Induction of cancer neoantigens facilitates development of clinically relevant models for the study of pancreatic cancer immunobiology.

Neoantigen burden and CD8 T cell infiltrate are associated with clinical outcome in pancreatic ductal adenocarcinoma (PDAC). A shortcoming of many genetic models of PDAC is the lack of neoantigen burden and limited T cell infiltrate. The goal of the present study was to develop clinically relevant models of PDAC by inducing cancer neoantigens in KP2, a cell line derived from the KPC model of PDAC. KP2 was treated with oxaliplatin and olaparib (OXPARPi), and a resistant cell line was subsequently cloned to generate multiple genetically distinct cell lines (KP2-OXPARPi clones). Clones A and E are sensitive to immune checkpoint inhibition (ICI), exhibit relatively high T cell infiltration, and have significant upregulation of genes involved in antigen presentation, T cell differentiation, and chemokine signaling pathways. Clone B is resistant to ICI and is similar to the parental KP2 cell line in terms of relatively low T cell infiltration and no upregulation of genes involved in the pathways noted above. Tumor/normal exome sequencing and in silico neoantigen prediction confirms successful generation of cancer neoantigens in the KP2-OXPARPi clones and the relative lack of cancer neoantigens in the parental KP2 cell line. Neoantigen vaccine experiments demonstrate that a subset of candidate neoantigens are immunogenic and neoantigen synthetic long peptide vaccines can restrain Clone E tumor growth. Compared to existing models, the KP2-OXPARPi clones better capture the diverse immunobiology of human PDAC and may serve as models for future investigations in cancer immunotherapies and strategies targeting cancer neoantigens in PDAC.

Dynamic generation of photonic spatial quantum states with an all-fiber platform.

Photonic spatial quantum states are a subject of great interest for applications in quantum communication. One important challenge has been how to dynamically generate these states using only fiber-optical components. Here we propose and experimentally demonstrate an all-fiber system that can dynamically switch between any general transverse spatial qubit state based on linearly polarized modes. Our platform is based on a fast optical switch based on a Sagnac interferometer combined with a photonic lantern and few-mode optical fibers. We show switching times between spatial modes on the order of 5 ns and demonstrate the applicability of our scheme for quantum technologies by demonstrating a measurement-device-independent (MDI) quantum random number generator based on our platform. We run the generator continuously over 15 hours, acquiring over 13.46 Gbits of random numbers, of which we ensure that at least 60.52% are private, following the MDI protocol. Our results show the use of photonic lanterns to dynamically create spatial modes using only fiber components, which due to their robustness and integration capabilities, have important consequences for photonic classical and quantum information processing.

Halo sign in fetal cytomegalovirus infection: cerebral imaging abnormalities and postmortem histopathology in 35 infected fetuses.

OBJECTIVE: To evaluate the correlation of periventricular echogenic halo (halo sign) with histopathological findings and its association with other brain imaging abnormalities in fetuses with cytomegalovirus (CMV) infection. METHODS: This was a retrospective study of fetuses diagnosed with severe CMV infection based on central nervous system (CNS) abnormalities seen on ultrasound, which had termination of pregnancy (TOP) or fetal demise at a single center from 2006 to 2021. All included cases had been evaluated by conventional complete fetal autopsy. A maternal-fetal medicine expert reanalyzed the images from the transabdominal and transvaginal neurosonography scans, blinded to the histological findings. The halo sign was defined as the presence of homogeneous periventricular echogenicity observed in all three fetal brain orthogonal planes (axial, parasagittal and coronal). Cases were classified according to whether the halo sign was the only CNS finding (isolated halo sign) or concomitant CNS anomalies were present (non-isolated halo sign). An expert fetal radiologist reanalyzed magnetic resonance imaging (MRI) examinations when available, blinded to the ultrasound and histological results. Hematoxylin-eosin-stained histologic slides were reviewed independently by two experienced pathologists blinded to the neuroimaging results. Ventriculitis was classified into four grades (Grades 0-3) according to the presence and extent of inflammation. Brain damage was categorized into two stages (Stage I, mild; Stage II, severe) according to the histopathological severity and progression of brain lesions. RESULTS: Thirty-five CMV-infected fetuses were included in the study, of which 25 were diagnosed in the second and 10 in the third trimester. One fetus underwent intrauterine demise and TOP was carried out in 34 cases. The halo sign was detected on ultrasound in 32 (91%) fetuses (23 in the second trimester and nine in the third), and it was an isolated sonographic finding in six of these cases, all in the second trimester. The median gestational age at ultrasound diagnosis of the halo sign was similar between fetuses in which this was an isolated and those in which it was a non-isolated CNS finding (22.6 vs 24.4 weeks; P = 0.10). In fetuses with a non-isolated halo sign, the severity of additional ultrasound findings was not associated with the trimester at diagnosis, except for microencephaly, which was more frequent in the second compared with the third trimester (10/18 (56%) vs 1/8 (13%); P = 0.04). With respect to histopathological findings, ventriculitis was observed in all fetuses with an isolated halo sign, but this was mild (Grade 1) in the majority of cases (4/6 (67%)). Extensive ventriculitis (Grade 2 or 3) was more frequent in fetuses with a non-isolated halo sign (21/26 (81%)) and those without a periventricular echogenic halo (2/3 (67%); P = 0.032). All fetuses with an isolated halo sign were classified as histopathological Stage I with no signs of brain calcifications, white-matter necrosis or cortical injury. On the other hand, 25/26 fetuses with a non-isolated halo sign and all three fetuses without a periventricular echogenic halo showed severe brain lesions and were categorized as histopathological Stage II. Among fetuses with a non-isolated halo, histological brain lesions did not progress with gestational age, although white-matter necrosis was more frequent, albeit non-significantly, in fetuses diagnosed in the second vs the third trimester (10/15 (67%) vs 3/11 (27%); P = 0.06). CONCLUSIONS: In CMV-infected fetuses, an isolated periventricular echogenic halo was observed only in the second trimester and was associated with mild ventriculitis without signs of white-matter calcifications or necrosis. When considering pregnancy continuation, detailed neurosonographic follow-up complemented by MRI examination in the early third trimester is indicated. The prognostic significance of the halo sign as an isolated finding is still to be determined. © 2023 International Society of Ultrasound in Obstetrics and Gynecology.

Arsenic and fluorine in groundwater in northern Mexico: spatial distribution and enrichment factors.

North-central Mexico has groundwater contaminated with arsenic (As) and fluoride (F). Based on the dispersion patterns of these solutes, their sources are linked to felsic volcanic rock fragments and secondary minerals (clays, iron oxyhydroxides) within the alluvium fill of the aquifers. However, little is known about the effect of the enrichment factors for F and As in this area. Natural enrichment factors include evaporation, Ca/Na, and competitive adsorption and desorption from solid phases. This study used 1237 groundwater quality data measurements from 305 sampling sites collected between 2012 and 2019 in the state of Durango in north-central Mexico. To determine the contribution of enrichment factors to As and F content, the study area was divided into four sections, two being in the mountainous part of the state and two in the high plateaus. The data were compared among sections and analyzed using Spearman correlation and Piper and Block diagrams. The results indicate that the main solute enrichment mechanisms are evaporation and weathering of silicates and evaporites. Among the four sections, As, pH, and HCO3 seemed not to vary, F varied slightly, and nitrate and total dissolved solids varied the most. The lack of variation in As among sections is associated to its strong adsorption to clay minerals and iron oxyhydroxides, whereas the diminished F content in the eastern sections is likely linked to the adsorption of F to precipitating calcite (since groundwater is saturated with respect to calcite (SIcalcite = 0.43) and undersaturated for fluorite (SIfluorite = - 1.16). These processes shed light on the distribution of F and As in this area, and are likely operating in other states in northern Mexico and in semi-arid areas elsewhere.

Ampicillin and Ceftriaxone Solution Stability at Different Temperatures in Outpatient Parenteral Antimicrobial Therapy.

The inclusion of ampicillin-containing regimens in outpatient parenteral antimicrobial therapy programs (OPAT) depends upon solution stability under conditions similar to those experienced in these programs. Lack of this information could hinder the inclusion in OPAT of patients suffering from Enterococcus faecalis infective endocarditis treated with ampicillin plus ceftriaxone. The purpose of this study is to determine the stability of ampicillin and ampicillin plus ceftriaxone solutions in a simulated outpatient setting conditions. Solutions of ampicillin 24 g/liter and ampicillin 24 g/liter combined with ceftriaxone 8 g/liter were stored at 25°C ± 2°C, 30°C ± 2°C and 37°C ± 2°C for 48 h. Chemical and physical stability were evaluated at 20, 24, 30, and 48 h after manufacturing. The solutions were considered stable if the percentage of intact drug was ≥90% and color and clearness remained unchanged. After 24 h of storage at a controlled temperature, ampicillin solution in 0.9% sodium chloride was found to be stable for 30 h at 25 and 30°C and for 24 h at 37°C. In the ampicillin plus ceftriaxone combined solution, both antibiotics were found to be stable after 30 h of storage at 25 and 30°C, but at 37°C, the stability criterion was not met at any time point. Our study offers solid evidence demonstrating that the concentrations of both drugs at two of the tested temperatures (25°C and 30°C) were stable for up to 30 h. Therefore, both ampicillin alone and ampicillin plus ceftriaxone solutions would be appropriate candidates for inclusion in OPAT programs.

Polarization-independent single-photon switch based on a fiber-optical Sagnac interferometer for quantum communication networks.

An essential component of future quantum networks is an optical switch capable of dynamically routing single photons. Here we implement such a switch, based on a fiber-optical Sagnac interferometer design. The routing is implemented with a pair of fast electro-optical telecom phase modulators placed inside the Sagnac loop, such that each modulator acts on an orthogonal polarization component of the single photons, in order to yield polarization-independent capability that is crucial for several applications. We obtain an average extinction ratio of more than 19 dB between both outputs of the switch. Our experiment is built exclusively with commercial off-the-shelf components, thus allowing direct compatibility with current optical communication systems.

Bond Order Densities in Real Space.

In this contribution we introduce the concept of bond order density (BOD) on the basis of a previous work on natural adaptive orbitals. We show that BODs may be used to visualize both the global spatial distribution of the covalent bond order and its eigencomponents, which we call bond(ing) channels. BODs can be equally computed at correlated and noncorrelated levels of theory and in ground or excited states, thus offering an appealing description of bond-forming, bond-breaking, and bond-evolution processes. We show the power of the approach by examining a number of homo- and heterodiatomics, including the controversial existence of a fourth bonding component in dicarbon, by analyzing a few interesting bonding situations in polyatomics and chemical transformations, and by exemplifying exotic bonding behaviors in simple excited electronic states.

Cosmological Constraints from Multiple Probes in the Dark Energy Survey.

The combination of multiple observational probes has long been advocated as a powerful technique to constrain cosmological parameters, in particular dark energy. The Dark Energy Survey has measured 207 spectroscopically confirmed type Ia supernova light curves, the baryon acoustic oscillation feature, weak gravitational lensing, and galaxy clustering. Here we present combined results from these probes, deriving constraints on the equation of state, w, of dark energy and its energy density in the Universe. Independently of other experiments, such as those that measure the cosmic microwave background, the probes from this single photometric survey rule out a Universe with no dark energy, finding w=-0.80_{-0.11}^{+0.09}. The geometry is shown to be consistent with a spatially flat Universe, and we obtain a constraint on the baryon density of Ω_{b}=0.069_{-0.012}^{+0.009} that is independent of early Universe measurements. These results demonstrate the potential power of large multiprobe photometric surveys and pave the way for order of magnitude advances in our constraints on properties of dark energy and cosmology over the next decade.

Antiplatelet therapy in patients undergoing oral surgery: A systematic review and meta-analysis.

BACKGROUND: The number of patients under antiplatelet therapy (APT) continues to raise as current recommendations foster this practice. Although some recommendations to manage this treatment during oral surgery procedures exist, these have methodological shortcomings that preclude them from being conclusive. MATERIAL AND METHODS: A systematic review and meta-analysis of the best current evidence was carried out; The Cochrane Library, EMBASE and MEDLINE databases were searched for Randomized Controlled Trials (RCT) concerning patients undergoing oral surgery with APT, other relevant sources were searched manually. RESULTS: 5 RCTs met the Inclusion criteria. No clear tendency was observed (RR= 0.97 CI 95%: 0,41-2,34; p=0,09; I2= 51%), moreover, they weren't clinically significant. CONCLUSIONS: According to these findings and as bleeding is a manageable complication it seems unreasonable to undermine the APT, putting the patient in danger of a thrombotic event and its high inherent morbidity, which isn't comparable in severity and manageability to the former."

[Psychomotor development from 0 to 4 years in indigenous children. A sistematic literature search]. / Desarrollo psicomotor de 0 a 4 años en infancia indígena. Revisión sistemática de la literatura.

INTRODUCTION: The objective of this study was to evaluate published articles regarding the development of indigenous children aged 0 to four years. SUBJECTS AND METHOD: Systematic literature search. Parti cipants: Primary studies with populations of indigenous children aged 0 to four years. Type of studies: Primary studies with qualitative or quantitative methodologies published in the last ten years until November 2015. Databases: MEDLINE, Digital Library of the University of Girona: CERCADOR, EMBASE, Scielo. SEARCH STRATEGY: sensitive and specific. Free terms, MeSH, and Boolean. RESULTS: Nine articles remain for analysis. There are six central subjects related to intracultural patterns of expected development in indigenous childhood: 1) physical, 2) language, 3) socio-cognitive, 4) emo tional, 5) teaching-learning, 6) psychosocial, which reveal the existence of categories of sociocultural and spiritual contents. There is no defined period of time associated with the education. Learning is through observation and participation. Development is understood as a whole, intertwining the social, cultural, natural and spiritual. CONCLUSION: Spirituality and nature are at the center. Time as a goal to gain skills does not have a cultural function to demonstrate the acquisition of the inherent va lues to the culture. To base the assessment of development exclusively on psychomotor development as monitoring guide is insufficient to assess the integrality and complexity of the advances, abilities, and skills of indigenous children.

Endocarditis caused by anaerobic bacteria.

BACKGROUND: Infective endocarditis (IE) caused by anaerobic bacteria is a rare and poorly characterized disease. Most data reported in the literature are from case reports [1-3]. Therefore, we assessed the situation of anaerobic IE (AIE) in Spain using the database of the Spanish Collaboration on Endocarditis (GAMES). METHODS: We performed a prospective study from 2008 to 2016 in 26 Spanish centers. We included 2491 consecutive cases of definite IE (Duke criteria). RESULTS: Anaerobic bacteria caused 22 cases (0.9%) of definite IE. Median age was 66 years (IQR, 56-73), and 19 (86.4%) patients were men. Most patients (14 [63.6%]) had prosthetic valve IE and all episodes were left-sided: aortic valves, 12 (54.5%); and mitral valves, 8 (36.4%). The most common pathogens were Propionibacterium acnes (14 [63.6%]), Lactobacillus spp (3 [13.63%]), and Clostridium spp. (2 [9.0%]), and the infection was mainly odontogenic. Fifteen of the 22 patients (68.2%) underwent cardiac surgery. Mortality was 18.2% during admission and 5.5% after 1 year of follow-up. When patients with AIE were compared with the rest of the cohort, we found that although those with AIE had a similar age and Charlson comorbidity index, they were more likely to have community-acquired IE (86.4% vs. 60.9%, p = 0.01), have undergone cardiac surgery (68.2% vs 48.7% p = 0.06), and have had lower mortality rates during admission (18.2% vs. 27.3%). CONCLUSION: IE due to anaerobic bacteria is an uncommon disease that affects mainly prosthetic valves and frequently requires surgery. Otherwise, there are no major differences between AIE and IE caused by other microorganisms.

[Vulvar squamous cell carcinoma in young women with HPV negative]. / Carcinoma epidermoide de vulva en mujer joven con VPH negative.

BACKGROUND: The vulvar cancer is the fourth more frequent neoplasia after the endometrial, cervix and ovarian cancer. Normally, it has been related to old women of ages from 70 to 80 years old. Rarely, it has been detected cases in adult or young women. However, its incidence has been increased in the last years and in more early years. It is for this change in the incidence and its appearance in early years why a possible etiology has been looked for, opening different hypothesis that go from that related to the HPV to those that study an inflammatory chronic process as the basis for the carcinogenesis. CLINICAL CASE: In this article, it has been presented the case of a woman who is 34 years old with negative VPH that made her debut with epidermoid carcinoma of the vulva moderately different and on purpose of the case, we do a revision of the literature existent. CONCLUSIONS: Vulvar cancer diagnosed in young women as in older, but with different trends, risk factors and natural history. The case reported here escapes the theories studied so far so needed new lines of inquiry to investigate this form of presentation young woman, without HPV infection.

New materials and complications of prostheses in humans: situation in Spain.

Prostheses or implantable medical devices (IMDs) are parts made of natural or artificial materials intended to replace a body structure and therefore must be well tolerated by living tissues. The types of IMDs currently available and usable are very varied and capable of replacing almost any human organ. A high but imprecise percentage of Spaniards are carriers of one or more IMDs to which they often owe their quality of life or survival. IMDs are constructed with different types of materials that are often combined in the same prosthesis. These materials must combine harmlessness to human tissues with high wear resistance. Their durability depends on many factors both on the host and the type of prosthesis, but the vast majority last for more than 10-15 years or remain in function for the lifetime of the patient. The most frequently implanted IMDs are placed in the heart or great vessels, joints, dental arches or breast and their most frequent complications are classified as non-infectious, particularly loosening or intolerance, and infectious. Complications, when they occur, lead to a significant increase in morbidity, their repair or replacement multiplies the health care cost and, on occasions, can cause the death of the patient. The fight against IMD complications is currently focused on the design of new materials that are more resistant to wear and infection and the use of antimicrobial substances that are released from these materials. Their production requires multidisciplinary technical teams, but also a willingness on the part of industry and health authorities that is not often found in Spain or in most European nations. Scientific production on prostheses and IMD in Spain is estimated to be less than 2% of the world total, and probably below what corresponds to our level of socio-economic development. The future of IMDs involves, among other factors, examining the potential role of Artificial Intelligence in their design, knowledge of tissue regeneration, greater efficiency in preventing infections and taking alternative treatments beyond antimicrobials, such as phage therapy. For these and other reasons, the Ramón Areces Foundation convened a series of experts in different fields related to prostheses and IMDs who answered and discussed a series of questions previously formulated by the Scientific Council. The following lines are the written testimony of these questions and the answers to them.

Ten years since the introduction of therapeutic hypothermia in neonates with perinatal hypoxic-ischaemic encephalopathy in Spain.

INTRODUCTION: More than a decade has passed since therapeutic hypothermia (TH) was introduced in Spain; this is the only neuroprotective intervention that has become standard practice in the treatment of perinatal hypoxic-ischaemic encephalopathy (HIE). This article aims to provide a current picture of the technique and to address the controversies surrounding its use. DEVELOPMENT: In the last 10 years, TH has been successfully implemented in the vast majority of tertiary hospitals in Spain, and more than 85% of newborns with moderate or severe HIE currently receive the treatment. The factors that can improve the efficacy of TH include early treatment onset (first 6 h of life) and the control of comorbid factors associated with perinatal asphyxia. In patients with moderate HIE, treatment onset after 6 h seems to have some neuroprotective efficacy. TH duration longer than 72 h or deeper hypothermia do not offer greater neuroprotective efficacy, but instead increase the risk of adverse effects. Controversy persists around the sedation of patients during TH, the application of the treatment in infants with mild HIE, and its application in other scenarios. Prognostic information and time frame are one of the most challenging aspects. CONCLUSIONS: TH is universal in countries with sufficient economic resources, although certain unresolved controversies remain. While the treatment is widespread in Spain, there is a need for devices for the transfer of these patients and their centralisation.

[Association between influenza vaccination and mortality due to COVID-19]. / Asociación entre la vacunación contra influenza y la mortalidad por COVID-19.

Background: It has recently been suggested that influenza vaccination may be a factor associated with decreased COVID-19 mortality. Methods: An age-matched case-control study based on hospital cases. We included subjects aged 18 years and older with a diagnosis of moderate to severe COVID-19. Infection was corroborated by RT-PCR test for SARS-COV-2. Deceased subjects were considered cases, controls were patients discharged due to improvement of acute symptoms. We used bivariate analysis to determine factors associated with death from COVID-19, and calculated odds ratios and 95% confidence intervals. Results: A total of 560 patients were included in the study, 214 (38.2%) were considered cases and 346 (61.7%) controls. A significant difference was observed with the presence of type 2 diabetes mellitus [54% vs. 39.3% between cases and controls, respectively (p=.04)] and having received influenza vaccination (p= .02). Type 2 diabetes mellitus was associated with higher COVID-19 mortality [OR 1.8 (95% CI 1.2-2.5) p=.01], whereas having been immunised against influenza in 2019 was associated with lower mortality in this group of patients [OR .6 (95% CI .4-.9) p=.02]. Conclusions: Influenza vaccination in the previous year appears to be associated with lower mortality from COVID-19; whereas type 2 diabetes mellitus is confirmed as a condition associated with higher mortality.

A rapid method for isolation of total DNA from pathogenic filamentous plant fungi.

DNA isolation from some fungal organisms of agronomic importance is difficult because they have cell walls or capsules that are relatively unsusceptible to lysis. We have developed a fast DNA isolation protocol for Fusarium oxysporum, which causes fusarium wilt disease in more than 100 plant species, and for Pyrenochaeta terrestris, which causes pink root in onions. This protocol was based on the sodium dodecyl sulfate/phenol method, without beta-mercaptoethanol and without maceration in liquid nitrogen; it uses phenol/chloroform extraction to remove proteins and co-precipitated polysaccharides. The A(260/280) absorbance ratios of isolated DNA were around 1.9, suggesting that the DNA fraction was pure and may be used for further analysis. Additionally, the A(260/230) values were higher than 1.8, suggesting negligible contamination by polysaccharides. The DNA isolated by this protocol is of sufficient quality for molecular applications; this technique could be applied to other organisms that have similar substances that hinder DNA extraction.

Ten years since the introduction of therapeutic hypothermia in neonates with perinatal hypoxic-ischaemic encephalopathy in Spain. / Una década después de la implantación en España de la hipotermia terapéutica en el recién nacido con encefalopatía hipóxico-isquémica perinatal.

INTRODUCTION: More than a decade has passed since therapeutic hypothermia (TH) was introduced in Spain; this is the only neuroprotective intervention that has become standard practice in the treatment of perinatal hypoxic-ischaemic encephalopathy (HIE). This article aims to provide a current picture of the technique and to address the controversies surrounding its use. DEVELOPMENT: In the last 10 years, TH has been successfully implemented in the vast majority of tertiary hospitals in Spain, and more than 85% of newborns with moderate or severe HIE currently receive the treatment. The factors that can improve the efficacy of TH include early treatment onset (first 6hours of life) and the control of comorbid factors associated with perinatal asphyxia. In patients with moderate HIE, treatment onset after 6hours seems to have some neuroprotective efficacy. TH duration longer than 72hours or deeper hypothermia do not offer greater neuroprotective efficacy, but instead increase the risk of adverse effects. Unclarified aspects are the sedation of patients during TH, the application of the treatment in infants with mild HIE, and its application in other scenarios. Prognostic information and time frame are one of the most challenging aspects. CONCLUSIONS: TH is universal in countries with sufficient economic resources, although certain unresolved controversies remain. While the treatment is widespread in Spain, there is a need for cooling devices for the transfer of these patients and their centralisation.