Hepatitis B virus (HBV) remains a dominant cause of hepatocellular carcinoma (HCC). Recently it was shown that HBV and woodchuck hepatitis virus (WHV) integrate into hepatocyte genome minutes after invasion. Retrotransposons and transposable sequences were frequent sites of the initial insertions suggesting a mechanism for spontaneous HBV DNA disperse throughout hepatocyte genome. Several somatic genes were also identified as early insertional targets in infected hepatocytes and woodchuck livers. Head-to-tail joints (HTJs) dominated amongst fusions indicating their creation by non-homologous-end-joining (NHEJ). Their formation coincided with robust oxidative damage of hepatocyte DNA. This was associated with activation of the poly(ADP-ribose) polymerase 1 (PARP1)-mediated dsDNA repair as reflected by augmented transcription of PARP1 and XRCC1, the PARP1 binding partner, OGG1, a responder to oxidative DNA damage, and by increased activity of NAD+, a marker of PARP1 activation, and HO1, an indicator of cell oxidative stress. The engagement of the PARP1-mediated NHEJ repair pathway explains HTJ format of the initial merges. The findings showed that HBV and WHV are immediate inducers of oxidative DNA damage, hijack dsDNA repair to integrate into hepatocyte genome and by this may initiate pro-oncogenic process. Tracking initial integrations may uncover early markers of HCC and help to explain HBV-associated oncogenesis.

Abstract Introduction:The Robert Koch Institute (RKI) managed the exchange of cross-border contact tracing data between public health authorities (PHA) in Germany and abroad during the COVID-19 pandemic. Aim: We aimed to describe the extent of RKI cross-border contact tracing and the challenges experienced. Methods:We analysed cross-border COVID-19 contact tracing events from 03 February to 05 April 2020 using information exchanged through the European “Early Warning Response System” (EWRS) as well as communication with International Health Regulation (IHR) national focal points. We described events by PHA involved, number of contact persons and exposure context. Results:The RKI processed 467 events, initiating contact to PHA 1,099 times (median 1, IQR [1;2]) and sharing data on 5,099 contact persons. Of 327 (70%) events with known exposure context, most common reported were exposures on aircraft 64 (14%), on cruise ships 24 (5%) and exposures related to non-transport contexts 210 (45%). Cruise ship and aircraft exposures yielded higher median numbers of authorities contacted (10[2;16], 4[2;11]) and contact persons (60 [9;269], 2[1;3]) than non-transport related exposures (1[1;6] and 1[1;2]), respectively. The median time spend on contact tracing activities was the highest for cruise ships: 5 days [IQR 3;9]. Conclusion:In the current COVID-19 pandemic cross-border contact tracing is considered a critical component of the outbreak response. While the majority of international contact tracing activities did not relate to exposure events in transport, they contributed substantially to the workload. The numerous communications highlight the need for fast and efficient global outbreak communication channels between PHA.

Fanconi anemia (FA) patients display an exacerbated risk of oral squamous cell carcinoma (OSCC) and precursor lesions at young ages, mainly at the oral cavity. As patients have defects in DNA repair mechanisms, standard-of-care treatments to OSCC such as radiotherapy and chemotherapy give rise to severe toxicities. New methods for early diagnosis are urgently necessary to allow treatments in early disease stages and achieve better clinical outcomes. We have conducted a prospective, longitudinal study whereby liquid biopsies from sixteen lesion/tumor-free patients were analyzed for the presence of mutations in cancer genes. DNA from saliva and plasma were sequentially collected and deep-sequenced, and the clinical evolution followed during a median time of around 2 years. In 9/16 FA patients we detected mutations in cancer genes (mainly TP53) with molecular allele frequencies (MAF) down to 0.07 %. Importantly, all patients having mutations and clinical follow-up data after mutation detection (n=6) developed oral precursor lesions or OSCC. Lead-time between mutation detection and tumor diagnosis ranged from 23 to 630 days. Strikingly, FA patients without mutations display significantly lower risk of developing precursor lesions or OSCC. Therefore, our diagnostic approach could help to stratify FA patients into risk groups, which would allow closer surveillance for OSCC or precursor lesions.

The physiological response to a psychological stressor broadly impacts energy metabolism. In-versely, changes in energy availability affect the physiological response to the stressor in terms of hypothalamus, pituitary adrenal axis (HPA) and sympathetic nervous system activation. Glu-cocorticoids, the endpoint of the HPA axis, are critical checkpoints in endocrine control of ener-gy homeostasis and have been linked to metabolic diseases including obesity, insulin resistance and type 2 diabetes. Glucocorticoids, through the glucocorticoid receptor, activate transcription of genes associated with glucose and lipid regulatory pathways and thereby control both physi-ological and pathophysiological systemic energy homeostasis. Here, we summarize the current knowledge of glucocorticoid functions in energy metabolism and systemic metabolic dysfunc-tion, particularly focusing on glucose and lipid metabolism. There are elements in the external environment that induce lifelong changes in the HPA axis stress response and glucocorticoid levels, the most prominent are early-life adversity, or exposure to traumatic stress. We hypothe-sise that when the HPA axis is so disturbed after early-life adversity, it will fundamentally alter hepatic gluconeogenesis, inducing hyperglycaemia, and hence crystalise the significant lifelong risk of developing either the metabolic syndrome, or type 2 diabetes. This gives a “Jekyll and Hyde” role to gluconeogenesis, providing the necessary energy in situations of acute stress, but driving towards pathophysiological consequences when the HPA axis has been altered.

The document sets out three differentiated proposals for the transport of medicines through RPAS with their respective regulations, adapted to different operational categories: open category, special category and military scope. In the open category, an economical and efficient solution is prioritized for urban and rural areas, complying with weight and height regulations, in addition to guaranteeing the stability and quality of medications during transportation. The special category allows more complex operations and in more adverse conditions, such as densely populated areas and long routes, incorporating advanced security measures and training for personnel. In the military field, RPAS are used in conflict zones and hard-to-reach areas, ensuring the safe and rapid delivery of medical supplies under extreme conditions. Success stories in different countries are highlighted, demonstrating significant improvements in delivery times and risk reduction for health personnel.

Adverse childhood experiences are known to program children for disrupted biological cycles, premature aging, microbiome dysbiosis, immune-inflammatory misregulation, and chronic disease multimorbidity. To date, the microbiome has not been a major focus of deprogramming efforts despite its emerging role in every aspect of ACE-related dysbiosis and dysfunction. This article examines: 1) the utility of incorporating microorganism-based, anti-aging approaches to combat ACE-programmed chronic diseases (also known as noncommunicable diseases and conditions, NCDs) and 2) microbiome regulation of core systems biology cycles that affect NCD comorbid risk. In this review microbiota influence over three key cyclic rhythms (circadian cycles, the sleep cycle, and the lifespan/longevity cycle) as well as tissue inflammation and oxidative stress are discussed as an opportunity to deprogram ACE-driven chronic disorders. Microbiota, particularly those in the gut, have been shown to affect host-microbe interactions regulating the circadian clock, sleep quality, as well as immune function/senescence and regulation of tissue inflammation. The microimmunosome is one of several systems biology targets of gut microbiota regulation. Furthermore, correcting misregulated inflammation and increased oxidative stress is key to protecting telomere length and lifespan/longevity and extending what has become known as the healthspan. This review article concludes that to reverse the tragedy of ACE-programmed NCDs and premature aging, managing the human holobiont microbiome should become a routine part of healthcare and preventative medicine across the life course.

Epoxy asphalt (EA) concrete is widely used in constructing long-span steel bridge pavements (SBDPs). This study aims to derive a fatigue damage evolution law, conducting an experimental investigation of SBDP. First, a general theoretical form of the fatigue damage evolution law of materials is established based on the thermal motion of atoms. Then, fatigue experiments demonstrate that this evolution law well represents the known damage–life relationships of SBDP. Taking into account the experimental relationships between damage and fatigue life under symmetrical cyclic loadings with different overload amplitudes and temperature variations, a detailed damage evolution law is deduced. Finally, the role of damage accumulation is discussed on the basis of the proposed damage evolution law for the extreme situation of heavy overload and severe environments. The results show that both heavy loading and falling temperatures increase the fatigue damage of SBDP considerably; therefore, SBDP should avoid heavy loading combined with winter temperatures. EA shows a fatigue life two to three times longer than that of modified matrix asphalt (SMA) or guss asphalt (GA). For the same thickness, EA pavement is demonstrated to be more suitable for an anti-fatigue design of large-span SBDP under high traffic flows and low temperatures.

Background: Although endoscopic submucosal dissection (ESD) can provide a high rate of curative resection, remaining gastric mucosa after ESD is at risk of metachronous recurrence. We investigated risk factors for metachronous superficial gastric epithelial neoplasms (MSGENs) following ESD. Methods: We conducted a retrospective cohort study including 369 patients with 382 lesions that underwent ESD for adenoma/early gastric cancer. The primary endpoint was to identify clinicopathological risk factors for the occurrence of MSGENs. The secondary endpoint was to evaluate the association of Helicobacter pylori (Hp) eradication with the MSGENs. Results: Twenty-seven MSGENs were occurred. The subjects were divided into MSGEN and not-MSGEN groups. There was a significantly higher frequency of histological intestinal metaplasia (HIM) and initial neoplasm location in upper or middle part (INUM) in the MSGEN group. The HIM group and INUM group had significantly higher cumulative incidence of MSGENs. We compared the 27 patients of MSGEN group and 27 patients of matched not-MSGEN (Mnot-MSGEN) group that was matched to the MSGEN group for variables including HIM and INUM. There was a significantly higher frequency of Hp spontaneous eradication in the MSGEN group. Conclusion: HIM, INUM and Hp spontaneous eradication may be clinicopathological risk factors for developing MSGENs after ESD.

The Environmental interactions contributed to the processes of settlement and development of the first settlers at southern Peru 15,000 BC. The determination of this process is based on paleoclimatic studies at southern Peru and ethnoarchaeological evidence. The determination of this process is based on paleoclimatic studies of southern Peru and ethnoarchaeological evidence; establishing as a result of this analysis the hypothesis of environmental interaction and territorial occupation of the first hunter-gatherer populations until their consolidation, dominating the geographical space from Tacna. The Disruptive disaster events and their effects on climate during the Peruvian Paleolithic resulted in the origin of local societies that shaped the Tiawanaku societies of the early horizon at Southern Peru and Northern Chile.

Individuals residing in more deprived areas have a lower diet quality. While several studies have shown that individuals with a lower diet quality have a higher mortality risk, a low quality diet might also lead to poor health in highly deprived areas. We aimed to examine the association between deprivation within an area and all-cause mortality risk according to diet quality. Methods: We conducted a population-based prospective study on 27994 men and 33273 women aged 45–75 years. Neighborhood deprivation was assessed using the Japanese areal deprivation index (ADI). Dietary intakes were assessed using a validated 147-item food frequency questionnaire. Subsequently, Japanese Food Guide Spinning Top scores were calculated. Hazard ratios (HR) and 95% confidence intervals (CI) of mortality were calculated according to tertiles of ADI by diet quality score. Results: Individuals residing in the most deprived area had the lowest dietary scores. During the 16.7-year follow-up, compared to individuals with a high quality diet residing in the least deprived area, individuals with a low quality diet had a higher risk of mortality according to increment of ADI (P trend = 0.02); the multivariate adjusted HR (95% CI) was 1.07 (1.00-1.15), 1.15 (1.07-1.24), and 1.18 (1.08-1.29) in those residing in the lowest through the highest third of ADI, respectively. However, individuals with a high quality diet had no significant association between ADI and mortality (P trend =0.87). Conclusion: A well-balanced diet may prevent early death associated with neighborhood socioeconomic status among those residing in highly deprived areas.

One in 12 babies is born with a rare genetic disease. Sadly, most cases are undetected until later age, missing time for early treatment and opportunity to prevent complications. Humanity has entered a new era where Big Data collected by governments, including 2D and 3D facial scans, are available. Many rare genetic diseases can be identified by artificial intelligence (AI) analysis of the facial photo. Phenotyping AI utilizations facilitate comprehensive and accurate genetic evaluations. AI processing of this Big Data to identify rare genetic diseases could bring unimaginable benefits to healthcare, although this would be a questionable step in terms of citizen privacy and could lead to future "Orwellian" ramifications with government abuse. Going forward, a balance must be found between protecting the privacy of citizens and the enticing use of AI for their health risks and cost savings through prevention. The unimaginable potential of AI early diagnostics from facial photos also raises various ethical and legal concerns. This paper presents concept, protentional methods and legal and other limitations within EU legal framework in contrast with potential benefits. This paper is focused on AI utilization to early diagnostic of rare genetic diseases. Shift of paradigm in the screening for rare genetic diseases in population with AI face analysis is expected to have a significant impact. The potential of AI algorithms utilizations similar to face2gene app in general population or systematically on Big governmental datasets recording facial traits changes in time can have significant impact on public health but at the same time give raise to profound concern as violation of one’s privacy.

Objectives: We aimed to clarify the endoscopic and clinicopathological features of raspberry-shaped gastric lesions (RSGLs) and to establish an endoscopic diagnostic algorithm for RSGLs. Methods: We collected RSGLs from an endoscopic database at our hospital between May 2009 and August 2021. All RSGLs were histopathologically classified and compared based on their endoscopic and clinicopathological characteristics. Results: Sixty-five RSGLs in 54 patients were classified into five histopathological types: gastric adenocarcinoma of foveolar type (GA-FV, n = 43), gastric adenocarcinoma of fundic-gland type (GA-FG, n = 2), gastric adenocarcinoma of fundic-gland mucosa type (GA-FGM, n = 4), hyperplastic polyp (HP, n = 12), and proton pump inhibitor-related lesion (PPI-L, n = 4). All RSGLs exhibited polygonal or curved marginal crypt epithelium (MCE). GA-FV lesions had homogenously reddish (95%) and irregular microvascular (MV) pattern (91%). GA-FG lesions were heterogeneously reddish with a submucosal tumor shape (100%) and had a regular MV pattern (50%). GA-FGM lesions were homogenously reddish (75%) and occasionally had a submucosal tumor shape (50%) with an irregular MV pattern (75%). HP and PPI-L were homogeneously reddish (93%), with linear or dotted MCE (81%) and a regular MV pattern (100%). Conclusion: Our diagnostic algorithm for RSGLs constructed using endoscopic features might be useful for the endoscopic differential diagnosis of RSGLs.

Non-suicidal self-injurious behavior (NSSI), prevalent in patients with non-psychotic mental disorders (NPMD), is associated with numerous adverse outcomes. Despite active research into the clinical and psychological aspects of NSSI, the underlying biological mechanisms remain obscure. Early adverse experiences are believed to induce long-lasting changes in neuroendocrine mechanisms of stress control playing a key role in NSSI development. The aim of the study was to evaluate parameters potentially predicting development of NSSI in female patients with NPMD. Eighty female patients over 18 years with NPMD and suicidal ideation (40 with and 40 without NSSI) and 48 age matching women without evidence of mental illness (healthy controls) were enrolled. Diagnostic interviews and self-report measures were used to assess childhood maltreatment, presence, frequency, and characteristics of suicidal and self-injurious thoughts and behaviors, the Beck Depression Inventory scale to assess severity of depression. Hypothalamic-pituitary-adrenal axis markers, hormones, and neurotrophic factors were measured in blood serum. The likelihood of developing NSSI in patients with NPMD was associated with early adverse family history and elevated adrenocorticotropic hormone levels. Dysregulation of hypothalamic-pituitary-adrenal axis as a result of early chronic stress experiences may represent critical biological mechanism promoting the development of NSSI behaviors in patients with NPMD.

Here we mathematically model black holes and the early universe following dynamics similar to RLC electrical models, focusing on their similarities at the singularity. We use this mathematically modelling to hypothesize the evolution of an expanding universe as the result of a black hole collapse followed by its evaporation. Or model consists of several steps defined by: (1) the formation of a black hole following general relativity equations; (2) growth of the black hole modelled as a resistance-capacitance-like electrical circuit; (3) expansion of space-time following the disintegration of the black hole, modelled by RLC-like dynamics. In updating this article, version 2, we will expand by presenting three additional examples related to the theory of the generalization Boltzmann's constant in curved space-time and the theory of general and especial relativity. We will calculate the critical mass to produce a black hole in the LHC, the existence of a high temperature Bose-Einstein condensate and finally we will demonstrate the existence of a tangential force to the repulsion force in the disintegration of subatomic particles. In the update of this article, version 3, we will expand to develop two examples. First, we will present the relationship between M-theory, extra dimensions with the theory of the generalization of Boltzmann's constant in curved space-time. Secondly, we will propose the idea of ​​updating the Lambda-CDM model, considering the primordial gravitational waves to correctly describe the evolution of the universe.

A retrospective cohort study was performed to determine the likelihood of malignant stroke after mechanical thrombectomy via ASPECTS-PASS score(A-P score), a novel scoring system using ASPECT score and number of arterial-passes. This prediction score is designed to help clinicians take early measures. Malignant stroke is defined as a large MCA infarct with mass effect that develops during the first 5 days following presentation and is associated with approximately 80% mortality. Previous studies have shown an association of low ASPECTS and high number of passes with poor outcome.We performed a retrospective cohort analysis on 78 patients with anterior circulation stroke who underwent mechanical thrombectomy at our hospital. We analyzed the likelihood of developing malignant stroke post thrombectomy in the first 5 days following successful recanalization (TICI ≽ 2b). Malignant stroke is defined as severe symptoms secondary to edema as evidenced by midline shift, cistern engorgement, and hemorrhagic conversion with edema. Patients with ASPECTS of 0-5 were excluded. We used two variables to predict the outcome: ASPECT score and number-of-passes. We used the equation ASPECT score minus number-of-passes (A-P) to arrive at a single number to predict the risk of malignant stroke. A-P scoring scale ranged from 0-9. Our study showed a statistically significant inverse relationship of A-P score and risk of malignant stroke. Approximately 90% of patients with A-P score < 5 developed malignant stroke in our study. A-P score can help predict malignant stroke post thrombectomy even after successful recanalization. Thus, A-P score of ≤ 5 suggests very high risk. (A-P) Score can assist clinicians to take early measures, and thereby prevent worse outcomes.

The official recommendations to manage COVID-19 in the outpatient setting focus on high-cost drugs (remdesivir, nirmatrelvir-ritonavir, molnupiravir), suffering from many problems. Therefore, one may consider also other treatments meeting these criteria: • promising effectiveness, based on favorable randomized controlled trials (RCTs) of sufficient validity. Even without definitive evidence, physicians and informed patients can consider them if they are also: • safe, to the state of knowledge • with a very favorable opportunity cost • biologically plausible/not implausible • accessible • without major commercial sponsors in the trials promoting them, and with researchers without major conflicts of interests. The main focus is on a limited group of functional foods and some their active ingredients, with further mention of other substances of different origin, yet fully meeting all the aforementioned criteria. The functional foods and substances described and discussed certainly do not cover all the known effective therapies for COVID-19 (in one case also for Long-COVID), but the only therapies proposed in this paper currently satisfy all the above criteria. The supporting scientific evidence will favor meta-analyses of RCTs that include the most definitive outcome: all-cause mortality, i.e. the outcome that most fully informed people tend to prioritize. Furthermore, the reported evidence favors clinical studies of the most valid design, i.e. RCTs.

Clinical and histological similarities between sarcoidosis and tuberculosis have driven repeated investigations looking for a mycobacterial cause of sarcoidosis. Over 50 years ago “anonymous mycobacteria” were suggested to have a role in the etiology of sarcoidosis. Both tuberculosis and sarcoidosis have a predilection for lung involvement though each can be found in any area of the body. A key histopathologic feature of both sarcoidosis and tuberculosis is the granuloma – while the tuberculous caseating granuloma has an area of caseous necrosis with a cheesy consistency; the non-caseating granuloma of sarcoidosis does not have this feature. This article reviews and reiterates the complicity of the infectious agent, Mycobacterium avium ss. paratuberculosis (MAP) as a cause of sarcoidosis. MAP is involved in a parallel story as the putative cause of Crohn’s disease, another disease featuring noncaseating granulomas. MAP is a zoonotic agent infecting ruminant animals and is found in dairy products and in environmental contamination of water and air. Despite increasing evidence tying MAP to several human diseases, there is a continued resistance to embracing its pleiotropic roles. "Who Moved My Cheese" is a simple yet powerful book that explores the ways in which individuals react to change. Extending the metaphor, the “non-cheesy” granuloma of sarcoidosis actually contains the difficult-to-detect “cheese”, MAP; MAP did not move, it was there all along.

Here we will electrically-quantum model the neutron and proton as a three-phase alternating current electric generator, for this, we will use the theory of three-phase electric generators and vector or phasor diagrams. We will use this model to hypothesize how the quarks that form neutrons and protons with a combined mass of 10 MeV/c², can generate, through quarks-antiquarks-gluon interactions, a mass of 939.56 MeV/c² for the neutron and a mass of 938.27 MeV/c² for the proton. Using quantum mechanics and the theory of the generalization of the Boltzmann constant in curved space-time we will calculate the number of quarks-antiquarks-gluons and gravitons inside a neutron. We will also analyse βˉ decay using vector diagrams, we will calculate the tension of the string T₀ and the length of the string ℓs between quarks-antiquark and finally, we will model a black hole using a neutron equivalent model. In version 2 of this article, we will update the vector diagrams of the βˉ decay and theoretically calculate the energy of the W⁻ boson, the Z⁰ boson, and the Θ angle, Θ = arc cos (W⁻/Z⁰). We will demonstrate, through vector diagrams, that quarks-antiquarks-gluon interactions are the cause of the origin of the W⁻ boson and the Z⁰ boson. We will also demonstrate how the fine structure constant α originates. It is important to make clear, in future updates, we will describe the relationship that exists between the theory described in this paper and the Isospin theory, flavour and colour theory

Here, applying the theory of the generalization of the Boltzmann constant in curved space-time, we will model the mechanism by which elementary particles are formed. We will determine the relationship between gravity and each of the elementary particles that form the standard model following analogies to that of stellar bodies. In order to achieve our goal, we will propose new models for photons, quarks and gluons; with this, we will demonstrate why there are stable and unstable elementary particles; why the first family of elementary particles forms hadrons and why the second and third families cannot form hadrons; why the fermions comply with the Pauli exclusion principle and why the bosons do not comply with the Pauli exclusion principle, etc. Finally, we will analyse the generalization of the ADS/CFT correspondence and propose a theory of everything (T.O.E.).

This literature review investigates how the diverse habitats of Baryonyx walkeri influenced its hunting strategies, with a focus on adaptations for piscivory and generalist predation. The spinosaurid theropod Baryonyx walkeri, known for its distinctive elongated snout and conical teeth, inhabited a variety of environments during the Early Cretaceous period. Fossil evidence suggests that Baryonyx frequented fluvial and lacustrine environments, leading to the hypothesis that its primary diet consisted of fish and other aquatic organisms. Detailed analysis of its cranial morphology reveals a suite of adaptations, including robust forelimbs with a large, sickle-shaped claw, ideal for catching slippery prey. Isotopic analysis of oxygen in Baryonyx indicates a significant reliance on fish and other similar organisms. Comparisons with modern analogs, such as crocodilians, provide further insight into the behavioral ecology of Baryonyx. This review integrates paleontological data with modern ecological analogs to reconstruct the hunting strategies of Baryonyx walkeri. The findings underscore the importance of habitat diversity in shaping the evolutionary pathways of predatory dinosaurs and contribute to a broader understanding of spinosaurid ecology and behavior.