Assessment of Surgical Procedural Time, Pedicle Screw Accuracy, and Clinician Radiation Exposure of a Novel Robotic Navigation System Compared With Conventional Open and Percutaneous Freehand Techniques: A Cadaveric Investigation

STUDY DESIGN: Cadaveric study. OBJECTIVE: To evaluate accuracy, radiation exposure, and surgical time of a new robotic-assisted navigation (RAN) platform compared with freehand techniques in conventional open and percutaneous procedures. METHODS: Ten board-certified surgeons inserted 16 pedicle screws at T10-L5 (n = 40 per technique) in 10 human cadaveric torsos. Pedicle screws were inserted with (1) conventional MIS technique (L2-L5, patient left pedicles), (2) MIS RAN (L2-L5, patient right pedicles), (3) conventional open technique (T10-L1, patient left pedicles), and (4) open RAN (T10-L1, patient right pedicles). Output included (1) operative time, (2) number of fluoroscopic images, and (3) screw accuracy. RESULTS: In the MIS group, compared with the freehand technique, RAN allowed for use of larger screws (diameter: 6.6 ± 0.6 mm vs 6.3 ± 0.5 mm; length: 50.3 ± 4.1 mm vs 46.9 ± 3.5 mm), decreased the number of breaches \u3e2 mm (0 vs 7), fewer fluoroscopic images (0 ± 0 vs 108.3 ± 30.9), and surgical procedure time per screw (3.6 ± 0.4 minutes vs 7.6 ± 2.0 minutes) (all CONCLUSION: RAN significantly improved accuracy and decreased radiation exposure in comparison to freehand techniques in both conventional open and percutaneous surgical procedures in cadavers. RAN significantly increased setup time compared with both conventional procedures

Hepcidin sequesters iron to sustain nucleotide metabolism and mitochondrial function in colorectal cancer epithelial cells

Colorectal cancer (CRC) requires massive iron stores, but the complete mechanisms by which CRC modulates local iron handling are poorly understood. Here, we demonstrate that hepcidin is activated ectopically in CRC. Mice deficient in hepcidin specifically in the colon tumour epithelium, compared with wild-type littermates, exhibit significantly diminished tumour number, burden and size in a sporadic model of CRC, whereas accumulation of intracellular iron by deletion of the iron exporter ferroportin exacerbates these tumour parameters. Metabolomic analysis of three-dimensional patient-derived CRC tumour enteroids indicates a prioritization of iron in CRC for the production of nucleotides, which is recapitulated in our hepcidin/ferroportin mouse CRC models. Mechanistically, our data suggest that iron chelation decreases mitochondrial function, thereby altering nucleotide synthesis, whereas exogenous supplementation of nucleosides or aspartate partially rescues tumour growth in patient-derived enteroids and CRC cell lines in the presence of an iron chelator. Collectively, these data suggest that ectopic hepcidin in the tumour epithelium establishes an axis to sequester iron in order to maintain the nucleotide pool and sustain proliferation in colorectal tumours

HIV-Neutralizing Activity of Cationic Polypeptides in Cervicovaginal Secretions of Women in HIV-Serodiscordant Relationships

HIV exposed seronegative (HESN) women represent the population most in need of a prophylactic antiviral strategy. Mucosal cationic polypeptides can potentially be regulated for this purpose and we here aimed to determine their endogenous expression and HIV neutralizing activity in genital secretions of women at risk of HIV infection.Cervicovaginal secretions (CVS) of Kenyan women in HIV-serodiscordant relationships (HESN, n = 164; HIV seropositive, n = 60) and low-risk controls (n = 72) were assessed for the cationic polypeptides HNP1–3, LL-37 and SLPI by ELISA and for HIV neutralizing activity by a PBMC-based assay using an HIV primary isolate. Median levels of HNP1–3 and LL-37 in CVS were similar across study groups. Neither HSV-2 serostatus, nor presence of bacterial vaginosis, correlated with levels of HNP1–3 or LL-37 in the HESN women. However, an association with their partner's viral load was observed. High viral load (>10,000 HIV RNA copies/ml plasma) correlated with higher levels of HNP1–3 and LL-37 (p = 0.04 and 0.03, respectively). SLPI was most abundant in the low-risk group and did not correlate with male partner's viral load in the HESN women. HIV neutralizing activity was found in CVS of all study groups. In experimental studies, selective depletion of cationic polypeptides from CVS rendered the remaining CVS fraction non-neutralizing, whereas the cationic polypeptide fraction retained the activity. Furthermore, recombinant HNP1–3 and LL-37 could induce neutralizing activity when added to CVS lacking intrinsic activity.These findings show that CVS from HESN, low-risk, and HIV seropositive women contain HIV neutralizing activity. Although several innate immune proteins, including HNP1–3 and LL-37, contribute to this activity these molecules can also have inflammatory properties. This balance is influenced by hormonal and environmental factors and in the present HIV serodiscordant couple cohort study we show that a partner's viral load is associated with levels of such molecules

Changes in agonist neural drive, hypertrophy and pre-training strength all contribute to the individual strength gains after resistance training.

PURPOSE: Whilst neural and morphological adaptations following resistance training (RT) have been investigated extensively at a group level, relatively little is known about the contribution of specific physiological mechanisms, or pre-training strength, to the individual changes in strength following training. This study investigated the contribution of multiple underpinning neural [agonist EMG (QEMGMVT), antagonist EMG (HEMGANTAG)] and morphological variables [total quadriceps volume (QUADSVOL), and muscle fascicle pennation angle (QUADSθ p)], as well as pre-training strength, to the individual changes in strength after 12 weeks of knee extensor RT. METHODS: Twenty-eight healthy young men completed 12 weeks of isometric knee extensor RT (3/week). Isometric maximum voluntary torque (MVT) was assessed pre- and post-RT, as were simultaneous neural drive to the agonist (QEMGMVT) and antagonist (HEMGANTAG). In addition QUADSVOL was determined with MRI and QUADSθ p with B-mode ultrasound. RESULTS: Percentage changes (∆) in MVT were correlated to ∆QEMGMVT (r = 0.576, P = 0.001), ∆QUADSVOL (r = 0.461, P = 0.014), and pre-training MVT (r = -0.429, P = 0.023), but not ∆HEMGANTAG (r = 0.298, P = 0.123) or ∆QUADSθ p (r = -0.207, P = 0.291). Multiple regression analysis revealed 59.9% of the total variance in ∆MVT after RT to be explained by ∆QEMGMVT (30.6%), ∆QUADSVOL (18.7%), and pre-training MVT (10.6%). CONCLUSIONS: Changes in agonist neural drive, quadriceps muscle volume and pre-training strength combined to explain the majority of the variance in strength changes after knee extensor RT (~60%) and adaptations in agonist neural drive were the most important single predictor during this short-term intervention

The role of APOBEC3B in lung tumor evolution and targeted cancer therapy resistance

In this study, the impact of the apolipoprotein B mRNA-editing catalytic subunit-like (APOBEC) enzyme APOBEC3B (A3B) on epidermal growth factor receptor (EGFR)-driven lung cancer was assessed. A3B expression in EGFR mutant (EGFRmut) non-small-cell lung cancer (NSCLC) mouse models constrained tumorigenesis, while A3B expression in tumors treated with EGFR-targeted cancer therapy was associated with treatment resistance. Analyses of human NSCLC models treated with EGFR-targeted therapy showed upregulation of A3B and revealed therapy-induced activation of nuclear factor kappa B (NF-κB) as an inducer of A3B expression. Significantly reduced viability was observed with A3B deficiency, and A3B was required for the enrichment of APOBEC mutation signatures, in targeted therapy-treated human NSCLC preclinical models. Upregulation of A3B was confirmed in patients with NSCLC treated with EGFR-targeted therapy. This study uncovers the multifaceted roles of A3B in NSCLC and identifies A3B as a potential target for more durable responses to targeted cancer therapy.</p

Federated learning enables big data for rare cancer boundary detection.

Although machine learning (ML) has shown promise across disciplines, out-of-sample generalizability is concerning. This is currently addressed by sharing multi-site data, but such centralization is challenging/infeasible to scale due to various limitations. Federated ML (FL) provides an alternative paradigm for accurate and generalizable ML, by only sharing numerical model updates. Here we present the largest FL study to-date, involving data from 71 sites across 6 continents, to generate an automatic tumor boundary detector for the rare disease of glioblastoma, reporting the largest such dataset in the literature (n = 6, 314). We demonstrate a 33% delineation improvement for the surgically targetable tumor, and 23% for the complete tumor extent, over a publicly trained model. We anticipate our study to: 1) enable more healthcare studies informed by large diverse data, ensuring meaningful results for rare diseases and underrepresented populations, 2) facilitate further analyses for glioblastoma by releasing our consensus model, and 3) demonstrate the FL effectiveness at such scale and task-complexity as a paradigm shift for multi-site collaborations, alleviating the need for data-sharing

Genomic Relationships, Novel Loci, and Pleiotropic Mechanisms across Eight Psychiatric Disorders

Genetic influences on psychiatric disorders transcend diagnostic boundaries, suggesting substantial pleiotropy of contributing loci. However, the nature and mechanisms of these pleiotropic effects remain unclear. We performed analyses of 232,964 cases and 494,162 controls from genome-wide studies of anorexia nervosa, attention-deficit/hyper-activity disorder, autism spectrum disorder, bipolar disorder, major depression, obsessive-compulsive disorder, schizophrenia, and Tourette syndrome. Genetic correlation analyses revealed a meaningful structure within the eight disorders, identifying three groups of inter-related disorders. Meta-analysis across these eight disorders detected 109 loci associated with at least two psychiatric disorders, including 23 loci with pleiotropic effects on four or more disorders and 11 loci with antagonistic effects on multiple disorders. The pleiotropic loci are located within genes that show heightened expression in the brain throughout the lifespan, beginning prenatally in the second trimester, and play prominent roles in neurodevelopmental processes. These findings have important implications for psychiatric nosology, drug development, and risk prediction.Peer reviewe