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Abstract Background Poor performance is a multifactorial syndrome of racehorses, commonly associated with subclinical disorders, which can be diagnosed by exercise testing. Objectives Describe the prevalence of medical causes of poor performance in Standardbreds unassociated with lameness, and evaluate their relationships with fitness variables measured by exercise treadmill test. Animals Hospital population of 259 nonlame Standardbred trotters referred for poor performance. Methods The horses' medical records were retrospectively reviewed. Horses underwent a diagnostic protocol including resting examination, plasma lactate concentration, treadmill test with continuous ECG and assessment of fitness variables, creatine kinase activity, treadmill endoscopy, postexercise tracheobronchoscopy, bronchoalveolar lavage (BAL), and gastroscopy. The prevalence of different disorders was evaluated, including cardiac arrhythmias, exertional myopathies, dynamic upper airway obstructions (DUAOs), exercise‐induced pulmonary hemorrhage (EIPH), moderate equine asthma (MEA), and gastric ulcers (EGUS). The associations of these disorders with fitness variables were investigated individually and using multivariable models. Results Moderate equine asthma and EGUS were the most common disorders, followed by EIPH, DUAOs, cardiac arrhythmias, and exertional myopathies. Hemosiderin score was positively correlated with BAL neutrophils, eosinophils, and mast cells; increased creatine kinase activity was associated with BAL neutrophilia, DUAOs, premature complexes, and squamous gastric disease. Treadmill velocity at a plasma lactate concentration of 4 mmol/L and at heart rate of 200 beats per minute was negatively affected by BAL neutrophilia, multiple DUAOs, exertional myopathies, and squamous gastric disease. Conclusions The multifactorial nature of poor performance was confirmed, with MEA, DUAOs, myopathies and EGUS representing the main diseases involved in fitness impairment.

Abstract Regeneration of the neuromuscular junction (NMJ) leverages on extensive exchange of factors released from motor axon terminals (MATs), muscle fibers and perisynaptic Schwann cells (PSCs), among which hydrogen peroxide (H2O2) is a major pro-regenerative signal. To identify critical determinants of NMJ remodeling in response to injury, we performed temporal transcriptional profiling of NMJs from 2 month-old mice during MAT degeneration/regeneration, and cross-referenced the differentially expressed genes with those elicited by H2O2 in SCs. We identified an enrichment in extracellular matrix (ECM) transcripts, including Connective Tissue Growth Factor (Ctgf), which is usually expressed during development. We discovered that Ctgf levels are increased in a Yes-associated protein (YAP)-dependent fashion in response to rapid, local H2O2 signaling generated by stressed mitochondria in the injured sciatic nerve, a finding highlighting the importance of signals triggered by mechanical force to motor nerve repair. Through sequestration of Ctgf or inactivation of H2O2, we delayed the recovery of neuromuscular function by impairing SC migration and, in turn, axon-oriented re-growth. These data indicate that H2O2 and its downstream effector Ctgf are pro-regenerative factors that enable axonal growth, and reveal a striking ECM remodeling process during nerve regeneration upon local H2O2 signaling. Our study identifies key transcriptomic changes at the regenerating NMJ, providing a rich source of pro-regenerative factors with potential for alleviating the consequences of peripheral nerve injuries.

Abstract Introduction Considering the reported efficacy of monoclonal antibodies (mAbs) directed against the Spike (S) protein of severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) in reducing disease severity, the aim of this study was to investigate the innate immune response before and after mAbs treatment in 72 vaccinated and 31 unvaccinated SARS‐CoV‐2 patients. Methods The mRNA levels of IFN‐I, IFN‐related genes and cytokines were evaluated using RT/real‐time quantitative PCR. Results Vaccinated patients showed increased rate of negative SARS‐CoV‐2 PCR tests on nasopharyngeal swab compared with unvaccinated ones after mAbs treatment (p = .002). Unvaccinated patients had lower IFN‐α/ω and higher IFN‐related genes (IFNAR1, IFNAR2, IRF9, ISG15, ISG56 and IFI27) and cytokines (IL‐6, IL‐10 and TGF‐β) mRNA levels compared to vaccinated individuals before mAbs (p

Backgroundwe evaluated the concordance between immunohistochemical p53 staining and TP53 mutations in a series of HGSOC. Moreover, we searched for prognostic differences between p53 overexpression and null expression groups.Methodspatients affected by HGSOC were included. For each case p53 immunohistochemical staining and molecular assay (Sanger sequencing) were performed. Kaplan-Meier survival analyses were undertaken to determine whether the type of TP53 mutation, or p53 staining pattern influenced overall survival (OS) and progression free survival (PFS).Results34 HGSOC were considered. All cases with a null immunohistochemical p53 expression (n=16) showed TP53 mutations (n=9 nonsense, n=4 in-frame deletion, n=2 splice, n=1 in-frame insertion). 16 out of 18 cases with p53 overexpression showed TP53 missense mutation. Follow up data were available for 33 out of 34 cases (median follow up time 15 month). We observed a significant reduction of OS in p53 null group [HR = 3.64, 95% CI 1.01-13.16].Conclusionimmunohistochemical assay is a reliable surrogate for TP53 mutations in most cases. Despite the small cohort and the limited median follow up, we can infer that HGSOC harboring p53 null mutations are a more aggressive subgroup.

Eastern Australia experienced record-breaking rainfall and flooding during 2022, which devastated communities and led to over AU$6 billion of damage. In this study, we conduct a multiscale analysis to understand why 2022 was unusually wet with multiple record-breaking rainfall events over the year. We assess the synoptic- and mesoscale conditions during three key periods: February–March, July, and October. These periods were chosen because they were impactful and represent three different seasons. Next, we examine the large-scale climate drivers and evaluate how unusual these events were compared to previous years. Finally, we discuss predictability and the possible impact of climate change on the drivers of heavy rainfall in eastern Australia. The exceptional rainfall was likely due to excessive slow-moving cyclones combined with ample atmospheric moisture flux. The key climate drivers (El Niño–Southern Oscillation, Indian Ocean dipole, and Southern Annular Mode) primed the synoptic conditions for frequent rain-bearing weather systems. There was limited predictability beyond the 1-week lead time for the February–March and July events, but the 1-month seasonal forecast for October indicated rainfall in eastern Australia. The complexity of multiday extreme rainfall makes it difficult to distinguish the role of climate change from natural variability. However, we highlight where future research could focus to help us understand climate risks to this region. Our results emphasize the importance of examining rainfall from multiple perspectives and considering the interactions between weather and climate scales because analyzing drivers in isolation is insufficient for explaining high-impact weather. [ABSTRACT FROM AUTHOR]

Background: This study evaluates the efficacy of intravitreal Faricimab in reducing pigment epithelium detachment (PED) and fluid volumes in both treatment-naïve eyes and eyes unresponsive to anti-VEGF mono-therapies, all diagnosed with type 1 macular neovascularization (T1 MNV) over a period of 12-month. Methods: A retrospective, single-center cohort study was conducted at the Jules Gonin Eye Hospital, Lausanne, Switzerland. Clinical records of treatment-naïve and non-responder switch patients presenting T1 MNV secondary to neovascular age-related macular degeneration (nAMD) from September 2022 to March 2023 were reviewed. Patients received a loading dose of three monthly Faricimab injections followed by a treat-and-extend (T&E) regimen. Multimodal imaging, including structural OCT and AI-assisted analysis, was used to quantify PED volumes and related fluid biomarkers at baseline, 3-month, 6-month, and 12-month follow-up. Statistical analyses included linear mixed models to evaluate differences and trends in intraretinal (IRF), subretinal fluid (SRF) and PED volumes. Results: 65 eyes of 65 patients were enrolled (female: 70.7%; mean age = 80.7yrs, SD = 6.9yrs). 80% had received anti-VEGF treatment (Switch group) and 20% were treatment-Naïve at baseline. At 12 months, intravitreal treatments were more frequent in the Switch group (mean number = 8.3 vs. 6.0; p = 0.009). BCVA improved at the 12-month follow-up in Naïve eyes (+ 6.9 ETDRS letters from baseline, p = 0.053) and was maintained in Switch eyes. No cases of intraocular inflammation were observed. Significant reduction in SRF and IRF volumes were noted in both groups. A significant reduction in PED volume was observed over the follow-up period in both groups (mean slope = -206 nL, 95%CL = -273/-138; p-value < 0.001). Conclusions: Intravitreal Faricimab significantly reduced PED volumes in both treatment-Naïve and non-responder Switch patients over 12 months. The study highlights Faricimab's potential as an effective treatment option for T1 MNV in nAMD, offering significant improvements in PED volume and related fluid biomarkers. [ABSTRACT FROM AUTHOR]

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The recent integration of citizen science with modern technology has greatly increased its applications and has allowed more people than ever to contribute to research across all areas of science. In particular, citizen science has been instrumental in the detection and monitoring of novel introduced species across the globe. This study provides the first records of Miomantis caffra Saussure, 1871, the South African Mantis, from the Australian mainland and uses records from four different citizen science and social media platforms in conjunction with museum records to track the spread of the species through the country. A total of 153 wild mantises and oothecae were observed across four states and territories (New South Wales, Norfolk Island, Victoria, and Western Australia) between 2009 and 2021. The large number of observations of the species in Victoria and the more recent isolated observations in other states and territories suggest that the species initially arrived in Geelong via oothecae attached to plants or equipment, likely from the invasive population in New Zealand. From there it established and spread outwards to Melbourne and eventually to other states and territories, both naturally and with the aid of human transport. We also provide a comparison of M. caffra to similar native mantises, specifically Pseudomantis albofimbriata (Stål, 1860), and comment on the potential impact and further spread of the species within Australia. Finally, we reiterate the many benefits of engaging directly with citizen scientists in biodiversity research and comment on the decision to include them in all levels of this research investigation.

BackgroundAnti-PCSK9 monoclonal antibodies are effective in reducing LDL-C and cardiovascular events by neutralizing circulating PCSK9. PCSK9, however, is also expressed in tissues, including the pancreas, and studies on PCSK9 KO mice have shown impaired insulin secretion. Statin treatment is already known to affect insulin secretion. Our aim was to conduct a pilot study to evaluate the effect of anti-PCSK9 mAb on glucose metabolism and β-cell function in humans.MethodsFifteen non-diabetic subjects, candidates for anti-PCSK9 mAb therapy, were enrolled. All underwent OGTT at baseline and after 6 months of therapy. During OGTT, insulin secretion parameters were derived from C-peptide by deconvolution (β cell glucose sensitivity). Surrogate insulin sensitivity indices were also obtained from OGTT (Matsuda).ResultsGlucose levels during OGTT were unchanged after 6 months of anti-PCSK9 mAb treatment, as well as insulin and C-peptide levels. The Matsuda index remained unchanged, while β-cell glucose sensitivity improved post-therapy (before: 85.3 ± 65.4; after: 118.6 ± 70.9 pmol min-1m-2mM-1; p

Abstract Background Neoadjuvant therapy with dual HER2 blockade improved pathological complete response (pCR) rate in HER2‐positive breast cancer patients. Nevertheless, it would be desirable to identify patients exquisitely responsive to single agent trastuzumab to minimize or avoid overtreatment. Herein, we evaluated the predictive and prognostic value of basal primary tumor miRNA expression profile within the trastuzumab arm of NeoALTTO study (ClinicalTrials.gov Identifier: NCT00553358). Methods RNA samples from baseline biopsies were randomized into training (n = 45) and testing (n = 47) sets. After normalization, miRNAs associated with Event‐free survival (EFS) and pCR were identified by univariate analysis. Multivariate models were implemented to generate specific signatures which were first confirmed, and then analyzed together with other clinical and pathological variables. Results We identified a prognostic signature including hsa‐miR‐153‐3p (HR 1.831, 95% CI: 1.34–2.50) and hsa‐miR‐219a‐5p (HR 0.629, 95% CI: 0.50–0.78). For two additional miRNAs (miR‐215‐5p and miR‐30c‐2‐3p), we found a statistically significant interaction term with pCR (p.interaction: 0.017 and 0.038, respectively). Besides, a two‐miRNA signature was predictive of pCR (hsa‐miR‐31‐3p, OR 0.70, 95% CI: 0.53–0.92, and hsa‐miR‐382‐3p, OR: 1.39, 95% CI: 1.01–1.91). Notably, the performance of this predictive miRNA signature resembled that of the genomic classifiers PAM50 and TRAR, and did not improve when the extended models were fitted. Conclusion Analyses of primary tumor tissue miRNAs hold the potential of a parsimonious tool to identify patients with differential clinical outcomes after trastuzumab based neoadjuvant therapy.

Habitat suitability modelling (HSM) is a tool that is increasingly being used to help guide decision making for conservation management. It can also be used to focus efforts of restoration in our oceans. To improve on model performance, the best available environmental data along with species distribution data are needed. Marine habitats tend to have ecological niches defined by physical environmental conditions and of particular importance for shallow water species is wave energy. In this study we examined the relative improvements to HSM outputs that could be achieved by producing high-resolution Delft-3D modelled wave height data to see if model predictions at a fine-scale can be improved. Seagrasses were used as an exemplar and comparisons at fine-scale showed considerable differences in the area predicted suitable for seagrass growth and greatly increased the importance of waves as a predictor variable when compared with open-source low resolution wave energy data.

BackgroundThe absence of breast cancer cells in surgical specimens, i.e., pathological complete response (pCR), is widely recognized as a favorable prognostic factor after neoadjuvant therapy. In contrast, the presence of disease at surgery characterizes a prognostically heterogeneous group of patients. Here, we challenged circulating microRNAs (miRNAs) at the end of neoadjuvant therapy as potential prognostic biomarkers in the NeoALTTO study.MethodsPatients treated within the trastuzumab arm (i.e., pre-operative weekly trastuzumab for 6 weeks followed by the addition of weekly paclitaxel for 12 weeks; post-operative FEC for 3 cycles followed by trastuzumab up to complete 1 year of treatment) were randomized into a training (n= 54) and testing (n= 72) set. RT-PCR-based high-throughput miRNA profile was performed on plasma samples collected at the end of neoadjuvant treatment of both sets. After normalization, circulating miRNAs associated with event free survival (EFS) were identified by univariate and multivariate Cox regression model.ResultsStarting from 23 circulating miRNAs associated with EFS in the training set, we generated a 3-circulating miRNA prognostic signature consisting of miR-185-5p, miR-146a-5p, miR-22-3p, which was confirmed in the testing set. The 3-circulating miRNA signature showed a C-statistic of 0.62 (95% confidence interval [95%CI] 0.53-0.71) in the entire study cohort. By resorting to a multivariate Cox regression model we found a statistical significant interaction between the expression values of miR-194-5p and pCR status (p.interaction =0.005) with an estimate Hazard Ratio (HR) of 1.83 (95%CI 1.14- 2.95) in patients with pCR, and 0.87 (95%CI 0.69-1.10) in those without pCR. Notably, the model including this interaction along with the abovementioned 3-circulating miRNA signature provided the highest discriminatory capability with a C-statistic of 0.67 (95%CI 0.58-0.76).ConclusionsCirculating miRNAs are informative to identify patients with different prognosis among those with heterogeneous response after trastuzumab-based neoadjuvant treatment, and may be an exploitable tool to select candidates for salvage adjuvant therapy.

We present observations and timing analyses of 68 millisecond pulsars (MSPs) comprising the 15 yr data set of the North American Nanohertz Observatory for Gravitational Waves (NANOGrav). NANOGrav is a pulsar timing array (PTA) experiment that is sensitive to low-frequency gravitational waves (GWs). This is NANOGrav’s fifth public data release, including both “narrowband” and “wideband” time-of-arrival (TOA) measurements and corresponding pulsar timing models. We have added 21 MSPs and extended our timing baselines by 3 yr, now spanning nearly 16 yr for some of our sources. The data were collected using the Arecibo Observatory, the Green Bank Telescope, and the Very Large Array between frequencies of 327 MHz and 3 GHz, with most sources observed approximately monthly. A number of notable methodological and procedural changes were made compared to our previous data sets. These improve the overall quality of the TOA data set and are part of the transition to new pulsar timing and PTA analysis software packages. For the first time, our data products are accompanied by a full suite of software to reproduce data reduction, analysis, and results. Our timing models include a variety of newly detected astrometric and binary pulsar parameters, including several significant improvements to pulsar mass constraints. We find that the time series of 23 pulsars contain detectable levels of red noise, 10 of which are new measurements. In this data set, we find evidence for a stochastic GW background.

We report multiple lines of evidence for a stochastic signal that is correlated among 67 pulsars from the 15 yr pulsar timing data set collected by the North American Nanohertz Observatory for Gravitational Waves. The correlations follow the Hellings–Downs pattern expected for a stochastic gravitational-wave background. The presence of such a gravitational-wave background with a power-law spectrum is favored over a model with only independent pulsar noises with a Bayes factor in excess of 10 ^14 , and this same model is favored over an uncorrelated common power-law spectrum model with Bayes factors of 200–1000, depending on spectral modeling choices. We have built a statistical background distribution for the latter Bayes factors using a method that removes interpulsar correlations from our data set, finding p = 10 ^−3 (≈3 σ ) for the observed Bayes factors in the null no-correlation scenario. A frequentist test statistic built directly as a weighted sum of interpulsar correlations yields p = 5 × 10 ^−5 to 1.9 × 10 ^−4 (≈3.5 σ –4 σ ). Assuming a fiducial f ^−2/3 characteristic strain spectrum, as appropriate for an ensemble of binary supermassive black hole inspirals, the strain amplitude is ${2.4}_{-0.6}^{+0.7}\times {10}^{-15}$ (median + 90% credible interval) at a reference frequency of 1 yr ^−1 . The inferred gravitational-wave background amplitude and spectrum are consistent with astrophysical expectations for a signal from a population of supermassive black hole binaries, although more exotic cosmological and astrophysical sources cannot be excluded. The observation of Hellings–Downs correlations points to the gravitational-wave origin of this signal.