High rate of union of scaphoid pseudoarthrosis treated with arthroscopic olecranon bone graft using antegrade percutaneous headless compression screw.

PURPOSE: The primary aim of this prospective study was to assess the healing rate of scaphoid pseudoarthrosis treated with wrist arthroscopy, olecranon bone graft and anterograde screw fixation. Clinical, radiological outcomes and complications were included as secondary aims. METHODS: All patients with scaphoid nonunion were selected between January 2017 and December 2022. Inclusion criteria were patients between 18 and 60 years of age, diagnosis of scaphoid pseudoarthrosis, complete clinical patient-reported outcomes (PROs), radiographic measurements, and underwent at least 1-year follow-up. Scaphoid pseudoarthrosis was treated arthroscopically with olecranon bone graft and anterograde screw fixation. Clinical assessment was performed through visual analog scale (VAS) for pain, QuickDASH (disability of the arm, shoulder, and hand) questionnaire, wrist range of motion using a standard goniometer, and grip strength in Kilograms with a Jamar hydraulic hand dynamometer. Clinical relevance was measured with the minimal clinical important difference (MCID) for VAS and QuickDASH. Scapholunate angle was measured. Union was assessed on CT scan. RESULTS: Seventeen patients were included with a mean follow-up of 17.2 months. Mean age was 30.1 years old and average time from injury to arthroscopic surgery was 11.1 months. At latest follow-up, there was an improvement in VAS pain score and QuickDASH score. Range of motion and grip strength increased at last follow-up. MCID threshold for the VAS and DASH score was reached by 100% and 94.1%, respectively. Union was achieved in 16 patients (94.1%) after a median of 16 weeks (IQR 16-20). CONCLUSIONS: Arthroscopic treatment of scaphoid pseudoarthrosis with olecranon bone graft and antegrade percutaneous headless compression screw allows a high grade of union and improves in pain and function at short term follow-up. MCID threshold for the VAS and DASH score was reached by 100% and 94.1%, respectively.

Silibinin is a suppressor of the metastasis-promoting transcription factor ID3.

BACKGROUND: ID3 (inhibitor of DNA binding/differentiation-3) is a transcription factor that enables metastasis by promoting stem cell-like properties in endothelial and tumor cells. The milk thistle flavonolignan silibinin is a phytochemical with anti-metastatic potential through largely unknown mechanisms. HYPOTHESIS/PURPOSE: We have mechanistically investigated the ability of silibinin to inhibit the aberrant activation of ID3 in brain endothelium and non-small cell lung cancer (NSCLC) models. METHODS: Bioinformatic analyses were performed to investigate the co-expression correlation between ID3 and bone morphogenic protein (BMP) ligands/BMP receptors (BMPRs) genes in NSCLC patient datasets. ID3 expression was assessed by immunoblotting and qRT-PCR. Luciferase reporter assays were used to evaluate the gene sequences targeted by silibinin to regulate ID3 transcription. In silico computational modeling and LanthaScreen TR-FRET kinase assays were used to characterize and validate the BMPR inhibitory activity of silibinin. Tumor tissues from NSCLC xenograft models treated with oral silibinin were used to evaluate the in vivo anti-ID3 effects of silibinin. RESULTS: Analysis of lung cancer patient datasets revealed a top-ranked positive association of ID3 with the BMP9 endothelial receptor ACVRL1/ALK1 and the BMP ligand BMP6. Silibinin treatment blocked the BMP9-induced activation of the ALK1-phospho-SMAD1/5-ID3 axis in brain endothelial cells. Constitutive, acquired, and adaptive expression of ID3 in NSCLC cells were all significantly downregulated in response to silibinin. Silibinin blocked ID3 transcription via BMP-responsive elements in ID3 gene enhancers. Silibinin inhibited the kinase activities of BMPRs in the micromolar range, with the lower IC50 values occurring against ACVRL1/ALK1 and BMPR2. In an in vivo NSCLC xenograft model, tumoral overexpression of ID3 was completely suppressed by systematically achievable oral doses of silibinin. CONCLUSIONS: ID3 is a largely undruggable metastasis-promoting transcription factor. Silibinin is a novel suppressor of ID3 that may be explored as a novel therapeutic approach to interfere with the metastatic dissemination capacity of NSCLC.

Healthy Lifestyle Is a Protective Factor from Moderate and Severe Relapses and Steroid Use in Inflammatory Bowel Disease: A Prospective Cohort Study.

BACKGROUND: A healthy lifestyle, including good adherence to a Mediterranean diet (MD) and regular physical exercise, may be an important factor during the course of inflammatory bowel disease (IBD). Our aim is to determine whether adherence to MD, physical activity, and the combination of both can impact on IBD course. METHODS: This prospective cohort study includes 693 IBD outpatients who were in remission with a median follow-up time of 27 months (interquartile range 22-29 months). Each patient completed a survey to assess their adherence to the MD and physical activity. Healthy lifestyle was considered to be a proper adherence to both MD and an active lifestyle. Relapse during follow-up, severity of relapses, need for systemic steroids, and therapy changes were recorded. RESULTS: During the follow-up period, 188 patients (27.1%) experienced relapse, of which 56.1% were moderate or severe. Among patients with relapse, 85 (45%) required treatment with corticosteroids, and 15 (7.9%) were hospitalized. Patients with ulcerative colitis (CU) were more adherent to healthy lifestyle than patients with Crohn's disease (P = .011). Healthy lifestyle was associated with lower risk of moderate and severe relapses (adjusted Hazard ratio [aHR], 0.250; 95% confidence interval [CI], 0.093-0.670) and steroids use (aHR 0.292; 95% CI, 0.103-0.828) in IBD patients and with lower risk of moderate and severe relapses (aHR 0.270; 95% CI, 0.093-0.789) in UC patients. CONCLUSIONS: Healthy lifestyle has a favorable influence on promoting a milder disease course, and thus should be a crucial part of clinical management of patients with IBD.

Healthy lifestyle including adherence to a Mediterranean diet and physical exercise has a favorable influence on promoting a milder disease course and thus should be a crucial part of clinical management of patients with IBD.

Genomic malaria surveillance of antenatal care users detects reduced transmission following elimination interventions in Mozambique.

Routine sampling of pregnant women at first antenatal care (ANC) visits could make Plasmodium falciparum genomic surveillance more cost-efficient and convenient in sub-Saharan Africa. We compare the genetic structure of parasite populations sampled from 289 first ANC users and 93 children from the community in Mozambique between 2015 and 2019. Samples are amplicon sequenced targeting 165 microhaplotypes and 15 drug resistance genes. Metrics of genetic diversity and relatedness, as well as the prevalence of drug resistance markers, are consistent between the two populations. In an area targeted for elimination, intra-host genetic diversity declines in both populations (p = 0.002-0.007), while for the ANC population, population genetic diversity is also lower (p = 0.0004), and genetic relatedness between infections is higher (p = 0.002) than control areas, indicating a recent reduction in the parasite population size. These results highlight the added value of genomic surveillance at ANC clinics to inform about changes in transmission beyond epidemiological data.

2-Cys peroxiredoxins contribute to thylakoid lipid unsaturation by affecting ω-3 fatty acid desaturase 8.

Fatty acid unsaturation levels affect chloroplast function and plant acclimation to environmental cues. However, the regulatory mechanism(s) controlling fatty acid unsaturation in thylakoid lipids is poorly understood. Here, we have investigated the connection between chloroplast redox homeostasis and lipid metabolism by focusing on 2-Cys peroxiredoxins (Prxs), which play a central role in balancing the redox state within the organelle. The chloroplast redox network relies on NADPH-dependent thioredoxin reductase C (NTRC), which controls the redox balance of 2-Cys Prxs to maintain the reductive activity of redox-regulated enzymes. Our results show that Arabidopsis (Arabidopsis thaliana) mutants deficient in 2-Cys Prxs contain decreased levels of trienoic fatty acids, mainly in chloroplast lipids, indicating that these enzymes contribute to thylakoid membrane lipids unsaturation. This function of 2-Cys Prxs is independent of NTRC, the main reductant of these enzymes, hence 2-Cys Prxs operates beyond the classic chloroplast regulatory redox system. Moreover, the effect of 2-Cys Prxs on lipid metabolism is primarily exerted through the prokaryotic pathway of glycerolipid biosynthesis and fatty acid desaturase 8 (FAD8). While 2-Cys Prxs and FAD8 interact in leaf membranes as components of a large protein complex, the levels of FAD8 were markedly decreased when FAD8 is overexpressed in 2-Cys Prxs-deficient mutant backgrounds. These findings reveal a function for 2-Cys Prxs, possibly acting as a scaffold protein, affecting the unsaturation degree of chloroplast membranes.

Fatty acid synthase (FASN) signalome: A molecular guide for precision oncology.

The initial excitement generated more than two decades ago by the discovery of drugs targeting fatty acid synthase (FASN)-catalyzed de novo lipogenesis for cancer therapy was short-lived. However, the advent of the first clinical-grade FASN inhibitor (TVB-2640; denifanstat), which is currently being studied in various phase II trials, and the exciting advances in understanding the FASN signalome are fueling a renewed interest in FASN-targeted strategies for the treatment and prevention of cancer. Here, we provide a detailed overview of how FASN can drive phenotypic plasticity and cell fate decisions, mitochondrial regulation of cell death, immune escape and organ-specific metastatic potential. We then present a variety of FASN-targeted therapeutic approaches that address the major challenges facing FASN therapy. These include limitations of current FASN inhibitors and the lack of precision tools to maximize the therapeutic potential of FASN inhibitors in the clinic. Rethinking the role of FASN as a signal transducer in cancer pathogenesis may provide molecularly driven strategies to optimize FASN as a long-awaited target for cancer therapeutics.

Programming of neural progenitors of the adult subependymal zone towards a glutamatergic neuron lineage by neurogenin 2.

Although adult subependymal zone (SEZ) neural stem cells mostly generate GABAergic interneurons, a small progenitor population expresses the proneural gene Neurog2 and produces glutamatergic neurons. Here, we determined whether Neurog2 could respecify SEZ neural stem cells and their progeny toward a glutamatergic fate. Retrovirus-mediated expression of Neurog2 induced the glutamatergic lineage markers TBR2 and TBR1 in cultured SEZ progenitors, which differentiated into functional glutamatergic neurons. Likewise, Neurog2-transduced SEZ progenitors acquired glutamatergic neuron hallmarks in vivo. Intriguingly, they failed to migrate toward the olfactory bulb and instead differentiated within the SEZ or the adjacent striatum, where they received connections from local neurons, as indicated by rabies virus-mediated monosynaptic tracing. In contrast, lentivirus-mediated expression of Neurog2 failed to reprogram early SEZ neurons, which maintained GABAergic identity and migrated to the olfactory bulb. Our data show that NEUROG2 can program SEZ progenitors toward a glutamatergic identity but fails to reprogram their neuronal progeny.

Luminescent Probe Based on Terbium-Carbon Quantum Dots for the Quantification of Imidacloprid in Caneberries.

We propose a modification of terbium-sensitized luminescence (TSL) by means of the introduction of nanoparticles to improve the sensitivity and selectivity of the analytical methods. TSL detection is usually based on the complexation between fluorescent organic compounds (the analytes) and terbium. The organic compound is then excited, and, after an energy transfer towards terbium, the latter emits the luminescence signal. Here, the modification consists of the introduction of nanoparticles (carbon quantum dots, CQDs) into the system. The carboxylic groups of CQDs react with terbium, providing an interesting time-resolved luminescence probe. We applied this system for the determination of the neonicotinoid imidacloprid (IMID). When IMID was introduced in the terbium-CQDs system, the luminescent signal (λexc/λem of 256/545 nm) was quenched, proportionally to IMID concentration in the range of 100-2500 ng·mL-1, obtaining a limit of detection of 30 ng·mL-1. A method detection limit of 0.9 mg·kg-1 was reached in caneberries, thus complying with the maximum residue level of 5 mg·kg-1 established by Codex Alimentarius. We performed recovery experiments in caneberries (blackberries, blueberries, raspberries, and mulberries), obtaining recovery yields close to 100% in all cases. These results show that the use of terbium ions-nanoparticles luminescence probes can be useful for screening purposes in quality control laboratories.

Genomic malaria surveillance of antenatal care users detects reduced transmission following elimination interventions in Mozambique.

Routine sampling of pregnant women at first antenatal care (ANC) visits could make Plasmodium falciparum genomic surveillance more cost-efficient and convenient in sub-Saharan Africa. We compared the genetic structure of parasite populations sampled from 289 first ANC attendees and 93 children from the community in Mozambique between 2015 and 2019. Samples were amplicon sequenced targeting 165 microhaplotypes and 15 drug resistance genes. Metrics of genetic diversity and relatedness, as well as the prevalence of drug resistance markers, were consistent between the two populations. In an area targeted for elimination, intra-host genetic diversity declined in both populations (p=0.002-0.007), while for the ANC population, population genetic diversity was also lower (p=0.0004), and genetic relatedness between infections were higher (p=0.002) than control areas, indicating a recent reduction in the parasite population size. These results highlight the added value of genomic surveillance at ANC clinics to inform about changes in transmission beyond epidemiological data.

Leveraging CD4 Cell Count at Entry Into Care to Monitor Success of Human Immunodeficiency Virus Prevention, Treatment, and Public Health Programming in the Greater St Louis Area Between 2017 and 2020.

CD4 cell count at entry into human immunodeficiency virus (HIV) care is a useful indicator of success of multiple steps in HIV public health programming. We demonstrate that CD4 cell count at care initiation was stable in St Louis between 2017 and 2019 but declined in 2020. Missouri efforts in the Ending the HIV Epidemic plan should focus on rapidly identifying individuals with undiagnosed HIV infection.

Endomapper dataset of complete calibrated endoscopy procedures.

Computer-assisted systems are becoming broadly used in medicine. In endoscopy, most research focuses on the automatic detection of polyps or other pathologies, but localization and navigation of the endoscope are completely performed manually by physicians. To broaden this research and bring spatial Artificial Intelligence to endoscopies, data from complete procedures is needed. This paper introduces the Endomapper dataset, the first collection of complete endoscopy sequences acquired during regular medical practice, making secondary use of medical data. Its main purpose is to facilitate the development and evaluation of Visual Simultaneous Localization and Mapping (VSLAM) methods in real endoscopy data. The dataset contains more than 24 hours of video. It is the first endoscopic dataset that includes endoscope calibration as well as the original calibration videos. Meta-data and annotations associated with the dataset vary from the anatomical landmarks, procedure labeling, segmentations, reconstructions, simulated sequences with ground truth and same patient procedures. The software used in this paper is publicly available.

Detecting temporal and spatial malaria patterns from first antenatal care visits.

Pregnant women attending first antenatal care (ANC) visits represent a promising malaria surveillance target in Sub-Saharan Africa. Here we assessed the spatio-temporal relationship between malaria at ANC (n=6,471), in children at the community(n=9,362) and at health facilities (n=15,467) in southern Mozambique (2016-2019). ANC P. falciparum rates detected by quantitative polymerase chain reaction mirrored rates in children, regardless of gravidity and HIV status (Pearson correlation coefficient [PCC]>0.8, χ²<1.1), with a 2-3 months lag. Only at rapid diagnostic test detection limits at moderate-to-high transmission, multigravidae showed lower rates than children (PCC=0.61, 95%CI[-0.12-0.94]). Seroprevalence against the pregnancy-specific antigen VAR2CSA reflected declining malaria trends (PCC=0.74, 95%CI[0.24-0.77]). 80% (12/15) of hotspots detected from health facility data using a novel hotspot detector, EpiFRIenDs, were also identified with ANC data. The results show that ANC-based malaria surveillance offers contemporary information on temporal trends and the geographic distribution of malaria burden in the community.

Acceptability and perceived barriers to reactive focal mass drug administration in the context of a malaria elimination program in Magude district, Southern Mozambique: A qualitative study.

This study analysed acceptability and perceived barriers to reactive focal mass drug administration (rfMDA) among community members exposed to community engagement campaigns and malaria elimination interventions in Magude district, following mass drug administration (MDA) in the same district. The study used a formative qualitative study design, consisting of 56 semi-structured interviews with community members, including community leaders, household heads, women of reproductive age, members of the community and adolescents, 4 semi-structured interviews with community health workers, 9 semi-structured interviews with healthcare professionals; and 16 focus group discussions with the general adult population. Data were collected between June and September 2017. A content thematic analysis approach was used to analyse the data. The results of this study showed that rfMDA was accepted due to awareness about the intervention, experience of a previous similar programme, the MDA campaign, and due to favourable perceptions built on the believe that rfMDA would help to prevent, treat and eliminate malaria in the community. Perceived barriers to rfMDA include lack of access to accurate information, reluctance to take a pregnancy test, concern on drug adverse reactions, and reluctance to take antimalarial drugs without any symptom. In conclusion, the community found rfMDA acceptable for malaria intervention. But more community engagement is needed to foster community involvement and self-appropriation of the malaria programme elimination.

Plastid 2-Cys peroxiredoxins are essential for embryogenesis in Arabidopsis.

The redox couple formed by NADPH-dependent thioredoxin reductase C (NTRC) and 2-Cys peroxiredoxins (Prxs) allows fine-tuning chloroplast performance in response to light intensity changes. Accordingly, the Arabidopsis 2cpab mutant lacking 2-Cys Prxs shows growth inhibition and sensitivity to light stress. However, this mutant also shows defective post-germinative growth, suggesting a relevant role of plastid redox systems in seed development, which is so far unknown. To address this issue, we first analyzed the pattern of expression of NTRC and 2-Cys Prxs in developing seeds. Transgenic lines expressing GFP fusions of these proteins showed their expression in developing embryos, which was low at the globular stage and increased at heart and torpedo stages, coincident with embryo chloroplast differentiation, and confirmed the plastid localization of these enzymes. The 2cpab mutant produced white and abortive seeds, which contained lower and altered composition of fatty acids, thus showing the relevance of 2-Cys Prxs in embryogenesis. Most embryos of white and abortive seeds of the 2cpab mutant were arrested at heart and torpedo stages of embryogenesis suggesting an essential function of 2-Cys Prxs in embryo chloroplast differentiation. This phenotype was not recovered by a mutant version of 2-Cys Prx A replacing the peroxidatic Cys by Ser. Neither the lack nor the overexpression of NTRC had any effect on seed development indicating that the function of 2-Cys Prxs at these early stages of development is independent of NTRC, in clear contrast with the operation of these regulatory redox systems in leaves chloroplasts.

Acceptability and perceived barriers to reactive focal mass drug administration in the context of a malaria elimination program in Magude district, Southern Mozambique: A qualitative study

This study analysed acceptability and perceived barriers to reactive focal mass drug administration (rfMDA) among community members exposed to community engagement campaigns and malaria elimination interventions in Magude district, following mass drug administration (MDA) in the same district. The study used a formative qualitative study design, consisting of 56 semi-structured interviews with community members, including community leaders, household heads, women of reproductive age, members of the community and adolescents, 4 semi-structured interviews with community health workers, 9 semi-structured interviews with healthcare professionals; and 16 focus group discussions with the general adult population. Data were collected between June and September 2017. A content thematic analysis approach was used to analyse the data. The results of this study showed that rfMDA was accepted due to awareness about the intervention, experience of a previous similar programme, the MDA campaign, and due to favourable perceptions built on the believe that rfMDA would help to prevent, treat and eliminate malaria in the community. Perceived barriers to rfMDA include lack of access to accurate information, reluctance to take a pregnancy test, concern on drug adverse reactions, and reluctance to take antimalarial drugs without any symptom. In conclusion, the community found rfMDA acceptable for malaria intervention. But more community engagement is needed to foster community involvement and self-appropriation of the malaria programme elimination.

Sialyltransferase Inhibitor Ac53FaxNeu5Ac Reverts the Malignant Phenotype of Pancreatic Cancer Cells, and Reduces Tumor Volume and Favors T-Cell Infiltrates in Mice.

Hypersialylation is a feature of pancreatic ductal adenocarcinoma (PDA) and it has been related to tumor malignancy and immune suppression. In this work, we have evaluated the potential of the sialyltransferase inhibitor, Ac53FaxNeu5Ac, to decrease tumor sialoglycans in PDA and to revert its malignant phenotype. Sialoglycans on PDA cells were evaluated by flow cytometry, and the functional impact of Ac53FaxNeu5Ac was assessed using E-selectin adhesion, migration, and invasion assays. PDA tumors were generated in syngeneic mice from KC cells and treated with Ac53FaxNeu5Ac to evaluate tumor growth, mice survival, and its impact on blocking sialic acid (SA) and on the tumor immune component. Ac53FaxNeu5Ac treatment on human PDA cells decreased α2,3-SA and sialyl-Lewisx, which resulted in a reduction in their E-selectin adhesion, and in their migratory and invasive capabilities. Subcutaneous murine tumors treated with Ac53FaxNeu5Ac reduced their volume, their SA expression, and modified their immune component, with an increase in CD8+ T-lymphocytes and NK cells. In conclusion, Ac53FaxNeu5Ac treatment weakened PDA cells' malignant phenotype, thereby reducing tumor growth while favoring anti-tumor immune surveillance. Altogether, these results show the positive impact of reducing SA expression by inhibiting cell sialyltransferases and open the way to use sialyltransferase inhibitors to target this dismal disease.

Metabolic syndrome before liver transplantation: does it have an impact on post liver transplantation outcome?

Introduction: metabolic syndrome (MS) and cardiovascular risk factors are common in liver transplant (LT) candidates and recipients. Cardiovascular events and de novotumors are increasingly common causes of mortality inliver transplant recipients. The aims of this study were i)to assess the prevalence of MS in LT recipients and itsgrowth over the years, and ii) to determine if the presenceof MS pre-LT is associated with a higher risk of post-LTcardiovascular events (CVE), de novo tumors, or early andlate survival.Patients and methods: a retrospective study was performedthat included LT recipients from January 2012 to December2017. Baseline features (MS before LT and at 1year post-LT)and outcomes (CVE, de novo tumors and survival) wererecorded. Results: a total of 483 recipients were included, MS waspresent in 20 % of pre-LT subjects with an increasingprevalence over time, from 16 % in 2012 to 34 % in 2017(p = 0.025). One-year post-LT, an additional 12 % had developed de novo MS. At a median of 56 months of follow-up,13 % developed a CVE and 9 % a de novo tumor. One and5-year survival rates were 91 % and 83 % in those with preLT MS, and 93 % and 85 % in those without it (p = 0.94). Thepresence of MS before LT was independently associatedwith a higher risk of post-LT CVE (HR: 2.66, 95 % CI: 1.6-4.4,p < 0.001) but not with de novo tumors (p = 0.94) nor earlyand late survival (p = 0.58 and p = 0.87).Conclusion: pre-LT MS is increasing among LT candidatesand is associated with a higher risk of post-LT morbidity(CVE) yet without affecting mortality. (AU)