Cretaceous ornithurine supports a neognathous crown bird ancestor.

The bony palate diagnoses the two deepest clades of extant birds: Neognathae and Palaeognathae1-5. Neognaths exhibit unfused palate bones and generally kinetic skulls, whereas palaeognaths possess comparatively rigid skulls with the pterygoid and palatine fused into a single element, a condition long considered ancestral for crown birds (Neornithes)3,5-8. However, fossil evidence of palatal remains from taxa close to the origin of Neornithes is scarce, hindering strong inferences regarding the ancestral condition of the neornithine palate. Here we report a new taxon of toothed Late Cretaceous ornithurine bearing a pterygoid that is remarkably similar to those of the extant neognath clade Galloanserae (waterfowl + landfowl). Janavis finalidens, gen. et sp. nov., is generally similar to the well-known Mesozoic ornithurine Ichthyornis in its overall morphology, although Janavis is much larger and exhibits a substantially greater degree of postcranial pneumaticity. We recovered Janavis as the first-known well-represented member of Ichthyornithes other than Ichthyornis, clearly substantiating the persistence of the clade into the latest Cretaceous9. Janavis confirms the presence of an anatomically neognathous palate in at least some Mesozoic non-crown ornithurines10-12, suggesting that pterygoids similar to those of extant Galloanserae may be plesiomorphic for crown birds. Our results, combined with recent evidence on the ichthyornithine palatine12, overturn longstanding assumptions about the ancestral crown bird palate, and should prompt reevaluation of the purported galloanseran affinities of several bizarre early Cenozoic groups such as the 'pseudotoothed birds' (Pelagornithidae)13-15.

Late Cretaceous neornithine from Europe illuminates the origins of crown birds.

Our understanding of the earliest stages of crown bird evolution is hindered by an exceedingly sparse avian fossil record from the Mesozoic era. The most ancient phylogenetic divergences among crown birds are known to have occurred in the Cretaceous period1-3, but stem-lineage representatives of the deepest subclades of crown birds-Palaeognathae (ostriches and kin), Galloanserae (landfowl and waterfowl) and Neoaves (all other extant birds)-are unknown from the Mesozoic era. As a result, key questions related to the ecology4,5, biogeography3,6,7 and divergence times1,8-10 of ancestral crown birds remain unanswered. Here we report a new Mesozoic fossil that occupies a position close to the last common ancestor of Galloanserae and fills a key phylogenetic gap in the early evolutionary history of crown birds10,11. Asteriornis maastrichtensis, gen. et sp. nov., from the Maastrichtian age of Belgium (66.8-66.7 million years ago), is represented by a nearly complete, three-dimensionally preserved skull and associated postcranial elements. The fossil represents one of the only well-supported crown birds from the Mesozoic era12, and is the first Mesozoic crown bird with well-represented cranial remains. Asteriornis maastrichtensis exhibits a previously undocumented combination of galliform (landfowl)-like and anseriform (waterfowl)-like features, and its presence alongside a previously reported Ichthyornis-like taxon from the same locality13 provides direct evidence of the co-occurrence of crown birds and avialan stem birds. Its occurrence in the Northern Hemisphere challenges biogeographical hypotheses of a Gondwanan origin of crown birds3, and its relatively small size and possible littoral ecology may corroborate proposed ecological filters4,5,9 that influenced the persistence of crown birds through the end-Cretaceous mass extinction.

Reconstructing locomotor ecology of extinct avialans: a case study of Ichthyornis comparing sternum morphology and skeletal proportions.

Avian skeletal morphology is associated with locomotor function, including flight style, swimming and terrestrial locomotion, and permits informed inferences on locomotion in extinct taxa. The fossil taxon Ichthyornis (Avialae: Ornithurae) has long been regarded as highly aerial, with flight similar to terns or gulls (Laridae), and skeletal features resembling foot-propelled diving adaptations. However, rigorous testing of locomotor hypotheses has yet to be performed on Ichthyornis, despite its notable phylogenetic position as one of the most crownward stem birds. We analysed separate datasets of three-dimensional sternal shape (geometric morphometrics) and skeletal proportions (linear measurements across the skeleton), to examine how well these data types predict locomotor traits in Neornithes. We then used this information to infer locomotor capabilities of Ichthyornis. We find strong support for both soaring and foot-propelled swimming capabilities in Ichthyornis. Further, sternal shape and skeletal proportions provide complementary information on avian locomotion: skeletal proportions allow better predictions of the capacity for flight, whereas sternal shape predicts variation in more specific locomotor abilities such as soaring, foot-propelled swimming and escape burst flight. These results have important implications for future studies of extinct avialan ecology and underscore the importance of closely considering sternum morphology in investigations of fossil bird locomotion.

Prehospital seizures: Short-term outcomes and risk stratification based in point-of-care testing.

BACKGROUND: Information for treatment or hospital derivation of prehospital seizures is limited, impairing patient condition and hindering patients risk assessment by the emergency medical services (EMS). This study aimed to determine the associated factors to clinical impairment, and secondarily, to determine risk factors associated to cumulative in-hospital mortality at 2, 7 and 30 days, in patients presenting prehospital seizures. METHODS: Prospective, multicentre, EMS-delivery study involving adult subjects with prehospital seizures, including five advanced life support units, 27 basic life support units and four emergency departments in Spain. All bedside variables: including demographic, standard vital signs, prehospital laboratory tests and presence of intoxication or traumatic brain injury (TBI), were analysed to construct a risk model using binary logistic regression and internal validation methods. RESULTS: A total of 517 patients were considered. Clinical impairment was present in 14.9%, and cumulative in-hospital mortality at 2, 7 and 30-days was 3.4%, 4.6% and 7.7%, respectively. The model for the clinical impairment indicated that respiratory rate, partial pressure of carbon dioxide, blood urea nitrogen, associated TBI or stroke were risk factors; higher Glasgow Coma Scale (GCS) scores mean a lower risk of impairment. Age, potassium, glucose, prehospital use of mechanical ventilation and concomitant stroke were risk factors associated to mortality; and oxygen saturation, a high score in GCS and haemoglobin were protective factors. CONCLUSION: Our study shows that prehospital variables could reflect the clinical impairment and mortality of patients suffering from seizures. The incorporation of such variables in the prehospital decision-making process could improve patient outcomes.

Prehospital Respiratory Early Warning Score for airway management in-ambulance: A score comparison.

BACKGROUND: Prehospital Respiratory Early Warning Scores to estimate the requirement for advanced respiratory support is needed. To develop a prehospital Respiratory Early Warning Score to estimate the requirement for advanced respiratory support. METHODS: Multicentre, prospective, emergency medical services (EMS)-delivered, longitudinal cohort derivationvalidation study carried out in 59 ambulances and five hospitals across five Spanish provinces. Adults with acute diseases evaluated, supported and discharged to the Emergency Department with high priority were eligible. The primary outcome was the need for invasive or non-invasive respiratory support (NIRS or IRS) in the prehospital scope at the first contact with the patient. The measures included the following: epidemiological endpoints, prehospital vital signs (respiratory rate, pulse oximetry saturation, fraction of inspired oxygen, systolic and diastolic mean blood pressure, heart rate, tympanic temperature and consciousness level by the GCS). RESULTS: Between 26 Oct 2018 and 26 Oct 2021, we enrolled 5793 cases. For NIRS prediction, the final model of the logistic regression included respiratory rate and pulse oximetry saturation/fraction of inspired oxygen ratio. For the IRS case, the motor response from the Glasgow Coma Scale was also included. The REWS showed an AUC of 0.938 (95% CI: 0.918-0.958), a calibration-in-large of 0.026 and a higher net benefit as compared with the other scores. CONCLUSIONS: Our results showed that REWS is a remarkably aid for the decision-making process in the management of advanced respiratory support in prehospital care. Including this score in the prehospital scenario could improve patients' care and optimise the resources' management.

Reversible Light-Induced Dimerization of Secondary Face Azobenzene-Functionalized ß-Cyclodextrin Derivatives.

ß-cyclodextrin (ßCyD) derivatives equipped with aromatic appendages at the secondary face exhibit tailorable self-assembling capabilities. The aromatic modules can participate in inclusion phenomena and/or aromatic-aromatic interactions. Supramolecular species can thus form that, at their turn, can engage in further co-assembling with third components in a highly regulated manner; the design of nonviral gene delivery systems is an illustrative example. Endowing such systems with stimuli responsiveness while keeping diastereomeric purity and a low synthetic effort is a highly wanted advancement. Here, we show that an azobenzene moiety can be "clicked" to a single secondary O-2 position of ßCyD affording 1,2,3-triazole-linked ßCyD-azobenzene derivatives that undergo reversible light-controlled self-organization into dimers where the monomer components face their secondary rims. Their photoswitching and supramolecular properties have been thoroughly characterized by UV-vis absorption, induced circular dichroism, nuclear magnetic resonance, and computational techniques. As model processes, the formation of inclusion complexes between a water-soluble triazolylazobenzene derivative and ßCyD as well as the assembly of native ßCyD/ßCyD-azobenzene derivative heterodimers have been investigated in parallel. The stability of the host-guest supramolecules has been challenged against the competitor guest adamantylamine and the decrease of the medium polarity using methanol-water mixtures. The collective data support that the E-configured ßCyD-azobenzene derivatives, in aqueous solution, form dimers stabilized by the interplay of aromatic-aromatic and aromatic-ßCyD cavity interactions after partial reciprocal inclusion. Photoswitching to the Z-isomer disrupts the dimers into monomeric species, offering opportunity for the spatiotemporal control of the organizational status by light.

Tracking the National Early Warning Score 2 from Prehospital Care to the Emergency Department: A Prospective, Ambulance-Based, Observational Study.

Aim of the study: To assess the prognostic ability of the National Early Warning Score 2 (NEWS2) at three time points of care -at the emergency scene (NEWS2-1), just before starting the transfer by ambulance to the hospital (NEWS2- 2), and at the hospital triage box (NEWS2-3)- to estimate in-hospital mortality after two days since the index event.Methods: Prospective, multicenter, ambulance-based, cohort ongoing study in adults (>18 years) consecutively attended by advanced life support (ALS) and evacuated with high-priority to the emergency departments (ED) between October 2018 and May 2021. Vital sign measures were used to calculate the NEWS2 score at each time point, then this score was entered in a logistic regression model as the single predictor. Two outcomes were considered: first, all-cause mortality of the patients within 2 days of presentation to EMS, and second, unplanned ICU admission. The calibration and scores comparison was performed by representing the predicted vs the observed risk curves according to NEWS score value.Results: 4943 patients were enrolled. Median age was 69 years (interquartile range 53- 81). The NEWS2-3 presented the better performance for all-cause two-day in-hospital mortality with an AUC of 0.941 (95% CI: 0.917-0.964), showing statistical differences with both the NEWS2-1 (0.872 (95% CI: 0.833-0.911); p < 0.003) and with the NEWS2- 2 (0.895 (95% CI: 0.866-0.925; p < 0.05). The calibration and scores comparison results showed that the NEWS2-3 was the best predictive score followed by the NEWS2-2 and the NEWS2-1, respectively.Conclusions: The NEWS2 has an excellent predictive performance. The score showed a very consistent response over time with the difference between "at the emergency scene" and "pre-evacuation" presenting the sharpest change with decreased threshold values, thus displaying a drop in the risk of acute clinical impairment.

Development of a prehospital lactic acidosis score for early-mortality. A prospective, multicenter, ambulance-based, cohort study.

BACKGROUND: Lactic acidosis is a clinical status related to clinical worsening. Actually, higher levels of lactate is a well-established trigger of emergency situations. The aim of this work is to build-up a prehospital early warning score to predict 2-day mortality and intensive care unit (ICU) admission, constructed with other components of the lactic acidosis besides the lactate. METHODS: Prospective, multicenter, observational, derivation-validation cohort study of adults evacuated by ambulance and admitted to emergency department with acute diseases, between January 1st, 2020 and December 31st, 2021. Including six advanced life support, thirty-eight basic life support units, referring to four hospitals (Spain). The primary and secondary outcome of the study were 2-day all-cause mortality and ICU-admission. The prehospital lactic acidosis (PLA) score was derived from the analysis of prehospital blood parameters associated with the outcome using a logistic regression. The calibration, clinical utility, and discrimination of PLA were determined and compared to the performance of each component of the score alone. RESULTS: A total of 3334 patients were enrolled. The final PLA score included: lactate, pCO2, and pH. For 2-day mortality, the PLA showed an AUC of 0.941 (95%CI: 0.914-0.967), a better performance in calibration, and a higher net benefit as compared to the other score components alone. For the ICU admission, the PLA only showed a better performance for AUC: 0.75 (95%CI: 0.706-0.794). CONCLUSIONS: Our results showed that PLA predicts 2-day mortality better than other lactic acidosis components alone. Including PLA score in prehospital setting could improve emergency services decision-making.

Insight into oral amphiphilic cyclodextrin nanoparticles for colorectal cancer: comprehensive mathematical model of drug release kinetic studies and antitumoral efficacy in 3D spheroid colon tumors.

Colorectal cancer (CRC) is the third most diagnosed cancer type globally and ranks second in cancer-related deaths. With the current treatment possibilities, a definitive, safe, and effective treatment approach for CRC has not been presented yet. However, new drug delivery systems show promise in this field. Amphiphilic cyclodextrin-based nanocarriers are innovative and interesting formulation approaches for targeting the colon through oral administration. In our previous studies, oral chemotherapy for colon tumors was aimed and promising results were obtained with formulation development studies, mucin interaction, mucus penetration, cytotoxicity, and permeability in 2D cell culture, and furthermore in vivo antitumoral and antimetastatic efficacy in early and late-stage colon cancer models and biodistribution after single dose oral administration. This study was carried out to further elucidate oral camptothecin (CPT)-loaded amphiphilic cyclodextrin nanoparticles for the local treatment of colorectal tumors in terms of their drug release behavior and efficacy in 3-dimensional tumor models to predict the in vivo efficacy of different nanocarriers. The main objective was to build a bridge between formulation development and in vitro phase and animal studies. In this context, CPT-loaded polycationic-ß-cyclodextrin nanoparticles caused reduced cell viability in CT26 and HT29 colon carcinoma spheroid tumors of mice and human origin, respectively. In addition, the release profile, which is one of the critical quality parameters in new drug delivery systems, was investigated mathematically by release kinetic modeling for the first time. The overall findings indicated that the strategy of orally targeting anticancer drugs such as CPT with positively charged poly-ß-CD-C6 nanoparticles to colon tumors for local and/or systemic efficacy is a promising approach.

Enhanced Gene Delivery Triggered by Dual pH/Redox Responsive Host-Guest Dimerization of Cyclooligosaccharide Star Polycations.

A robust strategy is reported to build perfectly monodisperse star polycations combining a trehalose-based cyclooligosaccharide (cyclotrehalan, CT) central core onto which oligoethyleneimine radial arms are installed. The architectural perfection of the compounds is demonstrated by a variety of physicochemical techniques, including NMR, MS, DLS, TEM, and GPC. Key to the strategy is the possibility of customizing the cavity size of the macrocyclic platform to enable/prevent the inclusion of adamantane motifs. These properties can be taken into advantage to implement sequential levels of stimuli responsiveness by combining computational design, precision chemistry and programmed host-guest interactions. Specifically, it is shown that supramolecular dimers implying a trimeric CT-tetraethyleneimine star polycation and purposely designed bis-adamantane guests are preorganized to efficiently complex plasmid DNA (pDNA) into transfection-competent nanocomplexes. The stability of the dimer species is responsive to the protonation state of the cationic clusters, resulting in dissociation at acidic pH. This process facilitates endosomal escape, but reassembling can take place in the cytosol then handicapping pDNA nuclear import. By equipping the ditopic guest with a redox-sensitive disulfide group, recapturing phenomena are prevented, resulting in drastically improved transfection efficiencies both in vivo and in vitro.

Comorbidity-adjusted NEWS predicts mortality in suspected patients with COVID-19 from nursing homes: Multicentre retrospective cohort study.

AIMS: To assess the prognostic accuracy of comorbidity-adjusted National Early Warning Score in suspected Coronavirus disease 2019 patients transferred from nursing homes by the Emergency Department. DESIGN: Multicentre retrospective cohort study. METHODS: Patients transferred by high-priority ambulances from nursing homes to Emergency Departments with suspected severe acute respiratory syndrome coronavirus 2 infection, from March 12 to July 31 2020, were considered. Included variables were: clinical covariates (respiratory rate, oxygen saturation, systolic blood pressure, heart rate, temperature, level of consciousness and supplemental oxygen use), the presence of comorbidities and confirmatory analytical diagnosis of severe acute respiratory syndrome coronavirus 2 infection. The primary outcome was a 2-day mortality rate. The discriminatory capability of the National Early Warning Score was assessed by the area under the receiver operating characteristic curve in two different cohorts, the validation and the revalidation, which were randomly selected from the main cohort. RESULTS: A total of 337 nursing homes, 10 advanced life support units, 51 basic life support units and 8 hospitals in Spain entailing 1,324 patients (median age 87 years) was involved in this study. Two-day mortality was 11.5% (152 cases), with a positivity rate of severe acute respiratory syndrome coronavirus 2 of 51.2%, 77.7% of hospitalization from whom 1% was of intensive care unit admission. The National Early Warning Score results for the revalidation cohort presented an AUC of 0.771, and of 0.885, 0.778 and 0.730 for the low-, medium- and high-level groups of comorbidities. CONCLUSION: The comorbidity-adjusted National Early Warning Score provides a good short-term prognostic criterion, information that can help in the decision-making process to guide the best strategy for each older adult, under the current pandemic. IMPACT: What problem did the study address? Under the current coronavirus disease 2019 pandemic, targeting older adults at high risk of deterioration in nursing homes remains challenging. What were the main findings? Comorbidity-adjusted National Early Warning Score helps to forecast the risk of clinical deterioration more accurately. Where and on whom will the research have impact? A high NEWS, with a low level of comorbidity is associated with optimal predictive performance, making these older adults likely to benefit from continued follow up and potentially hospital referral under the current coronavirus disease 2019 pandemic.

Prehospital troponin as a predictor of early clinical deterioration.

BACKGROUND AND OBJECTIVES: Elevated troponin T (cTnT) values are associated with comorbidities and early mortality, in both cardiovascular and noncardiovascular diseases. The objective of this study is to evaluate the prognostic accuracy of the sole utilization of prehospital point-of-care cardiac troponin T to identify the risk of early in-hospital deterioration, including mortality within 28 days. METHODS: We conducted a prospective, multicentric, controlled, ambulance-based, observational study in adults with acute diseases transferred with high priority by ambulance to emergency departments, between 1 January and 30 September 2020. Patients with hospital diagnosis of acute coronary syndrome were excluded. The discriminative power of the predictive cTnT was assessed through a discrimination model trained using a derivation cohort and evaluated by the area under the curve of the receiver operating characteristic on a validation cohort. RESULTS: A total of 848 patients were included in our study. The median age was 68 years (25th-75th percentiles: 50-81 years), and 385 (45.4%) were women. The mortality rate within 28 days was 12.4% (156 cases). The predictive ability of cTnT to predict mortality presented an area under the curve of 0.903 (95% CI: 0.85-0.954; P < .001). Risk stratification was performed, resulting in three categories with the following optimal cTnT cut-off points: high risk greater than or equal to 100, intermediate risk 40-100 and low risk less than 40 ng/L. In the high-risk group, the mortality rate was 61.7%, and on the contrary, the low-risk group presented a mortality of 2.3%. CONCLUSIONS: The implementation of a routine determination of cTnT on the ambulance in patients transferred with high priority to the emergency department can help to stratify the risk of these patients and to detect unknown early clinical deterioration.

Trifaceted Mickey Mouse Amphiphiles for Programmable Self-Assembly, DNA Complexation and Organ-Selective Gene Delivery.

Instilling segregated cationic and lipophilic domains with an angular disposition in a trehalose-based trifaceted macrocyclic scaffold allows engineering patchy molecular nanoparticles leveraging directional interactions that emulate those controlling self-assembling processes in viral capsids. The resulting trilobular amphiphilic derivatives, featuring a Mickey Mouse architecture, can electrostatically interact with plasmid DNA (pDNA) and further engage in hydrophobic contacts to promote condensation into transfectious nanocomplexes. Notably, the topology and internal structure of the cyclooligosaccharide/pDNA co-assemblies can be molded by fine-tuning the valency and characteristics of the cationic and lipophilic patches, which strongly impacts the transfection efficacy in vitro and in vivo. Outstanding organ selectivities can then be programmed with no need of incorporating a biorecognizable motif in the formulation. The results provide a versatile strategy for the construction of fully synthetic and perfectly monodisperse nonviral gene delivery systems uniquely suited for optimization schemes by making cyclooligosaccharide patchiness the focus.

miR-927 has pro-viral effects during acute and persistent infection with dengue virus type 2 in C6/36 mosquito cells.

Dengue virus (DENV) is an important flavivirus that is transmitted to humans by Aedes mosquitoes, where it can establish a persistent infection underlying vertical and horizontal transmission. However, the exact mechanism of persistent DENV infection is not well understood. Recently miR-927 was found to be upregulated in C6/36-HT cells at 57 weeks of persistent infection (C6-L57), suggesting its participation during this type of infection. The aim of this study was to determine the role of miR-927 during infection with DENV type 2. The results indicate an overexpression of miR-927 in C6-L57 cells and acutely infected cells according to the time of infection and the m.o.i. used. The downregulation of miR-927 in C6-L57 cells results in a reduction of both viral titre and viral genome copy number. The overexpression of miR-927 in C6-L40 and C6/36 cells infected at an m.o.i. of 0.1 causes an increase in both viral titre and viral genome copy number, suggesting a pro-viral activity of miR-927. In silico prediction analysis reveals target mRNAs for miR-927 are implicated in post-translational modifications (SUMO), translation factors (eIF-2B), the innate immune system (NKIRAS), exocytosis (EXOC-2), endocytosis (APM1) and the cytoskeleton (FLN). The expression levels of FLN were the most affected by both miR-927 overexpression and inhibition, and FLN was determined to be a direct target of miR-927 by a dual-luciferase gene reporter assay. FLN has been associated with the regulation of the Toll pathway and either overexpression or downregulation of miR-927 resulted in expression changes of antimicrobial peptides (Cecropins A and G, and Defensin D) involved in the Toll pathway response.

Tuning the Topological Landscape of DNA-Cyclodextrin Nanocomplexes by Molecular Design.

Original molecular vectors that ensure broad flexibility to tune the shape and surface properties of plasmid DNA (pDNA) condensates are reported herein. The prototypic design involves a cyclodextrin (CD) platform bearing a polycationic cluster at the primary face and a doubly linked aromatic module bridging two consecutive monosaccharide units at the secondary face that behaves as a topology-encoding element. Subtle differences at the molecular level then translate into disparate morphologies at the nanoscale, including rods, worms, toroids, globules, ellipsoids, and spheroids. In vitro evaluation of the transfection capabilities revealed marked selectivity differences as a function of nanocomplex morphology. Remarkably high transfection efficiencies were associated with ellipsoidal or spherical shapes with a lamellar internal arrangement of pDNA chains and CD bilayers. Computational studies support that the stability of such supramolecular edifices is directly related to the tendency of the molecular vector to form noncovalent dimers upon DNA templating. Because the stability of the dimers depends on the protonation state of the polycationic clusters, the coaggregates display pH responsiveness, which facilitates endosomal escape and timely DNA release, a key step in successful transfection. The results provide a versatile strategy for the construction of fully synthetic and perfectly monodisperse nonviral gene delivery systems uniquely suited for optimization schemes.

Click Synthesis of Size- and Shape-Tunable Star Polymers with Functional Macrocyclic Cores for Synergistic DNA Complexation and Delivery.

The architectural perfection and multivalency of dendrimers have made them useful for biodelivery via peripheral functionalization and the adjustment of dendrimer generations. Modulation of the core-forming and internal matrix-forming structures offers virtually unlimited opportunities for further optimization, but only in a few cases this has been made compatible with strict diastereomeric purity over molecularly diverse series, low toxicity, and limited synthetic effort. Fully regular star polymers built on biocompatible macrocyclic platforms, such as hyperbranched cyclodextrins, offer advantages in terms of facile synthesis and flexible compositions, but core elaboration in terms of shape and function becomes problematic. Here we report the synthesis and characterization of star polymers consisting of functional trehalose-based macrocyclic cores (cyclotrehalans, CTs) and aminothiourea dendron arms, which can be efficiently synthesized from sequential click reactions of orthogonal monomers, display no cytotoxicity, and efficiently complex and deliver plasmid DNA in vitro and in vivo. When compared with some commercial cationic dendrimers or polymers, the new CT-scaffolded star polymers show better transfection efficiencies in several cell lines and structure-dependent cell selectivity patterns. Notably, the CT core could be predefined to exert Zn(II) complexing or molecular inclusion capabilities, which has been exploited to synergistically boost cell transfection by orders of magnitude and modulate the organ tropism in vivo.

Transurethral ventral buccal mucosa graft inlay for treatment of distal urethral strictures: international multi-institutional experience.

PURPOSE: To critically evaluate a multi-institutional patient cohort undergoing single-stage distal urethral repair using a novel transurethral buccal mucosa graft inlay urethroplasty technique (TBMGI). METHODS: A retrospective multi-institutional review of consecutive patients with fossa navicularis (FN) strictures treated with a single-stage TBMGI technique at 12 institutions from March 2014-March 2018 was performed. Patient demographics, stricture characteristics, clinical and patient-reported outcomes were analyzed. The primary outcomes were stricture recurrence and complications. Secondary outcomes were change in maximum urinary flow rate (Qmax), PVR, and changes in IPSS, SHIM and global response assessment (GRA) questionnaire responses. Descriptive statistical analysis was used for evaluation of outcomes. RESULTS: Sixty-eight men met inclusion criteria. Median age and stricture length were 60 years (IQR 48-69) and 2 cm (IQR 2-3), respectively. Most common stricture etiology was lichen sclerosus (34%). Median operative time and EBL were 72 min (IQR 50-120) and 20 mL (IQR 10-43), respectively. Fifty-seven men completed ≥ 12-month follow-up. At a median follow-up of 17 months (IQR 13-22), 54 patients (95%) remained stricture-free. Median Qmax improved from 5 to 18 mL/s (p < 0.0001), PVR 76-21 mL (p < 0.0001), and IPSS 15-5 (p < 0.0001); IPSS-QOL score: 5-1 (p < 0.0001). SHIM score did not significantly change following repair (median 22-21 p = 0.85). On GRA assessment, a majority of men reported "marked" (64%) or "moderate" (28%) overall improvement. No patient developed fistula, glanular dehiscence, graft necrosis or chordee. CONCLUSIONS: This novel minimally invasive transurethral urethroplasty technique is feasible and has demonstrated generalizable outcomes in a multi-institutional cohort with varying etiologies.

Human astroviruses: in silico analysis of the untranslated region and putative binding sites of cellular proteins.

Human astrovirus (HAstV) constitutes a major cause of acute gastroenteritis in children. The viral 5' and 3' untranslated regions (UTR) have been involved in the regulation of several molecular mechanisms. However, in astrovirues have been less characterized. Here, we analyzed the secondary structures of the 5' and 3' UTR of HAstV, as well as their putative target sites that might be recognized by cellular factors. To our knowledge, this is the first bioinformatic analysis that predicts the HAstV 5' UTR secondary structure. The analysis showed that both the UTR sequence and secondary structure are highly conserved in all HAstVs analyzed, suggesting their regulatory role of viral activities. Notably, the UTRs of HAstVs contain putative binding sites for the serine/arginine-rich factors SRSF2, SRSF5, SRSF6, SRSF3, and the multifunctional hnRNPE2 protein. More importantly, putative binding sites for PTB were localized in single-stranded RNA sequences, while hnRNPE2 sites were localized in double-stranded sequence of the HAstV 5' and 3' UTR structures. These analyses suggest that the combination of SRSF proteins, hnRNPE2 and PTB described here could be involved in the maintenance of the secondary structure of the HAstVs, possibly allowing the recruitment of the replication complex that selects and recruits viral RNA replication templates.

Prognostic value of lactate in prehospital care as a predictor of early mortality.

BACKGROUND: Prehospital Emergency Medical Services must attend to patients with complex physiopathological situations with little data and in the shortest possible time. The objective of this work was to study lactic acid values and their usefulness in the prehospital setting to help in clinical decision-making. STUDY DESIGN: We conducted a longitudinal prospective, observational study on patients over 18 years of age who, after being evaluated by the Advanced Life Support Unit, were taken to the hospital between April and June 2018. We analyzed demographic variables, prehospital lactic acid values and early mortality (<30 days). The area under the curve of the receiver operating characteristic was calculated for the prehospital value of lactic acid. RESULTS: A total of 279 patients were included in our study. The median age was 68 years (interquartile range: 54-80 years). Overall 30-day mortality was 9% (25 patients). The area under the curve for lactic acid to predict overall mortality at 30 days of care was 0.82 (95% CI: 0.76-0.89). The lactate value with the best sensitivity and specificity overall was 4.25 mmol/L with a sensitivity of 84% (95% CI: 65.3-93.6) and specificity of 70% (95% CI: 65.0-76.1). CONCLUSIONS: The level of lactic acid can be a complementary tool in the field of prehospital emergencies that will guide us early in the detection of critical patients.

Voiding symptoms obtained by open versus directed anamnesis as predictors of voiding dysfunction in women.

OBJECTIVES: To determine the differences between voiding symptoms obtained by open anamnesis (VS-Open) versus voiding symptoms obtained by directed anamnesis (VSDirected) to predict voiding dysfunction in women. MATERIALS AND METHODS: Retrospective study of women with prior anti-incontinence surgery evaluated during 5 years. In a standardized clinical history taking, each patient was asked to answer question number fi ve of the UDI-6 questionnaire ("Do you experience any difficulty emptying your bladder?"). If the answer was positive, the following voiding symptoms spontaneously described by the patient were documented: slow urine stream, straining to void, intermittent stream and feeling of incomplete bladder emptying, which were considered VS-Open. If the answer to this question was negative or if the patient had not reported the four voiding symptoms, she was asked in a directed manner about the presence of each of them, which were considered VS-Directed. Voiding dysfunction was considered the presence of a maximum fl ow ≤ 12 mL/s and/ or a postvoid residual > 100 mL. RESULTS: Ninety-one women are analyzed. Eighteen patients presented voiding dysfunction (19.8%), There was a statistical association between voiding dysfunction and the presence of any VS-Open (p = 0.037) and straining to void obtained by open anamnesis (p = 0.013). Sensitivity, specificity, PPV, NPV, positive likelihood ratio and negative likelihood ratio, respectively, were 44.4% and 27.8%, 80.8% and 94.5%, 36.3% and 55.6%, 85.5% and 84.1%, 2.324 and 5.129, and 0.686 and 0.764. There was no statistical association between voiding dysfunction and VS-Directed. CONCLUSIONS: VS-Open may predict better voiding dysfunction than VS-Directed in women.