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Ventricular tachycardia (VT) is a life-threatening heart rhythm and has long posed a complex challenge in the field of cardiology. Recent developments in advanced imaging modalities have aimed to improve comprehension of underlying arrhythmic substrate for VT. To this extent, high-resolution cardiac magnetic resonance (CMR) and cardiac computed tomography (CCT) have emerged as tools for accurately visualizing and characterizing scar tissue, fibrosis, and other critical structural abnormalities within the heart, providing novel insights into VT triggers and substrate. However, clinical implementation of knowledge derived from these advanced imaging techniques in improving VT treatment and guiding invasive therapeutic strategies continues to pose significant challenges. A pivotal concern lies in the absence of standardized imaging protocols and analysis methodologies, resulting in a large variance in data quality and consistency. Furthermore, the clinical significance and outcomes associated with VT substrate characterization through CMR and CCT remain dynamic and subject to ongoing evolution. This highlights the need for refinement of these techniques before their reliable integration into routine patient care can be realized. The primary objectives of this study are twofold: firstly, to provide a comprehensive overview of the studies conducted over the last 15 years, summarizing the current available literature on imaging-based assessment of VT substrate. Secondly, to critically analyze and evaluate the selected studies, with the aim of providing valuable insights that can inform current clinical practice and future research.

ABSTRACT Aquatic ecosystems are often negatively affected by invasive species. However, biotic resistance by native species, either by competition or predation, can reduce the impacts of invasions by non‐native species. The Western Mosquitofish (Gambusia affinis) is one of the most impactful invasive species of freshwater fish and cause declines in native fish populations. Using two mesocosm experiments conducted in different years, we examined the ecological interactions between juveniles of the native fish, Bluegill Sunfish (Lepomis macrochirus), and adults of the invasive fish, G. affinis. We found evidence for interactions between L. macrochirus and G. affinis. However, interactions did not appear symmetric, with L. macrochirus generally more affected by intraspecific interactions than interspecific interactions whereas G. affinis was more affected by interspecific interactions than intraspecific interactions. The presence of either species of fish led to a decrease in the number of large zooplankton and a tendency for a decrease in the total number of zooplankton. Based on these results, native L. macrochirus appear to be able to reduce the ability of non‐native G. affinis to establish or maintain populations through both competition and predation (i.e., acting as an intraguild predator). The consistency of our results across both experiments, with their different designs and their occurring in different years, gives weight to these conclusions. The reduction of or prevention of establishment of populations of invasive G. affinis would likely benefit the aquatic communities of ponds with fish, especially small‐bodied native fish.

Abstract The M4 muscarinic acetylcholine receptor (M4 mAChR) has emerged as a drug target of high therapeutic interest due to its expression in regions of the brain involved in the regulation of psychosis, cognition, and addiction. The mAChR agonist, xanomeline, has provided significant improvement in the Positive and Negative Symptom Scale (PANSS) scores in a Phase II clinical trial for the treatment of patients suffering from schizophrenia. Here we report the active state cryo-EM structure of xanomeline bound to the human M4 mAChR in complex with the heterotrimeric Gi1 transducer protein. Unexpectedly, two molecules of xanomeline were found to concomitantly bind to the monomeric M4 mAChR, with one molecule bound in the orthosteric (acetylcholine-binding) site and a second molecule in an extracellular vestibular allosteric site. Molecular dynamic simulations supports the structural findings, and pharmacological validation confirmed that xanomeline acts as a dual orthosteric and allosteric ligand at the human M4 mAChR. These findings provide a basis for further understanding xanomeline’s complex pharmacology and highlight the myriad of ways through which clinically relevant ligands can bind to and regulate GPCRs.

The Tarantula Nebula in the Large Magellanic Cloud is known for its high star formation activity. At its center lies the young massive star cluster R136, providing a significant amount of the energy that makes the nebula shine so brightly at many wavelengths. Recently, young massive star clusters have been suggested to also efficiently produce very high-energy cosmic rays, potentially beyond PeV energies. Here, we report the detection of very-high-energy γ -ray emission from the direction of R136 with the High Energy Stereoscopic System, achieved through a multicomponent, likelihood-based modeling of the data. This supports the hypothesis that R136 is indeed a very powerful cosmic-ray accelerator. Moreover, from the same analysis, we provide an updated measurement of the γ -ray emission from 30 Dor C, the only superbubble detected at TeV energies presently. The γ -ray luminosity above 0.5 TeV of both sources is (2–3) × 10 ^35 erg s ^−1 . This exceeds by more than a factor of 2 the luminosity of HESS J1646−458, which is associated with the most massive young star cluster in the Milky Way, Westerlund 1. Furthermore, the γ -ray emission from each source is extended with a significance of >3 σ and a Gaussian width of about 30 pc. For 30 Dor C, a connection between the γ -ray emission and the nonthermal X-ray emission appears likely. Different interpretations of the γ -ray signal from R136 are discussed.

Removal of non-native plants is known to increase overall native cover within degraded communities that contain at least a small percentage of native plant cover. We investigated the mechanisms behind this pattern, asking whether removal of non-native annual species increases the density and species richness of the native community through increased seedling recruitment or through the growth of established native shrubs. We also investigated whether the effectiveness of non-native removal was influenced by region (coastal versus inland) and whether there was a threshold of native cover required for invasive removal to be effective. We established 13 study sites (7 coastal and 6 inland) located throughout the Nature Reserve of Orange County, CA, USA. Each degraded site contained four paired plots corresponding to a range of existing native plant cover: low 20–29%, medium-low 30–39%, medium-high 40–49%, and high cover 50–59% with one plot per pair subjected to non-native removal. We collected plant density, species richness, and established native shrub volume measurements to clarify the effectiveness of non-native removal. Non-native plant removal reduced non-native annual recruitment, increased that of native shrub seedlings, but had no impact on native forb recruitment. Non-native removal increased the number and reduced mortality of established native shrubs but did not influence shrub size. Native seedling density, species richness, and established native shrub number were highest inland, but coastal sites had larger adult shrubs. We found that non-native removal was most effective for increasing native density and species richness for degraded inland sites with less than 40% of existing native cover. The initial native cover did not affect established shrub volume or number. Our results confirm the importance of non-native plant removal in areas with medium-low or low native cover to increase native recruitment, species richness, adult shrub number, and to reduce established shrub mortality, especially during extreme drought.

Abstract Background Glioblastoma is the most frequent and malignant primary brain tumor. Even in the subgroup with O-6-methylguanine-DNA methyltransferase (MGMT) promoter methylation and favorable response to first-line therapy, survival after relapse is short (12 months). Standard therapy for recurrent MGMT-methylated glioblastoma is not standardized and may consist of re-resection, re-irradiation, and chemotherapy with temozolomide (TMZ), lomustine (CCNU), or a combination thereof. Preclinical results show that meclofenamate (MFA), originally developed as a nonsteroidal anti-inflammatory drug (NSAID) and registered in the USA, sensitizes glioblastoma cells to temozolomide-induced toxicity via inhibition of gap junction-mediated intercellular cytosolic traffic and demolishment of tumor microtube (TM)-based network morphology. Methods In this study, combined MFA/TMZ therapy will be administered (orally) in patients with first relapse of MGMT-methylated glioblastoma. A phase I component (6–12 patients, 2 dose levels of MFA + standard dose TMZ) evaluates safety and feasibility and determines the dose for the randomized phase II component (2 × 30 patients) with progression-free survival as the primary endpoint. Discussion This study is set up to assess toxicity and first indications of efficacy of MFA repurposed in the setting of a very difficult-to-treat recurrent tumor. The trial is a logical next step after the identification of the role of resistance-providing TMs in glioblastoma, and results will be crucial for further trials targeting TMs. In case of favorable results, MFA may constitute the first clinically feasible TM-targeted drug and therefore might bridge the idea of a TM-targeted therapeutic approach from basic insights into clinical reality. Trial registration EudraCT 2021-000708-39 . Registered on 08 February 2021

GRB 221009A is the brightest gamma-ray burst (GRB) ever detected. To probe the very-high-energy (VHE; >100 GeV) emission, the High Energy Stereoscopic System (H.E.S.S.) began observations 53 hr after the triggering event, when the brightness of the moonlight no longer precluded observations. We derive differential and integral upper limits using H.E.S.S. data from the third, fourth, and ninth nights after the initial GRB detection, after applying atmospheric corrections. The combined observations yield an integral energy flux upper limit of ${{\rm{\Phi }}}_{\mathrm{UL}}^{95 \% }=9.7\times {10}^{-12}\,\mathrm{erg}\,{\mathrm{cm}}^{-2}\,{{\rm{s}}}^{-1}$ above E _thr = 650 GeV. The constraints derived from the H.E.S.S. observations complement the available multiwavelength data. The radio to X-ray data are consistent with synchrotron emission from a single electron population, with the peak in the spectral energy distribution occurring above the X-ray band. Compared to the VHE-bright GRB 190829A, the upper limits for GRB 221009A imply a smaller gamma-ray to X-ray flux ratio in the afterglow. Even in the absence of a detection, the H.E.S.S. upper limits thus contribute to the multiwavelength picture of GRB 221009A, effectively ruling out an IC-dominated scenario.

In 2021 July, PKS 1510−089 exhibited a significant flux drop in the high-energy γ -ray (by a factor 10) and optical (by a factor 5) bands and remained in this low state throughout 2022. Similarly, the optical polarization in the source vanished, resulting in the optical spectrum being fully explained through the steady flux of the accretion disk and the broad-line region. Unlike the aforementioned bands, the very-high-energy γ -ray and X-ray fluxes did not exhibit a significant flux drop from year to year. This suggests that the steady-state very-high-energy γ -ray and X-ray fluxes originate from a different emission region than the vanished parts of the high-energy γ -ray and optical jet fluxes. The latter component has disappeared through either a swing of the jet away from the line of sight or a significant drop in the photon production efficiency of the jet close to the black hole. Either change could become visible in high-resolution radio images.

Magnetic fields in galaxies and galaxy clusters are believed to be the result of the amplification of intergalactic seed fields during the formation of large-scale structures in the universe. However, the origin, strength, and morphology of this intergalactic magnetic field (IGMF) remain unknown. Lower limits on (or indirect detection of) the IGMF can be obtained from observations of high-energy gamma rays from distant blazars. Gamma rays interact with the extragalactic background light to produce electron−positron pairs, which can subsequently initiate electromagnetic cascades. The gamma-ray signature of the cascade depends on the IGMF since it deflects the pairs. Here we report on a new search for this cascade emission using a combined data set from the Fermi Large Area Telescope and the High Energy Stereoscopic System. Using state-of-the-art Monte Carlo predictions for the cascade signal, our results place a lower limit on the IGMF of B > 7.1 × 10 ^−16 G for a coherence length of 1 Mpc even when blazar duty cycles as short as 10 yr are assumed. This improves on previous lower limits by a factor of 2. For longer duty cycles of 10 ^4 (10 ^7 ) yr, IGMF strengths below 1.8 × 10 ^−14 G (3.9 × 10 ^−14 G) are excluded, which rules out specific models for IGMF generation in the early universe.

BackgroundThe Latinx population in the United States has experienced high rates of infection, hospitalization, and death since the beginning of the COVID-19 pandemic. There is little data on the knowledge, attitude, and practices (KAP) specifically in Latinx communities in the United States. ObjectiveWe aimed to assess COVID-19 KAP and vaccine hesitancy among a Latinx cohort in the early stages of the COVID-19 pandemic (from July 2020 to October 2020), at a unique time when a vaccine was not available. MethodsParticipants aged ≥18 years were recruited at a primary care clinic in Southern California and asked to self-report sociodemographic characteristics, KAP, and vaccine hesitancy. A subset of the participants answered the vaccine hesitancy assessment as it was added after the start of data collection. KAP items were summed to create composite scores, with higher scores reflecting increased COVID-19 knowledge, positive attitudes toward the COVID-19 pandemic, and disease prevention practices. Bivariate and multivariable regression models were fitted to test associations between sociodemographic characteristics and KAP scores. For our analysis, we only included patients who self-identified as Latinx. ResultsOur final data set included 265 participants. The participants had a mean age of 49 (IQR 38.5-59) years, and 72.1% (n=191) were female, 77% (n=204) had at most a high school degree, 34.7% (n=92) had an annual income

Objectives To investigate the mortality rate for neck of femur fractures treated with arthroplasty at a tertiary level unit in South Africa and to evaluate the effect of known risk factors for mortality in neck of femur fractures treated with arthroplasty in the South African context. Design Retrospective cohort study. The main outcome was to determine mortality rates during in hospital stay, at 3 months, 6 months 1 year post surgery. The secondary outcome was to determine factors influencing mortality at 30 days, 6 months and 12 months post-surgery. Results Mortality rate was 3.3% in hospital, 5.6% at 30 days and 26.7% at 1 year. Age >79, ASA score >3, and cementing of the femur had statistically increased mortality risk ( P < .001). Average length of hospital stay was 12.3 ± 5.1 days (range 3.0-41.0 days) with 73% of patients discharged back to pre-hospital home. Conclusion Mortality rates after femur neck fracture arthroplasty in South Africa are slightly higher at 1 year compared to international data. However, the rates are comparably low during hospital stay, 30 day and at 6 months post-surgical intervals.

Abstract The study of survival outliers of glioblastoma can provide important clues on gliomagenesis as well as on the ways to alter clinical course of this almost uniformly lethal cancer type. However, there has been little consensus on genetic and epigenetic signatures of the long-term survival outliers of glioblastoma. Although the two classical molecular markers of glioblastoma including isocitrate dehydrogenase 1 or 2 (IDH1/2) mutation and O6-methylguanine DNA methyltransferase (MGMT) promoter methylation are associated with overall survival rate of glioblastoma patients, they are not specific to the survival outliers. In this study, we compared the two groups of survival outliers of glioblastoma with IDH wild-type, consisting of the glioblastoma patients who lived longer than 3 years (n = 17) and the patients who lived less than 1 year (n = 12) in terms of genome-wide DNA methylation profile. Statistical analyses were performed to identify differentially methylated sites between the two groups. Functional implication of DNA methylation patterns specific to long-term survivors of glioblastoma were investigated by comprehensive enrichment analyses with genomic and epigenomic features. We found that the genome of long-term survivors of glioblastoma is differentially methylated relative to short-term survivor patients depending on CpG density: hypermethylation near CpG islands (CGIs) and hypomethylation far from CGIs. Interestingly, these two patterns are associated with distinct oncogenic aspects in gliomagenesis. In the long-term survival glioblastoma-specific sites distant from CGI, somatic mutations of glioblastoma are enriched with higher DNA methylation, suggesting that the hypomethylation in long-term survival glioblastoma can contribute to reduce the rate of somatic mutation. On the other hand, the hypermethylation near CGIs associates with transcriptional downregulation of genes involved in cancer progression pathways. Using independent cohorts of IDH1/2- wild type glioblastoma, we also showed that these two patterns of DNA methylation can be used as molecular markers of long-term survival glioblastoma. Our results provide extended understanding of DNA methylation, especially of DNA hypomethylation, in cancer genome and reveal clinical importance of DNA methylation pattern as prognostic markers of glioblastoma.

Since the initial identification of the novel coronavirus SARS-CoV-2 in December of 2019, researchers have raced to understand its pathogenesis and begun devising vaccine and treatment strategies. An accurate understanding of the body's temporal immune response against SARS-CoV-2 is paramount to successful vaccine development and disease progression monitoring. To provide insight into the antibody response against SARS-CoV-2, plasma samples from 181 PCR-confirmed COVID-19 patients collected at various timepoints post-symptom onset (PSO) were tested for the presence of anti-SARS-CoV-2 IgM and IgG antibodies via lateral flow. Additionally, 21 donors were tracked over time to elucidate patient-specific immune responses. We found sustained levels of anti-SARS-CoV-2 antibodies past 130 days PSO, with 99% positivity observed at 31-60 days PSO. By 61-90 days PSO, the percentage of IgM-/IgG+ results were nearly equal to that of IgM+/IgG+ results, demonstrating a shift in the immune response with a decrease in IgM antibody levels. Results from this study not only provide evidence that the antibody response to COVID-19 can persist for over 4 months, but also demonstrates the ability of Easy Check™ to monitor seroconversion and antibody response of patients. Easy Check was sufficiently sensitive to detect antibodies in patient samples as early as 1-4 days PSO with 86% positivity observed at 5-7 days PSO. Further studies are required to determine the longevity and efficacy of anti-SARS-CoV-2 antibodies, and whether they are protective against re-infection.

Introduction: Geriatric patients with a fragility fracture of the hip (FFH) are especially prone to sarcopenia with poor functional outcomes and quality of life. We assessed the prevalence of sarcopenia in older South African patients with FFH. Risk factors for sarcopenia were also investigated. Materials and Methods: From August 1 to November 30, 2018, all older patients with FFH were invited to participate. Sarcopenia was diagnosed based on the revised criteria of the European Working Group on Sarcopenia in Older People (EWGSOP2). Handgrip strength (HGS) and muscle strength were assessed. Muscle quantity was determined by dual-energy X-ray absorptiometry. Demographic information was collected, and 25-hydroxyvitamin D (25[OH]D) status was determined. Results: Of the 100 hip fracture cases, 65 were enrolled, and 52% (34/65) were sarcopenic (women: 62%; men: 38%). HGS accurately identified sarcopenia (sensitivity and specificity: 100%). Patients >80 years of age had a prevalence of sarcopenia twice (18/21 [83%]) that of younger patients (18/44 [36%]). Women with sarcopenia were smaller than those without (weight: p < 0.001; height: p < 0.001; body mass index: p = 0.018). Low 25(OH)D was almost universally present, with median 25(OH)D levels significantly lower in the patients with sarcopenia (27 nmol/L [interquartile range {IQR}: 20–39] vs. 40 nmol/L [IQR: 29–53]). Several risk factors, including advanced age; female sex; a smaller body size, especially among women; limited physical activity; and low 25(OH)D levels, were identified. Discussion: The accuracy of HGS testing in this cohort underscores EWGSOP2’s recommendation that muscle strength is key to sarcopenia. Further study and follow-up are required to determine the clinical relevance of sarcopenia among FFH patients. Conclusion: The prevalence of sarcopenia in our FFH population is high. Sarcopenia is associated with poor patient outcomes following surgical intervention. Orthopaedic surgeons should therefore be cognizant of the presentation and associated risk of sarcopenia as our patient populations age.

Glioblastoma (GB) is the most common and aggressive primary brain tumor in adults and currently incurable. Despite multimodal treatment regimens, median survival in unselected patient cohorts is

Context: Carpal tunnel syndrome (CTS) is a common neuropathy accounting for up to 90% of all entrapment neuropathies of the upper limb. Identifying potential risk factors might aid in the prevention of this injury. This systematic review aims to identify the current known non-occupational risk factors for CTS as published in three electronic databases. Evidence Acquisition: Three electronic databases PubMed, Web of Knowledge, and SpringerLink were searched using the keywords “CARPAL TUNNEL SYNDROME RISK” for all published articles up to September 2015. Based on the inclusion and exclusion criteria, 2755 unique titles were independently analyzed and narrowed to a final list of 83 articles. Only articles with a level of evidence of I, II, or III were included, in accordance with robust study design and data analysis methods. The level of certainty for each risk factor was determined using previously defined criteria. Results: A total of 83 articles were included, which defined 29 individual, non-occupational risk factors. Only sex and previous musculoskeletal disorder/injury were found to have a moderate level of certainty to modify the risk of CTS. All other risk factors were evaluated as having a low level of certainty. Conclusions: Considering the large number of studies reporting on non-occupational CTS risk factors as well as the differences in reporting between studies, a lack of consistency is observed in the current review. This review does, however, offer a broad outlook on the literature and the current evidence for risk factors commonly believed to be associated with altered CTS risk. Although several risk factors are commonly believed to be associated with altered risk of CTS, the current evidence to support these beliefs is limited. Prospective cohort studies, larger sample sizes, and consistent and robust measures of risk should be used in future research.

Direct effects of human disturbance on animal populations are well documented across habitats, biomes, and species, but indirect effects of diel have received less attention. An emerging field in applied ecology involves behavioral avoidance of or attraction to humans and their trappings. We posit trophic consequences, in terms of relative risk, for four species of mammals, each of which strongly avoids human activity, in urban reserves of coastal southern California. Two species, one predator and one prey, avoid human activity via a temporal shift to become "more nocturnal"-the species' activity is centered near dawn on days without human activity but nearer to midnight on days with human activity. Diel shifts have brought the species into greater overlap, respectively, with a key prey and a key predator, overlap that may increase encounter rate and thus increase relative risk of predation, with potential consequences for trophic dynamics and cascades: increased risk of predation may depress prey population, either directly (e.g., mortality) or indirectly (e.g., "landscape of fear"). Human use of reserves, especially in high population density regions, needs to be reconsidered either to reduce access or to restrict access entirely to areas that may provide refuge to both predators and prey.

We have investigated nuclear dynamics in bound and dissociating acetylene molecular ions in a time-resolved reaction microscopy experiment with a pair of few-cycle pulses. Vibrating bound acetylene cations or dissociating dications are produced by the first pulse. The second pulse probes the nuclear dynamics by ionization to higher charge states and Coulomb explosion of the molecule. For the bound cations, we observed vibrations in acetylene (HCCH) and its isomer vinylidene (CCHH) along the CC-bond with a periodicity of around 26 fs. For dissociating dication molecules, a clear indication of enhanced ionization is found to occur along the CH- and CC-bonds after 10 fs to 40 fs. The time-dependent ionization processes are simulated using semi-classical on-the-fly dynamics revealing the underling mechanisms.

Metal nanotip photoemitters have proven to be versatile in fundamental nanoplasmonics research and applications, including, e.g., the generation of ultrafast electron pulses, the adiabatic focusing of plasmons, and as light-triggered electron sources for microscopy. Here, we report the generation of high energy photoelectrons (up to 160 eV) in photoemission from single-crystalline nanowire tips in few-cycle, 750-nm laser fields at peak intensities of (2-7.3) × 1012 W/cm2. Recording the carrier-envelope phase (CEP)-dependent photoemission from the nanowire tips allows us to identify rescattering contributions and also permits us to determine the high-energy cutoff of the electron spectra as a function of laser intensity. So far these types of experiments from metal nanotips have been limited to an emission regime with less than one electron per pulse. We detect up to 13 e/shot and given the limited detection efficiency, we expect up to a few ten times more electrons being emitted from the nanowire. Within the investigated intensity range, we find linear scaling of cutoff energies. The nonlinear scaling of electron count rates is consistent with tunneling photoemission occurring in the absence of significant charge interaction. The high electron energy gain is attributed to field-induced rescattering in the enhanced nanolocalized fields at the wires apex, where a strong CEP-modulation is indicative of the attosecond control of photoemission.