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HPV16 is the most oncogenic type of human papillomaviruses (HPV). Integration of HPV into the human genome is an important mechanism of carcinogenesis but is absent in at least 30% of HPV16+ tumors. We applied long-read whole-genome sequencing (WGS) to cervical cancer cell lines and tumors to characterize HPV16 carcinogenesis in the absence of integration. Large tandem arrays of full-length and unique truncated viral genomes integrated into multiple chromosomes were identified in two HPV16+ cell lines. The dispersion of characteristic viral variants to multiple integration sites indicates that viral deletions formed as extrachromosomal DNA (a phenomenon we term HPV superspreading). In addition, we identified an HPV16+ cell line with unintegrated (episomal) DNA that has tandem arrays of full-length, truncated, and rearranged HPV16 genomes (multimer episomes). Cytogenetic analysis of this cell line shows intense extrachromosomal HPV staining, including structures resembling double-minute chromosomes. WGS of HPV16+ cervical tumor samples from Latin America revealed that 11 of 20 tumors with only episomal HPV (EP) had intact monomer episomes. The remaining nine EP tumors had multimer and rearranged HPV genomes. The majority (80%) of HPV rearrangements and deletions disrupted the E1 and E2 genes, and EP tumors overexpressed the E6 and E7 viral oncogenes, a similar profile to tumors with HPV integration. Tumors with putative multimer HPV integrations display HPV multimers and concatemers of human and viral sequences. Our data uncovered a novel mechanism for HPV16 to cause cancer without integration through aberrant episomal replication, forming rearranged, mutated, and multimer episomes. Significance: Multimers of the HPV genome are generated in cervical tumors replicating as extrachromosomal episomes, which is associated with deletion and rearrangement of the HPV genome and provides a mechanism for oncogenesis without integration.

Background Non-physician practitioners (NPPS), including nurse practitioners (NPs) and physician assistants (PAs) are expanding their scope of practice outside of primary care and performing more procedures in dermatology. Objective To understand the scope and geographic pattern of practice by NPs and PAs in dermatology in the US. Methods Cross-sectional retrospective cohort analysis of dermatology practices in the 2014 Medicare Physician/Supplier Procedure Summary Master File, which reflects Part B carrier and durable medical equipment fee-for-service claims in the US. Results Over 4 million procedures were billed independently by NPs and PAs, which accounts for 11.51% of all. Injection, simple repair, and biopsy were the most commonly billed by non-physician practitioners, but complex procedures were also increasingly billed independently by NPs and PAs. Proportions of their claims are higher in the East Coast, Midwest, and Mountain states. Limitations Data is at the state level, limited to Medicare beneficiaries, and doesn’t include billing incident-to physicians. Conclusions This study demonstrated the increasing scope of practice of NPs and PAs in dermatology, despite limited training and lack of uniform regulations. To ensure quality and safety of care, it is prudent to set benchmarks for proper supervision and utilization of procedures in dermatology.

O presente trabalho teve como objetivo avaliar a percepção de estudantes de medicina veterinária e profissionais médicos veterinários quanto ao leite destinado ao consumo humano. O estudo foi realizado por meio da aplicação de um questionário elaborado na plataforma Google Forms®. Das 70 respostas obtidas, 43 (61,4%) foram de profissionais graduados em medicina veterinária e 27 (38,6%) graduandos nesse curso. As respostas apresentadas mostraram que 60 (85,7%) dos indivíduos consomem leite, sendo que o produto de maior consumo é o leite UAT, representado por 42 pessoas (70%). Dos 10 indivíduos que não consomem leite, 6 (60%) não o fazem por não se adaptarem ao sabor do leite, 2 (20%) por receio de fraudes, 1 (10%) pela intolerância à lactose e 1 (10%) pela alergia à proteína do leite. Quanto à presença de conservantes no leite UAT, 46 indivíduos (65,7%) acreditam que este possui conservantes. Quanto à veiculação de doenças, 68 indivíduos (97,1%) acreditam que o leite seja passível de transmitir doenças. Quando questionados sobre o que os auxilia na decisão de compra do leite, a maioria informou (47 participantes - 67,1%) observar a data de fabricação e de validade. Observou-se que mesmo entre os profissionais que possuem conhecimento prévio sobre tecnologia e inspeção de leite, ainda existe o conceito de que o leite UAT possui conservantes, sendo menos saudável. Entretanto, os entrevistados demonstraram conhecimento sobre a possibilidade de veiculação de patógenos no leite que não tenha sido submetido ao tratamento térmico.

The European Space Agency is studying two large-class missions bound to operate in the decade of the 30s, and aiming at investigating the most energetic and violent phenomena in the Universe. $Athena$ is poised to study the physical conditions of baryons locked in large-scale structures from the epoch of their formation, as well as to yield an accurate census of accreting super-massive black holes down to the epoch of reionization; LISA will extend the hunt for Gravitational Wave (GW) events to the hitherto unexplored mHz regime. We discuss in this paper the science that their concurrent operation could yield, and present possible $Athena$ observational strategies. We focus on Super-Massive (M$\lesssim10^7\rm M_{\odot}$) Black Hole Mergers (SMBHMs), potentially accessible to $Athena$ up to $z\sim2$. The simultaneous measurement of their electro-magnetic (EM) and GW signals may enable unique experiments in the domains of astrophysics, fundamental physics, and cosmography, such as the magneto-hydrodynamics of fluid flows in a rapidly variable space-time, the formation of coronae and jets in Active Galactic Nuclei, and the measurement of the speed of GW, among others. Key to achieve these breakthrough results will be the LISA capability of locating a SMBHM event with an error box comparable to, or better than the field-of-view of the $Athena$ Wide Field Imager ($\simeq0.4\,$deg$^2$) and $Athena$ capability to slew fast to detect the source during the inspiral phase and the post-merger phase. Together, the two observatories will open in principle the exciting possibility of truly concurrent EM and GW studies of the SMBHMs, Comment: 17 pages, 8 figures. Accepted for publication in MNRAS

Background Lentigo maligna/lentigo maligna melanoma (LM/LMM) can present with subclinical extension that may be difficult to define preoperatively and lead to incomplete excision and potential recurrence. Preliminarily studies have used reflectance confocal microscopy (RCM) to assess LM/LMM margins. Objective To evaluate the correlation of LM/LMM subclinical extension defined by RCM compared to the gold standard histopathology. Methods Prospective study of LM/LMM patients referred for dermatologic surgery. RCM was performed at the clinically-defined initial surgical margin followed by margin-controlled staged excision with paraffin-embedded tissue and histopathology was correlated with RCM results. Results Seventy-two patients were included. Mean age was 66.8 years (SD 11.1; 38 – 89 years); 69.4% were males. 70/72 (97.2%) lesions were located on the head neck with mean largest clinical diameter of 1.3cm (0.3 – 5 cm). Diagnostic accuracy for detection of residual melanoma in the tumor debulk (after biopsy) had a sensitivity of 96.7% and a specificity of 66.7% when compared to the histopathology. RCM margin assessment revealed an overall agreement with final histopathology of 85.9% (kappa 0.71; p Limitations No RCM imaging beyond initial planned margins was performed. Conclusion RCM showed moderate to excellent overall agreement between RCM imaging of LM/LMM and histopathology of staged excision margins.

The objective of this observational study was to compare the metabolic status of dairy cows during the last 6 wk of gestation based on colostrum volume and Ig content. For this, healthy Holstein cows were randomly selected from 3 commercial herds in Michigan. In each farm, four cohorts of 21 cows (one per season), stratified by parity, were enrolled (n=228). Cows were blood sampled weekly during the last 6 wk of gestation, and biomarkers related to nutrient utilization, oxidant status, and inflammation were quantified in serum. Cows were milked within 6 h of calving and the volume of colostrum produced was recorded and an aliquot collected. Concentration of IgG, IgA, and IgM were measured by radial immunodiffusion. Cows were grouped into high colostrum producer (HCP) or low (LCP), high IgG (HIG) or low (LIG), high IgA (HIA) or low (LIA), and high IgM (HIM) or low (LIM). For volume category, we arbitrarily defined 6 L of colostrum (4 L for first and 2 L for second feeding of calves) as the cut-off point, whereas for IgG we used the industry standard of ≥ 50g/L. To create groups of low and high IgM or IgA, we used the median of these Ig as the cutoff point. Colostrum volume was lowest in winter, but no differences were observed among parity groups. Conversely, colostrum IgG concentration was highest in fall and winter, but colostrum IgM was lowest at these seasons. However, colostrum Ig content only showed a negative weak correlation with volume (Spearman rho < -0.28). Compared to LCP, HCP cows had higher concentrations of antioxidant potential, BHB and lower cholesterol and oxidant status index. HIG cows showed higher concentrations of glucose compared to LIG. HIA cows had higher concentrations of cholesterol, reactive oxygen and nitrogen species, oxidant status index, and total protein, while BHB, and glucose were lower compared with LIA. Biomarkers of metabolic stress were not significantly different between HIM and LIM. Nevertheless, the differences observed did not result in differences in inflammatory status between animals in any of the colostrum variable categories analyzed, suggesting that physiological homeostasis was not disrupted during late gestation in association with the colostrum variables studied. Overall, the great variability observed in colostrum variables suggests that colostrogenesis is a complex and multifactorial process. However, our results suggest that greater availability of antioxidants during late gestation could support the production of higher volumes of colostrum, which needs to be explored in future trials.INTERPRETIVE SUMMARYChanges in biomarkers of metabolic stress during late gestation of dairy cows associated with colostrum volume and immunoglobulins content.By Rossi et al., page XXXX. We investigated associations between metabolic stress during the last 6 wk of gestation and the volume and immunoglobulin content of the colostrum produced. We observed that cows producing more than 6 L of colostrum exhibited increased metabolic activity during late gestation. Also, a greater blood antioxidant activity throughout late gestation was observed in cows with higher yields of colostrum, suggesting that greater availability of antioxidants might support the production of higher volumes of colostrum. Therefore, further studies should evaluate whether supplementation with additional antioxidants supplement during late gestation can improve colostrum yield.

Measurement of the surface free energy (SFE) of a material allows the prediction of its adhesion properties.

Wastewater flowrate exhibits valuable information on the conditions in a sewer line. However, existing hardware flowrate sensors are rather expensive, vulnerable to fouling and breakages, and require frequent and laborious maintenance. Therefore, they are typically only mounted in a few key locations of a sewer system, leading to a lack of important information in a major part of the network. Utilizing more cost-effective sensors and a soft sensor approach is advisable for estimating the flowrate at locations where hardware sensors are lacking. Here, the development and testing of a data-driven soft sensor for estimating the wastewater flowrate based on the water level information obtained from a low-cost ultrasonic distance sensor are presented. The research included a long-term functionality testing period of the sensor in a cold region. The soft sensor-based flowrate was applied to estimate inflow and infiltration, indicating the conditions of the sewer line. The harsh conditions inside the sewer manhole caused challenges for the reliability of the distance measurement based on an ultrasonic principle. With the developed model-based soft sensor, it seems possible to accurately estimate the wastewater flowrate. Together with additional information, it might also enable accurate monitoring of inflows and infiltrations.

Axicabtagene ciloleucel (axi-cel) is an anti-CD19 chimeric antigen receptor (CAR) T cell therapy approved for relapsed/refractory large B cell lymphoma (LBCL) and has treatment with similar efficacy across conventional LBCL subtypes. Toward patient stratification, we assessed whether tumor immune contexture influenced clinical outcomes after axi-cel. We evaluated the tumor microenvironment (TME) of 135 pre-treatment and post-treatment tumor biopsies taken from 51 patients in the ZUMA-1 phase 2 trial. We uncovered dynamic patterns that occurred within 2 weeks after axi-cel. The biological associations among Immunoscore (quantification of tumor-infiltrating T cell density), Immunosign 21 (expression of pre-defined immune gene panel) and cell subsets were validated in three independent LBCL datasets. In the ZUMA-1 trial samples, clinical response and overall survival were associated with pre-treatment immune contexture as characterized by Immunoscore and Immunosign 21. Circulating CAR T cell levels were associated with post-treatment TME T cell exhaustion. TME enriched for chemokines (CCL5 and CCL22), γ-chain receptor cytokines (IL-15, IL-7 and IL-21) and interferon-regulated molecules were associated with T cell infiltration and markers of activity. Finally, high density of regulatory T cells in pre-treatment TME associated with reduced axi-cel–related neurologic toxicity. These findings advance the understanding of LBCL TME characteristics associated with clinical responses to anti-CD19 CAR T cell therapy and could foster biomarker development and treatment optimization for patients with LBCL.

Optical fibres enable to design of new textile-based sensors for an unobtrusive, continuous, and long-term acquisition of photoplethysmography (PPG) signals. However, no research has been done about the accuracy of measuring blood oxygen saturation (SpO2) and the feasibility of PPG-based blood pressure measurement. This proof-ofconcept study examined these aspects for a woven sensing patch applied on the forehead in five healthy participants. During a controlled desaturation study, SpO2 estimation revealed an amplitude of the root-mean-squared error (ARMS) of 3.6%, and acceptable signal quality for blood pressure estimation was achieved for 40% of all data. These results indicate that textile-based sensors can reach the required PPG signal quality to simultaneously estimate multiple vital signs, including blood pressure.

The authors wish to thank J.M. Torrejón for the organization of the Athena-multi-messenger Workshops, held on November 27 - 29, 2018, in Alicante, Spain and on 5 May 2020 - 6 May 2020 in videoconference., In this paper we explore the scientific synergies between Athena and some of the key multi-messenger facilities that should be operative concurrently with Athena. These facilities include LIGO A+, Advanced Virgo+ and future detectors for ground-based observation of gravitational waves (GW), LISA for space-based observations of GW, IceCube and KM3NeT for neutrino observations, and CTA for very high energy observations. These science themes encompass pressing issues in astrophysics, cosmology and fundamental physics such as: the central engine and jet physics in compact binary mergers, accretion processes and jet physics in Super-Massive Binary Black Holes (SMBBHs) and in compact stellar binaries, the equation of state of neutron stars, cosmic accelerators and the origin of Cosmic Rays (CRs), the origin of intermediate and high-Z elements in the Universe, the Cosmic distance scale and tests of General Relativity and the Standard Model. Observational strategies for implementing the identified science topics are also discussed. A significant part of the sources targeted by multi-messenger facilities is of transient nature. We have thus also discussed the synergy of Athena with wide-field high-energy facilities, taking THESEUS as a case study for transient discovery. This discussion covers all the Athena science goals that rely on follow-up observations of high-energy transients identified by external observatories, and includes also topics that are not based on multi-messenger observations, such as the search for missing baryons or the observation of early star populations and metal enrichment at the cosmic dawn with Gamma-Ray Bursts (GRBs)., Open Access funding provided thanks to the CRUE-CSIC agreement with Springer Nature., This research has been supported by the European Union’s Horizon 2020 programme under the AHEAD (grant agreement number 654215) and AHEAD2020 project (grant agreement n. 871158). FJC and SMN acknowledges funding under project RTI2018-096686-B-C21 funded by MCIN/AEI/10.13039/501100011033 and by “ERDF A way of making Europe”, and by the Unidad de Excelencia María de Maeztu, ref. MDM-2017-0765.

The processes that transport sediment from the coastline to the shelf edge are key components of the sedimentary source-to-sink system, determining basin-margin building, deepwater deposition, organic-material accumulation, and the long-term carbon cycle. Research on shelf sediment transport has been aided recently by advances in modeling and marine technology. In this study we provide a much needed review of up-to-date findings on how sediment moves from the outer shelf onto the upper slope, and we summarize four dominant shelf-to-slope drivers: 1) river currents, 2) reworking storm waves and longshore currents, 3) strong tidal currents supplementing river outflow, and 4) small-scale to very large-scale gravity collapse of the shelf-edge area.

Risk-reducing operations are an important part of the management of hereditary predisposition to cancer. In selected cases, they can considerably reduce the morbidity and mortality associated with cancer in this population.The Brazilian Society of Surgical Oncology (BSSO) developed this guideline to establish national benchmarks for cancer risk-reducing operations.The guideline was prepared from May to December 2021 by a multidisciplinary team of experts to discuss the surgical management of cancer predisposition syndromes. Eleven questions were defined and assigned to expert groups that reviewed the literature and drafted preliminary recommendations. Following a review by the coordinators and a second review by all participants, the groups made final adjustments, classified the level of evidence, and voted on the recommendations.For all questions including risk-reducing colectomy, gastrectomy, and thyroidectomy, a major agreement was achieved by the participants, always using accessible alternatives.This and its accompanying article represent the first guideline in cancer risk reduction surgery developed by the BSSO and it should serve as an important reference for the management of families with cancer predisposition.

Type I interferon (IFN-I) mediates tissue damage in a wide range of kidney disorders, directly affecting the biology and function of several renal cell types including podocytes, mesangial, endothelial, and parietal epithelial cells. Enhanced IFN-I signaling is observed in the context of viral infections, autoimmunity (e.g., systemic lupus erythematosus), and type 1 interferonopathies, rare monogenic disorders characterized by constitutive activation of the IFN-I pathway. All these IFN-I–related disorders can cause renal dysfunction and share pathogenic and histopathological features. Collapsing glomerulopathy, a histopathological lesion characterized by podocyte loss, collapse of the vascular tuft, and parietal epithelial cell proliferation, is commonly associated with viral infections, has been described in type 1 interferonopathies such as Aicardi-Goutières syndrome and stimulator of IFN genes–associated vasculopathy with onset in infancy, and can also be induced by recombinant IFN therapy. In all these conditions, podocytes and parietal epithelial cells seem to be the primary target of IFN-I–mediated damage. Additionally, immune-mediated glomerular injury is common to viral infections, systemic lupus erythematosus, and type 1 interferonopathies such as coatomer subunit-α syndrome (COPA) and DNASE1L3 deficiency, diseases in which IFN-I apparently promotes immune-mediated kidney injury. Finally, kidney pathology primarily characterized by vascular lesions (e.g., thrombotic microangiopathy and vasculitis) is a hallmark of type 1 interferonopathy adenosine deaminase 2 deficiency as well as of systemic lupus erythematosus, viral infections, and IFN therapy. Defining the nosology, pathogenic mechanisms, and histopathological patterns of IFN-I–related kidney disorders has diagnostic and therapeutic implications, especially considering the likely near-term availability of novel drugs targeting the IFN-I pathway.