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We consider the computability and complexity of decision questions for Probabilistic Finite Automata (PFA) with sub-exponential ambiguity. We show that the emptiness problem for strict and non-strict cut-points of polynomially ambiguous commutative PFA remains undecidable, implying that the problem is undecidable when inputs are from a letter monotonic language. We show that the problem remains undecidable over a binary input alphabet when the input word is over a bounded language, in the noncommutative case. In doing so, we introduce a new technique based upon the Turakainen construction of a PFA from a Weighted Finite Automata which can be used to generate PFA of lower dimensions and of subexponential ambiguity. We also study freeness/injectivity problems for polynomially ambiguous PFA and study the border of decidability and tractability for various cases., Comment: Amended an issue regarding commutativity of matrices in Theorem 1 to show why the matrices commute

OBJECTIVES The aim of this study was to assess the impact of access-site crossover in patients with acute coronary syndrome undergoing invasive management via radial or femoral access. BACKGROUND There are limited data on the clinical implications of access-site crossover. METHODS In the MATRIX (Minimizing Adverse Haemorrhagic Events by Transradial Access Site and Systemic Implementation of Angiox)-Access trial, 8,404 patients with acute coronary syndrome were randomized to radial or femoral access. Patients undergoing access-site crossover or successful access site were investigated. Thirty-day coprimary outcomes were a composite of death, myocardial infarction, or stroke (major adverse cardiovascular events [MACE]) and a composite of MACE or Bleeding Academic Research Consortium type 3 or 5 bleeding (net adverse clinical events [NACE]). RESULTS Access-site crossover occurred in 183 of 4,197 patients (4.4%) in the radial group (mainly to femoral access) and 108 of 4,207 patients (2.6%) in the femoral group (mainly to radial access). In multivariate analysis, the risk for coprimary outcomes was not significantly higher with radial crossover compared with successful radial (MACE: adjusted rate ratio [adjRR]: 1.25; 95% confidence interval [CI]: 0.81 to 1.93; p = 0.32; NACE: adjRR: 1.40; 95% CI: 0.94 to 2.06; p = 0.094) or successful femoral access (MACE: adjRR: 1.17; 95% CI: 0.76 to 1.81; p = 0.47; NACE: adjRR: 1.26; 95% CI: 0.86 to 1.86; p = 0.24). Access site-related Bleeding Academic Research Consortium type 3 or 5 bleeding was higher with radial crossover than successful radial access. Femoral crossover remained associated with higher risks for MACE (adjRR: 1.84; 95% CI: 1.18 to 2.87; p = 0.007) and NACE (adjRR: 1.69; 95% CI: 1.09 to 2.62; p = 0.019) compared with successful femoral access. Results remained consistent after excluding patients with randomized access not attempted. CONCLUSIONS Crossover from radial to femoral access abolishes the bleeding benefit offered by the radial over femoral artery but does not appear to increase the risk for MACE or NACE compared with successful radial or femoral access. (Minimizing Adverse Haemorrhagic Events by Transradial Access Site and Systemic Implementation of Angiox [MATRIX]; NCT01433627) (C) 2021 by the American College of Cardiology Foundation. The MATRIX trial was sponsored by Societa Italiana di Cardiologia Invasiva (a nonprofit organization), which received grant support from The Medicines Company and Terumo. This substudy did not receive any direct or indirect funding. Dr. Leonardi has received grants and personal fees from AstraZeneca, Bristol Myers Squibb/ Pfizer, and Chiesi; and has received personal fees from Bayer outside the submitted work. Dr. Vranckx has received personal fees from AstraZeneca, Terumo, CSL Behring, Daiichi-Sankyo, and Bayer Health Care outside the submitted work. Dr. Frigoli is affiliated with CTU Bern, University of Bern, which has a staff policy of not accepting honoraria or consultancy fees. However, CTU Bern is involved in the design, conduct, or analysis of clinical studies funded by not-forprofit and for- profit organizations. In particular, pharmaceutical and medical device companies provide direct funding to some of these studies. For an up- to-date list of CTU Bern's conflicts of interest, see http://www.ctu.unibe.ch/research/declaration_of_interest/index_eng. html. Dr. Windecker has received research and educational grants to the institution from Abbott, Amgen, Bristol Myers Squibb, Bayer, Boston Scientific, Biotronik, Cardinal Health, CardioValve, CSL Behring, Daiichi- Sankyo, Edwards Lifesciences, Johnson & Johnson, Medtronic, Querbet, Polares, Sanofi, Terumo, and Sinomed; serves as an unpaid member of the steering and/or executive groups of trials funded by Abbott, Abiomed, Amgen, Bristol Myers Squibb, Boston Scientific, Biotronik, Cardiovalve, Edwards Lifesciences, MedAlliance, Medtronic, Polares, Sinomed, V-Wave, and Xeltis (but has not received personal payments from any pharmaceutical company or device manufacturer); and is a member of the steering and/or executive committee groups of several investigator- initiated trials that receive funding from industry without impact on his personal remuneration. Dr. Valgimigli has received grants and personal fees from Abbott, Terumo, and AstraZeneca; has received personal fees from Chiesi, Bayer, Daiichi-Sankyo, Amgen, Alvimedica, Biosensors, and Idorsia; and has received grants from Medicure outside the submitted work. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose. Valgimigli, M (corresponding author), Ente Osped Cantonale, Cardioctr Ticino Inst, Via Tesserete 48, CH-6900 Lugano, Switzerland. marco.valgimigli@cardiocentro.org

DSBs are harmful lesions produced through endogenous metabolism or by exogenous agents such as ionizing radiation, that can trigger genomic rearrangements. We have recently shown that exposure to 2 Gy of X-rays has opposite effects on the induction of Shh-dependent MB in NHEJ- and HR-deficient Ptch1+/− mice. In the current study we provide a comprehensive link on the role of HR/NHEJ at low doses (0.042 and 0.25 Gy) from the early molecular changes through DNA damage processing, up to the late consequences of their inactivation on tumorigenesis. Our data indicate a prominent role for HR in genome stability, by preventing spontaneous and radiation-induced oncogenic damage in neural precursors of the cerebellum, the cell of origin of MB. Instead, loss of DNA-PKcs function increased DSBs and apoptosis in neural precursors of the developing cerebellum, leading to killing of tumor initiating cells, and suppression of MB tumorigenesis in DNA-PKcs-/-/Ptch1+/− mice. Pathway analysis demonstrates that DNA-PKcs genetic inactivation confers a remarkable radiation hypersensitivity, as even extremely low radiation doses may deregulate many DDR genes, also triggering p53 pathway activation and cell cycle arrest. Finally, by showing that DNA-PKcs inhibition by NU7441 radiosensitizes human MB cells, our in vitro findings suggest the inclusion of MB in the list of tumors beneficiating from the combination of radiotherapy and DNA-PKcs targeting, holding promise for clinical translation.

The study of decomposition by using accumulated degree days (ADDs) has been suggested not only in terrestrial decay but also for water-related deaths. Previous studies have demonstrated that the accumulation of thermal energy as a function of the post-mortem submersion interval (PMSI) can be derived from a descriptive decompositional scoring system (DSS). In order to verify how useful can the total aquatic decomposition score (TADS) for ADD prediction be, a comparative taphonomic study has been performed between two series of bodies: 16 corpses found floating in shallower waters with a presumptive PMSI from 3 to 118 days and exposed to water temperatures (Tw) between 10.5 and 20.3 °C approximately equating from a minimum of 46 to 1.392 ADD; 52 bodies, all victims of a single shipwreck, found in sequestered environments and subjected to constant Tw of 4 °C for 210 days approximately equating to 840 ADD. The two series of bodies have revealed different stages of decay and a large DSS variability. In most of bodies, freshly formed adipocere was able to delay the appearance of later decompositional stages explaining why most of the bodies were in relatively good condition. Although promising, the accuracy of the TADS model can be affected by adipocere and animal activity. The TADS model suffers of the same limitations for ADD calculations as they can give a false perception of accuracy due to the complexity of integrating all changing factors affecting human decay in sequestered and non-sequestered marine environments (currents, animal activity, water temperatures, depth of submersion).

Purpose: To investigate the dose and spatial dependence of abscopal radiation effects occurring in vivo in the mouse, along with their tumorigenic potential in the central nervous system (CNS) of a radiosensitive mouse model. Methods and Materials: Patched1 (Ptch1)+/- mice, carrying a germ-line heterozygous inactivating mutation in the Ptch1 gene and uniquely susceptible to radiation damage in neonatal cerebellum, were exposed directly to ionizing radiation (1, 2, or 3 Gy of x-rays) or treated in a variety of partial-body irradiation protocols, in which the animals' head was fully protected by suitable lead cylinders while the rest of the body was exposed to x-rays in full or in part. Apoptotic cell death was measured in directly irradiated and shielded cerebellum shortly after irradiation, and tumor development was monitored in lifetime groups. The same endpoints were measured using different shielding geometries in mice irradiated with 3 or 10 Gy of x-rays. Results: Although dose-dependent cell death was observed in off-target cerebellum for all doses and shielding conditions tested, a conspicuous lack of abscopal response for CNS tumorigenesis was evident at the lowest dose of 1 Gy. By changing the amount of exposed body volume, the shielding geometry could also significantly modulate tumorigenesis depending on dose. Conclusions: We conclude that interplay between radiation dose and exposed tissue volume plays a critical role in nontargeted effects occurring in mouse CNS under conditions relevant to humans. These findings may help understanding the mechanisms of long-range radiation signaling in harmful effects, including carcinogenesis, occurring in off-target tissues. © 2013 Elsevier Inc. All rights reserved.