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Netrin-1 is a neural guidance factor that regulates migration and positioning of neural crest-derived cells during embryonic development. Depending on the type of Netrin-1 receptor expression, cells are either attracted or repulsed by Netrin-1. Postnatal expression of Netrin-1 is detected in brain, colon, liver, and kidney, which are common sites of cancer metastasis, including melanoma. Thus, understanding the dynamics between Netrin-1 and its receptors could explain the attraction of melanoma towards these Netrin-1-expressing tissues. Here, we investigate whether the Netrin-1-attractive receptor Neogenin can affect migration of melanoma cells towards a Netrin-1 source. Results from Western blot (WB) analysis show higher expression of Neogenin in aggressive compared to non-aggressive melanoma cells. Cell migration experiments show increased migration of Neogenin-expressing aggressive melanoma cells towards exogenous, soluble recombinant human Netrin-1 and towards a Netrin-1-expressing cell line. Furthermore, WB reveals ERK1/2 activation and increased N-cadherin expression in Neogenin-expressing aggressive melanoma cells treated with rhNetrin-1. Moreover, treatment with anti-Neogenin blocking antibody caused decreased migration towards Netrin-1-expressing cells and reduced ERK1/2 activity in Neogenin-expressing aggressive melanoma cells. These results suggest Neogenin may play a role during migration of melanoma cells towards Netrin-1 via ERK1/2 signaling.

Objectives To evaluate the efficacy of oral colistin-neomycin in preventing multidrug-resistant Enterobacterales (MDR-E) infections in solid organ transplant (SOT) recipients. Methods Multicentre, open-label, parallel-group, controlled trial with balanced (1:1) randomization in five transplant units. SOT recipients were screened for MDR-E intestinal colonization (extended-spectrum β-lactamase or carbapenemase producing) before transplantation and +7 and + 14 days after transplantation and assigned 1:1 to receive treatment with colistin sulfate plus neomycin sulfate for 14 days (decolonization treatment (DT) group) or no treatment (no decolonization treatment (NDT) group). The primary outcome was diagnosis of an MDR-E infection. Safety outcomes were appearance of adverse effects, mainly diarrhoea, rash, nausea and vomiting. Patients were monitored weekly until 30 days after treatment. Intention-to-treat analysis was performed. Results MDR-E rectal colonization was assessed in 768 SOT recipients; 105 colonized patients were included in the clinical trial, 53 receiving DT and 52 NDT. No significant decrease in the risk of infection by MDR-E was observed in the DT group (9.4%, 5/53) compared to the NDT group (13.5%, 7/52) (relative risk 0.70; 95% confidence interval 0.24–2.08; p 0.517). Four patients (5.6%), three (5.6%) in the DT group and one (1.9%) in the NDT group, developed colistin resistance. Twelve patients (22.7%) in the DT group had diarrhoea, eight related to treatment (15.0%); one patient (1.8%) developed skin rash and another (1.8%) nausea and vomiting. Two patients (3.8%) in the NDT group developed diarrhoea. Conclusions DT does not reduce MDR-E infections in SOT. Colistin resistance and adverse effects such as diarrhoea are a potential issue that must be taken seriously.

espanolObjetivo. Nuestro estudio tiene como objetivo describir las caracteristicas clinicas y evolucion de los pacientes infectados por SARS-CoV-2 tratados con siltuximab, de acuerdo con el protocolo local, con objetivo de bloquear precozmente la actividad de la Interleukina-6 evitando la progresion de la cascada inflamatoria. Pacientes y metodos. Estudio retrospectivo de los primeros 31 pacientes con COVID-19 tratados con siltuximab en el Hospital Clinic de Barcelona y en el Hospital Universitario de Salamanca, en el periodo de marzo a abril, que tenian una PCR en frotis nasal positiva para SARS-CoV-2. Resultados. Fueron incluidos 31 pacientes tratados con siltuximab, con una mediana (RIC) de edad de 62 anos (56-71) y una prevalencia de varones del 71%. La comorbilidad mas frecuente fue la hipertension arterial (48%). La mediana de dosis administrada de siltuximab fue 800 mg con un rango de 785 mg a 900 mg. Siete pacientes recibieron siltuximab como terapia de rescate despues de una dosis de tocilizumab. Al final del estudio, un total de 26 (83.9) pacientes recibieron alta hospitalaria vivos. La tasa de mortalidad fue de 16.1%, sin embargo, solo 1 de los 24 pacientes que recibieron siltuximab como primera linea de tratamiento fallecio (4%). Conclusiones. Siltuximab es una alternativa bien tolerada al uso de tocilizumab como primera linea de tratamiento para pacientes con neumonia por COVID-19 dentro de los primeros 10 dias de sintomas y con proteina C-reactiva elevada. EnglishObjectives. The study aims to describe characteristics and clinical outcome of patients with SARS-CoV-2 infection that received siltuximab according to a protocol that aimed to early block the activity of IL-6 to avoid the progression of the inflammatory flare. Patients and methods. Retrospective review of the first 31 patients with SARS-CoV-2 treated with siltuximab, in Hospital Clinic of Barcelona or Hospital Universitario Salamanca, from March to April 2020 with positive polymerase-chain reaction (PCR) from a nasopharyngeal swab. Results. The cohort included 31 cases that received siltuximab with a median (IQR) age of 62 (56-71) and 71% were males. The most frequent comorbidity was hypertension (48%). The median dose of siltuximab was 800 mg ranging between 785 and 900 mg. 7 patients received siltuximab as a salvage therapy after one dose of tocilizumab. At the end of the study, a total of 26 (83.9) patients had been discharged alive and the mortality rate was 16.1% but only 1 out of 24 that received siltuximab as a first line option (4%). Conclusions. Siltuximab is a well-tolerated alternative to tocilizumab when administered as a first line option in patients with COVID-19 pneumonia within the first 10 days from symptoms onset and high C-reactive protein.

Objectives. In some patients the immune response triggered by SARS-CoV-2 is unbalanced, presenting an acute respiratory distress syndrome which in many cases requires intensive care unit (ICU) admission. The limitation of ICU beds has been one of the major burdens in the management around the world; therefore, clinical strategies to avoid ICU admission are needed. We aimed to describe the influence of tocilizumab on the need of transfer to ICU or death in non-critically ill patients. Material and methods. A retrospective study of 171 patients with SARS-CoV-2 infection that did not qualify as requiring transfer to ICU during the first 24h after admission to a conventional ward, were included. The criteria to receive tocilizumab was radiological impairment, oxygen demand or an increasing of inflammatory parameters, however, the ultimate decision was left to the attending physician judgement. The primary outcome was the need of ICU admission or death whichever came first. Results. A total of 77 patients received tocilizumab and 94 did not. The tocilizumab group had less ICU admissions (10.3% vs. 27.6%, P=0.005) and need of invasive ventilation (0 vs 13.8%, P=0.001). In the multivariable analysis, tocilizumab remained as a protective variable (OR: 0.03, CI 95%: 0.007-0.1, P=0.0001) of ICU admission or death. Conclusions. Tocilizumab in early stages of the inflammatory flare could reduce an important number of ICU admissions and mechanical ventilation. The mortality rate of 10.3% among patients receiving tocilizumab appears to be lower than other reports. This is a non-randomized study and the results should be interpreted with caution.

Objectives To describe the burden, epidemiology and outcomes of co-infections and superinfections occurring in hospitalized patients with coronavirus disease 2019 (COVID-19). Methods We performed an observational cohort study of all consecutive patients admitted for ≥48 hours to the Hospital Clinic of Barcelona for COVID-19 (28 February to 22 April 2020) who were discharged or dead. We describe demographic, epidemiologic, laboratory and microbiologic results, as well as outcome data retrieved from electronic health records. Results Of a total of 989 consecutive patients with COVID-19, 72 (7.2%) had 88 other microbiologically confirmed infections: 74 were bacterial, seven fungal and seven viral. Community-acquired co-infection at COVID-19 diagnosis was uncommon (31/989, 3.1%) and mainly caused by Streptococcus pneumoniae and Staphylococcus aureus. A total of 51 hospital-acquired bacterial superinfections, mostly caused by Pseudomonas aeruginosa and Escherichia coli, were diagnosed in 43 patients (4.7%), with a mean (SD) time from hospital admission to superinfection diagnosis of 10.6 (6.6) days. Overall mortality was 9.8% (97/989). Patients with community-acquired co-infections and hospital-acquired superinfections had worse outcomes. Conclusions Co-infection at COVID-19 diagnosis is uncommon. Few patients developed superinfections during hospitalization. These findings are different compared to those of other viral pandemics. As it relates to hospitalized patients with COVID-19, such findings could prove essential in defining the role of empiric antimicrobial therapy or stewardship strategies.

BACKGROUND Photodynamic therapy (PDT) has become one of the most effective therapies for the treatment of actinic keratosis, allowing the removal of more than one lesion in a single session. However, the pain sustained by the patient during treatment and local skin reactions can limit its use. OBJECTIVES To determine the efficacy and safety of combined PDT (daylight PDT followed by conventional PDT) vs conventional PDT 12 weeks after treatment. METHODS The study was performed as a randomized, single-center, non-inferiority clinical trial with two parallel groups. A total of 51 patients with grade I and II AKs on the scalp or face were randomized. Twenty-five patients received one session of combined PDT (combPDT), and 26 patients received one session of conventional PDT (cPDT). The primary endpoint was the reduction of AKs, 12 weeks after treatment. The secondary endpoint was the reduction in pain and local skin reaction. RESULTS The reduction rate of grade I and II AKs was similar in combPDT and cPDT, showing no statistically significant differences between both groups, 76.67% vs 86.63% [P = .094] and 80.48% vs 83.08% [P = .679], respectively. However, pain was significantly lower in the combPDT group (2.56 vs 5, P

La reconstrucción del párpado inferior sigue siendo un reto, especialmente la reparación de defectos que abarcan más de la mitad de su superficie horizontal. El colgajo de Hughes del párpado superior ipsilateral es la técnica quirúrgica de elección para los tumores de gran tamaño del párpado inferior. Presentamos el caso de una paciente con carcinoma basocelular superficial de párpado inferior izquierdo que fue intervenida con extirpación del tumor con margen de seguridad y reparación del defecto primario mediante este colgajo. Describimos la técnica de Hughes paso a paso, sus potenciales complicaciones, así como los puntos clave en su ejecución para conseguir unos resultados satisfactorios., Lower eyelid reconstrution remains a challenge, especially the repair of defects that cover more than a half of its horizontal surface. The Hughes flap of the ipsilateral upper eyelid is the surgical technique of choice for large tumors of the lower eyelid. We present the case of a patient with superficial basal cell carcinoma of the lower left eyelid who underwent surgery with excision of the tumor with margin of safety and repair of the primary defect using this flap. We describe the Hughes technique step by step, its potential complications, as well as the key points in its execution to achieve satisfactory results.

We aimed to ascertain the interaction and effects of combined reactivations of BK virus and cytomegalovirus on kidney graft function. All consecutive kidney transplant recipients (KTR) between 2003 and 2016 were included. Of 1976 patients who received a kidney transplant, 23 (1.2%) presented BKV-associated nephropathy (BKVAN). Factors independently associated with BKVAN were diabetes mellitus (odds ratios (OR) 3.895%, confidence intervals (CI) (1.4–10.5)), acute allograft rejection (OR 2.8 95%, CI (1.1–7.6)) and nephrostomy requirement (OR 4.195%, CI (1.3–13)). Cytomegalovirus infection was diagnosed in 19% of KTR patients. Recipients with BKVAN presented more frequently with cytomegalovirus (CMV) infection compared to patients without BKVAN (39% vs. 19%, p = 0.02). Acute allograft rejection (OR 2.95%, CI (1.4–2.4)) and nephrostomy requirement (OR 2.95%, CI (1.2–3)) were independently associated with CMV infection. Sixteen patients (69%) with BKVAN had graft dysfunction at one-year post-transplant and eight of them (35%) lost their graft. Patients presenting with BKVAN and graft loss presented more frequently a cytomegalovirus infection (OR 2.295%, CI (1.3–4.3)). In conclusion, we found a relation between CMV infection and graft loss in patients presenting BKVAN, suggesting that patients with CMV reactivation should be actively screened for BKV.

ImportanceIdentifying undetected clinical signs is imperative in the prevention of SARS-CoV-2.ObjectiveTo establish the prevalence of clinical gustatory and olfactory dysfunctions in patients with COVID-19 pneumonia. Clinical outcomes and recovery rates associated with gustatory and olfactory dysfunctions were also assessed.DesignA prospective study was performed in 80 patients admitted to Hospital Clínic of Barcelona (Spain) for COVID-19 pneumonia. Patients were re-evaluated in the ward daily until discharge. Gustatory and olfactory dysfunction symptoms were retrospectively collected from emergency room (ER) charts after first assessments. Follow-up was performed in telemedicine consultation.SettingThe single-centre study was performed in a hospitalisation ward at a university hospital.ParticipantsConsecutive patients meeting hospitalisation criteria for COVID-19 pneumonia were eligible. Study exclusion criteria were patients who could not speak, had previous gustatory and olfactory dysfunctions or whose PCR tests for SARS-CoV-19 were negative.InterventionsSystematic assessment of gustatory and olfactory symptoms with standardised questions.Outcome(s)Prevalence of gustatory and olfactory dysfunctions in patients with COVID-19 pneumonia.ResultsOf the 80 study subjects, 62.5% were male and the median age was 57 years. Half of the cohort (n=40) presented with comorbidities. The prevalence of chemosensitive disorder was 73.8% (n=59) (95% CI: 63.8 to 83.8), although self-reported symptoms were recorded in only 26.3% (n=21) of patients in the ER. Gustatory and olfactory dysfunctions were observed in 58.8% (n=47) and 55% (n=44) of cases, respectively. They were also the first symptoms in 25% (n=20) of patients. Anosmia was associated with ageusia, OR: 7, 95% CI: 2.3 to 21.8, p=0.001). No differences in clinical outcomes were observed when patients with and without gustatory and olfactory dysfunctions were compared. Recovery rates were 20% (n=10) and 85% (n=42) at days 7 and 45, respectively.ConclusionThe prevalence of gustatory and olfactory dysfunctions in COVID-19 pneumonia was much higher than in self-report. Presence of gustatory and olfactory dysfunctions was not a predictor of clinical outcomes.

BACKGROUND The diagnosis of invasive aspergillosis (IA) can be problematic in solid organ transplantation (SOT). The prognosis greatly varies according to the type of transplant, and the impact of prophylaxis is not well defined. PATIENTS AND METHODS The Diaspersot cohort analyses the impact of IA in SOT in Spain during the last 10 years. Proven and probable/putative IA was included. RESULTS We analysed 126 cases of IA. The incidences of IA were as follows: 6.5%, 2.9%, 1.8% and 0.6% for lung, heart, liver and kidney transplantation, respectively. EORTC/MSG criteria confirmed only 49.7% of episodes. Tree-in-bud sign or ground-glass infiltrates were present in 56.3% of patients, while serum galactomannan (optical density index >0.5) was positive in 50.6%. A total of 41.3% received combined antifungal therapy. Overall mortality at 3 months was significantly lower (p

In the context of the coronavirus disease 2019 (COVID-19) pandemic, we aimed to evaluate the impact of anti-cytokine therapies (AT) in kidney transplant recipients requiring hospitalization due to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. This is an observational retrospective study, which included patients from March to May 2020. An inverse probability of treatment weighting from a propensity score to receive AT was used in all statistical analyses, and we applied a bootstrap procedure in order to calculate an estimation of the 2.5th and 97.5th percentiles of odds ratio (OR). outcomes were measured using an ordinal scale determination (OSD). A total of 33 kidney recipients required hospitalization and 54% of them received at least one AT, mainly tocilizumab (42%), followed by anakinra (12%). There was no statistical effect in terms of intensive care unit (ICU) admission, respiratory secondary infections (35% vs. 7%) or mortality (16% vs. 13%) comparing patients that received AT with those who did not. Nevertheless, patients who received AT presented better outcomes during hospitalization in terms of OSD ≥5 ((OR 0.31, 2.5th, 97.5th percentiles (0.10, 0.72)). These analyses indicate, as a plausible hypothesis, that the use of AT in kidney transplant recipients presenting with COVID-19 could be beneficial, even though multicenter randomized control trials using these therapies in transplanted patients are needed.

Highlights • Almost two thirds of patients with SARS-CoV-2 infection present with hypocalcemia at hospital admission. • Hypocalcemia at admission is related to high oxygen support requirement any time during hospitalization. • Patients with hypocalcemia at admission had two times more probability to be admitted to the Intensive Care Unit during hospitalization than patients with normal calcium at admission., Background Calcium is an essential ion for pathogen survival and virulence and is involved in the regulation of the inflammatory response. Hypocalcemia is a common laboratory finding in critically ill patients. Data regarding levels of calcium in SARS-CoV-2 infection is scarce. Patients with SARS-CoV-2 infection who present with hypocalcemia could have a worse outcome. Methods We performed a retrospective analysis of hospitalized patients with SARS-CoV-2 infection and included all patients who had any serum calcium measurement in the first 72 hours since hospital admission. Main objective was to investigate the relation of low serum calcium with adverse outcome, measured by the requirement of high oxygen support – defined as high flow nasal cannula oxygen, non-invasive mechanical ventilation and/or invasive ventilation-, intensive care unit admission or death. Results A total of 316 patients were included in the study. Median age was 65 years (IQR 55-74), 65% were men. Hypocalcemia within 72 hours since hospital admission was present in 63% of patients. A higher number of patients in the hypocalcemia group required high oxygen support during hospitalization (49% vs 32%; p = 0,01) and were admitted to the ICU (42% vs 26%; p = 0,005). No differences in mortality were observed between groups. Conclusions Hypocalcemia is frequent in hospitalized patients with SARS-CoV-2 infection and can identify patients with worse outcome. More studies are needed to understand the role of calcium metabolism in SARS-CoV-2 infection and to address the clinical implications and therapeutic interventions it might have.

Mycobacterium caprae, a member of the Mycobacterium tuberculosis complex, causes tuberculosis in humans and animals, but the incidence in humans is very low worldwide. Direct contact with animals and with unpasteurized dairy products is the most frequent source of contagion. Cutaneous tuberculosis supposes a diagnostic challenge due to its variety of clinical manifestations and the difficulty in demonstrating resistant acid-alcohol bacilli in histological samples. In cases of high suspicion, the initiation of antituberculosis treatment should be considered empirically. Combined therapeutic regimens are necessary to prevent long-term resistance and complications, although the duration of treatment has not been fully established.

In Spain, with full confinement measures and coinciding with the pandemic, pediatricians and dermatologists have received, through teledermatology/teleconsultation and social networks, a barrage of diverse images, which have subsequently allowed us to approach some of them by direct physical examination of early and late skin manifestations associated with SARS-Cov-2 infection. We designed a retrospective, cross-sectional study to evaluate the dermatological care of all those patients under the age of 16 who consulted, in person or telematically, for acral lesions (chilblain-like or erythema multiforme-like) in the context of the Coronavirus disease (COVID-19) pandemic, since 15 March 2020 to 24 April 2020, both included in the health area of the Hospital Universitario San Cecilio de Granada. Of all the patients collected, 18 (66%) were male and the overall mean age was 14.44 years. All lacked a personal history of interest and denied previous episodes of chilblains or Raynaud's phenomenon/disease. The clinic was limited to purpuric lesions located on acral regions distributed on hands and feet. Dermatologists and pediatricians should be aware of the lesions associated with COVID-19 infection and their possible complications. It remains to be identified if there are different dermatological patterns in the pediatric and adult population.

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A 42-year-old female with a personal history of Grade II infiltrating ductal breast carcinoma, treated under surgical procedure in 2018, whose hormonal profile included estrogen, progesteronic and HER-2 positive receptors, and a Ki67 proliferative index (20-25%), was referred to our dermatological outpatient clinic complaining worsening of her chronic spontaneous urticaria. The patient was under treatment with etuximide, exemestane, anastrozole, and trastuzumab. Our patient reported intermittent episodes of hives of 8 years of evolution with good control with second-generation antihistamines. However, in the past year, the intensity and frequency of the outbreaks was increased with the development of angioedema until completing 23 consultations through the emergency department being treated in all of the episodes with short cycles of oral corticosteroids. This case reported is particularly complex due to different points that we develop below: (a) oncological patient as special population; (b) differential diagnosis with other forms of urticaria such as vasculitis urticaria, inducible urticaria, and autoimmune progesterone dermatitis; (c) spontaneous chronic urticaria of difficult control at labeled dose of omalizumab; (d) concomitant treatment with another biological drug.

MEDICAL IMAGE

Objective To assess the performance of differential time to positivity (DTP) for the diagnosis of catheter-related bloodstream infections (CRBSI). Methods From all episodes of bloodstream infections (BSI) diagnosed during a 15-year period (2003–17) those in which a paired set of blood cultures drawn from a catheter and a peripheral vein were positive for the same microorganism and had a clinically and/or microbiologically defined source were selected. To assess diagnostic discrimination ability and accuracy of DTP for CRBSI, area under the receiver operating characteristic curves (AUC) and performance characteristics of a DTP ≥2 h were computed. Results A total of 512 BSI were included, of which 302 (59%) were CRBSI. Discrimination ability of DTP was low for Staphylococcus aureus (AUC 0.656 ± 0.06), coagulase-negative staphylococci (AUC 0.618 ± 0.081), enterococci (AUC 0.554 ± 0.117) and non-AmpC-producing Enterobacteriaceae (AUC 0.653 ± 0.053); moderate for Pseudomonas aeruginosa (AUC 0.841 ± 0.073), and high for AmpC-producing Enterobacteriaceae (AUC 0.944 ± 0.039). For the entire sample, DTP had a low-to-moderate discrimination ability (AUC 0.698 ± 0.024). A DTP ≥2 h has a low sensitivity for coagulase-negative staphylococci (60%) and very low for S. aureus (34%), enterococci (40%) and non-AmpC-producing Enterobacteriaceae (42%). A DTP cut-off of 1 h improved sensitivity (90%) for AmpC-producing Enterobacteriaceae. Conclusions Differential time to positivity performs well for diagnosing CRBSI only when AmpC-producing Enterobacteriaceae and P. aeruginosa are involved. Performance is low for common Gram-positive organisms and non-AmpC-producing enteric bacilli; a negative test should not be used to rule out CRBSI due to these microorganisms. A DTP ≥1 h may improve accuracy for AmpC-producing Enterobacteriaceae, particularly Enterobacter spp.

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Se evaluo el efecto de la temperatura (29, 32 y 35oC) y del tiempo (2, 4 y 6 dias) de curado, a humedades relativas de 85 a 95%, sobre las propiedades termicas de los almidones de camote, variedad INA-100, cuyas raices estuvieron 50 dias almacenadas entre 12.8 a 15.6°C y 85 a 90% de humedad relativa. Se evaluaron las muestras de nueve tratamientos de curado y una muestra testigo que no fue curada, en tres repeticiones. Se determino que la entalpia de gelatinizacion (ΔH) en el almidon de camote no vario por efecto del curado, disminuyendo en promedio ligeramente (-1.17J/g) respecto al testigo. Tambien, la temperatura inicial (To) y pico (Tp) de gelatinizacion se incrementaron en promedio por efecto del curado; mientras que la temperatura final (Te) disminuyo ligeramente y el rango de la temperatura de gelatinizacion (Te-To) disminuyo en todos los tratamientos. El curado podria ser considerado una tecnologia que modifica los almidones de camote, incrementando la To y Tp, y disminuyendo la Te y el (Te-To). Esta forma de modificar los almidones no tiene impacto ambiental y es mas segura que las modificaciones quimicas.

Candida peritonitis is a potentially life-threatening infection after abdominal transplantation, although there is scant information regarding its incidence and outcome. We analysed the incidence rate and outcome of Candida peritonitis in 717 liver or pancreas transplant recipients. Five cases of Candida peritonitis were diagnosed, representing the second most frequent cause of invasive fungal infection in the cohort. The incidence rate of Candida peritonitis during the first 30 days after transplantation was 6.5 cases/10 000 transplant days in pancreas recipients and 1.2 cases/10 000 transplant days in liver recipients (P = 0.035). Four of the five patients received an echinocandin in combination with other antifungal. All patients were alive and with good graft function at 1-year follow-up. In our series, Candida peritonitis in liver and pancreas transplant recipients was not uncommon and had a good prognosis.

A partir de una reflexión clínica delos trastornos límite se introduce un faro deorientación que permite dilucidar, en su seno, laneurosis y la psicosis. Starting with a clinical reflection on the limit disorders, a guidance headlight is introduced in order to clear up, in itself, the neurosis and the psychosis.