Statistical analysis plan for the multicenter, open, randomized controlled clinical trial to assess the efficacy and safety of intravenous tirofiban vs aspirin in acute ischemic stroke due to tandem lesion, undergoing recanalization therapy by endovascular treatment (ATILA trial).

RATIONALE: In-stent reocclusion after endovascular therapy has a negative impact on outcomes in acute ischemic stroke (AIS) due to tandem lesions (TL). Optimal antiplatelet therapy approach in these patients to avoid in-stent reocclusion is yet to be elucidated. AIMS: To assess efficacy and safety of intravenous tirofiban versus intravenous aspirin in patients undergoing MT plus carotid stenting in the setting of AIS due to TL. SAMPLE SIZE ESTIMATES: Two hundred forty patients will be enrolled, 120 in every treatment arm. METHODS AND DESIGN: A multicenter, prospective, randomized, controlled (aspirin group), assessor-blinded clinical trial will be conducted. Patients fulfilling the inclusion criteria will be randomized at MT onset to the experimental or control group (1:1). Intravenous aspirin will be administered at a 500-mg single dose and tirofiban at a 500-mcg bolus followed by a 200-mcg/h infusion during the first 24 h. All patients will be followed for up to 3 months. STUDY OUTCOMES: Primary efficacy outcome will be the proportion of patients with carotid in-stent thrombosis within the first 24 h after MT. Primary safety outcome will be the rate of symptomatic intracranial hemorrhage. DISCUSSION: This will be the first clinical trial to assess the best antiplatelet therapy to avoid in-stent thrombosis after MT in patients with TL. TRIAL REGISTRATION: The trial is registered as NCT05225961. February, 7th, 2022.

Antibiotic use and outcome in patients with negative blood cultures, a new target population for antimicrobial stewardship interventions: A prospective multicentre cohort (NO-BACT).

OBJECTIVES: To evaluate the appropriateness of antimicrobial treatment and the risk factors for mortality in patients with negative blood cultures (BC), in order to evaluate whether this population would be a suitable target for antimicrobial stewardship (AMS) interventions. METHODS: A multicentre prospective cohort study of patients with negative BC in three Spanish hospitals between October 2018 and July 2019 was performed. The main endpoints were the appropriateness of antimicrobial treatment (evaluated by two investigators according to local guidelines) and 30-day mortality. Cox-regression was performed to estimate the association between variables and 30-day mortality. RESULTS: Of 1011 patients in whom BC was obtained, these were negative in 803 (79%) and were included; 30-day mortality was 9% (70 patients); antibiotic treatment was considered inappropriate in 299 (40%) of 747 patients evaluated at day 2, and in 266 (46%) of 573 at day 5-7. The variables independently associated with increased risk of 30-day mortality were higher age (HR 1.05; 95% CI 1.03-1.07), neoplasia (HR 2.73; 95% CI 1.64-4.56), antibiotic treatment in the 48 h prior to BC extraction (HR 2.06; 95% CI 1.23-3.43) and insufficient antibiotic coverage at day 2 after BC obtainment (HR 2.35; 95% CI 1.39-4.00). Urinary, catheter and biliary sources of infection were associated with lower risk (HR 0.40; 95% CI 0.20-0.81). CONCLUSIONS: Antimicrobial treatment is frequently inappropriate among patients with negative BC; insufficient antibiotic coverage at day 2 was associated with mortality. These results suggest that patients with negative BC are a suitable population for AS interventions. SUMMARY: Antimicrobial treatment in patients with negative blood culture was frequently inappropriate, and inappropriate coverage at day 2 was associated with increased risk of death. These data support the consideration of this population as a potential target for antimicrobial stewardship interventions.

The Need for the Closer Monitoring of Novel Drugs in MS: A Siponimod Retrospective Cohort Study (Realhes Study).

BACKGROUND: Severe cases of lymphopenia have been reported during siponimod clinical trials, which may negatively impact its benefit/risk profile. OBJECTIVE: We aimed to evaluate the incidence of lymphopenia following the initiation of siponimod treatment in clinical practice. The secondary objectives included the analysis of factors predisposing to and the clinical relevance of lymphopenia events. METHODS: In this multicenter retrospective cohort study, information collected from the medical records of 129 patients with MS from 15 tertiary hospitals in Spain who initiated treatment with Siponimod were followed-up for at least 3 months, including at least one lymphocyte count evaluation per patient. RESULTS: Of the 129 patients, 121 (93.6%) reported lymphopenia events, including 110 (85.3%) with grade ≤ 3 and 11 (8.5%) with grade 4 lymphopenia, higher than those reported in the pivotal clinical trial (73.3% and 3.3% for grade ≤ 3 and grade 4 lymphopenia, respectively). The study included an unexpectedly high proportion of male subjects (72.9%), which might have led to an underestimation of the actual magnitude of the risk. CONCLUSIONS: In this study, the incidence and severity of lymphopenia after starting siponimod treatment were higher than those reported in previous clinical trials. Therefore, our results reinforce the need for the closer monitoring of novel MS drugs in clinical practice, as well as larger and longer follow-up studies to properly characterize this risk.

Safety and efficacy of tirofiban in acute ischemic stroke due to tandem lesions undergoing mechanical thrombectomy: A multicenter randomized clinical trial (ATILA) protocol.

Background: In-stent thrombosis after mechanical thrombectomy (MT) worsen outcomes in acute ischemic stroke (AIS) due to tandem lesions (TL). Although an optimal antiplatelet therapy is needed, the best approach to avoid in-stent thrombosis is yet to be elucidated. Hypothesis: Low-dose intravenous tirofiban is superior to intravenous aspirin in avoiding in-stent thrombosis in patients undergoing MT plus carotid stenting in the setting of AIS due to TL. Methods: The ATILA-trial is a multicenter, prospective, phase IV, randomized, controlled (aspirin group as control), assessor-blinded clinical trial. Patients fulfilling inclusion criteria (AIS due to TL, ASPECTS ⩾ 6, pre-stroke modified Rankin Scale ⩽2 and onset <24 h) will be randomized (1:1) at MT onset to experimental (intravenous tirofiban) or control group (intravenous aspirin). Intravenous aspirin will be administered at a 500 mg single dose and tirofiban at a 500 µg bolus followed by a 200 µg/h infusion during first 22 h. All patients will be followed up to 3 months. Sample size estimated is 240 patients. Outcomes: The primary efficacy outcome is the proportion of patients with carotid in-stent thrombosis within the first 24 h after MT. The primary safety outcome is the rate of symptomatic intracranial hemorrhage. Secondary outcomes include functional independence defined as modified Rankin Scale 0-2, proportion of patients undergoing rescue therapy due to in-stent aggregation during MT and carotid reocclusion at 30 days. Discussion: ATILA-trial will be the first clinical trial regarding the best antiplatelet therapy to avoid in-stent thrombosis after MT in patients with TL. Trial registration: NCT0522596.

Nivel de conocimientos sobre bioseguridad en estudiantes de Enfermería durante la pesquisa de COVID-19 / Level of knowledge about biosafety in Nursing students during the COVID-19 screening

Fundamento: la bioseguridad es considerada como una norma preventiva universal para reducir factores de riesgo, está orientada en el ámbito de la salud al fomento de la seguridad, y la protección de profesionales y estudiantes en contextos de riesgo. Objetivo: valorar el nivel de conocimientos en estudiantes de Enfermería sobre las medidas de bioseguridad durante la pesquisa de COVID-19. Métodos: se realizó un estudio descriptivo de corte transversal en el período comprendido de febrero a octubre 2021, en Camagüey, Cuba. Se aplicaron métodos teóricos para la fundamentación de la investigación, y empíricos: la observación participante y encuesta confeccionada por los autores. Se establecieron como variables: área de salud, cifra de estudiantes contagiados, posibles causas de contagio y nivel de conocimientos sobre bioseguridad. Resultados: hubo mayor representación de estudiantes del municipio Santa Cruz (15 %). El área de salud con más contagios fue Previsora con un 6,25 %. Las posibles causas de contagio identificadas se refieren a la conducta higiénico-sanitaria durante la pesquisa: dificultades en el uso de la mascarilla, la distancia física entre estudiantes y con la población objeto de pesquisa, y uso de desinfectante 91,25 %, 87,50 % y 82,50 % respectivamente. Conclusiones: se valoró que el nivel de conocimientos en estudiantes de Enfermería sobre las medidas de bioseguridad durante la pesquisa de COVID-19 fue bajo, a pesar de haber recibido un curso de capacitación previo a la actividad, y su presencia en los programas de estudio.

Background: biosafety is considered a universal preventive norm to reduce risk factors, it is oriented in the field of health to promote safety, and the protection of professionals and students in risk contexts. Objective: to assess the level of knowledge in Nursing students about biosafety measures during COVID-19 screening. Methods: a descriptive cross-sectional study was carried out in the period from February to October 2021, in Camagüey, Cuba. Theoretical methods were applied for the foundation of the research, and empirical ones: participant observation and survey made by the authors. The following variables were established: health area, number of infected students, possible causes of infection, and level of knowledge about biosafety. Results: there was a greater representation of students from the Santa Cruz municipality (15%). The health area with the most infections was Previsora ​​with 6.25%. The possible causes of contagion identified refer to hygienic-sanitary behavior during the investigation: difficulties in the use of the mask, the physical distance between students and with the population under investigation, and the use of disinfectant 91.25%, 87, 50% and 82.50% respectively. Conclusions: it was assessed that the level of knowledge in Nursing students about biosafety measures during the COVID-19 screening was low, despite having received a training course prior to the activity, and their presence in the study programs.

Experiencia sobre el proceso de salud-enfermedad-atención en pacientes con artritis reumatoidea pertenecientes a la comunidad Wichí de Misión Chaqueña "El Algarrobal", Salta / Experience on the health-disease-care process in patients with rheumatoid arthritis belonging to the Wichí community of Mission Chaqueña "El Algarrobal", Salta

Introducción: se ha reportado que la prevalencia de artritis reumatoidea (AR) en la comunidad Wichí representa la más alta informada por el Grupo Latinoamericano para el Estudio de las Enfermedades Reumáticas en los Pueblos Originarios (GLADERPO). El objetivo de este estudio fue describir la experiencia sobre el proceso de salud-enfermedad-atención de pacientes con AR de la comunidad Wichí de Misión Chaqueña "El Algarrobal", Salta. Materiales y métodos: estudio narrativo. Diseño de corte etnográfico. Se realizaron entrevistas semi-estructuradas y observaciones registradas. Se utilizaron guías de entrevistas y observación. Los aspectos incluidos fueron: concepción del proceso salud-enfermedad, percepción de la AR en la vida diaria, el acceso al sistema de salud, utilización de recursos tradicionales y de medicina tradicional. Resultados: se realizaron 10 entrevistas. Los aspectos más relevantes fueron la concepción del proceso salud-enfermedad asociado al trauma social pasado y al concepto de voluntad Wichí. Se evidenció la combinación de estrategias para mejorar el dolor (biomedicina, medicina tradicional y acompañamiento religioso). Además, se observó una relación unidireccional con el sistema de salud. Conclusiones: la AR es una enfermedad con un impacto negativo en la comunidad Wichí. Se requieren otras actividades, desde otras disciplinas, para mejorar el acceso al sistema de salud y la continuidad de los tratamientos.

Introduction: the prevalence of rheumatoid arthritis (RA) in the Wichí community has already been published, representing the highest reported by the Grupo Latinoamericano para el Estudio de las Enfermedades Reumáticas en los Pueblos Originarios (GLADERPO). The objective was to describe the experience of the health-disease-care process of patients with RA from the Wichí community of Misión Chaqueña "El Algarrobal", Salta. Materials and methods: study with ethnographic design. Semi-structured interviews and recorded observations were conducted. Interview and observation guides were used. The aspects included were: conception of the health-disease process; perception of RA in daily life, access to the health system, use of traditional resources and traditional medicine. Results: ten interviews were conducted. The most relevant aspects were the conception of the health-disease process, associated with past social trauma and the concept of "Wichí good will". The combination of strategies to improve pain (biomedicine, traditional medicine and religious accompaniment) was evidenced. In addition, a unidirectional relationship with the health system was observed. Conclusions: RA is a disease with a negative impact on the Wichí community. Other activities from other disciplines are necessary to improve access to the health system and continuity of treatment.

Factors associated with recruitment success in the phase 2a study of aztreonam-avibactam development programme: a descriptive qualitative analysis among sites in Spain.

OBJECTIVE: Successful clinical trials are subject to recruitment. Recently, the REJUVENATE trial, a prospective phase 2a open-label, single-arm interventional clinical trial conducted within the Innovative Medicines Initiative-supported Combatting Bacterial Resistance in Europe-Carbapenem Resistance project, was published, with 85% of the recruitment performed in Spain. We analysed the recruitment success in this trial by establishing a model of recruitment practice. METHODS: A descriptive qualitative study was performed from May 2016 to October 2017 at 10 participating Spanish centres. Data were extracted from: (1) feasibility questionnaires to assess the centre's potential for patient enrolment; (2) delegation of responsibility records; (3) pre-screening records including an anonymised list of potentially eligible and (4) screening and enrolment records. A descriptive analysis of the features was performed by the participating centre. Pearson's and Spearman's correlation coefficients were calculated to determine factors of recruitment success. RESULTS: The highest recruitment rate was observed in Hospitals 3 and 6 (58.8 and 47.0 patients per month, respectively). All the study teams were multidisciplinary with a median of 15 members (range: 7-22). Only Hospitals 3, 5 and 6 had dedicated nursing staff appointed exclusively to this study. Moreover, in those three hospitals and in Hospital 9, the study coordinator performed exclusive functions as a research planner, and did not assume these functions for the other hospitals. The univariate analysis showed a significant association between recruitment success and months of recruitment (p=0.024), number of staff (p<0.001), higher number of pharmacists (p=0.005), infectious disease specialists (p<0.001), the presence of microbiologist in the research team (p=0.018) and specifically dedicated nursing staff (p=0.036). CONCLUSIONS: The existence of broad multidisciplinary teams with staff dedicated exclusively to the study as well as the implementation of a well-designed local patient assessment strategy were the essential optimisation factors for recruitment success in Spain. TRIAL REGISTRATION NUMBER: NCT02655419; EudraCT 2015-002726-39; analysis of pre-screened patients.

Gravidez heterotópica espontânea: implicações de um diagnóstico tardio / Spontaneous heterotopic pregnancy: implications of a late diagnosis

A gestação heterotópica é uma entidade rara, principalmente se resultante de concepção natural. O diagnóstico é ultrassonográfico, porém a gestação intrauterina concomitante contribui para a dificuldade propedêutica. Neste relato de caso, a detecção foi tardia, a ultrassonografia não identificou a gestação heterotópica e apenas durante a avaliação intraoperatória, por meio de uma cirurgia de emergência devido a choque hemorrágico, houve o reconhecimento. A suspeita de uma gestação heterotópica deve ser sempre aventada quando sinais clínicos típicos (sangramento, dor abdominal) estão presentes, mesmo na ausência de fatores de risco ou imagens anômalas na ecografia. Assim, uma intervenção precoce menos invasiva pode ser realizada, reduzindo a morbimortalidade materna e do feto intrauterino. Este relato de caso destaca uma situação incomum dentro dessa patologia rara: diagnóstico tardio, apenas no segundo trimestre de gestação, sem evidência prévia ultrassonográfica, certificada apenas durante o intraoperatório. O manejo cirúrgico preciso permitiu a manutenção da gravidez intrauterina.(AU)

Heterotopic pregnancy is a rare entity, especially if it is resulted from natural conception. The diagnosis is ultrasonographic, but the concomitant intrauterine pregnancy contributes to the propaedeutic difficulty. In this case report, the detection was late, the ultrasonography did not identify heterotopic pregnancy and, only during intraoperative evaluation through emergency surgery, exploratory laparotomy, there was recognition. The suspicion of a heterotopic pregnancy should always be raised when typical clinical signs (bleeding, abdominal pain) are present, even in absentia of risk factors or anomalous images on ultrasound. Thus, a less invasive early intervention can be performed, reducing maternal and intrauterine fetus morbimortality. This case report highlights an unusual situation within this rare pathology: late diagnosis, only in the second trimester of pregnancy, without previous ultrasound evidence, certified only during the intraoperative period. Precise surgical management allowed the maintenance of intrauterine pregnancy.(AU)

Risk factors for unfavorable outcome and impact of early post-transplant infection in solid organ recipients with COVID-19: A prospective multicenter cohort study.

The aim was to analyze the characteristics and predictors of unfavorable outcomes in solid organ transplant recipients (SOTRs) with COVID-19. We conducted a prospective observational cohort study of 210 consecutive SOTRs hospitalized with COVID-19 in 12 Spanish centers from 21 February to 6 May 2020. Data pertaining to demographics, chronic underlying diseases, transplantation features, clinical, therapeutics, and complications were collected. The primary endpoint was a composite of intensive care unit (ICU) admission and/or death. Logistic regression analyses were performed to identify the factors associated with these unfavorable outcomes. Males accounted for 148 (70.5%) patients, the median age was 63 years, and 189 (90.0%) patients had pneumonia. Common symptoms were fever, cough, gastrointestinal disturbances, and dyspnea. The most used antiviral or host-targeted therapies included hydroxychloroquine 193/200 (96.5%), lopinavir/ritonavir 91/200 (45.5%), and tocilizumab 49/200 (24.5%). Thirty-seven (17.6%) patients required ICU admission, 12 (5.7%) suffered graft dysfunction, and 45 (21.4%) died. A shorter interval between transplantation and COVID-19 diagnosis had a negative impact on clinical prognosis. Four baseline features were identified as independent predictors of intensive care need or death: advanced age, high respiratory rate, lymphopenia, and elevated level of lactate dehydrogenase. In summary, this study presents comprehensive information on characteristics and complications of COVID-19 in hospitalized SOTRs and provides indicators available upon hospital admission for the identification of SOTRs at risk of critical disease or death, underlining the need for stringent preventative measures in the early post-transplant period.

Prevalence of musculoskeletal disorders and rheumatic diseases in an Argentinean indigenous Wichi community.

OBJECTIVE: To estimate the prevalence of musculoskeletal disorders (MSK) and rheumatic diseases in an indigenous Wichi population in Argentina. METHODS: This is a cross-sectional, community-based study using the Community-Oriented Program for the Control of Rheumatic Diseases (COPCORD) methodology in ≥ 18-year-old subjects. Validated surveys were conducted by trained interviewers. Subjects with MSK pain (positive cases) were evaluated by internists and rheumatologists for diagnosis and treatment. RESULTS: A total of 648 interviews were performed (90.4% of the census population). Mean age was 37.5 years (SD 14.8), and 379 (58.5%) were female. The mean years of education was 7.0 (SD 3.7); 552 subjects (85.2%) were covered by the public health care system. A total of 216 (33.3%) subjects had MSK pain in the last 7 days. Rheumatic disease prevalence was as follows: mechanical back pain (19.0%), rheumatic regional pain syndrome (5.2%), osteoarthritis (3.2%), rheumatoid arthritis (RA) (3.2%), inflammatory back pain (1.2%), undifferentiated arthritis (0.3%), Sjögren syndrome (0.15%), and fibromyalgia (0.15%). RA patients included 19 (90.5%) women and 9 (42.9%) with RA family history. One hundred percent were seropositive and 66.7% showed radiologic erosions. The mean of Disease Activity Score [DAS-28 (ESR)] at the time of diagnosis was 5.1 (SD 1.5) and the Health Assessment Questionnaire Disability Index (HAQ-DI) was 0.8 (SD 0.4). CONCLUSION: RA prevalence was 3.2%, one of the highest reported using the COPCORD methodology in indigenous and non-indigenous peoples in Latin America, with a high percentage of family cases. Pain and functional capacity were the variables allowing patients' early referral to a specialist. Key Points • The RA prevalence was 3.2%, one of the highest reported using COPCORD methodology in indigenous and non-indigenous peoples in Latin America. • The patients with RA had high percentage of familiar history of RA. • The pain and functional capacity were the variables associated with a diagnosis of any rheumatic disease and should be considered for early referral. • The mean of the delay in the diagnosis was 5.8 years. In this community, the lack of the "migration health" phenomenon may be a social determinant that negatively impacts their health.

Assessing the impact on intestinal microbiome and clinical outcomes of antibiotherapy optimisation strategies in haematopoietic stem cell transplant recipients: study protocol for the prospective multicentre OptimBioma study.

INTRODUCTION: Haematopoietic stem cell transplantation (HSCT) is a life-saving treatment for a number of haematological diseases. Graft versus host disease (GVHD) is its main complication and hampers survival. There is strong evidence that intestinal microbiota diversity of the recipient may increase the risk of GVHD worsening survival. Antibiotic regimens used during the early phase of the transplant may influence clinical outcomes by reducing intestinal microbiota diversity. Present guidelines of European Conference on Infections in Leukaemia exhort to optimising antibiotic use in haematological patients including HSCT recipients. The present study aims to investigate if, in HSCT recipients, the optimisation of antibacterial use may preserve intestinal microbiota composition reducing the incidence and severity of acute GVHD and improving relevant clinical outcomes. METHODS AND ANALYSIS: This is a prospective longitudinal observational study of two cohorts of HSCT recipients: (1) the intervention cohort includes patients treated in centres in which a predefined strategy of antibiotherapy optimisation is implemented, with the objective of optimising and reducing antibiotic administration according to clinical criteria and (2) the control cohort includes patients treated in centres in which a classic permissive strategy of antibiotic prophylaxis and treatment is used. Adult patient receiving a first HSCT as a treatment for any haematological condition are included. Clinical variables are prospectively recorded and up to five faecal samples are collected for microbiota characterisation at prestablished peritransplant time points. Patients are followed since the preconditioning phase throughout 1-year post-transplant and four follow-up visits are scheduled. Faecal microbiota composition and diversity will be compared between both cohorts along with acute GVHD incidence and severity, severe infections rate, mortality and overall and disease-free survival. ETHICS AND DISSEMINATION: The study was approved between 2017 and 2018 by the Ethical Committees of participant centres. Study results will be disseminated through peer-reviewed journals and national and international scientific conferences. TRIAL REGISTRATION NUMBER: NCT03727113.

Pharmacokinetics and safety of aztreonam/avibactam for the treatment of complicated intra-abdominal infections in hospitalized adults: results from the REJUVENATE study.

OBJECTIVES: To investigate pharmacokinetics (PK) and safety (primary objectives) and efficacy (secondary objective) of the investigational monobactam/ß-lactamase inhibitor combination aztreonam/avibactam in patients with complicated intra-abdominal infection (cIAI). METHODS: This Phase 2a open-label, multicentre study (NCT02655419; EudraCT 2015-002726-39) enrolled adults with cIAI into sequential cohorts for 5-14 days treatment. Cohort 1 patients received an aztreonam/avibactam loading dose of 500/137 mg (30 min infusion), followed by maintenance doses of 1500/410 mg (3 h infusions) q6h; Cohort 2 received 500/167 mg (30 min infusion), followed by 1500/500 mg (3 h infusions) q6h. Cohort 3 was an extension of exposure at the higher dose regimen. Doses were adjusted for creatinine clearance of 31-50 mL/min (Cohorts 2 + 3). All patients received IV metronidazole 500 mg q8h. PK, safety and efficacy were assessed. RESULTS: Thirty-four patients (Cohort 1, n = 16; Cohorts 2 + 3, n = 18) comprised the modified ITT (MITT) population. Mean exposures of aztreonam and avibactam in Cohorts 2 + 3 were consistent with those predicted to achieve joint PK/pharmacodynamic target attainment in >90% patients. Adverse events (AEs) were similar between cohorts. The most common AEs were hepatic enzyme increases [n = 9 (26.5%)] and diarrhoea [n = 5 (14.7%)]. Clinical cure rates at the test-of-cure visit overall were 20/34 (58.8%) (MITT) and 14/23 (60.9%) (microbiological-MITT population). CONCLUSIONS: Observed AEs were consistent with the known safety profile of aztreonam monotherapy, with no new safety concerns identified. These data support selection of the aztreonam/avibactam 500/167 mg (30 min infusion) loading dose and 1500/500 mg (3 h infusions) maintenance dose q6h regimen, in patients with creatinine clearance >50 mL/min, for the Phase 3 development programme.

Opportunities for antibiotic optimisation and outcome improvement in patients with negative blood cultures: study protocol for a cluster-randomised crossover trial, the NO-BACT study.

INTRODUCTION: Patients with negative blood cultures (BCx) represent 85%-90% of all patients with BCx taken during hospital admission. This population usually includes a heterogeneous group of patients admitted with infectious diseases or febrile syndromes that require a blood culture. There is very little evidence of the clinical characteristics and antibiotic treatment given to these patients. METHODS AND ANALYSIS: In a preliminary exploratory prospective cohort study of patients with BCx taken, the clinical/therapeutic characteristics and outcomes/antimicrobial stewardship opportunities of a population of patients with negative BCx will be analysed. In the second phase, using a cluster randomised crossover design, the implementation of an antimicrobial stewardship intervention targeting patients with negative BCx will be evaluated in terms of quality of antimicrobial use (duration and de-escalation), length of hospital stay and mortality. ETHICS AND DISSEMINATION: This study has been and registered with clinicaltrials.gov. The findings of our study may support the implementation in clinical practice of an antimicrobial stewardship intervention to optimise the use of antibiotics in patients with negative BCx. The results of this study will be published in peer-reviewed journals and disseminated at national and international conferences. TRIAL REGISTRATION NUMBER: NCT03535324.

Colistin versus meropenem in the empirical treatment of ventilator-associated pneumonia (Magic Bullet study): an investigator-driven, open-label, randomized, noninferiority controlled trial.

BACKGROUND: Colistin is recommended in the empirical treatment of ventilator-associated pneumonia (VAP) with a high prevalence of carbapenem-resistant gram-negative bacilli (CR-GNB). However, the efficacy and safety of colistin are not well defined. METHODS: A multicenter prospective randomized trial conducted in 32 European centers compared the efficacy and safety of colistin (4.5 million unit loading dose followed by a maintenance dose of 3 million units every 8 h) versus meropenem (2 g every 8 h), both in combination with levofloxacin (500 mg every 12 h) for 7-14 days in patients with late VAP. Between May 2012 and October 2015, 232 patients were randomly assigned to the 2 treatment groups. The primary endpoint was mortality at 28 days after randomization in the microbiologically modified intention-to-treat (mMITT) population. Secondary outcomes included clinical and microbiological cure, renal function at the end of the treatment, and serious adverse events. The study was interrupted after the interim analysis due to excessive nephrotoxicity in the colistin group; therefore, the sample size was not achieved. RESULTS: A total of 157 (67.7%) patients were included in the mMITT population, 36 of whom (22.9%) had VAP caused by CR-GNB. In the mMITT population, no significant difference in mortality between the colistin group (19/82, 23.2%) and the meropenem group (19/75, 25.3%) was observed, with a risk difference of - 2.16 (- 15.59 to 11.26, p = 0.377); the noninferiority of colistin was not demonstrated due to early termination and limited number of patients infected by carbapenem-resistant pathogens. Colistin plus levofloxacin increased the incidence of renal failure (40/120, 33.3%, versus 21/112, 18.8%; p = 0.012) and renal replacement therapy (11/120, 9.1%, versus 2/112, 1.8%; p = 0.015). CONCLUSIONS: This study did not demonstrate the noninferiority of colistin compared with meropenem, both combined with levofloxacin, in terms of efficacy in the empirical treatment of late VAP but demonstrated the greater nephrotoxicity of colistin. These findings do not support the empirical use of colistin for the treatment of late VAP due to early termination. TRIAL REGISTRATION: ClinicalTrials.gov, NCT01292031. Registered 9 February 2011.

Investigation of the psychological factors associated with fissured tongue / Investigação dos fatores psicológicos associados à língua fissurada

ABSTRACT Objective: This study aimed to investigate the correlation between FT and anxiety. Methods: The sample consisted of 95 participants categorized into two groups: a) G-FT, 48 patients with FT and b) CG, 47 healthy participants. All patients were submitted to complete oral and dermatological examinations. The anxiety levels were measured using the State-Trait Anxiety Inventory (STAI). A p-value of < 0.05 was considered significant. Results: Fourteen (30%) patients reported awareness of having FT and 9 (64%) were women. Symptoms like burning feeling were reported by 3 (6%) only patients, all of then women. None of the control group patients presented these symptoms. In both groups, control and FT, the average scores of trait-anxiety were slightly higher than state-anxiety. There were no statistically significant differences between the FT and the control group related to the state-anxiety (p=0.724) and the trait-anxiety (p=0.680) scores. Study limitations: This study was limited by the number of subjects. Conclusion: Although moderate state-anxiety and trait-anxiety scores were determined, anxiety, as an environmental factor may not play a significant role in the development of FT. Considering FT as a multifactorial disease, probably a genetic component is necessary for expression.

RESUMO Objetivo: Investigar a correlação entre língua fissurada e ansiedade. Métodos: A amostra consistiu em 95 participantes divididos em dois grupos: a) G-LF, 48 pacientes com língua fissurada e b) CG, 47 participantes saudáveis. Os pacientes foram submetidos aos exames orais e dermatológicos. Os níveis de ansiedade foram medidos utilizando o Inventário de Ansiedade de Traçado do Estado (IDATE). Um valor de p <0,05 foi considerado significativo. Resultados: Quatorze (30%) pacientes relataram ter consciência de língua fissurada e 9 (64%) eram mulheres. Sintomas como sensação de queimação foram relatados por apenas 3 (6%) pacientes. Nenhum dos pacientes do grupo controle apresentou esses sintomas. Nos dois grupos, controle e língua fissurada, os escores médios de ansiedade-tração foram ligeiramente superiores ao estado-ansiedade. Não houve diferenças estatisticamente significativas entre grupo língua fissurada e o grupo controle, relacionado ao estado-ansiedade (p = 0,724) e os achados traço-ansiedade (p = 0,680). Limitação: Este estudo é limitado devido o tamanho da amostra. Conclusão: Embora tenham sido determinados valores moderados de ansiedade de estado e traço-ansiedade, a ansiedade, como fator ambiental, pode não desempenhar um papel significativo no desenvolvimento de língua fissurada. Considerando língua fissurada como uma doença multifatorial, é necessário um componente genético para a expressão.

Avaliação do traço e estado de ansiedade em pacientes com Glossite Migratória Benigna / Evaluation of trait and state anxiety in patients with Benign Migratory Glossitis

Objetivo: avaliar estado e traço de ansiedade em pacientes com glossite migratória benigna (GMB). O estudo consistiu de 78 pacientes com GMB, apresentando ou não ocorrência simultânea de língua fissurada. Um grupo controle de 48 pacientes, sem lesões orais e/ou cutâneas, também foi incluído no estudo. Foi aplicado o Inventário de Traço-Estado de Ansiedade (STAI). Resultados: estado moderado e pontuações de ansiedade-traço foram observados nos grupos. Não houve diferenças estatisticamente significativas nos escores de ansiedade entre os grupos GMB e controle. Conclusão: a ansiedade não parece desempenhar um papel significativo na GMB, apesar dos níveis moderados observados em pacientes com GMB. No entanto, o estado emocional pode ser um fator determinante para as diferentes formas de manifestações de GMB.

Objective: To assess state and trait anxiety in patients with benign migratory glossitis (GMB). The study consisted of 78 patients with GMB, presenting or not simultaneous occurrence of fissured tongue. A control group of 48 patients without oral lesions and / or skin, was also included in the study. Inventory -Trait State Anxiety (STAI) was applied. Results: moderate state and trait anxiety scores were observed in groups. There were no statistically significant differences in anxiety scores between the GMB and control groups. Conclusion: The anxiety seems to play a significant role in the GMB, despite moderate levels observed in patients with GMB. However, the emotional state can be a determining factor for the different forms of manifestations of GMB.

[Monitoring respiratory syncytial virus through the Spanish influenza surveillance system, 2006-2014]. / Vigilancia del virus respiratorio sincitial en el marco del Sistema de Vigilancia de la Gripe en España, 2006-2014.

INTRODUCTION: The aim of the study is to analyze the information on respiratory syncytial virus (RSV) obtained through the Spanish Influenza Surveillance System (SISS) and to study its usefulness as supplementary information for the characterization of influenza epidemics. METHODS: The temporal patterns of both RSV and influenza viruses were analyzed by patterns comparing the weekly viral detection rates from 2006 to 2014. RESULTS: In general, the RSV circulation was characterized by showing a peak between 52-1 weeks, and circulated from 2 to 8 weeks before/prior to influenza viruses. CONCLUSION: RSV information obtained from the SISS is useful for the characterization of influenza epidemics in Spain.

The European I-MOVE Multicentre 2013-2014 Case-Control Study. Homogeneous moderate influenza vaccine effectiveness against A(H1N1)pdm09 and heterogenous results by country against A(H3N2).

BACKGROUND: In the first five I-MOVE (Influenza Monitoring Vaccine Effectiveness in Europe) influenza seasons vaccine effectiveness (VE) results were relatively homogenous among participating study sites. In 2013-2014, we undertook a multicentre case-control study based on sentinel practitioner surveillance networks in six European Union (EU) countries to measure 2013-2014 influenza VE against medically-attended influenza-like illness (ILI) laboratory-confirmed as influenza. Influenza A(H3N2) and A(H1N1)pdm09 viruses co-circulated during the season. METHODS: Practitioners systematically selected ILI patients to swab within eight days of symptom onset. We compared cases (ILI positive to influenza A(H3N2) or A(H1N1)pdm09) to influenza negative patients. We calculated VE for the two influenza A subtypes and adjusted for potential confounders. We calculated heterogeneity between sites using the I(2) index and Cochrane's Q test. If the I(2) was <50%, we estimated pooled VE as (1 minus the OR)×100 using a one-stage model with study site as a fixed effect. If the I(2) was >49% we used a two-stage random effects model. RESULTS: We included in the A(H1N1)pdm09 analysis 531 cases and 1712 controls and in the A(H3N2) analysis 623 cases and 1920 controls. For A(H1N1)pdm09, the Q test (p=0.695) and the I(2) index (0%) suggested no heterogeneity of adjusted VE between study sites. Using a one-stage model, the overall pooled adjusted VE against influenza A(H1N1)pdm2009 was 47.5% (95% CI: 16.4-67.0). For A(H3N2), the I(2) was 51.5% (p=0.067). Using a two-stage model for the pooled analysis, the adjusted VE against A(H3N2) was 29.7 (95% CI: -34.4-63.2). CONCLUSIONS: The results suggest a moderate 2013-2014 influenza VE against A(H1N1)pdm09 and a low VE against A(H3N2). The A(H3N2) estimates were heterogeneous among study sites. Larger sample sizes by study site are needed to prevent statistical heterogeneity, decrease variability and allow for two-stage pooled VE for all subgroup analyses.