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Background Individuals with autism spectrum disorder (ASD) exhibit frequent behavioral deficits in facial emotion recognition (FER). It remains unknown whether these deficits arise because facial emotion information is not encoded in their neural signal or because it is encodes but fails to translate to FER behavior (deployment). This distinction has functional implications, including constraining when differences in social information processing occur in ASD, and guiding interventions (i.e., developing prosthetic FER vs. reinforcing existing skills). Methods We utilized a discriminative and contemporary machine learning approach—deep convolutional neural networks—to classify facial emotions viewed by individuals with and without ASD (N = 88) from concurrently recorded electroencephalography signals. Results The convolutional neural network classified facial emotions with high accuracy for both ASD and non-ASD groups, even though individuals with ASD performed more poorly on the concurrent FER task. In fact, convolutional neural network accuracy was greater in the ASD group and was not related to behavioral performance. This pattern of results replicated across three independent participant samples. Moreover, feature importance analyses suggested that a late temporal window of neural activity (1000–1500 ms) may be uniquely important in facial emotion classification for individuals with ASD. Conclusions Our results reveal for the first time that facial emotion information is encoded in the neural signal of individuals with (and without) ASD. Thus, observed difficulties in behavioral FER associated with ASD likely arise from difficulties in decoding or deployment of facial emotion information within the neural signal. Interventions should focus on capitalizing on this intact encoding rather than promoting compensation or FER prostheses.

The use of novel small molecule inhibitors alone or in combination with anti-CD20 monoclonal antibodies for chronic lymphocytic leukemia (CLL) has raised a number of questions on efficacy, tolerability, long-term treatment adherence in patients with heterogeneous clinical features. To fill this gap, we designed a study focusing on treatment sequencing in patients with CLL in order to (i) compare the outcome of patients treated with chemoimmunotherapy (CIT) combinations in first-line versus those receiving Bruton's tyrosine kinase inhibitors (BTKi); (ii) characterize the efficacy and tolerability of venetoclax-based regimens; (ii) understand the impact of treatment sequencing when it comes to chemo-free options including venetoclax after BTKi and vice versa. Data from consecutive sets of patients diagnosed with CLL between 2000-2020 attended at 77 institutions affiliated with ERIC were collected and analyzed. Collected variables included: demographics, clinical stage at diagnosis, IGHV gene somatic hypermutation status; cytogenetic status for chromosomes 11q, 13q 17p and 12 determined by fluorescence in situ hybridization; TP53 gene mutation status; treatment; treatment response; discontinuation; reason for discontinuation; death. We included 9173 patients with a diagnosis of CLL who received at least one line of treatment. The median age at diagnosis was 67 years with a male:female ratio of 1.9. The median follow-up was 78 months (IQR, 48-120 months). Regarding novel targeted agents, 1860/9173 (20.2%) patients had received at least one line of treatment with BTKi (ibrutinib, n=1788; acalabrutinib, n=72) over the disease course; 631/9173 (6.9%) with venetoclax; and, 447/9173 (4.9%) with the PI3K inhibitor idelalisib. Seventy-nine patients were treated with both BTKi and venetoclax (59 BTKi followed by BCL2i, 20 vice versa). At last follow-up, 5870/9173 patients (64.0%) were alive, 3229/9173 (35.2%) died and 74/9173 (0.8%) were lost to follow-up. Patients treated with BTKi in first-line were enriched for TP53 aberrations [del(17p) 27.6%, TP53 mutation 26.3%] and unmutated IGHV genes (69%) and obtained an ORR of 87.7%. Of these, 136 (26.3%) discontinued treatment after a median of 1.2 years (0.07-5.98); main reasons of discontinuation were toxicity (40.5%) and failure (26.2%). Among 631 patients treated with venetoclax at any line, 100 (15.8%) received BCL2 +/- anti-CD20 as first-line; 170 (26.9%) as second line (125 previously treated with CIT, 27 with BTKi); and, 361 as third or subsequent line. ORR ranged between 71.5% (≥3 lines) with 30.5% CR/CRi to 90.3% (first-line) with 68.1% CR/CRi. Treatment discontinuation was due to toxicity in 28.6% of patients treated in the first-line, and 17.6% and 21.8% of patients treated in second and third-or-higher-line, respectively. Disease progression led to treatment discontinuation in 14.3%, 20.6% and 33.6% in first, second and third-or-higher line, respectively. CIT was used as front-line treatment in 5465 patients (59.6%). Of these, 2070 (37.9%) and 1018 (18.6%) patients received a second and third line of treatment, respectively. The great majority (865/1086 cases, 79.7%) of patients who received a second line before 2014 were retreated with CIT, most commonly Bendamustine-Rituximab (284/1086, 26.1%) and Fludarabine-Cyclophosphamide-Rituximab (252/1086, 23.2%); alemtuzumab monotherapy was used in 55/1086 (5%) of patients. After 2014, 415/984 patients (42.1%) were retreated with BTKi; 93 (9.5%) with venetoclax; 70 (7.2%) with idelalisib; 50 (5%) with Alemtuzumab monotherapy, and 315 (32%) with CIT. Similarly, in the third-or-higher line of treatment, most patients (86.3%) were retreated with CIT before 2014, while BTKi, BCL2i, and PI3Ki were mainly used after 2014 (in 43.1%, 15.7% and 14.7% of cases, respectively). Finally, our cohort included 1075 patients with TP53 aberrations. The ORR of patients receiving BTKis (n=171) as first-line of treatment was 86.5% (22.2 CR+64.3 PR), while the ORR with venetoclax +/- anti-CD20 (n=15) was 91% (45.5% CR+45.5 PR). Patients treated with CIT (n=694) had an ORR of 68.7% (28.3% CR+40.4% PR). In conclusion, in a large international study we provide real world data regarding the selection and sequencing of treatment in CLL, charting a major shift in treatment patterns before and after the introduction of novel trargeted agents and confirming their efficacy even in high-risk CLL. Disclosures Scarfo: Janssen: Honoraria, Other: Travel grants; Astra Zeneca: Honoraria; Abbvie: Honoraria. Iacoboni: BMS/Celgene, Gilead, Novartis, Janssen, Roche: Honoraria. Collado: Abbvie,: Other: pharmaceutical Company, Research Funding; Janssen: Other: Pharmaceutical Company, Research Funding. Galimberti: AbbVie, Janssen: Honoraria, Other: Travel grants; Incyte: Speakers Bureau. García-Serra: AbbVie: Other: Educational grands; Janssen: Other: Educational grants; Novartis: Other: Educational grants. Gozzetti: Janssen: Honoraria; AbbVie: Honoraria. Hatzimichael: Amgen, Roche, Genesis, Novartis, Bristol Mayer Squibb, Celgene, Pfizer: Consultancy; Abbvie, Amgen, Bristol Mayer Squibb, MSD, Gilead, Janssen Cilag, Genesis Pharma, Roche, Takeda: Honoraria. Herishanu: AbbVie: Honoraria, Research Funding; Janssen: Honoraria; Roche: Honoraria; Medison: Honoraria. Jaksic: Roche, Oktal-Pharma/Celtrion, Sandoz: Consultancy, Honoraria. Kater: Janssen, AstraZeneca: Other: Ad Board, steering committee, Research Funding; Abbvie: Honoraria, Other: Ad Board, Research Funding; BMS, Roche/Genentech: Other: Ad Board, , Research Funding; Genmab, LAVA: Other: Ad Board, Steering Committee. Kotsianidis: Astellas: Other: NONE, Research Funding, Speakers Bureau; Genesis: Consultancy, Other: NONE; Janssen Hellas: Consultancy, Other: NONE, Speakers Bureau; Bristol Hellas: Consultancy, Other: NONE, Research Funding, Speakers Bureau; Novartis Hellas: Consultancy, Other: NONE, Research Funding, Speakers Bureau; Abbvie: Consultancy, Other: NONE, Research Funding, Speakers Bureau. Kreitman: NIH: Patents & Royalties: Moxetumomab Pasudotox; Genentech: Research Funding; Teva: Research Funding; AstraZeneca/MedImmune: Research Funding; Innate: Research Funding; GSK/Novartis: Research Funding; Array BioPharma/Pfizer: Research Funding. Laribi: BeiGene: Other: Personal Fees; Jansen: Research Funding; Novartis: Other: Personal Fees, Research Funding; Astellas Phama, Inc.: Other: Personal Fees; AstraZeneca: Other: Personal Fees; Le Mans Hospital: Research Funding; Takeda: Other: Personal Fees, Research Funding; AbbVie: Other: Personal Fees, Research Funding; IQONE: Other: Personal Fees. Lopez-Garcia: Roche: Other: Speaker Honoraria, Travel and accommodation grants; Novonordisk: Other: Speaker Honoraria; Fresenius: Other: Speaker Honoraria; Celgene: Other: Speaker Honoraria; Abbvie: Other: Speaker Honoraria, Advisor, Travel and accommodation grants; Janssen: Other: Speaker Honoraria, Advisor, Travel and accommodation grants, Research Funding. Milosevic: Roche: Honoraria; Abbvie,: Honoraria; Janssen: Honoraria; Sandoz: Honoraria. Reda: Beigene: Consultancy; Astra Zeneca: Consultancy; Abbvie: Consultancy; Janssen: Consultancy. Ruchlemer: AbbVie: Consultancy, Honoraria, Research Funding. Šimkovič: Janssen, Gilead, Roche, AstraZeneca, and AbbVie: Other: consultancy fees, advisory board participation fees, travel grants, and honoraria; University Hospital Hradec Kralove: Current Employment; AbbVie: Consultancy, Current equity holder in publicly-traded company, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accommodations, Expenses; AstraZeneca: Consultancy, Membership on an entity's Board of Directors or advisory committees; Janssen-Cilag: Consultancy, Honoraria, Other: Travel, Accommodations, Expenses; Merck: Current equity holder in publicly-traded company; Eli Lilly: Current equity holder in publicly-traded company; J&J: Current equity holder in publicly-traded company; Gilead: Other: Travel, Accommodations, Expenses. Špaček: AbbVie, AstraZeneca, Gilead, Janssen, and Roche: Honoraria. Tadmor: Janssen: Consultancy, Honoraria, Research Funding; AbbVie: Consultancy, Honoraria, Research Funding. Visentin: Italfarmaco and Gilead: Speakers Bureau. Vassilakopoulos: AstraZeneca: Honoraria; Amgen: Honoraria, Research Funding; Pfizer: Research Funding; Dr. Reddy's: Research Funding; Novartis: Consultancy, Honoraria; GlaxoSmithKline: Honoraria, Other: Travel; Merck: Honoraria, Research Funding; Integris: Honoraria; Roche: Consultancy, Honoraria, Other: Travel; Genesis Pharma: Consultancy, Honoraria, Other: Travel; Takeda: Consultancy, Honoraria, Other: Travel, Research Funding; AbbVie: Consultancy, Honoraria; Karyopharm: Research Funding. Vitale: Janssen: Honoraria. Yáñez: Gilead-Kite, Janssen, AbbVie, AstraZeneca, Beigene, Roche, Pfizer, Jazz, BMS, and Merck: Other: Advisory board participation fees ; Janssen, AbbVie, AstraZeneca, Gilead-Kite, Roche, Pfizer, and Merck: Speakers Bureau. Antic: AbbVie, Janssen, and Roche: Honoraria. Coscia: Janssen: Honoraria, Other, Research Funding; Gilead: Honoraria; AstraZeneca: Honoraria; AbbVie: Honoraria, Other. Cuneo: AstraZeneca: Consultancy, Speakers Bureau; Janssen: Consultancy, Speakers Bureau; Gilead: Consultancy, Speakers Bureau; AbbVie: Consultancy, Speakers Bureau. Gaidano: Beigene: Membership on an entity's Board of Directors or advisory committees; Incyte: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Astrazeneca: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Abbvie: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Guièze: Janssen: Consultancy, Honoraria; Abbvie: Consultancy, Honoraria, Research Funding; Roche: Consultancy, Honoraria; Astrazeneca: Consultancy, Honoraria. Laurenti: AstraZeneca: Consultancy, Honoraria; AbbVie: Consultancy, Honoraria, Research Funding; Roche: Honoraria, Research Funding; Gilead: Honoraria; Janssen: Consultancy, Honoraria; BeiGene: Honoraria. Murru: Abbvie: Consultancy, Honoraria, Other: travel and accommodation; Janssen: Consultancy, Honoraria. Sportoletti: AstraZeneca: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; AbbVie: Consultancy, Honoraria. Tam: Beigene: Research Funding; Janssen: Research Funding; Abbvie: Research Funding; Loxo: Honoraria; Beigene: Honoraria; Janssen: Honoraria; Abbvie: Honoraria. Trněný: Amgen: Consultancy, Honoraria; Bristol-Myers Squibb: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accommodations, Expenses; Gilead Sciences: Consultancy, Honoraria, Other: Travel, Accommodations, Expenses; Incyte: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accommodations, Expenses; MorphoSys: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accommodations, Expenses; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accommodations, Expenses; Celgene: Consultancy; 1st Faculty of Medicine, Charles University, General Hospital in Prague: Current Employment; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Portola: Honoraria, Membership on an entity's Board of Directors or advisory committees; AstraZeneca: Honoraria; AbbVie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accommodations, Expenses. Bosch Albareda: Janssen: Consultancy, Honoraria, Research Funding, Speakers Bureau; Gilead: Consultancy, Honoraria; Abbvie: Consultancy; AstraZeneca: Consultancy, Honoraria, Research Funding; Roche: Consultancy, Honoraria, Research Funding, Speakers Bureau; Takeda: Honoraria, Research Funding; Novartis: Honoraria, Research Funding; Kite: Honoraria; Sanofi: Honoraria; Lilly: Honoraria. Doubek: Janssen-Cilag, AbbVie, AstraZeneca, Amgen, Gilead, Novartis: Honoraria, Research Funding. Chatzidimitriou: Abbvie: Honoraria, Research Funding; Janssen: Honoraria, Research Funding. Ghia: AbbVie: Consultancy, Honoraria, Research Funding; Acerta/AstraZeneca: Consultancy, Honoraria, Research Funding; AstraZeneca: Consultancy, Honoraria, Research Funding; ArQule/MSD: Consultancy, Honoraria; BeiGene: Consultancy, Honoraria; Celgene/Juno/BMS: Consultancy, Honoraria; Gilead: Consultancy, Research Funding; Janssen: Consultancy, Honoraria, Research Funding; Roche: Consultancy, Honoraria; Sunesis: Research Funding. Stamatopoulos: AstraZeneca: Honoraria, Research Funding; Abbvie: Honoraria, Research Funding; Gilead: Honoraria, Research Funding; Janssen: Honoraria, Research Funding.

Castleman disease is a rare lymphoproliferative disorder. Co-presentation with polyneuropathy, organomegaly, endocrinopathy, monoclonal protein, and skin changes (POEMS syndrome) has been documented in 11-30% of Castleman disease cases. POEMS syndrome is a rare paraneoplastic disorder characterized by polyneuropathy, organomegaly, endocrinopathy, monoclonal protein, and skin changes. Not all features are required to make the diagnosis. We report a case of a woman who presented with a 1-year history of a left-side supraclavicular swelling associated with constitutional symptoms and symmetrical paresthesia of the lower limbs. In addition, she had skin hyperpigmentation, multiple supra and infra-diaphragmatic lymphadenopathies, hepatosplenomegaly and osteosclerotic lesions. Serum immunofixation was positive for immunoglobulin G-kappa gammopathy. A lymph node excisional biopsy was compatible with Castleman disease. The diagnosis of POEMS syndrome associated with Castleman disease was made. Our patient started treatment with a combination of bortezomib, cyclophosphamide, and dexamethasone with clinical and analytical improvement. Current treatment of POEMS syndrome associated with Castleman disease is focused on the management of POEMS syndrome. Early diagnosis requires a high index of suspicion and is crucial to reduce morbidity and mortality. This case report aims to raise awareness about this rare entity. J Med Cases. 2021;12(10):400-404 doi: https://doi.org/10.14740/jmc3759

BACKGROUND & AIMS Patients with chronic hepatitis C and stage 3 fibrosis are thought to remain at risk of hepatocellular carcinoma after sustained virological response. We investigated this risk in a large cohort of patients with well-defined stage 3 fibrosis. METHODS We performed a multicentre, ambispective, observational study of chronic hepatitis C patients with sustained virological response after treatment with direct-acting antivirals started between January and December 2015. Baseline stage 3 was defined in a two-step procedure: we selected patients with transient elastography values of 9.5-14.5 kPa and subsequently excluded those with nodular liver surface, splenomegaly, ascites or collaterals on imaging, thrombopenia or esophago-gastric varices. Patients were screened twice-yearly using ultrasound. RESULTS The final sample comprised 506 patients (median age, 57.4 years; males, 59.9%; diabetes, 17.2%; overweight, 44.1%; genotype 3, 8.9%; HIV coinfection, 18.4%; altered liver values, 15.2%). Median follow-up was 33.7 (22.1-39.1) months. Five hepatocellular carcinomas and 1 cholangiocarcinoma were detected after a median of 29.4 months (95% CI: 26.8-39.3), with an incidence of 0.47/100 patients/year (95% CI: 0.17-1.01). In the multivariate analysis, only males older than 55 years had a significant higher risk (hazard ratio 7.2 [95% CI: 1.2-41.7; P = .029]) with an incidence of 1.1/100 patients/year (95% CI: 0.3-2.8). CONCLUSIONS In a large, well-defined cohort of patients with baseline hepatitis C stage-3 fibrosis, the incidence of primary liver tumours was low after sustained virological response and far from the threshold for cost-effectiveness of screening, except in males older than 55 years.

Background: Large prospective studies on the safety of Mohs micrographic (MMS) surgery are scarce, and most focus on a single type of surgical adverse event. Mid-term scar alterations and functional loss have not been described. Objectives: To describe the risk of MMS complications and the risk factors for them. Methods: A nationwide prospective cohort collected all adverse events on consecutive patients in 22 specialised centres. We used multilevel mixed-effects logistic regression to find out factors associated with adverse events. Results: 5,017 patients were included, with 14,421 patient-years of follow-up. 7.0% had some perioperative morbidity and 6.5% had mid-term and scar-related complications. The overall risk of complications was mainly associated with use of antiaggregant/anticoagulant and larger tumours, affecting deeper structures, not reaching a tumour-free border, and requiring complex repair. Age and outpatient setting were not linked to the incidence of adverse events. Risk factors for haemorrhage (0.9%) were therapy with antiaggregant/anticoagulants, tumour size, duration of surgery, and unfinished surgery. Wound necrosis (1.9%) and dehiscence (1.0%) were associated with larger defects and complex closures. Immunosuppression was only associated with an increased risk of necrosis. Surgeries reaching deeper structures, larger tumours and previous surgical treatments were associated with wound infection (0.9%). Aesthetic scar alterations (5.4%) were more common in younger patients, with larger tumours, in H-area, and in flap and complex closures. Risk factors for functional scar alterations (1.7%) were the need for general anaesthesia, larger tumours that had received previous surgery, and flaps or complex closures. Conclusions: MMS shows a low risk of complications. Most of the risk factors for complications were related to tumour size and depth, and the resulting need for complex surgery. Antiaggregant/anticoagulant intake was associated with a small increase in the risk of haemorrhage, that probably does not justify withdrawal. Age and outpatient setting were not linked to the risk of adverse events.

Neuroprotection in acute stroke has not been successfully translated from animals to humans. Animal research on promising agents continues largely in rats and mice which are commonly available to researchers. However, controversies continue on the most suitable species to model the human situation. Generally, putative agents seem less effective in mice as compared with rats. We hypothesized that this may be due to inter-species differences in stroke response and that this might be manifest at a genetic level. Here we used whole-genome microarrays to examine the differential gene regulation in the ischemic penumbra of mice and rats at 2 and 6 h after permanent middle cerebral artery occlusion (pMCAO; Raw microarray CEL data files are available in the GEO database with an accession number GSE163654). Differentially expressed genes (adj. p ≤ 0.05) were organized by hierarchical clustering, correlation plots, Venn diagrams and pathway analyses in each species and at each time-point. Emphasis was placed on genes already known to be associated with stroke, including validation by RT-PCR. Gene expression patterns in the ischemic penumbra differed strikingly between the species at both 2 h and 6 h. Nearly 90% of significantly regulated genes and most pathways modulated by ischemia differed between mice and rats. These differences were evident globally, among stroke-associated genes, immediate early genes, genes implicated in stress response, inflammation, neuroprotection, ion channels, and signal transduction. The findings of this study may have significant implications for the choice of species for screening putative stroke therapies.

COVID-19 patients elicit strong responses to the nucleocapsid (N) protein of SARS-CoV-2 but binding antibodies are also detected in prepandemic individuals, indicating potential crossreactivity with common cold human coronaviruses (HCoV) and questioning its utility in seroprevalence studies. We investigated the immunogenicity of the full-length and shorter fragments of the SARS-CoV-2 N protein, and the crossreactivity of antibodies with HCoV. We identified a C-terminus region in SARS-CoV2 N of minimal sequence homology with HCoV that was more specific for SARS-CoV-2 and highly immunogenic. IgGs to the full-length SARS-CoV-2 N also recognized N229E N, and IgGs to HKU1 N recognized SARS-CoV-2 N. Crossreactivity with SARS-CoV-2 was stronger for alpha- rather than beta-HCoV despite having less sequence identity, revealing the importance of conformational recognition. Higher preexisting IgG to OC43 N correlated with lower IgG to SARS-CoV-2 N in rRT-PCR negative individuals, reflecting less exposure and indicating a potential protective association. Antibodies to SARS-CoV-2 N were higher in patients with more severe and longer duration of symptoms and in females. IgGs remained stable for at least 3 months, while IgAs and IgMs declined faster. In conclusion, N protein is a primary target of SARS-CoV-2-specific and HCoV crossreactive antibodies, both of which may affect the acquisition of immunity to COVID-19.

Graphical abstract, Highlights • A comprehensive diagnostic approach is taken in the cardiovascular source of embolism. • Cardiovascular imaging has a role in the cardiac source of embolism. • Three-dimensional echocardiography illustrates sinus of Valsalva thrombosis.

Purpose The COVID-19 pandemic has led to the cancellation or deferment of many elective cancer surgeries. We performed a systematic review on the oncological effects of delayed surgery for patients with localised or metastatic renal cell carcinoma (RCC) in the targeted therapy (TT) era. Method The protocol of this review is registered on PROSPERO(CRD42020190882). A comprehensive literature search was performed on Medline, Embase and Cochrane CENTRAL using MeSH terms and keywords for randomised controlled trials and observational studies on the topic. Risks of biases were assessed using the Cochrane RoB tool and the Newcastle–Ottawa Scale. For localised RCC, immediate surgery [including partial nephrectomy (PN) and radical nephrectomy (RN)] and delayed surgery [including active surveillance (AS) and delayed intervention (DI)] were compared. For metastatic RCC, upfront versus deferred cytoreductive nephrectomy (CN) were compared. Results Eleven studies were included for quantitative analysis. Delayed surgery was significantly associated with worse cancer-specific survival (HR 1.67, 95% CI 1.23–2.27, p

Background. Visual inspection and biopsy is the current standard of care for oral cancer diagnosis, but is subject to misinterpretation and consequently to misdiagnosis. Topically applied PARPi-FL is a molecularly specific, fluorescent contrast-based approach that may fulfil the unmet need for a simple, in vivo, non-invasive, cost-effective, point-of-care method for the early diagnosis of oral cancer. Here, we present results from a phase I safety and feasibility study on fluorescent, topically applied PARPi-FL. Twelve patients with a histologically proven squamous cell carcinoma of the oral cavity (OSCC) gargled a PARPi-FL solution for 60 seconds (15 mL, 100 nM, 250 nM, 500 nM, or 1000 nM), followed by gargling a clearing solution for 60 seconds. Fluorescence measurements of the lesion and surrounding oral mucosa were taken before PARPi-FL application, after PARPi-FL application and after clearing. Blood pressure, oxygen levels, clinical chemistry and CBC were obtained before and after tracer administration. Results. PARPi-FL was well-tolerated by all patients without any safety concerns. When analyzing the fluorescence signal, all malignant lesions showed a significant differential in contrast after administration of PARPi-FL, with the highest increase occurring at the highest dose level (1000 nM), where all patients had a tumor-to-margin fluorescence signal ratio of > 3. A clearing step was essential to increase signal specificity, as it clears unbound PARPi-FL trapped in normal anatomical structures. PARPi-FL tumor cell specificity was confirmed by ex vivo tabletop confocal microscopy. We have demonstrated that the fluorescence signal arose from the nuclei of tumor cells, endorsing our macroscopic findings.Conclusions. A PARPi-FL swish & spit solution is a rapid and non-invasive diagnostic tool that preferentially localizes fluorescent contrast to OSCC. This technique holds promise for the early detection of OSCC based on in vivo optical evaluation and targeted biopsy of suspicious lesions in the oral cavity. Clinicaltrials.gov - NCT03085147, registered on March 21st, 2017.

Immune checkpoint inhibitors (ICI) such as anti-programmed cell death protein 1 (PD-1) or anti-programmed death-ligand 1 (PDL-1) antibodies represent a breakthrough in the treatment of advanced neoplasms such as melanoma, lung, or renal cancer. The therapeutic use of these agents is rapidly growing in both active as well as adjuvant settings. Anti-PD-1 agents such as pembrolizumab or nivolumab target PD-1 present on the surface of T cells and other immune cells, enhancing the antitumoral response. Although they offer a better safety profile than anti-CTLA-4 antibodies such as ipilimumab, immune-related adverse events (irAE) still have an important impact on morbidity during treatment. Gastrointestinal and skin irAE are the most frequent adverse events associated with their use and tend to occur early in treatment. Maculopapular rash and lichenoid dermatitis are among the most common skin irAE, affecting approximately 3%-20% of the patients. Most of these reactions are mild and are easily managed with topical corticosteroids, rendering immunotherapy withdrawal unnecessary. Psoriasis might also be exacerbated or present as de novo, both with nivolumab or pembrolizumab, although the exact incidence rate has not been established. This immune-related psoriasis has also been observed during ipilimumab therapy, but its severity has not been defined according to clinical scales such as the psoriasis area severity index (PASI), body surface area (BSA), or physician's global assessment (PGA). Most published series report mild cases with a good outcome after treatment with topical steroids, ultraviolet B phototherapy, or acitretin. Here, we describe 3 patients with moderate to severe psoriasis related to nivolumab treatment, with a favorable response to apremilast and no impairment of antitumoral efficacy.

Background Studies suggest lower risk of breast cancer in women with HIV versus without HIV. These estimates may be biased by lower life expectancy and younger age distribution of women with HIV. Our analysis evaluated this bias and characterized secular trends in breast cancer among women with HIV initiating antiretroviral therapy. We hypothesized breast cancer risk would increase over time as mortality decreased. Setting Women with HIV prescribed antiretroviral therapy in the North American AIDS Cohort Collaboration on Research and Design (NA-ACCORD) from 1997 through 2016. Methods We estimated breast cancer hazard (cause-specific hazard ratios) and cumulative incidence accounting for competing risks (subdistribution hazard ratios) to assess changes in breast cancer risk over time. This was assessed overall (1997-2016) and within/across calendar periods. Analyses were adjusted for race/ethnicity and inverse probability weighted for cohort. Cumulative incidence was graphically assessed by calendar period and race/ethnicity. Results We observed 11,587 women during 1997-2016, contributing 63 incident breast cancer diagnoses and 1,353 deaths [73,445 person-years (median follow-up = 4.5 years)]. Breast cancer cumulative incidence was 3.2% for 1997-2016. We observed no secular trends in breast cancer hazard or cumulative incidence. There were annual declines in the hazard and cumulative incidence of death (cause-specific hazard ratios and subdistribution hazard ratios: 0.89, 95% confidence interval: 0.87 to 0.91) which remained within and across calendar periods. Conclusions These findings contradict the hypothesis of increasing breast cancer risk with declining mortality over time among women with HIV, suggesting limited impact of changing mortality on breast cancer risk. Additional inquiry is merited as survival improves among women with HIV.

In the context of the current COVID-19 pandemic, higher morbidity and mortality have been reported in older adults. This age group presents physiological changes and its own clinical conditions such as frailty, dementia, among others.To describe the characteristics of COVID-19 patients, both over and under 80 years old, by conducting a systematic review of the literature describing case reports, and to summarize and critically assess these characteristics.Systematic review. The study was registered on the Registry of Health Research Projects (PRISA) of the Peruvian National Institute of Health (code EI00000631). Five electronic databases (Scopus, PubMed, PubMed Central, LILACS, and SCIELO) were systematically searched during the period between December 31, 2019 and April 16, 2020. The search focused on case reports, case studies, and case series of older people with COVID-19 infection aged over or under 80 years. When selecting the cases, priority was given to clinical and epidemiological profile, laboratory and imaging patterns, and comprehensive geriatric evaluation.1,149 articles were identified; after applying the filters, a total of 15 publications of case reports and complete records of 27 older adults were obtained. The most frequent age group was between 60 to 69 years old. There is little literature regarding case reports of older adults aged over 80 years. The most frequent parameters were hypertension, fever, cough, respiratory distress, ground-glass opacification in chest radiography and tomography. Furthermore, decrease in PaOThis systematic review found little available information of patients under 80 years old, and far less for those over 80 years old, and an absence of comprehensive geriatric assessment.No contexto da atual pandemia de covid-19, maior morbidade e mortalidade têm sido relatadas em idosos. Sabe-se que essa faixa etária apresenta alterações fisiológicas e condições clínicas próprias, como fragilidade, demência, entre outras.Descrever as características de pacientes com covid-19, maiores e menores de 80 anos, por meio de uma revisão sistemática da literatura que descreve relatos de casos, e resumir e avaliar criticamente essas características.Revisão sistemática. O estudo foi registrado no Registro de Projetos de Pesquisa em Saúde (PRISA) do Instituto Nacional de Saúde do Peru (código EI00000631). Local: cinco bases de dados eletrônicas (Scopus, PubMed, PubMed Central, LILACS e SCIELO) foram sistematicamente pesquisadas entre 31 de dezembro de 2019 e 16 de abril de 2020. A busca se concentrou em relatos de caso, estudos de caso e séries de casos mais antigos pessoas com infecção por SARS-CoV-2 com mais e menos de 80 anos. Na seleção dos casos, a prioridade foi dada ao perfil clínico e epidemiológico, padrões laboratoriais e de imagem, e avaliação geriátrica abrangente.Foram identificados 1.149 artigos. Após a aplicação dos filtros, obteve-se um total de 15 publicações de relatos de caso e registros completos de 27 idosos. A faixa etária mais frequente foi de 60 a 69 anos. Há pouca literatura sobre relatos de casos de adultos com mais de 80 anos. Os parâmetros mais frequentes foram hipertensão, febre, tosse, dificuldade respiratória, vidro fosco na radiografia e tomografia de tórax. Também foram observados diminuição da PaO2 / FiO2 e linfócitos, e aumento da proteína C reativa e Interleucina 6.Esta revisão sistemática encontrou poucas informações disponíveis sobre pacientes com menos de 80 anos, em quantidade ainda menor para aqueles com mais de 80 anos, além de uma ausência de avaliação geriátrica abrangente.

Supplemental Digital Content is available in the text., Background: Cardiac involvement among hospitalized patients with severe coronavirus disease 2019 (COVID-19) is common and associated with adverse outcomes. This study aimed to determine the prevalence and clinical implications of COVID-19 cardiac involvement in young competitive athletes. Methods: In this prospective, multicenter, observational cohort study with data from 42 colleges and universities, we assessed the prevalence, clinical characteristics, and outcomes of COVID-19 cardiac involvement among collegiate athletes in the United States. Data were collected from September 1, 2020, to December 31, 2020. The primary outcome was the prevalence of definite, probable, or possible COVID-19 cardiac involvement based on imaging definitions adapted from the Updated Lake Louise Imaging Criteria. Secondary outcomes included the diagnostic yield of cardiac testing, predictors for cardiac involvement, and adverse cardiovascular events or hospitalizations. Results: Among 19 378 athletes tested for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, 3018 (mean age, 20 years [SD, 1 year]; 32% female) tested positive and underwent cardiac evaluation. A total of 2820 athletes underwent at least 1 element of cardiac triad testing (12-lead ECG, troponin, transthoracic echocardiography) followed by cardiac magnetic resonance imaging (CMR) if clinically indicated. In contrast, primary screening CMR was performed in 198 athletes. Abnormal findings suggestive of SARS-CoV-2 cardiac involvement were detected by ECG (21 of 2999 [0.7%]), cardiac troponin (24 of 2719 [0.9%]), and transthoracic echocardiography (24 of 2556 [0.9%]). Definite, probable, or possible SARS-CoV-2 cardiac involvement was identified in 21 of 3018 (0.7%) athletes, including 15 of 2820 (0.5%) who underwent clinically indicated CMR (n=119) and 6 of 198 (3.0%) who underwent primary screening CMR. Accordingly, the diagnostic yield of CMR for SARS-CoV-2 cardiac involvement was 4.2 times higher for a clinically indicated CMR (15 of 119 [12.6%]) versus a primary screening CMR (6 of 198 [3.0%]). After adjustment for race and sex, predictors of SARS-CoV-2 cardiac involvement included cardiopulmonary symptoms (odds ratio, 3.1 [95% CI, 1.2, 7.7]) or at least 1 abnormal triad test result (odds ratio, 37.4 [95% CI, 13.3, 105.3]). Five (0.2%) athletes required hospitalization for noncardiac complications of COVID-19. During clinical surveillance (median follow-up, 113 days [interquartile range=90 146]), there was 1 (0.03%) adverse cardiac event, likely unrelated to SARS-CoV-2 infection. Conclusions: SARS-CoV-2 infection among young competitive athletes is associated with a low prevalence of cardiac involvement and a low risk of clinical events in short-term follow-up.

Background: The success of unrelated haemopoietic cell transplantation (HCT) is limited by graft-versus-host disease (GVHD), which is the main post-transplantation challenge when HLA-matched donors are unavailable. A sequence dimorphism in exon 1 of HLA-B gives rise to leader peptides containing methionine (Met; M) or threonine (Thr; T), which differentially influence natural killer and T-cell alloresponses. The main aim of the study was to evaluate the role of the leader dimorphism in GVHD after HLA-B-mismatched unrelated HCT. Methods: We did a retrospective cohort study of 33 982 patients who received an unrelated HCT done in Australia, Europe, Japan, North America, and the UK between Jan 1, 1988, and Dec 31, 2016. Data were contributed by participants of the International Histocompatibility Working Group in Hematopoietic Cell Transplantation. All cases were included and there were no exclusion criteria. Multivariate regression models were used to assess risks associated with HLA-A, HLA-B, HLA-C, HLA-DRB1, and HLA-DQB1 mismatching. Among the 33 982 transplantations, the risks of GVHD associated with HLA-B M and T leaders were established in 17 100 (50·3%) HLA-matched and 1457 (4·3%) single HLA-B-mismatched transplantations using multivariate regression models. Leader frequencies were defined in 2 004 742 BeTheMatch US registry donors. Findings: Between Jan 20, 2017, and March 11, 2019, we assessed 33 982 HCTs using multivariate regression models for the role of HLA mismatching on outcome. Median follow-up was 1841 days (IQR 909–2963). Mortality and GVHD increased with increasing numbers of HLA mismatches. A single HLA-B mismatch increased grade 3–4 acute GVHD (odds ratio [OR] 1·89, 95% CI 1·53–2·33; p

Background Uncertainty about the optimal respiratory support strategies in critically ill COVID-19 patients is widespread. While the risks and benefits of noninvasive techniques versus early invasive mechanical ventilation (IMV) are intensely debated, actual evidence is lacking. We sought to assess the risks and benefits of different respiratory support strategies, employed in intensive care units during the first months of the COVID-19 pandemic on intubation and intensive care unit (ICU) mortality rates. Methods Subanalysis of a prospective, multinational registry of critically ill COVID-19 patients. Patients were subclassified into standard oxygen therapy ≥10 L/min (SOT), high-flow oxygen therapy (HFNC), noninvasive positive-pressure ventilation (NIV), and early IMV, according to the respiratory support strategy employed at the day of admission to ICU. Propensity score matching was performed to ensure comparability between groups. Results Initially, 1421 patients were assessed for possible study inclusion. Of these, 351 patients (85 SOT, 87 HFNC, 87 NIV, and 92 IMV) remained eligible for full analysis after propensity score matching. 55% of patients initially receiving noninvasive respiratory support required IMV. The intubation rate was lower in patients initially ventilated with HFNC and NIV compared to those who received SOT (SOT: 64%, HFNC: 52%, NIV: 49%, p = 0.025). Compared to the other respiratory support strategies, NIV was associated with a higher overall ICU mortality (SOT: 18%, HFNC: 20%, NIV: 37%, IMV: 25%, p = 0.016). Conclusion In this cohort of critically ill patients with COVID-19, a trial of HFNC appeared to be the most balanced initial respiratory support strategy, given the reduced intubation rate and comparable ICU mortality rate. Nonetheless, considering the uncertainty and stress associated with the COVID-19 pandemic, SOT and early IMV represented safe initial respiratory support strategies. The presented findings, in agreement with classic ARDS literature, suggest that NIV should be avoided whenever possible due to the elevated ICU mortality risk.

Respiratory infections are life-threatening and therapeutic antibodies (Ab) have a tremendous opportunity to benefit to patients with pneumonia due to multidrug resistance bacteria or emergent virus, before a vaccine is manufactured. In respiratory infections, inhalation of anti-infectious Ab may be more relevant than intravenous (IV) injection-the standard route-to target the site of infection and improve Ab therapeutic index. One major challenge associated to Ab inhalation is to prevent protein instability during the aerosolization process. Ab drug development for IV injection aims to design a high-quality product, stable to different environment stress. In this study, we evaluated the suitability of Ab formulations developed for IV injection to be extended for inhalation delivery. We studied the aerosol characteristics and the aggregation profile of three Ab formulations developed for IV injection after nebulization, with two mesh nebulizers. Although the formulations for IV injection were compatible with mesh nebulization and deposition into the respiratory tract, the Ab were more unstable during nebulization than exposition to a vigorous shaking. Overall, our findings indicate that Ab formulations developed for IV delivery may not easily be repurposed for inhalation delivery and point to the requirement of a specific formulation development for inhaled Ab. Graphical abstract Supplementary Information The online version contains supplementary material available at 10.1007/s13346-021-00967-w.

Thromboembolic events are frequent in patients with COVID-19 infection, and no cases of bilateral renal infarctions have been reported. We present the case of a 41-year-old female patient with diabetes mellitus and obesity who attended the emergency department for low back pain, respiratory failure associated with COVID-19 pneumonia, diabetic ketoacidosis, and shock. The patient had acute kidney injury and required hemodialysis. Contrast abdominal tomography showed bilateral renal infarction and anticoagulation was started. Kidney infarction cases require high diagnostic suspicion and possibility of starting anticoagulation.

Severe malaria (SM) is a major public health problem in malaria-endemic countries. Sequestration of Plasmodium falciparum–infected erythrocytes in vital organs and the associated inflammation leads to organ dysfunction. MicroRNAs (miRNAs), which are rapidly released from damaged tissues into the host fluids, constitute a promising biomarker for the prognosis of SM. We applied next-generation sequencing to evaluate the differential expression of miRNAs in SM and in uncomplicated malaria (UM) in children in Mozambique. Six miRNAs were associated with in vitro P. falciparum cytoadhesion, severity in children, and P. falciparum biomass. Relative expression of hsa-miR-4497 quantified by TaqMan-quantitative reverse transcription PCR was higher in plasma of children with SM than those with UM (p

Introduction More than 180 million people have been infected by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and more than 4 million coronavirus disease-2019 (COVID-19) patients have died in 1.5 years of the pandemic. A novel therapeutic vaccine (NASVAC) has shown to be safe and to have immunomodulating and antiviral properties against chronic hepatitis B (CHB). Materials and methods A phase I/II, open-label controlled and randomized clinical trial of NASVAC as a postexposure prophylaxis treatment was designed with the primary aim of assessing the local and systemic immunomodulatory effect of NASVAC in a cohort of suspected and SARS-CoV-2 risk-contact patients. A total of 46 patients, of both sexes, 60 years or older, presenting with symptoms of COVID-19 were enrolled in the study. Patients received NASVAC (100 μg per Ag per dose) via intranasal at days 1, 7, and 14 and sublingual, daily for 14 days. Results and discussion The present study detected an increased expression of toll-like receptors (TLR)-related genes in nasopharyngeal tonsils, a relevant property considering these are surrogate markers of SARS protection in the mice model of lethal infection. The HLA-class II increased their expression in peripheral blood mononuclear cell's (PBMC's) monocytes and lymphocytes, which is an attractive property taking into account the functional impairment of innate immune cells from the periphery of COVID-19-infected subjects. NASVAC was safe and well tolerated by the patients with acute respiratory infections and evidenced a preliminary reduction in the number of days with symptoms that needs to be confirmed in larger studies. Conclusions Our data justify the use of NASVAC as preemptive therapy or pre-/postexposure prophylaxis of SARS-CoV-2 and acute respiratory infections in general. The use of NASVAC or their active principles has potential as immunomodulatory prophylactic therapies in other antiviral settings like dengue as well as in malignancies like hepatocellular carcinoma where these markers have shown relation to disease progression. How to cite this article Fleites YA, Aguiar J, Cinza Z, et al. HeberNasvac, a Therapeutic Vaccine for Chronic Hepatitis B, Stimulates Local and Systemic Markers of Innate Immunity: Potential Use in SARS-CoV-2 Postexposure Prophylaxis. Euroasian J Hepato-Gastroenterol 2021;11(2):59-70.

Background Inflammatory response plays an important role in many processes related to acute ischemic stroke (AIS). Calprotectin (S100A8/S100A9), released by monocytes and neutrophils, is a key protein in the regulation of inflammation and thrombosis. The purpose of this study is to evaluate the association of circulating calprotectin with other inflammatory biomarkers and AIS prognosis, as well as the calprotectin content in stroke thrombi. Methods Among the 748 patients treated at a comprehensive stroke center between 2015 and 2017, 413 patients with confirmed acute ischemic injury were prospectively evaluated. Patients with systemic inflammation or infection at onset were excluded. Plasma calprotectin was measured by ELISA in blood samples of AIS patients within the first 24 h. Univariate and multivariate logistic regression models were performed to evaluate its association with mortality and functional independence (FI) at 3 months (defined as modified Rankin Scale < 3) and hemorrhagic transformation (HT) after ischemic stroke. Further, S100A9 was localized by immunostaining in stroke thrombi (n = 44). Results Higher calprotectin levels were associated with 3-month mortality, HT, and lower 3-month FI. After adjusting for potential confounders, plasma calprotectin remained associated with 3-month mortality [OR (95% CI) 2.31 (1.13–4.73)]. Patients with calprotectin ≥ 2.26 μg/mL were 4 times more likely to die [OR 4.34 (1.95–9.67)]. Addition of calprotectin to clinical variables led to significant improvement in the discrimination capacity of the model [0.91 (0.87–0.95) vs 0.89 (0.85–0.93); p < 0.05]. A multimarker approach demonstrated that patients with increased calprotectin, CRP, and NLR had the poorest outcome with a mortality rate of 42.3% during follow-up. S100A9 protein, as part of the heterodimer calprotectin, was present in all thrombi retrieved from AIS patients. Mean S100A9 content was 3.5% and tended to be higher in patients who died (p = 0.09). Moreover, it positively correlated with platelets (Pearson r 0.46, p < 0.002), leukocytes (0.45, p < 0.01), and neutrophil elastase (0.70, p < 0.001) thrombus content. Conclusions Plasma calprotectin is an independent predictor of 3-month mortality and provides complementary prognostic information to identify patients with poor outcome after AIS. The presence of S100A9 in stroke thrombi suggests a possible inflammatory mechanism in clot formation, and further studies are needed to determine its influence in resistance to reperfusion.

Introduction and objectives Extracellular matrix turnover is a major determinant of cardiac remodeling in heart failure. Sacubitril/valsartan decreases serum levels of procollagen type I amino-terminal peptide (PINP) and procollagen type III amino-terminal peptide (PIIINP), but its correlation with reverse remodeling is unknown. The purpose of this study is to determine the effect of sacubitril/valsartan on the profibrotic PINP and PIIINP biomarkers and their association with reverse cardiac remodeling in patients with heart failure with reduced ejection fraction (HFrEF). Methods Prospective, single-center, open-label study of 401 outpatients with HFrEF initiated with sacubitril/valsartan treatment according to Guideline-Directed Medical Therapy. Change in serum levels of PINP, PIIINP, left ventricle end-diastolic volume index, left ventricle end-systolic volume index and left ventricle ejection fraction were analyzed from baseline to 12-month follow-up. Results Baseline levels of PINP and PIIINP were highest (above-median) in 63 patients with ischemic cardiomyopathy and 19 with idiopathic dilated cardiomyopathy, decreasing −36 μg/L for PINP (95%CI, 78–93; P Conclusions These findings suggest that changes in fibrosis markers induced by sacubitril-valsartan therapy in HFrEF are related to reverse cardiac remodeling in patients with higher PINP and PIIINP levels.

Sporotrichosis is a subcutaneous mycosis that affects humans and animals, with a typically subacute or chronic evolution, caused by Sporothrix spp., a dimorphic fungus. Although the cutaneous form is the most frequent presentation, the ocular involvement has been more frequently diagnosed in endemic areas, affecting mainly children and the elderly. Approximately 80% of affected patients have the lymphocutaneous form, while only 2.3% have conjunctival lesions, with 0.7% showing primary ocular involvement. We describe two cases of sporotrichosis with ocular involvement in children through inoculation by felines, with a good response to antifungal treatment.

Resumen El vaciamiento gástrico normal refleja un esfuerzo coordinado entre diferentes regiones del estómago y el duodeno, y también una modulación extrínseca por parte del sistema nervioso central y factores del intestino distal. Los principales eventos relacionados con el vaciamiento gástrico normal incluyen el fondo de relajación para acomodar la comida, contracciones antrales para triturar partículas grandes de comida, contracción pilórica para permitir la liberación de comida del estómago y coordinación antropiloroduodenal de los fenómenos motores de relajación. La dismotilidad gástrica incluye el vaciamiento tardío del estómago (gastroparesia), vaciamiento gástrico acelerado (síndrome de dumping) y otras disfunciones motoras, como el deterioro del fondo de distensión, que se encuentra con mayor frecuencia en la dispepsia funcional. Los síntomas de la gastroparesia son inespecíficos y pueden simular otros trastornos estructurales. Abstract Normal gastric emptying reflects a coordinated effort between different regions of the stomach and the duodenum, and also an extrinsic modulation by the central nervous system and distal bowel factors. The main events related to normal gastric emptying include relaxation of the fundus to accommodate food, antral contractions to triturate large food particles, the opening of the pyloric sphincter to allow the release of food from the stomach, and anthropyloroduodenal coordination for motor relaxation. Gastric dysmotility includes delayed emptying of the stomach (gastroparesis), accelerated gastric emptying (dumping syndrome), and other motor dysfunctions, e.g., deterioration of the distending fundus, most often found in functional dyspepsia. The symptoms of gastroparesis are nonspecific and may mimic other structural disorders.

Objective Survival analysis of patients with prostate cancer (PCa) with adverse prognostic factors (APF) treated with radical prostatectomy (RP) and salvage radiotherapy (SRT) after biochemical recurrence (BR) or biochemical persistence (BP). Materials and methods Retrospective analysis of 446 patients with at least one of the following APF: Gleason score ≥8, pathologic stage ≥pT3 and/or positive surgical margins. BR criteria used was PSA level over 0.4 ng/ml. A survival analysis using Kaplan–Meier was performed to compare the different variable categories with log-rank test. In order to identify risk factors for SRT response and cancer specific survival (CSS) we performed univariate and multivariate analyses using Cox regression. Results Mean follow up: 72 (IQR 27–122) months, mean time to BR: 42 (IQR 20–112) months, mean PSA level at BR: 0.56 (IQR 0.42–0.96). BR was present in 36.3% of the patients. Biochemical response to SRT was observed in 121 (75.7%) patients. Recurrence-free survival (RFS) rates after SRT at 3, 5, 8 and 10 years were 95.7%, 92.3%, 87.9%, and 85%; overall survival (OS) rates after 5, 10 and 15 years was 95.6%, 86.5% and 73.5%, respectively. CSS rates at 5, 10 and 15 years were 99.1%, 98.1% and 96.6%. Only time to BR Conclusions In these patients, RP only controls the disease in approximately half of the cases. Multimodal sequential treatment (RP + SRT when needed) increases this control, achieving high CSS rates and biochemical control in over 87% of the patients. Patients with time to recurrence >24 months responded better to rescue treatment.

Background An ultrasensitive malaria rapid diagnostic test (RDT) was recently developed for the improved detection of low-density Plasmodium falciparum infections. This study aimed to compare the diagnostic performance of the PfHRP2-based Abbott Malaria Ag P. falciparum ultrasensitive RDT (uRDT) to that of the conventional SD-Bioline Malaria Ag P. falciparum RDT (cRDT) when performed under field conditions. Methods Finger-prick blood samples were collected from adults and children in two cross-sectional surveys in May of 2017 in southern Mozambique. Using real-time quantitative PCR (RT-qPCR) as the reference method, the age-specific diagnostic performance indicators of the cRDT and uRDT were compared. The presence of histidine-rich protein 2 (HRP2) and Plasmodium lactate dehydrogenase (pLDH) antigens was evaluated in a subset from dried blood spots by a quantitative antigen assay. pfhrp2 and pfhrp3 gene deletions were assessed in samples positive by RT-qPCR and negative by both RDTs. Results Among the 4,396 participants with complete test results, the sensitivity of uRDTs (68.2; 95% CI 60.8 to 74.9) was marginally better than that of cRDTs (61.5; 95% CI 53.9 to 68.6) (p-value = 0.004), while the specificities were similar (uRDT: 99.0 [95% CI 98.6 to 99.2], cRDT: 99.2 [95% CI 98.9 to 99.4], p-value = 0.02). While the performance of both RDTs was lowest in ≥ 15-year-olds, driven by the higher prevalence of low parasite density infections in this group, the sensitivity of uRDTs was significantly higher in this age group (54.9, 95% CI 40.3 to 68.9) compared to the sensitivity of cRDTs (39.2, 95% CI 25.8 to 53.9) (p-value = 0.008). Both RDTs detected P. falciparum infections at similar geometric mean parasite densities (112.9 parasites/μL for uRDTs and 145.5 parasites/μL for cRDTs). The presence of HRP2 antigen was similar among false positive (FP) samples of both tests (80.5% among uRDT-FPs and 84.4% among cRDT-FPs). Only one false negative sample was detected with a partial pfhrp2 deletion. Conclusion This study showed that the uRDTs developed by Abbott do not substantially outperform SD-Bioline Pf malaria RDTs in the community and are still not comparable to molecular methods to detect P. falciparum infections in this study setting.

Background To assess the possible impact of antiretroviral therapy improvements, aging, and comorbidities, we examined trends in all-cause and cause-specific hospitalization rates among persons with HIV (PWH) from 2005 to 2015. Methods In 6 clinical cohorts, we followed PWH in care (≥1 outpatient CD4 count or HIV load [VL] every 12 months) and categorized ICD codes of primary discharge diagnoses using modified Clinical Classifications Software. Poisson regression estimated hospitalization rate ratios for calendar time trends, adjusted for demographics, HIV risk factor, and annually updated age, CD4, and VL. Results Among 28 057 patients (125 724 person-years), from 2005 to 2015, the median CD4 increased from 389 to 580 cells/µL and virologic suppression from 55% to 85% of patients. Unadjusted all-cause hospitalization rates decreased from 22.3 per 100 person-years in 2005 (95% confidence interval [CI], 20.6–24.1) to 13.0 in 2015 (95% CI, 12.2–14.0). Unadjusted rates decreased for almost all diagnostic categories. Adjusted rates decreased for all-cause, cardiovascular, and AIDS-defining conditions, increased for non-AIDS–defining infection, and were stable for most other categories. Conclusions Among PWH with increasing CD4 counts and viral suppression, unadjusted hospitalization rates decreased for all-cause and most cause-specific hospitalizations, despite the potential effects of aging, comorbidities, and cumulative exposure to HIV and antiretrovirals.

Background Many cutaneous manifestations have been described in possible association with the COVID-19 pandemic, including acral lesions resembling chilblains. The underlying pathomechanisms of COVID-19 chilblains are not fully understood. The aim of this study was to describe the clinical, pathological, and laboratory findings of a series of patients who developed chilblains during the COVID-19 outbreak and to investigate the possible factors that could be involved in the pathogenesis of these lesions. Methods We conducted a prospective cohort study that included 54 patients who presented with chilblains during the highest peak in the incidence of COVID-19 in Cantabria (northern Spain). Skin biopsies were performed on 10 of these patients who presented with recent lesions. Laboratory investigations, including immunological analysis, serological studies, and the assessment of cryoproteins, were also performed. Results Most patients presented erythematous plaques located on the toes and/or purpuric macules located on the feet. Histopathological findings were compatible with those of idiopathic chilblains. Immunohistochemical evaluation showed C3d and C4d deposits in the vessel walls in seven cases. The autoimmunity panel was negative in most of our series. Cryoprotein testing showed positive cryofibrinogen in two-thirds (66.7%) of the patients assessed. On follow-up, most patients presented almost complete resolution, although six patients required prednisone and antiaggregant drug treatment. Conclusions This study shows, for the first time to our knowledge, a high prevalence of cryofibrinogenemia in patients with chilblains during the COVID-19 pandemic. Cryofibrinogenemia could be implicated in the pathogenesis of chilblains related to COVID-19.

Introduction Recurrence trends after renal cell cancer (RCC) nephrectomy are not clearly defined. Objective To evaluate recurrence trends according to recurrence risk groups (RRG). Methods Retrospective analysis of 696 patients with RCC treated with nephrectomy between 1990−2010. Three RRG were defined according to the presence of anatomopathological variables (pTpN stage, nuclear grade, tumor necrosis (TN), sarcomatoid differentiation (SD), positive resection margin (RM)): - Low RG (LRG):pT1pNx-0 G1–4, pT2pNx-0 G1–2; no TN, SD and/or RM(+) - Intermediate RG (IRG):pT2pNx-0 G3–4;pT3–4pNx-0 G1–2; LRG with TN. - High RG (HRG):pT3–4pNx-0 G3–4;pT1–4pN+;IRG with TN and/or SD; LRG with SD and/or RM (+). The Kaplan-Meier method has been used to evaluate recurrence-free survival as a function of RRG. The log-rank test was used to evaluate differences between survival curves. Results The median follow-up was 105 (IQR 63–148) months. Of the total series, 177 (25.4%) patients presented recurrence: distant 15.9%, local 4.9% and 4.6% distant and local. The recurrence rate varied according to the RRG with values of 72.9% for HRG, 16.9% for IRG and 10.2% for LRG (P = .0001). Most cases in LRG presented single organ recurrence (72.2%) (P = .006). The LRG experienced recurrence as single metastasis in 50% of cases, compared to 30% and 18.6% in IRG and HRG, respectively (P = .009). The most common sites of recurrence were lung and abdomen. Lung recurrence predominated in the HRG (72.9%) (P = .0001) and abdominal, in the LRG (83.3%) with a tendency to significance (P = .15). Conclusions Recurrence rates (especially bone and lung) increase with higher RG. Single organ recurrences and single metastases are more frequent in LRG.

Aim To explore the experiences of self-disgust in people with epilepsy and their understandings about this. Design A qualitative study informed by thematic analysis. Method Ten adults (out of 43 individuals initially interested in taking part, with 38 of those with levels of self-disgust categorised as high) with epilepsy and uncontrolled seizures were recruited online and participated in a telephone semi-structured interview. Results Three themes illustrated the development and experiences of self-disgust in adults with epilepsy and uncontrolled seizures, and how participants attempted to manage this. The first theme described the development of self-disgust as a result of the physical manifestations of seizures but also the experiences of others’ disgust reactions to seizures and an expectation of rejection. The second theme described the enduring and often unescapable experiences of self-disgust, with the final theme illustrating how participants attempted to manage experiences of self-disgust, particularly through avoidance. Discussion This study was the first to explore qualitatively the experiences of self-disgust in people with epilepsy. People with epilepsy experience disgust in reaction to the physical symptoms of seizures and these disgust-based feelings appeared to become internalized following others’ disgust reactions. Avoidance as a strategy to manage self-disgust could be protective but might have inadvertently maintained feelings of self-disgust.

Our aim was to assess the cognitive and emotional state, as well as related-changes in the glucocorticoid receptor (GR), the corticotropin-releasing factor (CRF) and the brain-derived neurotrophic factor (BDNF) expression of adolescent C57BL/6J male mice after a 5-week two-bottle choice protocol (postnatal day [pd]21 to pd52). Additionally, we wanted to analyse whether the behavioural and neurobiological effects observed in late adolescence (pd62) lasted until adulthood (pd84). Behavioural testing revealed that alcohol during early adolescence increased anxiety-like and compulsive-related behaviours, which was maintained in adulthood. Concerning cognition, working memory was only altered in late adolescent mice, whereas object location test performance was impaired in both ages. In contrast, novel object recognition remained unaltered. Immunohistochemical analysis showed that alcohol during adolescence diminished BDNF+ cells in the cingulate cortex, the hippocampal CA1 layer and the central amygdala. Regarding hypothalamic-pituitary-adrenal axis (HPA) functioning, alcohol abuse increased the GR and CRF expression in the hypothalamic paraventricular nucleus and the central amygdala. Besides this, GR density was also higher in the prelimbic cortex and the basolateral amygdala, regardless of the animals' age. Our findings suggest that adolescent alcohol exposure led to long-term behavioural alterations, along with changes in BDNF, GR and CRF expression in limbic brain areas involved in stress response, emotional regulation and cognition. post-print 4591 KB

Background The updated Veterans Aging Cohort Study (VACS) Index 2.0 combines general and human immunodeficiency virus (HIV)–specific biomarkers to generate a continuous score that accurately discriminates risk of mortality in diverse cohorts of persons with HIV (PWH), but a score alone is difficult to interpret. Using data from the North American AIDS Cohort Collaboration (NA-ACCORD), we translate VACS Index 2.0 scores into validated probability estimates of mortality. Methods Because complete mortality ascertainment is essential for accurate calibration, we restricted analyses to cohorts with mortality from the National Death Index or equivalent sources. VACS Index 2.0 components were ascertained from October 1999 to April 2018. Mortality was observed up to March 2019. Calibration curves compared predicted (estimated by fitting a gamma model to the score) to observed mortality overall and within subgroups: cohort (VACS/NA-ACCORD subset), sex, age 500 copies/mL, CD4 count Results Among 37230 PWH in VACS and 8061 PWH in the NA-ACCORD subset, median age was 53 and 44 years; 3% and 19% were women; and 48% and 39% were black. Discrimination in NA-ACCORD (C-statistic = 0.842 [95% confidence interval {CI}, .830–.854]) was better than in VACS (C-statistic = 0.813 [95% CI, .809–.817]). Predicted and observed mortality largely overlapped in VACS and the NA-ACCORD subset, overall and within subgroups. Conclusions Based on this validation, VACS Index 2.0 can reliably estimate probability of all-cause mortality, at various follow-up times, among PWH in North America.

This study aimed to evaluate the pre- and post-operative quality-of-life of patients submitted to the resection of pituitary adenoma via endoscopic transsphenoidal. This was a prospective study on patients submitted to endoscopic transsphenoidal pituitary surgery with the harvest of a nasoseptal flap who responded to the questionnaires FV-36 and SNOT-22 in the pre-operative and in months 1, 3 and 6 following the surgical procedure. A total of 42 patients submitted to pituitary adenoma resection surgery via endoscopic transsphenoidal with a nasoseptal flap were recruited. In all of the physical and mental domains (SF-36) evaluated, there was an improvement in the long-term evaluation (6 months), compared to the pre-operative, as well as in the site-specific evaluation (SNOT-22). The global and site-specific questionnaires in the 6th post-operative month follow-up presented an important improvement in all the physical and mental domains evaluated, as well as in nasal function in the perception of the patients submitted to pituitary adenoma resection via endoscopic transsphenoidal, demonstrating the safety and efficiency of the procedure.

To determine the effect of a maternal vegan diet on pregnancy outcome. This is a prospective observational study. Women with a singleton pregnancy who maintained the same diet prior to, and throughout current pregnancy were enrolled. Stratification was performed according to diet type: vegans, lacto–ovo–vegetarians, fish-eaters, and omnivores. Overall, 273 women were enrolled, of them, 112 omnivores, 37 fish-eaters, 64 lacto–ovo–vegetarians, and 60 vegans. The vegan diet was significantly associated with an increased risk of small-for-gestational-age newborns compared only to an omnivore diet (RR = 5.9, 95% CI, 1.2–21.8). The incidence of preterm birth was similar in all groups. Vegans had lower birthweight compared to lacto–ovo–vegetarians (3015 ± 420 g vs. 3285 ± 482 g, P = 0.004), and to omnivores (3328 ± 495 g, P

Malaria continues to be a major global health problem, with over 228 million cases and 405,000 deaths estimated to occur annually. Rapid and accurate diagnosis of malaria is essential to decrease the burden and impact of this disease, particularly in children. We aimed to review the main available techniques for the diagnosis of clinical malaria in endemic settings and explore possible future options to improve its rapid recognition.literature relevant to malaria diagnosis was identified through electronic searches in Pubmed, with no language or date restrictions and limited to humans.Light microscopy is still considered the gold standard method for malaria diagnosis and continues to be at the frontline of malaria diagnosis. However, technologies as rapid diagnostic tests, mainly those who detect histidine-rich protein-2, offer an accurate, rapid and affordable alternative for malaria diagnosis in endemic areas. They are now the technique most extended in endemic areas for parasitological confirmation. In these settings, PCR-based assays are usually restricted to research and they are not currently helpful in the management of clinical malaria. Other technologies, such as isothermal methods could be an interesting and alternative approach to PCR in the future.

OBJECTIVES: To review current data for the role of prostate specific membrane antigen (PSMA) radioligand therapy (RLT) for patients with advanced prostate cancer. This review provides an update for multidisciplinary teams on the current and potential future applications of theranostics in prostate cancer. METHODS: Narrative review focussing on PSMA as a target for RLT, and data using RESULTS: RLT with PSMA is an exciting therapeutic alternative to the existing management options already in use for patients with metastatic castrate-resistant prostate cancer (mCRPC). To date, most evidence exists regarding small-molecule PSMA inhibitors bound to beta-emitting radioisotopes such as 177Lu (Lu-PSMA). Prospective phase II data supports the safety and efficacy of Lu-PSMA in men with heavily pre-treated progressive mCRPC, and several late-phase randomised trials of Lu-PSMA are underway, with many more in the pipeline. Early results are encouraging, indicating that the theranostic approach may play a vital role in management of advanced prostate cancer and perhaps even in much earlier disease states. CONCLUSIONS: PSMA RLT is a promising new treatment option for men with mCPRC, and may also have utility in less advanced prostate cancer.

Introduction: This study was conducted to report the refractive and visual outcome after Scleral Fixated Intraocular Lens (SFIOL) implantation in children with nontraumatic ectopia lentis. Methods: Retrospective review of the medical records of 25 eyes of 15 patients who underwent SFIOL implantation in children with non-traumatic ectopia lentis. Results: The mean best corrected visual acuity (BCVA) before SFIOL implantation was 1.07 ± 0.9 logMar units [median: 0.9, Interquartile range (ΙQR): 0.415 to 1.555] which improved to 0.41 ± 0.33 logMar units (median: 0.22, ΙQR: 0.180 to 1.555) at two months postoperative follow up. In phakic group, the mean spherical refraction preoperatively was -12.04 ± 7.82 DS (dioptre sphere) (IQR: +16 to -5.875) and postoperatively was +0.93 ± 2.67DS (IQR: -0.375 to +2). In aphakic group, the mean spherical refraction preoperatively was +12.22 ± 2.05 DS and postoperatively was +1.2 ± 1.9 DS. The mean total astigmatism preoperatively was -6.44 ± 4.95 DC (dioptre cylinder) (median: 6, IQR: -10.50 to +2) and postoperatively was -1.47 ± 0.98 DC (median: -1.5, IQR: -2 to - 0.625 ). The mean IOL induced astigmatism was -1.01 ± 0.95 DC (median -0.75, IQR: -1.33 to - 0.25). The spherical refractive equivalent was within 2 Diopter (D) of the target refraction calculated preoperatively in 20 eyes and in five eyes it was more than 2 D. Conclusion: SFIOL implantation is associated with good visual outcome with a significant improvement in the refractive error. However, a longer follow up is required to assess the change of refraction and the stability of the SFIOL.

BACKGROUND: This retrospective cohort study aims to define the clinical findings and outcomes of every patient admitted to a district general hospital in Surrey with COVID-19 in March 2020, providing a snapshot of the first wave of infection in the UK. This study is the first detailed insight into the impact of frailty markers on patient outcomes and provides the infection rate among healthcare workers. METHODS: Data were obtained from medical records. Outcome measures were level of oxygen therapy, discharge and death. Patients were followed up until 21 April 2020. RESULTS: 108 patients were included. 34 (31%) died in hospital or were discharged for palliative care. 43% of patients aged over 65 died. The commonest comorbidities were hypertension (49; 45%) and diabetes (25; 23%). Patients who died were older (mean difference ±SEM, 13.76±3.12 years; p

To examine the health-related quality of life of children with cerebral palsy and its relationship with their use of health resources, taking into account sociodemographic factors concerning the family context.Cross-sectional study of children with cerebral palsy in Granada (Spain). Quality of life was evaluated with PedsQL questionnaire.A total of 75 children were analysed (mean age 7.41 years; SD 4.37; 50.7% male). They made an average of 22.80 visits (SD 12.43) per year; greater use was made of resources by children who had been diagnosed with cerebral palsy for45 months (36.00 vs. 26.93 visits per year, p 0.0001). Older children suffered more fatigue and pain. Children aged 2-4 years who presented with fatigue had more hospitalizations (r = -0.35; p = 0.20), whereas those4 years who had a higher quality of life for daily activities had made more visits to hospital AE (r = 0.35, p = 0.043). Among the children studied, there was no significant association between HRQOL and the parents' education or occupation.These findings highlight variables that may influence children's quality of life and their use of health resources, identifying certain profiles of children who might need individualized interventions.These findings could inform services provided by paediatric nurses to children with cerebral palsy, to individualize interventions and improve patient centred care.

PURPOSE In the HER2CLIMB study, patients with human epidermal growth factor receptor 2 (HER2)–positive breast cancer with brain metastases (BMs) showed statistically significant improvement in progression-free survival (PFS) with tucatinib. We describe exploratory analyses of intracranial efficacy and survival in participants with BMs. PATIENTS AND METHODS Patients were randomly assigned 2:1 to tucatinib or placebo, in combination with trastuzumab and capecitabine. All patients underwent baseline brain magnetic resonance imaging; those with BMs were classified as active or stable. Efficacy analyses were performed by applying RECIST 1.1 criteria to CNS target lesions by investigator assessment. CNS-PFS (intracranial progression or death) and overall survival (OS) were evaluated in all patients with BMs. Confirmed intracranial objective response rate (ORR-IC) was evaluated in patients with measurable intracranial disease. RESULTS There were 291 patients with BMs: 198 (48%) in the tucatinib arm and 93 (46%) in the control arm. The risk of intracranial progression or death was reduced by 68% in the tucatinib arm (hazard ratio [HR], 0.32; 95% CI, 0.22 to 0.48; P < .0001). Median CNS-PFS was 9.9 months in the tucatinib arm versus 4.2 months in the control arm. Risk of death was reduced by 42% in the tucatinib arm (OS HR, 0.58; 95% CI, 0.40 to 0.85; P = .005). Median OS was 18.1 versus 12.0 months. ORR-IC was higher in the tucatinib arm (47.3%; 95% CI, 33.7% to 61.2%) versus the control arm (20.0%; 95% CI, 5.7% to 43.7%; P = .03). CONCLUSION In patients with HER2-positive breast cancer with BMs, the addition of tucatinib to trastuzumab and capecitabine doubled ORR-IC, reduced risk of intracranial progression or death by two thirds, and reduced risk of death by nearly half. To our knowledge, this is the first regimen to demonstrate improved antitumor activity against BMs in patients with HER2-positive breast cancer in a randomized, controlled trial.

To determine the influence of maternal diets on maternal and umbilical cord blood levels of vitamin B12, folic acid, ferritin, and hemoglobin. A prospective observational study on women who maintained the same diet for at least 3 months prior to, and throughout current pregnancy. Women were divided according to their diet. Diet questionnaires were filled in during the 3rd trimester. Blood samples for complete blood counts and levels of ferritin, vitamin B12, folate, and albumin were taken from the women prior to delivery and from the umbilical cord immediately after delivery. The 273 enrolled women included 112 omnivores, 37 pescatarians, 64 vegetarians, and 60 vegans. There were no significant differences in the maternal B12 levels between the study groups (P = 0.426). Vegans had lower maternal ferritin levels compared to pescatarians (27 ± 17 vs 60 ± 74 ng/ml, respectively, P = 0.034), but not compared to vegetarians (P = 0.597), or omnivores (P = 1.000). There were no significant differences in the umbilical cord B12, folate, ferritin, and hemoglobin levels between the study groups. A sub-analysis that compared women who consumed multivitamins, B12 and iron supplements during pregnancy to women who did not, revealed differences in the levels of umbilical-cord B12 (1002 ± 608 vs 442 ± 151 pg/ml, respectively, P = 0.000) and maternal blood B12 (388 ± 209 vs 219 ± 95 pg/ml, respectively, P = 0.030) only among vegans, but not among omnivores. Vegan diet does not change the umbilical cord levels of B12, folic acid, ferritin, and hemoglobin. Vegans who do not take any vitamin supplementation are at greater risk for B12 deficiency than omnivores.

A 12-year-old patient diagnosed with congenital toxoplasmosis, with no systemic treatment at the time, who presented with a decreased visual acuity (VA) in his left eye (LE). On examination, VA in the LE was 0.05 and the fundus examination revealed a focus of chorioretinitis adjacent to a pigmented macular scar, as well as a large associated subretinal haemorrhage. After confirming the diagnosis of choroidal neovascular membrane secondary to ocular toxoplasmosis, treatment was started with systemic anti-toxoplasmosis drugs and two anti-VEGF intravitreal injections separated by one month. Finally, the patients had a VA in LE of 0.4, with reabsorption of the haemorrhage, leaving an inactive pigmented macular scar. The use of anti-VEGF intravitreal injections in cases of ocular toxoplasmosis has been associated with a reactivation of old lesions, so the prophylactic use of oral anti-toxoplasmosis drugs is recommended in these cases.

Macrophages are key effector cells in obesity-associated inflammation. G protein-coupled receptor kinase 2 (GRK2) is highly expressed in different immune cell types. Using LysM-GRK2+/− mice, we uncover that a reduction of GRK2 levels in myeloid cells prevents the development of glucose intolerance and hyperglycemia after a high fat diet (HFD) through modulation of the macrophage pro-inflammatory profile. Low levels of myeloid GRK2 confer protection against hepatic insulin resistance, steatosis and inflammation. In adipose tissue, pro-inflammatory cytokines are reduced and insulin signaling is preserved. Macrophages from LysM-GRK2+/− mice secrete less pro-inflammatory cytokines when stimulated with lipopolysaccharide (LPS) and their conditioned media has a reduced pathological influence in cultured adipocytes or naïve bone marrow-derived macrophages. Our data indicate that reducing GRK2 levels in myeloid cells, by attenuating pro-inflammatory features of macrophages, has a relevant impact in adipose-liver crosstalk, thus preventing high fat diet-induced metabolic alterations., We acknowledge support by Ministerio de Economía y Competitividad (MINECO/FEDER), Spain (grant SAF2017-84125-R to FM and CM and SAF2017-82436R to LB); CIBER de Enfermedades Cardiovasculares (CIBERCV). Instituto de Salud Carlos III, Spain (grant CB16/11/00278 to F.M., CB16/11/00222 to L.B., and, PI15/01114 to Francisco Tinaones (Universidad De Málaga, Spain), co-funded with European FEDER contribution); European Foundation for the Study of Diabetes (EFSD) Novo Nordisk Partnership for Diabetes Research in Europe Grant (to F.M.); and Programa de Actividades en Biomedicina de la Comunidad de Madrid-B2017/BMD-3671-INFLAMUNE to FM and MF.. I.M.-I. was supported by the “MS type I” program (CP16/00163). The authors thank the Metagenomic Platform of the Centro de Investigación Biomédica en Red de Fisiopatología de la Obesidad y la Nutrición, CIBERobn, Instituto de Salud Carlos III (ISCIII), Spain. We appreciate the help of the CBMSO Facilities, in particular Flow Cytometry, Genomics and Animal Care. We acknowledge Paula Ramos for technical support. We also acknowledge the institutional support to the CBMSO from Fundación Ramón Areces.

Objective To analyze the use of intracranial pressure (ICP) and cerebral oximetry monitoring in patients with severe traumatic brain injury (TBI) according to the Spanish Trauma ICU Registry (RETRAUCI). Methods We included TBI patients with Glasgow Coma Scale score ≤8. Hypotheses were tested using the Student-T or Wilcoxon tests (quantitative variables) and the Chi-square test (categorical variables). Multivariate analysis using logistic regression was performed to analyze the variables associated with the use of ICP monitoring . Results We analyzed 1463 patients. Age 49.1 years. Males 1130 (77.3%). Mechanism of injury: falls in 350 cases (23.9%). ISS 27.9. Uni- or bilateral mydriasis was present in 39.3% of the patients. Neurosurgical intervention within 24 h was performed in 331 patients (22.7%). ICP was monitored in 635 patients (45.1%), pbtO2 in 122 patients (8.6%), SjVO2 in 19 patients (1.34%) and NIRS was used in 25 cases (1.77%). In the multivariate analysis, age, bilateral mydriasis at admission and previous use of antiplatelets or anticoagulants was inversely related with ICP monitoring. Severity of injury and the need of neurosurgical intervention increased the probability of ICP monitoring. Conclusions Our study shows a picture of ICP monitoring in severe TBI patients in our environment. Use of cerebral oximetry techniques is very limited.

Cirurgia bariàtrica; Endoscòpia; Malaltia per reflux gastroesofàgic Cirugía bariátrica; Endoscopia; Enfermedad por reflujo gastroesofágico Bariatric surgery; Endoscopy; Gastroesophageal reflux disease Background and Objectives: Bariatric surgery remains the gold standard treatment for morbidly obese patients. Roux-en-y gastric bypass and laparoscopic sleeve gastrectomy are the most frequently performed surgeries worldwide. Obesity has also been related to gastroesophageal reflux disease (GERD). The management of a preoperative diagnosis of GERD, with/without hiatal hernia before bariatric surgery, is mandatory. Endoscopy can show abnormal findings that might influence the final type of surgery. The aim of this article is to discuss and review the evidence related to the endoscopic findings after bariatric surgery. Materials and Methods: A systematic review of the literature has been conducted, including all recent articles related to endoscopic findings after bariatric surgery. Our review of the literature has included 140 articles, of which, after final review, only eight were included. The polled articles included discussion of the endoscopy findings after roux-en-y gastric bypass and laparoscopic sleeve gastrectomy. Results: We found that the specific care of bariatric patients might include an endoscopic diagnosis when GERD symptoms are present. Conclusions: Recent evidence has shown that endoscopic follow-up after laparoscopic sleeve gastrectomy could be advisable, due to the pathological findings in endoscopic procedures in asymptomatic patients.

Altres ajuts: This research was supported by a grant from SENACYT FID 16-201 to J. P. C. and A. V., Secretar ́ıa Nacional de Ciencia y Tecnolog ́ıa from Panama; by the grant for neglected diseases studies in Panama 1.11.1.3.703.01.55.120 from the Ministry of Economy and Finance of Panama to J. P. C. and A. V.; and by ERANet17/HLH-0271. Scott Weaver also supported this study through the World Reference Center for Emerging Viruses and Arboviruses, NIH grant R24AI120942. Dr. Lescano is sponsored by the training grant D43 TW007393 awarded by the Fogarty International Center of the US National Institutes of Health. J. L. M. is a doctoral candidate studying an Epidemiological Research Doctorate at Universidad Peruana Cayetano Heredia under FONDECYT/CIENCIACTIVA scholarship EF033-235-2015 and also supported by training grant D43 TW007393. A. V. is a member of the Sistema Nacional de Investigación de Panamá (SNI), SENACYT. E. S. was supported by the Spanish Ministerio de Ciencia Innovaci ́on y Universidades (MICINN) through a Ramon y Cajal agreement (RYC-2016-21120). Alphaviruses (Togaviridae, Alphavirus) are arthropod-borne single-stranded RNA pathogens that cause febrile and neurologic disease in much of Latin America. However, many features of Alphavirus epidemiology remain unknown. In 2011, we undertook a cross-sectional study in Nueva Esperanza, an indigenous community in the Peruvian Amazon. Here, we present the first serologic evidence of Mayaro (MAYV), Venezuelan equine encephalitis (VEE) complex alphavirus, Una (UNAV), and Madariaga (MADV) viruses reported in humans (24%, 16%, 13%, and 1.5%, respectively) from an Amazonian indigenous community in Peru. Hunting activity and cohabiting with hunters were the main risk factors for Mayaro seroconversion, but only hunting was associated with UNAV seropositivity. Our results suggest that alphavirus infection in this region is common, but we highlight the high UNAV seroprevalence found and corroborate the low MADV prevalence reported in this region. Furthermore, MAYV-neutralizing antibodies were also detected in stored samples from wild animals (18%) hunted by Nueva Esperanza inhabitants and another mestizo community located close to Iquitos. Further serological surveys of VEE complex alphaviruses, UNAV, and MADV in wild animals and assessing the ability of the MAYV seropositive species to transmit the virus will be relevant.

Background The wide scale and severity of consequences of tobacco use, benefits derived from cessation, low rates of intervention by healthcare professionals, and new opportunities stemming from novel communications technologies are the main factors motivating this project. Thus, the purpose of this study is to assess the effectiveness of an intervention that helps people cease smoking and increase their nicotine abstinence rates in the long term via a chat-bot, compared to usual practice, utilizing a chemical validation at 6 months. Methods Design: Randomized, controlled, multicentric, pragmatic clinical trial, with a 6-month follow-up. Setting: Healthcare centers in the public healthcare system of the Community of Madrid (Madrid Regional Health Service). Participants: Smokers > 18 years of age who attend a healthcare center and accept help to quit smoking in the following month. N = 460 smokers (230 per arm) who will be recruited prior to randomization. Intervention group: use of a chat-bot with evidence-based contents to help quit smoking. Control group: Usual treatment (according to the protocol for tobacco cessation by the Madrid Regional Health Service Main variable: Continuous nicotine withdrawal with chemical validation (carbon monoxide in exhaled air). Intention-to-treat analysis. Difference between groups in continuous abstinence rates at 6 months with their corresponding 95% confidence interval. A logistic regression model will be built to adjust for confounding factors. Results: First expected results in January 2020. Discussion Providing science-based evidence on the effectiveness of clinical interventions via information technologies, without the physical presence of a professional, is essential. In addition to being more efficient, the characteristics of these interventions can improve effectiveness, accessibility, and adherence to treatment. From an ethics perspective, this new type of intervention must be backed by scientific evidence to circumvent pressures from the market or particular interests, improve patient safety, and follow the standards of correct practices for clinical interventions. Trial registration ClinicalTrials.gov, reference number NCT 03445507.

Previous reports have warned about the influence of spinal cord injury (SCI) on the pharmacokinetics of various drugs. However, the role of SCI in the efficacy and safety of pharmacotherapy remains unknown. Thereby, our aim was to explore the role of SCI on pharmacokinetics and anti-inflammatory effect of naproxen in response to a local inflammatory challenge. Rats received a severe contusive SCI at T9 or sham injury. Pharmacokinetics of a single intravenous dose of naproxen (10 mg kg-1) was studied at days 1 and 15 post-surgery. For the anti-inflammatory assessment, carrageenan was subcutaneously injected in forelimb and hindlimb paws at the same post-surgery periods, and naproxen efficacy was evaluated measuring paw swelling. Plasma protein concentrations and body weight changes were also determined. Plasma naproxen levels and pharmacokinetic parameters were unchanged by acute injury, but subacute injury generated alterations in volume of distribution, clearance, and bioavailability, resulting in significantly reduced plasma naproxen concentrations, in the absence of changes in plasma proteins. Assessment of naproxen anti-inflammatory activity during the acute stage of injury could not be determined because of carrageenan failure to elicit swelling. During the subacute stage, naproxen anti-inflammatory effect on forelimbs (above injury) was similar to that observed in sham-injured animals, while it was almost absent in paralyzed hindlimbs. Under conditions of SCI and peripheral inflammation, pharmacokinetics and anti-inflammatory activity of naproxen vary according to post-injury timing and neurological status of the assessed region.