Cerebroprotective Effects of the TLR4-Binding DNA Aptamer ApTOLL in a Rat Model of Ischemic Stroke and Thrombectomy Recanalization.

ApTOLL, a TLR4 modulator aptamer, has demonstrated cerebroprotective effects in a permanent ischemic stroke mouse model, as well as safety and efficacy in early phase clinical trials. We carried out reverse translation research according to STAIR recommendations to further characterize the effects and mechanisms of ApTOLL after transient ischemic stroke in rats and to better inform the design of pivotal clinical trials. Adult male rats subjected to transient middle cerebral artery occlusion were treated either with ApTOLL or the vehicle intravenously at different doses and time-points. ApTOLL was compared with TAK-242 (a TLR4 inhibitor). Female rats were also studied. After neurofunctional evaluation, brains were removed for infarct/edema volume, hemorrhagic transformation, and histologic determinations. Peripheral leukocyte populations were assessed via flow cytometry. ApTOLL showed U-shaped dose-dependent cerebroprotective effects. The maximum effective dose (0.45 mg/kg) was cerebroprotective when given both before reperfusion and up to 12 h after reperfusion and reduced the hemorrhagic risk. Similar effects occurred in female rats. Both research and clinical ApTOLL batches induced slightly superior cerebroprotection when compared with TAK-242. Finally, ApTOLL modulated circulating leukocyte levels, reached the brain ischemic tissue to bind resident and infiltrated cell types, and reduced the neutrophil density. These results show the cerebroprotective effects of ApTOLL in ischemic stroke by reducing the infarct/edema volume, neurofunctional impairment, and hemorrhagic risk, as well as the peripheral and local immune response. They provide information about ApTOLL dose effects and its therapeutic time window and target population, as well as its mode of action, which should be considered in the design of pivotal clinical trials.

Secondary fracture prevention in Spanish primary care: results of the PREFRAOS Study.

This study demonstrated a large treatment gap in elderly subjects experiencing fragility fracture in Spanish primary care, a low treatment persistence among subjects who do receive treatment, and more than one-quarter having no follow-up visits post-fracture. These data highlight the need to improve secondary fracture prevention in primary care. PURPOSE: To describe osteoporosis (OP) treatment patterns and follow-up in subjects with fragility fracture seen in Spanish primary care (PC). METHODS: This observational, retrospective chart review included subjects aged ≥ 70 years listed in the centers' records (November 2018 to March 2020), with ≥ 1 fragility fracture and prior consultation for any reason; subjects who had participated in another study were excluded. Outcomes included OP treatments and follow-up visits post-fragility fracture. RESULTS: Of 665 subjects included, most (87%) were women; overall mean (SD) age, 82 years. Fewer than two thirds (61%) had received any prior OP treatment (women, 65%; men, 38%); of these, 38% had received > 1 treatment (women, 25%; men, 13%). Among treated subjects, the most frequent first-line treatments were alendronate (43%) and RANKL inhibitor denosumab (22%), with a higher discontinuation rate and shorter treatment duration observed for alendronate (discontinuation, 42% vs 16%; median treatment duration, 2.5 vs 2.1 years). Over one-quarter (26%) of subjects had no follow-up visits post-fragility fracture, with this gap higher in women than men (35% versus 25%). The most common schedule of follow-up visits was yearly (43% of subjects with a fragility fracture), followed by half-yearly (17%) and biennial (10%), with a similar trend in men and women. Most OP treatments were prescribed by PC physicians, other than teriparatide and zoledronate. CONCLUSIONS: Across Spanish PC, we observed a large gap in the treatment and follow-up of elderly subjects experiencing a fragility fracture. Our data highlights the urgent need to improve secondary fracture prevention in PC.

Effect of a national guideline on postoperative troponin surveillance: a retrospective cohort study.

PURPOSE: We aimed to evaluate the effect of the 2017 Canadian Cardiovascular Society (CCS) guidelines on troponin surveillance after noncardiac surgery. METHODS: This was a single-centre, retrospective, observational study. Patients aged 40 yr or older undergoing intermediate- to high-risk elective noncardiac surgery between 2016 and 2021 were included. We compared the number and percentage of troponin tests ordered before and after the guidelines were published and compared patient characteristics, specifically cardiovascular comorbidity, using odds ratio's (OR) with 95% confidence intervals (CIs). Outcomes were myocardial injury, myocardial infarction (MI), and in-hospital mortality. RESULTS: The cohort included 36,386 patients and the median age was 63 yr. Between 2016 and 2018, troponin surveillance was done in 2,461 (13%) of the 19,046 patients, compared with 2,398 (14%) of the 17,340 patients who had surgery between 2019 and 2021 (OR, 1.08; 95% CI, 1.02 to 1.15). Patients who had surgery in the second period had less cardiovascular comorbidity; the adjusted OR for troponin surveillance was 1.14 (95% CI, 1.07 to 1.21). In the two periods, troponin was elevated in 561 (2.9%) and 470 (2.7%) patients, an MI was documented in 54 (0.3%) and 36 (0.2%) patients, and 95 (0.5%) and 73 (0.4%) patients died, respectively. After adjustment for baseline differences in the two periods, the ORs for MI and mortality were 0.83 (95% CI, 0.54 to 1.27) and 0.88 (95% CI, 0.64 to 1.19), respectively. CONCLUSION: Although the odds of troponin ordering were slightly but significantly higher after publication of the CCS guidelines, the odds for detecting an MI and for mortality did not change.

RéSUMé: OBJECTIF: Notre objectif était d'évaluer l'effet des lignes directrices 2017 de la Société canadienne de cardiologie (SCC) sur le monitorage de la troponine après une chirurgie non cardiaque. MéTHODE: Il s'agissait d'une étude observationnelle rétrospective monocentrique. Les patient·es âgé·es de 40 ans ou plus bénéficiant d'une chirurgie non cardiaque non urgente à risque intermédiaire à élevé entre 2016 et 2021 ont été inclus·es. Nous avons comparé le nombre et le pourcentage de tests de troponine prescrits avant et après la publication des lignes directrices et comparé les caractéristiques des patient·es, en particulier la comorbidité cardiovasculaire, en utilisant le rapport de cotes (RC) avec des intervalles de confiance (IC) à 95 %. Les critères d'évaluation comprenaient les lésions myocardiques, l'infarctus du myocarde (IM) et la mortalité hospitalière. RéSULTATS: La cohorte comprenait 36 386 personnes et l'âge médian était de 63 ans. Entre 2016 et 2018, le monitorage de la troponine a été réalisé chez 2461 (13 %) des 19 046 patient·es, contre 2398 (14 %) des 17 340 patient·es opéré·es entre 2019 et 2021 (RC, 1,08; IC 95%, 1,02 à 1,15). Les patient·es qui ont bénéficié d'une intervention chirurgicale au cours de la deuxième période présentaient moins de comorbidité cardiovasculaire; le RC ajusté pour le monitorage de la troponine était de 1,14 (IC 95 %, 1,07 à 1,21). Au cours des deux périodes, la troponine était élevée chez 561 (2,9 %) et 470 (2,7 %) patient·es, un IM a été documenté chez 54 (0,3 %) et 36 (0,2 %) patient·es, et 95 (0,5 %) et 73 (0,4 %) patient·es sont décédé·es, respectivement. Après ajustement pour tenir compte des différences initiales au cours des deux périodes, les RC pour l'IM et la mortalité étaient de 0,83 (IC 95 %, 0,54 à 1,27) et de 0,88 (IC 95 %, 0,64 à 1,19), respectivement. CONCLUSION: Bien que les probabilités de commande de troponine aient été légèrement mais significativement plus élevées après la publication des lignes directrices de la SCC, les probabilités de détection d'un IM et de mortalité n'ont pas changé.

Gastric variceal bleeding as a form of presentation of a pancreatic neuroendocrine tumor / Sangrado por varices gástricas como forma de presentación de un tumor neuroendocrino pancreático

NETs (neuroendocrine tumors) constitute a heterogeneous group of epithelial-type neoplasms with a predominantly neuroendocrine differentiation. Although the most common locations are the pancreas, digestive tract, and lung, this type of neoplasm can arise in virtually any organ in the body. They are rare tumors with a wide variety of clinical presentations. Symptomatic tumors are more frequent in younger patients and present at more advanced pathological stages. We present the case of a 42-year-old male with idiopathic splenomegaly and bicytopenia (anaemia and thrombocytopenia) under study by haematology department who was admitted due to an episode of melena and hemoglobin of 4.5 mg/dl. Isolated gastric varices (IGV1) with red spots were confirmed at gastroscopy and endoscopic variceal obturation using cyanoacrylate was performed in two sessions. An endoscopic ultrasonography was performed, showing thrombosis of the splenic vein extending towards the splenoportal confluence with anechoic serpiginous structures outside and inside the gastric wall suggestive of collateral circulation with gastric varices (GV). An increase in portal caliber was observed, with no signs of liver cirrhosis. Computed tomography confirms the findings. Two months/week/days later he was readmitted with rebleeding signs after starting anticoagulant treatment, so it was decided to perform a splenectomy due to failure of the endoscopic treatment. Histology revealed infiltration of the spleen by a well-differentiated neuroendocrine tumor (NET). Gallium PET/CT and Octreotid scan showed uptake in the body and tail of the pancreas with positivity for somatostatin receptors previously undetected by other means. Finally, treatment was completed with distal pancreatectomy and splenoportal axis trombectomy with vascular esplenic resection and the patient was discharged from hospital.(AU)

Gastric variceal bleeding as a form of presentation of a pancreatic neuroendocrine tumor.

NETs (neuroendocrine tumors) constitute a heterogeneous group of epithelial-type neoplasms with a predominantly neuroendocrine differentiation. Although the most common locations are the pancreas, digestive tract, and lung, this type of neoplasm can arise in virtually any organ in the body. They are rare tumors with a wide variety of clinical presentations. Symptomatic tumors are more frequent in younger patients and present at more advanced pathological stages. We present the case of a 42-year-old male with idiopathic splenomegaly and bicytopenia (anaemia and thrombocytopenia) under study by haematology department who was admitted due to an episode of melena and hemoglobin of 4.5 mg/dl. Isolated gastric varices (IGV1) with red spots were confirmed at gastroscopy and endoscopic variceal obturation using cyanoacrylate was performed in two sessions. An endoscopic ultrasonography was performed, showing thrombosis of the splenic vein extending towards the splenoportal confluence with anechoic serpiginous structures outside and inside the gastric wall suggestive of collateral circulation with gastric varices (GV). An increase in portal caliber was observed, with no signs of liver cirrhosis. Computed tomography confirms the findings. Two months/week/days later he was readmitted with rebleeding signs after starting anticoagulant treatment, so it was decided to perform a splenectomy due to failure of the endoscopic treatment. Histology revealed infiltration of the spleen by a well-differentiated neuroendocrine tumor (NET). Gallium PET/CT and Octreotid scan showed uptake in the body and tail of the pancreas with positivity for somatostatin receptors previously undetected by other means. Finally, treatment was completed with distal pancreatectomy and splenoportal axis trombectomy with vascular esplenic resection and the patient was discharged from hospital.

Anticipatory Antifungal Treatment in Critically Ill Patients with SARS-CoV-2 Pneumonia.

BACKGROUND: The aim of this study was to investigate the incidence of COVID-19-associated pulmonary aspergillosis (CAPA) in critically ill patients and the impact of anticipatory antifungal treatment on the incidence of CAPA in critically ill patients. METHODS: Before/after observational study in a mixed intensive care unit (ICU) of a university teaching hospital. The study took place between March 2020 and June 2022. Inclusion criteria were critically ill patients with severe SARS-CoV-2 pneumonia requiring invasive mechanical ventilation. Two analysis periods were compared according to whether or not antifungal therapy was given early. RESULTS: A total of 160 patients with severe SARS-CoV-2 pneumonia and invasive mechanical ventilation were included. The incidence of CAPA in the first study period was 19 out of 58 patients (32.75%); during the second period, after implementation of the intervention (anticipatory antifungal therapy), the incidence of CAPA decreased to 10.78% (11 out of 102 patients). In patients with CAPA under invasive mechanical ventilation, the mortality rate decreased from 100% to 64%. CONCLUSIONS: Anticipating antifungal treatment in patients with SARS-CoV-2 pneumonia under invasive mechanical ventilation was associated with a decrease in the incidence and mortality of pulmonary aspergillosis.

Trombosis de seno venoso asociada con infección por SARS-CoV-2 / Cerebral venous thrombosis associated with SARS-Cov-2 infection

RESUMEN INTRODUCCION: La trombosis del seno venoso se considera una de las causas más infrecuentes de enfermedad cerebrovascular (ECV), prevalente en la edad joven. Suele tener un inicio insidioso, lo cual dificulta su diagnóstico y el inicio oportuno del tratamiento, y se encuentra asociada con múltiples factores de riesgo, incluyendo estados de hipercoagulabilidad, como en aquellos pacientes que cursan con infección por SARS-CoV-2. REPORTE DE CASO: Se presentan dos casos clínicos de pacientes con alteraciones neurológicas, diplopia y estatus epiléptico, en quienes se documentó por medio de la sintomatologia y de estudios imagenológicos, trombosis venosas extensas de localización infrecuente, se descartaron las principales etiologías asociadas, y el único nexo asociado fue la infección por SARS-CoV-2. Ambos pacientes recibieron tratamiento con anticoagulación parenteral, al que respondieron de forma exitosa, por lo cual se logró el alta posteriormente con anticoagulación oral. DISCUSIÓN: Es imprescindible el conocimiento de esta enfermedad, asociada con una alta sospecha diagnóstica, dadas sus manifestaciones clínicas variadas y su asociación cada vez más frecuente con infección por covid-19.

ABSTRACT INTRODUCTION: Venous sinus thrombosis is considered one of the most infrequent causes of cerebrovascular disease (CVD), prevalent in young people. It usually has an insidious onset which difficult its diagnosis and timely initiation of treatment and is associated with multiple risk factors including hypercoagulable states, as in those patients with SARS-CoV-2 (severe acute respiratory syndrome coronavirus-2) infection. CASE REPORT: The following are 2 clinical cases of patients with neurological alterations, diplopia, and status epilepticus, in whom extensive venous thrombosis of infrequent location was documented through symptomatology and imaging studies, ruling out the main associated etiologies, with the only associated nexus: SARS-CoV-2 infection. Both patients received treatment with parenteral anticoagulation, responding successfully and were subsequently discharged with oral anticoagulation. DISCUSSION: It is essential to be aware of this disease associated with a high diagnostic suspicion given its varied clinical manifestations and its increasingly frequent association with COVID-19 infection.

Evaluating the message of an ongoing communication campaign to reduce the duration of untreated psychosis in a Latinx community in the United States.

AIM: Initiatives aimed at reducing the duration of untreated psychosis (DUP) attempt to increase the community's level of psychosis literacy. Most of these efforts, however, have failed to reduce DUP. One plausible explanation is that the campaigns do not actually increase psychosis literacy. To date, there have been few efforts to assess whether the campaign messaging does indeed increase psychosis literacy prior to or during the campaign. This study evaluated whether the message of the La CLAve DUP reduction program delivered during the campaign increased the psychosis literacy of a U.S. Latinx community. METHODS: The sample consisted of 81 Latinx community residents aged 15-84. Two community health educators of the La CLAve campaign facilitated workshops using a narrative film to initiate a conversation in the community about the signs of psychosis and the importance of professional help-seeking early in the illness course. Psychosis literacy was assessed via questionnaires pertaining to a hypothetical vignette administered before and after the workshops. RESULTS: The psychosis literacy of participants increased after the workshops in several domains. Participants' knowledge of multiple psychotic symptoms, self-efficacy in their ability to recognize psychosis in others, and correct attributions of a hypothetical vignette's psychotic symptoms significantly increased. No changes were observed in recommendations for professional help-seeking. CONCLUSIONS: These findings provide support for the effectiveness of the La CLAve messaging in increasing psychosis literacy of U.S. Latinx community residents. Evidence-based campaign messaging is needed to increase the success of DUP reduction programs especially among underserved communities.

Incidence of and factors associated with SARS-CoV-2 infection among people living with HIV in Southern Spain after one year of pandemic.

Whether people living with HIV (PLWH) are at greater risk of acquiring SARS-CoV-2 infection is currently unknown. Prospective serologic studies may allow seroincidence analyses, where all infections are accurately identified. Because of this, we evaluated the incidence of associated factors with and the clinical outcome of SARS-CoV-2 infection in PLWH in Southern Spain. This prospective cohort study included PLWH from a Tertiary University Hospital in Southern Spain. Patients were enrolled in the study if (1) they had attended as outpatients our Unit from 1 August 2019 to 8 February 2020 and (2) had two subsequent evaluations from 9 February 2020 to 4 March 2021. SARS-CoV-2 infections were diagnosed by PCR, antigen detection or serology. Seven hundred and nine PLWH were included in the study. Of them, 55 [7.8%, 95% confidence interval (95% CI) 5.9%-9.9%] patients developed SARS-CoV-2 infection. Between 18 May and 29 November 2020, the rate of seroconversion was 5.3% (95% CI: 3.1%-9.0%) for the general population in the area of Seville and 2.3% (95% CI: 1.3%-2.6%) for PLWH in this study (p = .001). After multivariable analysis, adjusted by age, sex, and risk factors for HIV infection, active tobacco use and CDC stage, active tobacco smoking was the only factor independently associated with lower risk of SARS-Cov-2 infection [Incidence rate ratio: 0.29 (95% CI 0.16-0.55) p < .001]. In conclusion, the incidence of SARS-CoV-2 infection among PLWH in Southern Spain during the ongoing pandemic was lower than that reported for the general population in the same area.

Increasing Social Connectedness for Underserved Older Adults Living With Depression: A Pre-Post Evaluation of PEARLS.

OBJECTIVE: To evaluate PEARLS effectiveness for increasing social connectedness among underserved older adults with depression. DESIGN: Multisite, pre-post single-group evaluation. SETTING: Community-based social service organizations (N = 16) in five U.S. states, purposively sampled for maximum variation of participants and providers. PARTICIPANTS: A total of 320 homebound older adults (mean(SD) age 72.9(9.6), 79% female, 44% people of color, 81% low-income, 61% living alone, average four chronic conditions) with clinically significant depression (PHQ-9 mean(SD) 12.7(4.6)). INTERVENTION: Four to 6 month home-based depression care management model delivered by trained front-line providers. MEASUREMENTS: Brief validated social connectedness scales: Duke Social Support Index 10-item (DSSI-10), PROMIS-Social Isolation (6-item), UCLA-Loneliness (3-item); sociodemographic and health measures. RESULTS: At baseline, PEARLS participants overall and with ≥1 of the following characteristics were less socially connected: younger (50-64), white, LGBTQ+, not partnered, not caregiving, living alone, financial limitations, chronic conditions, and/or recently hospitalized. Six-months post-PEARLS enrollment, participants significantly increased social interactions and satisfaction with social support (DSSI-10 t[312] = 5.2, p <0.001); and reduced perceived isolation (PROMIS t[310] = 6.3, p <0.001); and loneliness (UCLA t[301] = 3.7, p =0.002), with small to moderate effect sizes (Cohen's d DSSI-10: 0.28, PROMIS-SI: 0.35, UCLA: 0.21). Increased social connectedness was associated with reduced depression. Improvements in social connectedness (except social interactions) persisted during early COVID-19. Being Latino and/or having difficulty paying for basic needs was associated with less improvement in post-PEARLS social connectedness. CONCLUSION: PEARLS has potential to improve social connectedness among underserved older adults, though additional supports may be needed for persons facing multiple social determinants of health. Further research is needed to establish causality.

Sample pooling for SARS-CoV-2 RT-PCR screening.

OBJECTIVE: To evaluate the efficacy of sample pooling compared to the individual analysis for the diagnosis of coronavirus disease 2019 (COVID-19) by using different commercial platforms for nucleic acid extraction and amplification. METHODS: A total of 3519 nasopharyngeal samples received at nine Spanish clinical microbiology laboratories were processed individually and in pools (342 pools of ten samples and 11 pools of nine samples) according to the existing methodology in place at each centre. RESULTS: We found that 253 pools (2519 samples) were negative and 99 pools (990 samples) were positive; with 241 positive samples (6.85%), our pooling strategy would have saved 2167 PCR tests. For 29 pools (made out of 290 samples), we found discordant results when compared to their correspondent individual samples, as follows: in 22 of 29 pools (28 samples), minor discordances were found; for seven pools (7 samples), we found major discordances. Sensitivity, specificity and positive and negative predictive values for pooling were 97.10% (95% confidence interval (CI), 94.11-98.82), 100%, 100% and 99.79% (95% CI, 99.56-99.90) respectively; accuracy was 99.80% (95% CI, 99.59-99.92), and the kappa concordant coefficient was 0.984. The dilution of samples in our pooling strategy resulted in a median loss of 2.87 (95% CI, 2.46-3.28) cycle threshold (Ct) for E gene, 3.36 (95% CI, 2.89-3.85) Ct for the RdRP gene and 2.99 (95% CI, 2.56-3.43) Ct for the N gene. CONCLUSIONS: We found a high efficiency of pooling strategies for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) RNA testing across different RNA extraction and amplification platforms, with excellent performance in terms of sensitivity, specificity and positive and negative predictive values.

Endothelin-1-Mediated Drug Resistance in EGFR-Mutant Non-Small Cell Lung Carcinoma.

Progression on therapy in non-small cell lung carcinoma (NSCLC) is often evaluated radiographically, however, image-based evaluation of said therapies may not distinguish disease progression due to intrinsic tumor drug resistance or inefficient tumor penetration of the drugs. Here we report that the inhibition of mutated EGFR promotes the secretion of a potent vasoconstrictor, endothelin-1 (EDN1), which continues to increase as the cells become resistant with a mesenchymal phenotype. As EDN1 and its receptor (EDNR) is linked to cancer progression, EDNR-antagonists have been evaluated in several clinical trials with disappointing results. These trials were based on a hypothesis that the EDN1-EDNR axis activates the MAPK-ERK signaling pathway that is vital to the cancer cell survival; the trials were not designed to evaluate the impact of tumor-derived EDN1 in modifying tumor microenvironment or contributing to drug resistance. Ectopic overexpression of EDN1 in cells with mutated EGFR resulted in poor drug delivery and retarded growth in vivo but not in vitro. Intratumoral injection of recombinant EDN significantly reduced blood flow and subsequent gefitinib accumulation in xenografted EGFR-mutant tumors. Furthermore, depletion of EDN1 or the use of endothelin receptor inhibitors bosentan and ambrisentan improved drug penetration into tumors and restored blood flow in tumor-associated vasculature. Correlatively, these results describe a simplistic endogenous yet previously unrealized resistance mechanism inherent to a subset of EGFR-mutant NSCLC to attenuate tyrosine kinase inhibitor delivery to the tumors by limiting drug-carrying blood flow and the drug concentration in tumors. SIGNIFICANCE: EDNR antagonists can be repurposed to improve drug delivery in VEGFA-secreting tumors, which normally respond to TKI treatment by secreting EDN1, promoting vasoconstriction, and limiting blood and drug delivery.

Acute hypokinetic-rigid syndrome following SARS-CoV-2 infection.

OBJECTIVE: To report a case of a patient infected with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) who acutely developed a hypokinetic-rigid syndrome. METHODS: Patient data were obtained from medical records from the Hospital Universitario 12 de Octubre in Madrid, Spain. [123I]-ioflupane dopamine transporter (DaT) SPECT images were acquired 4 hours after a single dose of 185 MBq of 123I-FP-CIT. Quantitative analysis was performed with DaTQUANT software providing the specific binding ratio and z score values of the striatum. RESULTS: We report a previously healthy 58-year-old man who developed hyposmia, generalized myoclonus, fluctuating and transient changes in level of consciousness, opsoclonus, and an asymmetric hypokinetic-rigid syndrome with ocular abnormalities after a severe SARS-CoV-2 infection. DaT-SPECT confirmed a bilateral decrease in presynaptic dopamine uptake asymmetrically involving both putamina. Significant improvement in the parkinsonian symptoms was observed without any specific treatment. CONCLUSION: This case study provides clinical and functional neuroimaging evidence to support that SARS-CoV-2 can gain access to the CNS, affecting midbrain structures and leading to neurologic signs and symptoms.

Towards the elimination of hepatitis C: implementation of reflex testing in Andalusia

BACKGROUND AND AIM: undiagnosed hepatitis C virus (HCV) infection and/or inadequate access to care are barriers to the elimination of HCV. Reflex testing has proven to facilitate referral to care, treatment and viral elimination. In this study, a reflex testing program was implemented in Andalusia and its impact on access to care was evaluated. PATIENTS AND METHODS: an observational, retrospective and prospective study was performed across diagnostic laboratories responsible for HCV diagnosis in southern Spain. After surveying the barriers to performing reflex testing, the number of patients that were not referred for care in 2016 was retrospectively studied (pre-reflex cohort). Subsequently, several measures were proposed to overcome the identified barriers. Finally, reflex testing was implemented and its impact evaluated. RESULTS: the pre-reflex cohort included information from 1,053 patients. Slightly more than half of the patients (n = 580; 55%) visited a specialist for treatment evaluation during a median period of 71 days (interquartile range = 35-134) since the date of diagnosis. The post-reflex cohort (September 2017 to March 2018) included 623 patients. Only 17% (n = 106) of the patients had not been referred for care or evaluated for treatment in a median period of 52 days (interquartile range = 28-86). CONCLUSIONS: in 2016, nearly half of new HCV diagnoses in southern Spain were not referred for care. Barriers to the implementation of reflex testing were overcome in our study. Moreover, this strategy was effectively implemented in 2017. Reflex testing contributed to improving referral for care. This program will contribute to the micro-elimination of hepatitis C in Spain

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Towards the elimination of hepatitis C: implementation of reflex testing in Andalusia.

BACKGROUND AND AIM: undiagnosed hepatitis C virus (HCV) infection and/or inadequate access to care are barriers to the elimination of HCV. Reflex testing has proven to facilitate referral to care, treatment and viral elimination. In this study, a reflex testing program was implemented in Andalusia and its impact on access to care was evaluated. PATIENTS AND METHODS: an observational, retrospective and prospective study was performed across diagnostic laboratories responsible for HCV diagnosis in southern Spain. After surveying the barriers to performing reflex testing, the number of patients that were not referred for care in 2016 was retrospectively studied (pre-reflex cohort). Subsequently, several measures were proposed to overcome the identified barriers. Finally, reflex testing was implemented and its impact evaluated. RESULTS: the pre-reflex cohort included information from 1,053 patients. Slightly more than half of the patients (n = 580; 55%) visited a specialist for treatment evaluation during a median period of 71 days (interquartile range = 35-134) since the date of diagnosis. The post-reflex cohort (September 2017 to March 2018) included 623 patients. Only 17% (n = 106) of the patients had not been referred for care or evaluated for treatment in a median period of 52 days (interquartile range = 28-86). CONCLUSIONS: in 2016, nearly half of new HCV diagnoses in southern Spain were not referred for care. Barriers to the implementation of reflex testing were overcome in our study. Moreover, this strategy was effectively implemented in 2017. Reflex testing contributed to improving referral for care. This program will contribute to the micro-elimination of hepatitis C in Spain.

Slow but Steady Wins the Race: Dissimilarities among New Dual Inhibitors of the Wild-Type and the V27A Mutant M2 Channels of Influenza A Virus.

New insights on the amantadine resistance mechanism of the V27A mutant were obtained through the study of novel, easily accessible 4-(1- and 2-adamantyl)piperidines, identified as dual binders of the wild-type and V27A mutant M2 channels of influenza A virus. Their antiviral activity and channel blocking ability were determined using cell-based assays and two-electrode voltage clamp (TEVC) technique on M2 channels, respectively. In addition, electrophysiology experiments revealed two interesting findings: (i) these inhibitors display a different behavior against the wild-type versus V27A mutant A/M2 channels, and (ii) the compounds display antiviral activity when they have kd equal or smaller than 10-6 while they do not exhibit antiviral activity when kd is 10-5 or higher although they may show blocking activity in the TEV assay. Thus, caution must be taken when predicting antiviral activity based on percent channel blockage in electrophysiological assays. These findings provide experimental evidence of the resistance mechanism of the V27A mutation to wild-type inhibitors, previously predicted in silico, offer an explanation for the lack of antiviral activity of compounds active in the TEV assay, and may help design new and more effective drugs.

MIC of amoxicillin/clavulanate according to CLSI and EUCAST: discrepancies and clinical impact in patients with bloodstream infections due to Enterobacteriaceae.

Objectives: To compare results of amoxicillin/clavulanate susceptibility testing using CLSI and EUCAST methodologies and to evaluate their impact on outcome in patients with bacteraemia caused by Enterobacteriaceae. Patients and methods: A prospective observational cohort study was conducted in 13 Spanish hospitals. Patients with bacteraemia due to Enterobacteriaceae who received empirical intravenous amoxicillin/clavulanate treatment for at least 48 h were included. MICs were determined following CLSI and EUCAST recommendations. Outcome variables were: failure at the end of treatment with amoxicillin/clavulanate (FEAMC); failure at day 21; and 30 day mortality. Classification and regression tree (CART) analysis and logistic regression were performed. Results: Overall, 264 episodes were included; the urinary tract was the most common source (64.7%) and Escherichia coli the most frequent pathogen (76.5%). Fifty-two isolates (19.7%) showed resistance according to CLSI and 141 (53.4%) according to EUCAST. The kappa index for the concordance between the results of both committees was only 0.24. EUCAST-derived, but not CLSI-derived, MICs were associated with failure when considered as continuous variables. CART analysis suggested a 'resistance' breakpoint of > 8/4 mg/L for CLSI-derived MICs; it predicted FEAMC in adjusted analysis (OR = 1.96; 95% CI: 0.98-3.90). Isolates with EUCAST-derived MICs >16/2 mg/L independently predicted FEAMC (OR = 2.10; 95% CI: 1.05-4.21) and failure at day 21 (OR= 3.01; 95% CI: 0.93-9.67). MICs >32/2 mg/L were only predictive of failure among patients with bacteraemia from urinary or biliary tract sources. Conclusions: CLSI and EUCAST methodologies showed low agreement for determining the MIC of amoxicillin/clavulanate. EUCAST-derived MICs seemed more predictive of failure than CLSI-derived ones. EUCAST-derived MICs >16/2 mg/L were independently associated with therapeutic failure.

Impact of the MIC of piperacillin/tazobactam on the outcome for patients with bacteraemia due to Enterobacteriaceae: the Bacteraemia-MIC project.

OBJECTIVE: Our objective was to evaluate the impact of low versus borderline MIC of piperacillin/tazobactam on the clinical outcomes of patients with bacteraemia caused by Enterobacteriaceae who were treated with that antimicrobial. PATIENTS AND METHODS: A prospective observational multicentre cohort study was conducted in 13 Spanish university hospitals. Patients >17 years old with bacteraemia due to Enterobacteriaceae who received empirical piperacillin/tazobactam treatment for at least 48 h were included. Outcome variables were clinical response at day 21, clinical response at end of treatment with piperacillin/tazobactam and all-cause 30 day mortality. Univariate and multivariate logistic regression analyses were performed. RESULTS: Overall, 275 patients were included in the analysis; 248 (90.2%) in the low MIC group (≤ 4 mg/L) and 27 (9.8%) in the borderline MIC group (8-16 mg/L). The biliary tract was the most common source of infection (48.4%) and Escherichia coli was the most frequent pathogen (63.3%). Crude 30 day mortality rates were 10.5% and 11.1% for the low MIC group and the borderline MIC group, respectively (relative risk = 1.06, 95% CI = 0.34-3.27, P = 1). Multivariate analysis of failure at day 21 and at end of treatment with piperacillin/tazobactam and 30 day mortality showed no trend towards increased clinical failure or mortality with borderline MICs (OR = 0.96, 95% CI = 0.18-4.88, P = 0.96; OR = 0.47, 95% CI = 0.10-2.26, P = 0.35; OR = 1.48, 95% CI = 0.33-6.68, P = 0.6). CONCLUSIONS: We did not find that higher piperacillin/tazobactam MIC within the susceptible or intermediate susceptibility range had a significant influence on the outcome for patients with bacteraemia due to Enterobacteriaceae.

Reduced Susceptibility to Cefepime in Clinical Isolates of Enterobacteriaceae Producing OXA-1 Beta-Lactamase.

An increase of Enterobacteriaceae isolates with reduced susceptibility to cefepime (FEP) and amoxicillin/clavulanate (AMC) has been observed in our area. The aim of this study was to characterize this antibiotic resistance phenotype and its molecular epidemiology. A total of 33 Enterobacteriaceae strains were studied. blaOXA-1 genes and their genetic environment were analyzed by polymerase chain reaction (PCR) and sequencing. Plasmids were transferred by conjugation and/or transformation and classified using PCR-based inc/rep typing and IncF subtyping. Escherichia coli isolates were typed by phylogroup, pulsed-field gel electrophoresis (PFGE) and multilocus sequence typing. Outer membrane proteins were studied by sodium dodecylsulfate-polyacrylamide gel electrophoresis and expression of blaOXA-1 genes by reverse transcription-PCR. FEP minimum inhibitory concentration yielded values of 1-16 mg/L. Twenty-nine (87.9%) isolates produced OXA-1, of which 24 (82.7%) were located in class 1 integron, and 9 (27.3%) produced TEM-1. Among the 24 E. coli OXA-1-producers, PFGE revealed two main clusters: one belonged to C-ST88 and the other to B23-ST131. Thirteen plasmids containing blaOXA-1 were transferred, nine belonged to IncF replicon (4 F2:A1:B-, 2 F1:A1:B1, 1 F1:A2:B-, 1 F18:A2:B1, 1 F5:A-:B1) and four were nontypeable. In conclusion, reduced susceptibility to FEP was mostly due to OXA-1 beta-lactamase. In E. coli, this increase is mainly due to the dissemination of two clones, which have captured different IncF plasmids. Among non-E. coli strains, five isolates produced OXA-1 and one isolate produced only TEM-1.

Adrenohepatic fusion: Adhesion or invasion in primary virilizant giant adrenal carcinoma? Implications for surgical resection. Two case report and review of the literature.

INTRODUCTION: Adrenohepatic fusion means union between the adrenal gland and the liver, intermingling its parenchymas. It is not possible to identify this condition by image tests. Its presence implies radical and multidisciplinar approach. PRESENTATION OF CASES: We report two female cases of 45 and 50 years old with clinical virilization and palpable mass on the abdominal right upper quadrant corresponding to adrenocortical carcinoma with hepatic fusion. The contrast-enhanced tomography showed an indistinguishable mass involving the liver and the right adrenal gland. In the first case, the patient had a two-time operation, the former removing only the adrenal carcinoma, and the second performing a radical surgery after an early relapse. In the second case, a radical right en bloc adrenohepatectomy was performed. Both cases were pathologically reported as liver-infiltrating adrenal carcinoma. Only in the second case the surgery was radical effective as first intention to treat, with 3 years of disease-free survival. DISCUSSION: ACC is a rare entity with poor prognosis. The major indicators of malignancy are tumour diameter over 6cm, local invasion or metastasis, secretion of corticosteroids, virilization and hypertension and hypokalaemia. The parenchymal fusion of the adrenal cortical layer can be misdiagnosed as hepatocellular carcinoma with adhesion with the Glisson capsule. AHF in such cases may be misinterpreted during surgery, what may impair its resectability, and therefore the survival. The surgical treatment must be performed en bloc, often using liver vascular control. Postoperative treatment must be offered immediately after surgery. CONCLUSION: We report two consecutive rare cases of adrenohepatic fusion in giant right adrenocortical carcinoma, not detectable by imaging, what has important implications for the surgical decision-making. As radical surgery is the best choice to offer a curative treatment, it has to be performed by a multidisciplinary well-assembled team, counting with endocrine and liver surgeons, and transplant surgeons in case of vena cava involvement, in order to maximize the disease-free survival.