W. , Morgan Catherine , Faull Richard L. M. , Hume Patria , Theadom Alice , Pedersen Mangor 
Published: August 2024

ABSTRACTEvidence has linked head trauma to increased risk factors for neuropathology, including acute mechanical deformation of the cortical sulcal fundus and, later, perivascular accumulation of hyperphosphorylated tau (p-tau) adjacent to these spaces related to chronic traumatic encephalopathy (CTE). Despite this, little is known about microstructural abnormalities and cellular dyshomeostasis at the acute stage of mild traumatic brain injury (mTBI) in humans, particularly in the cortex. To address this gap in the literature, we designed the first architectonically-motivated quantitative susceptibility mapping (QSM) study to assess regional patterns of positive (iron-related) and negative (myelin-, calcium-, and protein-related) magnetic susceptibility in cortical regions of interest (ROI) following mTBI. Depth- and curvature-specific positive and negative QSM values were compared between 25 males with acute (< 14 days) sports-related mTBI (sr-mTBI) and 25 age-matched male controls across 34 cortical ROIs. Bilateral between-group analyses were conducted on specific ROI curvature bins (crown, bank, and fundus) as well as a combined curvature measure, across 21 cortical depths, for each ROI. Correlations between positive and negative susceptibility were analysed for age, brain injury severity, and the number of days since injury. We observed significant group differences in magnetic susceptibility for depth, curvature, and ROIs. Our results suggest a trauma-induced pattern of likely iron deposition preferential to superficial, perivascular-adjacent spaces in the sulci of the parahip-pocampal gyrus. Co-localised decreases in diamagnetism in the same region suggest dual pathology of neural substrates, the biological mechanisms behind which remain speculative. Significant correlations were found between magnetic susceptibility and age, both in ROIs and cortical depths distinct from those showing sr-mTBI-related differences. Little to no relationship was observed between magnetic susceptibility and subjective markers of injury or injury latency. The coherence between our findings and pathognomonic patterns of misfolded proteins in trauma-related neurodegeneration is interesting, which may have implications for the role of brain iron in microstructural cortical tissue damage after a mild brain injury. Further longitudinal research is needed to elucidate the long-term implications of our findings.
Discovery of potent SARS-CoV-2 nsp3 macrodomain inhibitors uncovers lack of translation to cellular antiviral response
Authors: Lee Alpha A. , Amick Isabelle , Aschenbrenner Jasmin C. , Barr Haim M. , Benjamin Jared , Brandis Alexander , Cohen Galit , Diaz-Tapia Randy , Duberstein Shirly , Dixon Jessica , Cousins David , Fairhead Michael , Fearon Daren , Frick James , Gayvert James , Godoy Andre S. , Griffin Ed J. , Huber Kilian , Koekemoer Lizbé , Lahav Noa , Marples Peter G. , McGovern Briana L. , Mehlman Tevie , Robinson Matthew C. , Singh Usha , Szommer Tamas , Tomlinson Charles W.E. , Vargo Thomas , von Delft Frank , Wang SiYi , White Kris , Williams Eleanor , Winokan Max 
Published: August 2024

AbstractA strategy for pandemic preparedness is the development of antivirals against a wide set of viral targets with complementary mechanisms of action. SARS-CoV-2 nsp3-mac1 is a viral macrodomain with ADP-ribosylhydrolase activity, which counteracts host immune response. Targeting the virus’ immunomodulatory functionality offers a differentiated strategy to inhibit SARS-CoV-2 compared to approved therapeutics, which target viral replication directly. Here we report a fragment-based lead generation campaign guided by computational approaches. We discover tool compounds which inhibit nsp3-mac1 activity at low nanomolar concentrations, and with responsive structure-activity relationships, high selectivity, and drug-like properties. Using our inhibitors, we show that inhibition of nsp3-mac1 increases ADP-ribosylation, but surprisingly does not translate to demonstrable antiviral activity in cell culture and iPSC-derived pneumocyte models. Further, no synergistic activity is observed in combination with interferon gamma, a main protease inhibitor, nor a papain-like protease inhibitor. Our results question the extent to which targeting modulation of innate immunity-driven ADP-ribosylation can influence SARS-CoV-2 replication. Moreover, these findings suggest that nsp3-mac1 might not be a suitable target for antiviral therapeutics development.
Metabolomic and transcriptomic remodeling of bone marrow myeloid cells in response to maternal obesity
Authors: Alharithi Yem J , Phillips Elysse A. , Wilson Tim D. , Couvillion Sneha P. , Nicora Carrie D. , Darakjian Priscila , Rakshe Shauna , Fei Suzanne S. , Counts Brittany , Metz Thomas O. , Searles Robert , Kumar Sushil , Maloyan Alina 
Published: August 2024

ABSTRACTMaternal obesity puts the offspring at high risk of developing obesity and cardio-metabolic diseases in adulthood. Here, using a mouse model of maternal high-fat diet (HFD)-induced obesity, we show that whole body fat content of the offspring of HFD-fed mothers (Off-HFD) increases significantly from very early age when compared to the offspring regular diet-fed mothers (Off-RD). We have previously shown significant metabolic and immune perturbations in the bone marrow of newly-weaned offspring of obese mothers. Therefore, we hypothesized that lipid metabolism is altered in the bone marrow Off-HFD in newly-weaned offspring of obese mothers when compared to the Off-RD. To test this hypothesis, we investigated the lipidomic profile of bone marrow cells collected from three-week-old offspring of regular and high fat diet-fed mothers. Diacylgycerols (DAGs), triacylglycerols (TAGs), sphingolipids and phospholipids, including plasmalogen, and lysophospholipids were remarkably different between the groups, independent of fetal sex. Levels of cholesteryl esters were significantly decreased in offspring of obese mothers, suggesting reduced delivery of cholesterol to bone marrow cells. This was accompanied by age-dependent progression of mitochondrial dysfunction in bone marrow cells. We subsequently isolated CD11b+ myeloid cells from three-week-old mice and conducted metabolomics, lipidomics, and transcriptomics analyses. The lipidomic profiles of these bone marrow myeloid cells were largely similar to that seen in bone marrow cells and included increases in DAGs and phospholipids alongside decreased TAGs, except for long-chain TAGs, which were significantly increased. Our data also revealed significant sex-dependent changes in amino acids and metabolites related to energy metabolism. Transcriptomic analysis revealed altered expression of genes related to major immune pathways including macrophage alternative activation, B-cell receptor signaling, TGFβ signaling, and communication between the innate and adaptive immune systems. All told, this study revealed lipidomic, metabolomic, and gene expression abnormalities in bone marrow cells broadly, and in bone marrow myeloid cells particularly, in the newly-weaned offspring of obese mothers, which might at least partially explain the progression of metabolic and cardiovascular diseases in their adulthood.
Assessing the combined effects of forest management and climate change on carbon and water fluxes in European beech forests
Authors: Saponaro Vincenzo , De Cáceres Miquel , Dalmonech Daniela , D’Andrea Ettore , Vangi Elia , Collalti Alessio 
Published: August 2024

AbstractThe consequences of climate change continue to threaten European forests, particularly for species located at the edges of their latitudinal and altitudinal ranges. While extensively studied in Central Europe, European beech forests require further investigation to understand how climate change will affect these ecosystems in Mediterranean areas. Proposed silvicultural options increasingly aim at sustainable management to reduce biotic and abiotic stresses and enhance these forest ecosystems’ resistance and resilience mechanisms. Process-based models (PBMs) can help us to simulate such phenomena and capture early stress signals while considering the effect of different management approaches. In this study, we focus on estimating sensitivity of two state-of-the-art PBMs forest models by simulating carbon and water fluxes at the stand level to assess productivity changes and feedback resulting from different climatic forcings as well as different management regimes. We applied the 3D-CMCC-FEM and MEDFATE forest models for carbon (C) and water (H2O) fluxes in in two sites of the Italian peninsula, Cansiglio in the north and Mongiana in the south, under managed vs. unmanaged scenarios and under current climate and different climatic scenarios (RCP4.5 and RCP8.5). To ensure confidence in the models’ results, we preliminary evaluated their performance in simulating C and H2O flux in three additional beech forests of the FLUXNET network along a latitudinal gradient spanning from Denmark to central Italy. The 3D-CMCC-FEM model achieved R² values of 0.83 and 0.86 with RMSEs of 2.53 and 2.05 for C and H2O fluxes, respectively. MEDFATE showed R² values of 0.76 and 0.69 with RMSEs of 2.54 and 3.01. At the Cansiglio site in northern Italy, both models simulated a general increase in C and H2O fluxes under the RCP8.5 climate scenario compared to the current climate. Still, no benefit in managed plots compared to unmanaged ones, as the site does not have water availability limitations, and thus, competition for water is low. At the Mongiana site in southern Italy, both models predict a decrease in C and H2O fluxes and sensitivity to the different climatic forcing compared to the current climate; and an increase in C and H2O fluxes when considering specific management regimes compared to unmanaged scenarios. Conversely, under unmanaged scenarios plots are simulated to experience first signals of mortality prematurely due to water stress (MEDFATE) and carbon starvation (3D-CMCC-FEM) scenarios. In conclusion, while management interventions may be considered a viable solution for the conservation of beech forests under future climate conditions at moister sites like Cansiglio, in drier sites like Mongiana conservation may not lie in management interventions alone.
Long-term monitoring of SARS-CoV-2 load and variant composition at a large metropolitan wastewater treatment plant using a simple two-step direct capture RNA extraction, droplet digital PCR, and targeted mutation assays
Authors: Balogh Steven J. , Sprouse George B. , Beckman Kenneth B. , Watson Ray H.B. , Johnson Darrell M. , Pinkerton Lee D. , Nollet Yabing H. , Sealock Adam W. , Atkins Walter S.C. , Selenke Laura M. , Kinney Joseph A. , Grady Patrick J.R. , Vanderbush Brandon , Daniel Jerry J. 
Published: August 2024

AbstractWastewater surveillance offers an objective, comprehensive, and cost-effective means of monitoring the prevalence and genomic heterogeneity of pathogens circulating in a community. Here, a novel two-step extraction procedure for the direct capture of SARS-CoV-2 RNA from raw wastewater is presented. Combined with reverse transcription-droplet digital polymerase chain reaction (RT-ddPCR) detection, the method provides a fast and sensitive method for measuring viral RNA concentrations in wastewater. The method was used to measure the concentration of SARS-CoV-2 RNA in daily samples of wastewater entering a major metropolitan wastewater treatment plant over the course of 32 months, from November 2020 through June 2023. In addition, targeted mutation assays were used with RT-ddPCR to characterize the evolving presence and prevalence of specific SARS-CoV-2 variant sub-lineages in the wastewater stream over time. The results demonstrate the utility of these methods to accurately measure the total load of SARS-CoV-2 RNA, and chronicle its evolving variant composition, in wastewater treatment plant influent, providing near-real-time characterization of COVID-19 disease prevalence and trends in the served community.Graphical abstract
SARS-CoV-2 Omicron subvariant genomic variation associations with immune evasion in Northern California: A retrospective cohort study
Authors: Nugent Joshua R. , Wood Mariah S. , Liu Liyan , Bullick Teal , Schapiro Jeffrey M. , Arunleung Phacharee , Gautham Gautham , Getabecha Shiffen , Morales Christina , Amsden Laura B. , Hsiao Crystal A. , Wadford Debra A. , Wyman Stacia K. , Skarbinski Jacek 
Published: August 2024

AbstractBackgroundThe possibility of association between SARS-CoV-2 genomic variation and immune evasion is not known among persons with Omicron variant SARS-CoV-2 infection.MethodsIn a retrospective cohort, using Poisson regression adjusting for sociodemographic variables and month of infection, we examined associations between individual non-lineage defining mutations and SARS-CoV-2 immunity status, defined as a) no prior recorded infection, b) not vaccinated but with at least one prior recorded infection, c) complete primary series vaccination, and/or d) primary series vaccination and ≥ 1 booster. We identified all non-synonymous single nucleotide polymorphisms (SNPs), insertions and deletions in SARS-CoV-2 genomes with ≥5% allelic frequency and population frequency of ≥5% and ≤95%. We also examined correlations between the presence of SNPs with each other, with subvariants, and over time.ResultsSeventy-nine mutations met inclusion criteria. Among 15,566 persons infected with Omicron SARS-CoV-2, 1,825 (12%) were unvaccinated with no prior recorded infection, 360 (2%) were unvaccinated with a recorded prior infection, 13,381 (86%) had a complete primary series vaccination, and 9,172 (58%) had at least one booster. After examining correlation between SNPs, 79 individual non-lineage defining mutations were organized into 38 groups. After correction for multiple testing, no individual SNPs or SNP groups were significantly associated with immunity status levels.ConclusionsGenomic variation identified within SARS-CoV-2 Omicron specimens was not significantly associated with immunity status, suggesting that contribution of non-lineage defining SNPs to immune evasion is minimal. Larger-scale surveillance of SARS-CoV-2 genomes linked with clinical data can help provide information to inform future vaccine development.
The SQUEEZE pilot trial: a trial to determine whether septic shock reversal is quicker in pediatric patients randomized to an early goal directed fluid-sparing strategy vs. usual care
Authors: Parker Melissa J. , Choong Karen , Fox-Robichaud Alison , Liaw Patricia C. , Thabane Lehana 
Published: August 2024

AbstractObjectiveThe overall objective of our research is to determine in children with septic shock whether use of a fluid-sparing strategy results in improved clinical outcomes without an increased risk of adverse events compared to usual care. The specific objective of this pilot randomized controlled trial was to evaluate the feasibility of a definitive multicenter trial to answer our research question.DesignPragmatic, 2-arm, parallel group, open label, prospective pilot randomized controlled trial including a nested biosample-based translational study.SettingPediatric tertiary care centrePatientsChildren aged 29 days to <18 years of age presenting to the Emergency Department or admitted to an in-patient ward (including the PICU) with suspected or confirmed septic shock and a need for ongoing resuscitation.InterventionsFluid-sparing vs. usual care resuscitation strategy continued until shock reversal. The fluid-sparing intervention comprised instructions to restrict fluid bolus therapy in conjunction with early initiation and/or preferential use of vasoactive medication support as a strategy to spare fluid while targeting the hemodynamic goals specified in the American College of Critical Care Medicine Surviving Sepsis Guidelines. The usual care strategy did not limit use of fluid bolus therapy.Measurements and Main Results53 were randomized to usual care (n=27) or fluid-sparing (n=26). Fifty-one participants were available for primary outcome analysis. Primary feasibility outcomes related to participant enrolment and protocol adherence. Enrolment rate was 1.8 (51/29); 95% confidence interval [CI]: 1.3-2.3 participants/month. Study procedures were implemented in 49/51 (96.1%), 95% CI: 86.5-99.5% participants within 1 hour of randomization in a median (quartile range [IQR]) of 8 (5, 15) minutes. The protocol required use of an exception to consent process and consent for ongoing participation was 48/51 (94.1%), 95% CI: 83.8-98.8%. There were no serious adverse events.ConclusionsWe concluded the large multicenter SQUEEZE Trial feasible to conduct. Trial Registration: ClinicalTrials.gov [NCT01973907]
Safety and efficacy of rapamycin on healthspan metrics after one year: PEARL Trial Results
Authors: Harinath Girish , Lee Virginia , Nyquist Andy , Moel Mauricio , Morgan Stefanie L. , Isman Anar , Zalzala Sajad 
Published: August 2024

AbstractBackgroundLow-dose rapamycin promotes longevity in mice, but clinical safety and longevity data effects in humans remain limited.ObjectivesEvaluate the long-term safety of intermittent low-dose rapamycin in a healthy, normative-aging human cohort.DesignThis decentralized double-blinded, randomized, placebo-controlled trial (NCT04488601, registered 2020-07-28) was performed over 48 weeks. Participants received placebo, 5mg or 10mg compounded rapamycin (equivalent to 1.43mg or 2.86mg of generic formulations) weekly. The primary outcome measure was visceral adiposity (by DXA scan), secondary outcomes were blood biomarkers, and lean tissue and bone mineral content (by DXA scan). Established surveys were utilized to evaluate health and well-being. Safety was assessed through adverse events and blood biomarker monitoring.ResultsAdverse and serious adverse events were similar across all groups. Visceral adiposity did not change significantly (ηp2=0.001,p=0.942), and changes in blood biomarkers remained within normal ranges. Lean tissue mass (ε2=0.202,p=0.013) and self-reported pain (ε2=0.168,p=0.015) improved significantly for women using 10mg rapamycin. Trends of improvement in bone mineral density were observed in males using 10mg rapamycin (ε2=0.221,p=0.061), but no other significant effects were observed.ConclusionsLow-dose, intermittent rapamycin administration over 48 weeks is relatively safe in healthy, normative-aging adults, and was associated with significant improvements in lean tissue mass and pain in women. Future work will evaluate benefits of a broader range of rapamycin doses on healthspan metrics for longevity, and will aim to more comprehensively establish efficacy.