A surge of light at the birth of a supernova.

It is difficult to establish the properties of massive stars that explode as supernovae. The electromagnetic emission during the first minutes to hours after the emergence of the shock from the stellar surface conveys important information about the final evolution and structure of the exploding star. However, the unpredictable nature of supernova events hinders the detection of this brief initial phase. Here we report the serendipitous discovery of a newly born, normal type IIb supernova (SN 2016gkg), which reveals a rapid brightening at optical wavelengths of about 40 magnitudes per day. The very frequent sampling of the observations allowed us to study in detail the outermost structure of the progenitor of the supernova and the physics of the emergence of the shock. We develop hydrodynamical models of the explosion that naturally account for the complete evolution of the supernova over distinct phases regulated by different physical processes. This result suggests that it is appropriate to decouple the treatment of the shock propagation from the unknown mechanism that triggers the explosion.

Are trunk stability and endurance determinant factors for whole-body dynamic balance in physically active young males? A multidimensional analysis.

OBJECTIVES: Determine if (a) a better trunk stability and endurance are associated with an improved whole-body dynamic balance, and if (b) the assessment tests can be interchanged within each capability. METHODS: Sixty-three physically active young males performed three trunk stability (i.e., the lumbopelvic stability, the unstable sitting and the sudden loading sitting tests), three trunk muscle endurance (i.e., the Biering-Sørensen, the side bridge and the front bridge tests) and four whole-body dynamic balance (i.e., the tandem and the single-leg stance, the Y-Balance, and the single-leg triple hop tests) tests two times. After assessing the reliability of the variables, a Pearson correlation analysis was performed. RESULTS: The correlations between trunk stability and endurance tests with dynamic balance tests were non-significant except for the unstable sitting test with both the tandem (r = 0.502) and the single-leg stance (r = 0.522) tests. Moreover, no relationships were observed between the trunk stability and the trunk muscle endurance tests. Interestingly, no relationships were found between most tests within each capability (i.e., trunk stability, trunk endurance, and dynamic balance) except: (i) the front bridge stability test and the back (r = 0.461) and the side (r = 0.499) bridge stability tests; (ii) the two side bridge endurance tests (r = 0.786); (iii) the tandem and the single-leg stance tests (0.439 ≤ r ≤ 0.463); (iv) the Y-Balance and the single-leg triple hop tests (0.446 ≤ r ≤ 0.477). CONCLUSION: Better trunk function does not seem to be a relevant factor for dynamic balance in young active males. In this population, specific measures are needed as the test interchangeability is questioned.

Evolution of appraisal tool usage preferences in PROSPERO records: a study of non-Cochrane systematic reviews.

OBJECTIVES: This research-on-research substudy uses a data-driven approach to investigate the range of appraisal tools in non-Cochrane systematic reviews and meta-analyses registered in the International Prospective Register of Systematic Reviews (PROSPERO). STUDY DESIGN AND SETTING: A comprehensive web scraping of all completed non-Cochrane registrations in PROSPERO from February 2011 to December 2017 was performed. The focus was classifying the appraisal tools based on study type, assessment aspects, and research topics. RESULTS: After analyzing 17,708 complete records, we found a predominant use of methodological quality assessment tools compared to those for reporting quality or risk of bias (RoB). This indicates a greater emphasis on methodological rigor in the studied protocols. Various tools for assessing methodological quality were observed, reflecting the complexity of such evaluations. Instruments designed for evaluating methodological or reporting quality were mainly intended for non-randomized clinical trials or observational studies, unlike RoB tools more commonly used in randomized clinical trials. No distinct trends in tool usage were observed in specific research conditions or domains, suggesting that tool choice is influenced more by study design than research topic. CONCLUSION: This study provides insights into the preferential use of various assessment tools in conducting non-Cochrane systematic reviews, as evidenced in PROSPERO records. The findings reveal various methodological assessment tools, underscoring their versatility across different study designs and research areas.

Increased synovial immunohistochemistry reactivity of TGF-ß1 in erosive peripheral psoriatic arthritis.

BACKGROUND: Immune and non-immune cells contribute to the pathology of chronic arthritis, and they can contribute to tissue remodeling and repair as well as disease pathogenesis. The present research aimed to analyze inflammation and bone destruction/regeneration biomarkers in patients with psoriatic arthritis (PsA), rheumatoid arthritis (RA), osteoarthritis (OA), and ankylosing spondylitis (AS). METHODS: Samples were obtained from the inflamed knee of patients with knee arthritis who had been referred for undergoing arthroscopies. The synovial membrane was processed for pathological description, IHC analysis, and quantification of mRNA expression ratio by qRT-PCR. Serum levels of TGF-ß1, IL-23, IL-6, IL-17 A, IL-22, Dkk1, Sclerostin, BMP2, BMP4, Wnt1, and Wnt5a were measured by ELISA. All these data were analyzed and compared with the demographic, clinical, blood tests, and radiological characteristics of the patients. RESULTS: The synovial membrane samples were obtained from 42 patients for IHC, extraction, and purification of RNA for synovial mRNA expression analysis, and serum for measuring protein levels from 38 patients. IHC reactivity for TGF-ß1 in the synovial tissue was higher in patients with psoriatic arthritis (p 0.036) and was positively correlated with IL-17 A (r = 0.389, p = 0.012), and Dkk1 (r = 0.388, p = 0.012). Gene expression of the IL-17 A was higher in PsA patients (p = 0.018) and was positively correlated with Dkk1 (r = 0.424, p = 0.022) and negatively correlated with BMP2 (r = -0.396, p = 0.033) and BMP4 (r = -0.472, p = 0.010). It was observed that IHC reactivity for TGF-ß1 was higher in patients with erosive PsA (p = 0.024). CONCLUSIONS: The IHC reactivity of TGF-ß1 in synovial tissue was higher in patients with erosive psoriatic arthritis, and TGF-ß1 was in relation to higher levels of gene expression of IL-17 A and Dkk1.

Biodistribution of naturally occurring radionuclides and radiocesium in wild European perch (Perca fluviatilis).

Wild European perch (Perca fluviatilis) is one of the most important freshwater fish species, in Sweden, due to its widespread and his value for recreational fishing. Little it is known regarding the biodistribution of naturally occurring radionuclides such as 238U, 234U, 226Ra, 210Po in perch. Therefore, in this study, perches from five lakes located in different counties in Sweden were collected to investigate the biodistribution of 238U, 234U, 226Ra, 210Po and 137Cs in organs and tissues of perch as well as their radiological impact. The results showed that uranium radionuclides ranged between 0.1 and 6 Bq/kg with an average value of 1.1 ± 1.5 Bq/kg. 226Ra varied from 0.4 to 8 Bq/kg with a mean concentration of 1.7 ± 1.9 Bq/kg. The ranged of 210Po was 0.5 - 250 Bq/kg, with an average value of 24 ± 52 Bq/kg. On the other hand, the highest activity concentration of 137Cs, 151 ± 1 Bq/kg, was detected in muscle samples of perch from Redsjösjön lake. For uranium radionuclides and 226Ra uptake from water is the main source whereas for 210Po and 137Cs the uptake is controlled by the perch diet. Regarding naturally occurring radionuclides, the perch tended to accumulated uranium radionuclides in fins, gills, and skin; 226Ra in bones, fins and skin and 210Po in the organs linked to digestive system. Finally, in case of consumption, it is advised the consumption of skinned fillets of perch due to the higher bioaccumulation of the radionuclides investigated in the skin and scales.

Tagetes lucida Cav. essential oil and the mixture of its main compounds are antibacterial and modulate antibiotic resistance in multi-resistant pathogenic bacteria.

We evaluated an essential oil (EO) of Tagetes lucida Cav. and the mixture of its main compounds against multi-drug resistant bacteria. We found that EO and the partially reconstituted blend of its main components have antibacterial activity and inhibit antibiotic resistance (ampicillin, chloramphenicol, nalidixic acid, vancomycin and imipenem) in strains of Staphylococcus aureus ATCC 29213 and Pseudomonas aeruginosa HIM-MR01. The T. lucida EO alone or added to the antibiotics showed antimicrobial activity against S. aureus and P. aeruginosa. The EO main bioactive compounds were methyl eugenol (relative abundance in EO: 46·15%), estragole (32·93%), linalool (2·48%) and geraniol (0·33%). The mixture (PREO) of those compounds at those proportions inhibited the growth of P. aeruginosa in 45% at 683·62 µg ml-1 and that of S. aureus in 51·7% at 39·04 µg ml-1 . The PREO had higher antibacterial and modulatory activities than the original EO. In conclusion, we overcame the unpredictability of EO activity (due to their natural variability) by determining which EO components inhibited bacteria and then producing a PREO to generate a reproducible mixture with predictable antibacterial and modulation of resistance activities. Thus, the PREO, and its components, show potential as alternatives to manage multidrug-resistant pathogens.

Multilevel regulation of the glass locus during Drosophila eye development.

Development of eye tissue is initiated by a conserved set of transcription factors termed retinal determination network (RDN). In the fruit fly Drosophila melanogaster, the zinc-finger transcription factor Glass acts directly downstream of the RDN to control identity of photoreceptor as well as non-photoreceptor cells. Tight control of spatial and temporal gene expression is a critical feature during development, cell-fate determination as well as maintenance of differentiated tissues. The molecular mechanisms that control expression of glass, however, remain largely unknown. We here identify complex regulatory mechanisms controlling expression of the glass locus. All information to recapitulate glass expression are contained in a compact 5.2 kb cis-acting genomic element by combining different cell-type specific and general enhancers with repressor elements. Moreover, the immature RNA of the locus contains an alternative small open reading frame (smORF) upstream of the actual glass translation start, resulting in a small peptide instead of the three possible Glass protein isoforms. CRISPR/Cas9-based mutagenesis shows that the smORF is not required for the formation of functioning photoreceptors, but is able to attenuate effects of glass misexpression. Furthermore, editing the genome to generate glass loci eliminating either one or two isoforms shows that only one of the three proteins is critical for formation of functioning photoreceptors, while removing the two other isoforms did not cause defects in developmental or photoreceptor function. Our results show that eye development and function is largely unaffected by targeted manipulations of critical features of the glass transcript, suggesting a strong selection pressure to allow the formation of a functioning eye.

Efficacy and Safety of Tranexamic Acid for the Control of Surgical Bleeding in Patients Under Liposuction.

Liposuction remains one of the most frequently performed cosmetic surgical procedures and its popularity is increasing every year. However, since its inception, justified concerns regarding patient safety have placed limits on the volume of fat that can be aspirated, influenced by hemodynamic fluctuations and blood loss during liposuction. Tranexamic acid (TXA) is an antifibrinolytic agent that competitively inhibits the conversion of plasminogen to plasmin, thus preventing the binding and degradation of fibrin. Despite the existence of evidence of the effectiveness of TXA in orthopedic and cardiac surgeries, there is little evidence of its use in liposuction. The objective of this study was to evaluate the efficacy and safety of tranexamic acid in the control of surgical bleeding in patients undergoing liposuction, through a prospective, open, randomized and controlled clinical trial. Two groups of 25 participants each were formed to whom the application of TXA in a tumescent solution prior to liposuction or liposuction with the traditional technique was randomly assigned. The results showed a decrease in blood loss reflected by the differences in the final hematocrit values, as well as decrease in the same per aspirated volume (p = 0.003). No adverse events were found related with the TXA application and no blood transfusions were required in this group, in contrast to the control group where the need for blood transfusion was present in 20% of the intervened participants. LEVEL OF EVIDENCE II: This journal requires that authors assign a level of evidence to each article. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors www.springer.com/00266.

Moderate to Severe Psoriasis in Pediatric and Young Patients: The BIOBADADERM Registry Experience. / Psoriasis moderada-grave en pacientes pediátricos y jóvenes: experiencia en el registro BIOBADADERM.

Childhood-onset psoriasis generally follows an indolent course but patients with moderate or severe disease may require systemic treatment. The aim of this study was to determine the relative proportion of children and young people aged up to 21 years with moderate to severe psoriasis in the BIOBADADERM registry and to analyze the characteristics of these patients, treatments used, and adverse events. Of the 3946 patients in the registry, 24 were aged 21 years or younger. They had mean age of 16.1 years on starting treatment. When the registry was started, they had a Psoriasis Area and Severity Index of 9.4 and 67% were being treated with a conventional systemic drug. Treatment was discontinued in 14 patients (58%) due to adverse events or a loss or lack of effectiveness. In conclusion, the BIOBADADERM registry shows that young people account for a small proportion of psoriasis patients receiving systemic treatment, and they are more likely to be treated using conventional systemic drugs.

Network meta-analysis of post-exposure prophylaxis randomized clinical trials.

OBJECTIVES: We performed a network meta-analysis of PEP randomized clinical trials to evaluate the best regimen. METHODS: After MEDLINE/Pubmed search, studies were included if: (1) were randomized, (2) comparing at least 2 PEP three-drug regimens and, (3) reported completion rates or discontinuation at 28 days. Five studies with 1105 PEP initiations were included and compared ritonavir-boosted lopinavir (LPV/r) vs. atazanavir (ATV) (one study), cobicistat-boosted elvitegravir (EVG/c) (one study), raltegravir (RAL) (one study) or maraviroc (MVC) (two studies). We estimated the probability of each treatment of being the best based on the evaluation of five outcomes: PEP non-completion at day 28, PEP discontinuation due to adverse events, PEP switching due to any cause, lost to follow-up and adverse events. RESULTS: Participants were mostly men who have sex with men (n = 832, 75%) with non-occupational exposure to HIV (89.86%). Four-hundred fifty-four (41%) participants failed to complete their PEP course for any reason. The Odds Ratio (OR) for PEP non-completion at day 28 in each antiretroviral compared to LPV/r was: ATV 0.95 (95% CI 0.58-1.56; EVG/c: OR 0.65 95% CI 0.30-1.37; RAL: OR 0.68 95% CI 0.41-1.13; and MVC: OR 0.69 95% CI 0.47-1.01. In addition, the rankogram showed that EVG/c had the highest probability of being the best treatment for the lowest rates in PEP non-completion at day 28, switching, lost to follow-up or adverse events and MVC for PEP discontinuations due to adverse events. CONCLUSIONS: Our study shows the advantages of integrase inhibitors when used as PEP, particularly EVG as a Single-Tablet Regimen.

Impact of switching to raltegravir and/or adding losartan in lymphoid tissue fibrosis and inflammation in people living with HIV. A randomized clinical trial.

BACKGROUND: Persistent inflammation and immune activation are associated with lymph node fibrosis and end-organ diseases in treatment-suppressed people living with HIV (PLWH). We investigated the effect of switching to raltegravir and/or adding losartan on lymphoid tissue fibrosis and on the inflammatory/immune-activation mediators in treated HIV patients. METHODS: Chronic HIV-infected patients treated with two nucleoside reverse transcriptase inhibitors (2NRTI) and one non-NRTI (NNRTI) or protease inhibitor (PI) during at least 48 weeks were randomized to four groups (n = 48): 2NRTI + efavirenz (EFV), 2NRTI + EFV + losartan, 2NRTI + raltegravir and 2NRTI + raltegravir + losartan for 48 weeks. Tonsillar biopsy and peripheral blood markers of CD4 and CD8 T-lymphocyte activation and senescence, monocyte activation and soluble markers of inflammation were determined at baseline and at week 48 and compared between groups. RESULTS: No changes in lymphoid tissue architecture were observed. Adding losartan had no impact on lymphocyte subsets. Conversely, patients who switched to raltegravir showed a higher decrease in all activated [CD4+CD38+HLA-DR+, -0.3 vs. 0.48 (P = 0.033); CD8+CD38+ HLA-DR+, -1.6 vs. 1.3 (P = 0.02)] and senescent [CD4+CD28-CD57+, -0.3 vs. 0.26 (P = 0.04); CD8+CD28-CD57+, -6.1 vs. 3.8 (P = 0.002)] T lymphocytes. In addition, the median CD4/CD8 ratio increased by 0.35 in patients in the raltegravir group vs. 0.03 in the other arms (P = 0.002). Differences between groups in monocyte subpopulations or soluble inflammation markers were not observed. CONCLUSIONS: Losartan had no effect on lymphoid fibrosis or immune activation/inflammation. Conversely, switching to a regimen with raltegravir significantly decreased activated and senescent T-lymphocyte subpopulations and increased CD4/CD8 ratio in successfully treated PLWH.

First Direct Measurement of an Astrophysical p-Process Reaction Cross Section Using a Radioactive Ion Beam.

We have performed the first direct measurement of the ^{83}Rb(p,γ) radiative capture reaction cross section in inverse kinematics using a radioactive beam of ^{83}Rb at incident energies of 2.4 and 2.7A MeV. The measured cross section at an effective relative kinetic energy of E_{cm}=2.393 MeV, which lies within the relevant energy window for core collapse supernovae, is smaller than the prediction of statistical model calculations. This leads to the abundance of ^{84}Sr produced in the astrophysical p process being higher than previously calculated. Moreover, the discrepancy of the present data with theoretical predictions indicates that further experimental investigation of p-process reactions involving unstable projectiles is clearly warranted.

Runs of homozygosity provide a genome landscape picture of inbreeding and genetic history of European autochthonous and commercial pig breeds.

ROHs are long stretches of DNA homozygous at each polymorphic position. The proportion of genome covered by ROHs and their length are indicators of the level and origin of inbreeding. Frequent common ROHs within the same population define ROH islands and indicate hotspots of selection. In this work, we investigated ROHs in a total of 1131 pigs from 20 European local pig breeds and in three cosmopolitan breeds, genotyped with the GGP Porcine HD Genomic Profiler. plink software was used to identify ROHs. Size classes and genomic inbreeding parameters were evaluated. ROH islands were defined by evaluating different thresholds of homozygous SNP frequency. A functional overview of breed-specific ROH islands was obtained via over-representation analyses of GO biological processes. Mora Romagnola and Turopolje breeds had the largest proportions of genome covered with ROH (~1003 and ~955 Mb respectively), whereas Nero Siciliano and Sarda breeds had the lowest proportions (~207 and 247 Mb respectively). The highest proportion of long ROH (>16 Mb) was in Apulo-Calabrese, Mora Romagnola and Casertana. The largest number of ROH islands was identified in the Italian Landrace (n = 32), Cinta Senese (n = 26) and Lithuanian White Old Type (n = 22) breeds. Several ROH islands were in regions encompassing genes known to affect morphological traits. Comparative ROH structure analysis among breeds indicated the similar genetic structure of local breeds across Europe. This study contributed to understanding of the genetic history of the investigated pig breeds and provided information to manage these pig genetic resources.

Patterning mechanisms diversify neuroepithelial domains in the Drosophila optic placode.

The central nervous system develops from monolayered neuroepithelial sheets. In a first step patterning mechanisms subdivide the seemingly uniform epithelia into domains allowing an increase of neuronal diversity in a tightly controlled spatial and temporal manner. In Drosophila, neuroepithelial patterning of the embryonic optic placode gives rise to the larval eye primordium, consisting of two photoreceptor (PR) precursor types (primary and secondary), as well as the optic lobe primordium, which during larval and pupal stages develops into the prominent optic ganglia. Here, we characterize a genetic network that regulates the balance between larval eye and optic lobe precursors, as well as between primary and secondary PR precursors. In a first step the proneural factor Atonal (Ato) specifies larval eye precursors, while the orphan nuclear receptor Tailless (Tll) is crucial for the specification of optic lobe precursors. The Hedgehog and Notch signaling pathways act upstream of Ato and Tll to coordinate neural precursor specification in a timely manner. The correct spatial placement of the boundary between Ato and Tll in turn is required to control the precise number of primary and secondary PR precursors. In a second step, Notch signaling also controls a binary cell fate decision, thus, acts at the top of a cascade of transcription factor interactions to define PR subtype identity. Our model serves as an example of how combinatorial action of cell extrinsic and cell intrinsic factors control neural tissue patterning.

What do asthmatic patients think about telemedicine visits?

Summary: Introduction. Due to the Coronavirus disease 2019 (COVID-19) outbreak and the national emergency state, virtual visits were implemented as an alternative to in-person visits. With this study we aimed to establish asthma patients' general satisfaction with the quality of health care provided by virtual visits (phone or video calls). Materials and methods. A questionnaire (9 questions) was published on the Facebook page of the Portuguese Association of Asthmatics. It was available online for general self-reported asthmatic patients to answer during one month, starting on 11st May 2020. The survey only allowed one answer per registered user. Results. Fifty-five responses were obtained. Patients were satisfied with communication with providers (> 88%); nevertheless, one-half evaluated the virtual visit as inferior when compared to in-person visits. About one third attributed a classification of 6 or less (0-10 scale, 0 being the worst and 10 the best consultation possible), but still most of the patients would either recommend it or use this kind of medical visits in the future, even outside the actual pandemic context. Patients also referred some important limitations, as lack of physical examination and the fact that the medical visit was more impersonal. Only 27% had technical issues accessing virtual visits. Positive aspects were also named, such as virtual visits being practical and avoiding the need to move to the hospital. Discussion and conclusions. Our survey revealed that small changes could further increase patients' satisfaction, adherence and confidence in telemedicine. Although presenting some limitations, virtual visits seem to be generally well accepted by asthmatic patients and it might be a good alternative for in-person visits, at leastin such difficult times when social distancing is recommended.

Association between xerostomia, oral and general health, and obesity in adults. A cross-sectional pilot study.

BACKGROUND: The objective of this study was to analyse the association between oral and general health variables and obesity indicators with the sensation of dry mouth or xerostomia as evaluated on the Xerostomia Inventory (XI). MATERIAL AND METHODS: A total of 354 randomly selected subjects participated in this cross-sectional pilot study and completed an anonymous questionnaire. Anthropometric, clinical, and xerostomic variables were evaluated. Kruskal-Wallis, ANOVA and Bonferroni test were used for multiple comparisons. ROC curves and multinomial logistic regression were used to determine the (OR) risk of xerostomia. RESULTS: A total of 30.7 % of respondents reported xerostomia based on XI. The dry mouth question, the XI taken as a "gold standard", showed a diagnostic sensitivity of 70.37 %, and a specificity of 83.27 % (AUC=0.768, p<0.001). Logistical regression showed the highest xerostomia OR was associated to patients with bad self-perceived health, 6.31 (CI 95% 2.89-13.80, p<0.001). In the model adjusted for tooth mobility, bone or respiratory diseases, and the consumption of anxiolytics and antidepressants, the OR was 3.46 (CI 95% 1.47-8.18, p=0.005). CONCLUSIONS: a high prevalence of xerostomia was found in this cross-sectional pilot study, which was significantly more frequent in women, and increased with age. Xerostomia was associated to several systemic diseases, psychological conditions, and oral functional disorders such as tooth mobility. These preliminary results can serve as the basis for developing guidelines for the application of innovative measures designed to improve the quality of life of individuals with xerostomia.

Serial electron microscopic reconstruction of the drosophila larval eye: Photoreceptors with a rudimentary rhabdomere of microvillar-like processes.

Photoreceptor cells (PRCs) across the animal kingdom are characterized by a stacking of apical membranes to accommodate the high abundance of photopigment. In arthropods and many other invertebrate phyla PRC membrane stacks adopt the shape of densely packed microvilli that form a structure called rhabdomere. PRCs and surrounding accessory cells, including pigment cells and lens-forming cells, are grouped in stereotyped units, the ommatidia. In larvae of holometabolan insects, eyes (called stemmata) are reduced in terms of number and composition of ommatidia. The stemma of Drosophila (Bolwig organ) is reduced to a bilateral cluster of subepidermal PRCs, lacking all other cell types. In the present paper we have analyzed the development and fine structure of the Drosophila larval PRCs. Shortly after their appearance in the embryonic head ectoderm, PRC precursors delaminate and lose expression of apical markers of epithelial cells, including Crumbs and several centrosome-associated proteins. In the early first instar larva, PRCs show an expanded, irregularly shaped apical surface that is folded into multiple horizontal microvillar-like processes (MLPs). Apical PRC membranes and MLPs are covered with a layer of extracellular matrix. MLPs are predominantly aligned along an axis that extends ventro-anteriorly to dorso-posteriorly, but vary in length, diameter, and spacing. Individual MLPs present a "beaded" shape, with thick segments (0.2-0.3 µm diameter) alternating with thin segments (>0.1 µm). We show that loss of the glycoprotein Chaoptin, which is absolutely essential for rhabdomere formation in the adult PRCs, does not lead to severe abnormalities in larval PRCs.

Beneficial Effects of Soluble Guanylyl Cyclase Stimulation and Activation in Sickle Cell Disease Are Amplified by Hydroxyurea: In Vitro and In Vivo Studies.

The complex pathophysiology of sickle cell anemia (SCA) involves intravascular hemolytic processes and recurrent vaso-occlusion, driven by chronic vascular inflammation, which result in the disease's severe clinical complications, including recurrent painful vaso-occlusive episodes. Hydroxyurea, the only drug frequently used for SCA therapy, is a cytostatic agent, although it appears to exert nitric oxide/soluble guanylyl cyclase (sGC) modulating activity. As new drugs that can complement or replace the use of hydroxyurea are sought to further reduce vaso-occlusive episode frequency in SCA, we investigated the effects of the sGC agonists BAY 60-2770 (sGC activator) and BAY 41-2272 (sGC stimulator) in the presence or absence of hydroxyurea on SCA vaso-occlusive mechanisms and cell recruitment both ex vivo and in vivo. These agents significantly reduced stimulated human SCA neutrophil adhesive properties ex vivo in association with the inhibition of surface ß2-integrin activation. A single administration of BAY 60-2770 or BAY 41-2272 decreased tumor necrosis factor cytokine-induced leukocyte recruitment in a mouse model of SCA vaso-occlusion. Importantly, the in vivo actions of both agonists were significantly potentiated by the coadministration of hydroxyurea. Erythroid cell fetal hemoglobin (HbF) elevation is also a major goal for SCA therapy. BAY 41-2272 but not BAY 60-2770 at the concentrations employed significantly induced γ-globin gene transcription in association with HbF production in cultured erythroleukemic cells. In conclusion, sGC agonist drugs could represent a promising approach as therapy for SCA, for use either as stand-alone treatments or in combination with hydroxyurea. SIGNIFICANCE STATEMENT: This preclinical study demonstrates that stimulators and activators of sGC are potent inhibitors of the adhesion and recruitment of leukocytes from humans and in mice with sickle cell anemia (SCA) and may represent a promising approach for diminishing vaso-occlusive episode frequency in SCA. Hydroxyurea, a drug already frequently used for treating SCA, was found to potentiate the beneficial effects of sGC agonists in in vivo studies, implying that these classes of compounds could be used alone or in combination therapy.

Post-exposure prophylaxis for HIV infection in sexual assault victims.

OBJECTIVES: Sexual assault (SA) is recognized as a public health problem of epidemic proportions. Guidelines recommend the administration of post-exposure prophylaxis (PEP) after an SA. However, few data are available about the feasibility of this strategy, and this study was conducted to assess this. METHODS: We conducted a retrospective, longitudinal, observational study in SA victims attending the Hospital Clinic in Barcelona from 2006 to 2015. A total of 1695 SA victims attended the emergency room (ER), of whom 883 met the PEP criteria. Five follow-up visits were scheduled at days 1, 10, 28, 90 and 180 in the out-patient clinic. The primary endpoint was PEP completion rate at day 28. Secondary endpoints were loss to follow-up, treatment discontinuation, occurrence of adverse events (AEs) and rate of seroconversion. RESULTS: The median age of participants was 25 years [interquartile range (IQR) 21-33 years] and 93% were female. The median interval between exposure and presentation at the ER was 13 h (IQR 6-24 h). The level of risk was appreciable in 47% (n = 466) of individuals. Of 883 patients receiving PEP, 631 lived in Catalonia. In this group, the PEP completion rate at day 28 was 29% (n = 183). The follow-up rate was 63% (n = 400) and 38% (n = 241) at days 1 and 28, respectively. Treatment discontinuation was present in 58 (15%) of 400 patients who attended at least the day 1 visit, the main reason being AEs (n = 35; 60%). AEs were reported in 226 (56%) patients, and were mainly gastrointestinal (n = 196; 49%). Only 211 (33%) patients returned for HIV testing at day 90. A single seroconversion was observed in a men who have sex with men (MSM) patient at day 120. CONCLUSIONS: Follow-up and compliance rates in SA victims were poor. In addition, > 50% of the patients experienced AEs, which were the main reason for PEP interruption. Strategies to increase follow-up testing and new better tolerated drug regimens must be investigated to address these issues.

Abatacept in interstitial lung disease associated with rheumatoid arthritis: national multicenter study of 263 patients.

OBJECTIVE: To assess the efficacy of abatacept (ABA) in RA patients with interstitial lung disease (ILD) (RA-ILD). METHODS: This was an observational, multicentre study of RA-ILD patients treated with at least one dose of ABA. ILD was diagnosed by high-resolution CT (HRCT). We analysed the following variables at baseline (ABA initiation), 12 months and at the end of the follow-up: Modified Medical Research Council (MMRC) scale (1-point change), forced vital capacity (FVC) or diffusion lung capacity for carbon monoxide (DLCO) (improvement or worsening ≥10%), HRCT, DAS on 28 joints evaluated using the ESR (DAS28ESR) and CS-sparing effect. RESULTS: We studied 263 RA-ILD patients [150 women/113 men; mean (s.d.) age 64.6 (10) years]. At baseline, they had a median duration of ILD of 1 (interquartile range 0.25-3.44) years, moderate or severe degree of dyspnoea (MMRC grade 2, 3 or 4) (40.3%), FVC (% of the predicted) mean (s.d.) 85.9 (21.8)%, DLCO (% of the predicted) 65.7 (18.3) and DAS28ESR 4.5 (1.5). The ILD patterns were: usual interstitial pneumonia (UIP) (40.3%), non-specific interstitial pneumonia (NSIP) (31.9%) and others (27.8%). ABA was prescribed at standard dose, i.v. (25.5%) or s.c. (74.5%). After a median follow-up of 12 (6-36) months the following variables did not show worsening: dyspnoea (MMRC) (91.9%); FVC (87.7%); DLCO (90.6%); and chest HRCT (76.6%). A significant improvement of DAS28ESR from 4.5 (1.5) to 3.1 (1.3) at the end of follow-up (P < 0.001) and a CS-sparing effect from a median 7.5 (5-10) to 5 (2.5-7.5) mg/day at the end of follow-up (P < 0.001) was also observed. ABA was withdrawn in 62 (23.6%) patients due to adverse events (n = 30), articular inefficacy (n = 27), ILD worsening (n = 3) and other causes (n = 2). CONCLUSION: ABA may be an effective and safe treatment for patients with RA-ILD.