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Background: Up to 30% of hospitalised patients with COVID-19 require advanced respiratory support, including high-flow nasal cannulas (HFNC), non-invasive mechanical ventilation (NIV), or invasive mechanical ventilation (IMV). We aimed to describe the clinical characteristics, outcomes and risk factors for failing non-invasive respiratory support in patients treated with severe COVID-19 during the first two years of the pandemic in high-income countries (HICs) and low middle-income countries (LMICs)., Methods: This is a multinational, multicentre, prospective cohort study embedded in the ISARIC-WHO COVID-19 Clinical Characterisation Protocol. Patients with laboratory-confirmed SARS-CoV-2 infection who required hospital admission were recruited prospectively. Patients treated with HFNC, NIV, or IMV within the first 24 h of hospital admission were included in this study. Descriptive statistics, random forest, and logistic regression analyses were used to describe clinical characteristics and compare clinical outcomes among patients treated with the different types of advanced respiratory support., Results: A total of 66,565 patients were included in this study. Overall, 82.6% of patients were treated in HIC, and 40.6% were admitted to the hospital during the first pandemic wave. During the first 24 h after hospital admission, patients in HICs were more frequently treated with HFNC (48.0%), followed by NIV (38.6%) and IMV (13.4%). In contrast, patients admitted in lower- and middle-income countries (LMICs) were less frequently treated with HFNC (16.1%) and the majority received IMV (59.1%). The failure rate of non-invasive respiratory support (i.e. HFNC or NIV) was 15.5%, of which 71.2% were from HIC and 28.8% from LMIC. The variables most strongly associated with non-invasive ventilation failure, defined as progression to IMV, were high leukocyte counts at hospital admission (OR [95%CI]; 5.86 [4.83-7.10]), treatment in an LMIC (OR [95%CI]; 2.04 [1.97-2.11]), and tachypnoea at hospital admission (OR [95%CI]; 1.16 [1.14-1.18]). Patients who failed HFNC/NIV had a higher 28-day fatality ratio (OR [95%CI]; 1.27 [1.25-1.30])., Conclusions: In the present international cohort, the most frequently used advanced respiratory support was the HFNC. However, IMV was used more often in LMIC. Higher leucocyte count, tachypnoea, and treatment in LMIC were risk factors for HFNC/NIV failure. HFNC/NIV failure was related to worse clinical outcomes, such as 28-day mortality. Trial registration This is a prospective observational study; therefore, no health care interventions were applied to participants, and trial registration is not applicable., (© 2022. The Author(s).)

Background: Resident miscommunication and fractured team dynamics are associated with decreased quality of patient care. Interventions to improve resident communication and team coordination include behavioral assessments, which promote leadership and communication skills., Methods: In this retrospective review, general and plastic surgery residents voluntarily completed the DISC (dominance, influence, steadiness, and compliance) behavioral assessment. This validated tool is composed of four behavioral categories: dominance (D), influence (I), steadiness (S), and compliance (C). It is used to classify an individual's natural and adapted behavior styles. Results were anonymously collected and analyzed using the Pearson chi-square test., Results: Of 94 surgery residents, 84 completed the survey (89 percent): 43 men and 41 women. Surgery residents combined had a significantly higher percentage of natural C's compared to the general population (23 percent versus 14 percent; p = 0.02). The majority of surgery residents adapted to C in the work environment (39 versus 36 percent; p = 0.85). There was a significant difference in male and female general surgery adapted D profiles (4 percent versus 23 percent; p = 0.05)., Conclusions: The pressure of accuracy in surgical residency attracts natural C individuals. Residents without a natural C behavioral profile tend to adapt to the C profile. The ability to recognize behavior traits is crucial in surgical residency. Developing a better understanding of one's own behavior will provide insight into personal risk factors for miscommunication and inefficient team dynamics., (Copyright © 2022 by the American Society of Plastic Surgeons.)

Background & Aim: Liver transplantation (LT) selection models for hepatocellular carcinoma (HCC) have not been proposed to predict waitlist dropout because of tumour progression. The aim of this study was to compare the alpha-foetoprotein (AFP) model and other pre-LT models in their prediction of HCC dropout., Methods: A multicentre cohort study was conducted in 20 Latin American transplant centres, including 994 listed patients for LT with HCC from 2012 to 2018. Longitudinal tumour characteristics, and patterns of progression were recorded at time of listing, after treatments and at last follow-up over the waitlist period. Competing risk regression models were performed, and model's discrimination was compared estimating Harrell's adapted c-statistics., Results: HCC dropout rate was significantly higher in patients beyond (24% [95% CI 16-28]) compared to those within Milan criteria (8% [95% IC 5%-12%]; p < .0001), with a SHR of 3.01 [95% CI 2.03-4.47]), adjusted for waiting list time and bridging therapies (c-index 0.63 [95% CI 0.57; 0.69). HCC dropout rates were higher in patients with AFP scores >2 (adjusted SHR of 3.17 [CI 2.13-4.71]), c-index of 0.71 (95% CI 0.65-0.77; p = .09 vs Milan). Similar discrimination power for HCC dropout was observed between the AFP score and the Metroticket 2.0 model. In patients within Milan, an AFP score >2 points discriminated two populations with a higher risk of HCC dropout (SHR 1.68 [95% CI 1.08-2.61])., Conclusions: Pre-transplant selection models similarly predicted HCC dropout. However, the AFP model can discriminate a higher risk of dropout among patients within Milan criteria., (© 2022 John Wiley & Sons A/S . Published by John Wiley & Sons Ltd.)

The International Severe Acute Respiratory and Emerging Infection Consortium (ISARIC) COVID-19 dataset is one of the largest international databases of prospectively collected clinical data on people hospitalized with COVID-19. This dataset was compiled during the COVID-19 pandemic by a network of hospitals that collect data using the ISARIC-World Health Organization Clinical Characterization Protocol and data tools. The database includes data from more than 705,000 patients, collected in more than 60 countries and 1,500 centres worldwide. Patient data are available from acute hospital admissions with COVID-19 and outpatient follow-ups. The data include signs and symptoms, pre-existing comorbidities, vital signs, chronic and acute treatments, complications, dates of hospitalization and discharge, mortality, viral strains, vaccination status, and other data. Here, we present the dataset characteristics, explain its architecture and how to gain access, and provide tools to facilitate its use., (© 2022. The Author(s).)

Background: Chagas disease is one of the leading causes of heart failure (HF) in Latin Americans, and there are limited data available that examine related costs of care for patients with HF. This study aimed to compare healthcare resource utilization and related costs for patients with HF, with and without Chagas disease., Methods: A prospective matched-cohort study comparing the healthcare costs for patients with HF with Chagas disease and care costs for patients with HF without Chagas disease was conducted between January 2019 and December 2019. Only direct costs have been estimated, including hospitalization costs, medications and other cardiovascular interventions, and clinical and laboratory follow-up for up to 1 year., Results: A total of 80 patients with chronic HF were included in the study. Of the 80 patients, 40 patients in the Chagas cohort and 40 patients in the non-Chagas cohort were matched for age, insurer and sex. From a social security system perspective, the total costs for the two cohorts during the study period were U$970,136. Specifically, the healthcare costs for the Chagas cohort were greater than the total healthcare costs for the non-Chagas group (U$511,931 versus U$458,205; p  = 0.6183) Most costs were associated with hospitalizations (65.5% versus 59.6%), with averages of U$12,798.5 and U$11,455.1 per person in the Chagas and non-Chagas groups, respectively. In both the Chagas (51.6%) and non-Chagas cohorts (54.5%), causes of readmission unrelated to HF outweighed causes of readmission related to HF. High incidences of hospital admissions were observed during the rainy (cold) season for both cohorts., Conclusions: Over a 12-month follow-up period, patients with chronic HF and Chagas consume as many healthcare resources as those with chronic HF and without Chagas. These data highlight the considerable and growing economic burden of HF on the Colombian health system., Competing Interests: Competing interests: The authors declared no potential conflicts of interest with respect to the research, authorship or publication, or both, of this article., (© The Author(s), 2022.)

Socioeconomic disparities remain prevalent among those who undergo breast reconstruction. At our institution, patients must meet certain criteria to become eligible for breast reconstruction. The purpose of this study was to determine the impact of socioeconomic factors on breast reconstruction eligibility, enrollment, choice, and completion at our large safety-net institution., Methods: A retrospective chart review of patients who underwent partial or total mastectomy at a large safety-net hospital from 2016 to 2019 was completed. Surgical and demographic data were compared across varying socioeconomic factors., Results: A total of 645 patients were included in the study. More patients of a racial minority had government-based insurance than White patients (89% versus 81%; P = 0.01). Those with government-based insurance had higher average hemoglobin A1c values (6.26 versus 6.0; P = 0.03), proportion of American Society of Anesthesiologists scores greater than III (46% versus 40%; P = 0.01), and smokers (23% versus 9%; P = 0.02) than those with private insurance. Diabetic patients, patients with an American Society of Anesthesiologists greater than III, and active smokers were significantly less likely to receive a plastic surgery consult. Patients with government-based insurance underwent immediate tissue expander placement at mastectomy at rates lower than those with private insurance (57% versus 69%; P = 0.01)., Conclusions: Barriers remain for socioeconomically disadvantaged patients to be eligible for, undergo, and complete breast reconstruction. Obesity, diabetes, smoking, and poor overall health were identified as the main barriers and were associated with racial minorities, government-based insurance, and lower incomes. Concerted effort through multidisciplinary teams is needed to maximize eligibility of socioeconomically disadvantaged breast cancer patients for reconstruction., (Copyright © 2022 The Authors. Published by Wolters Kluwer Health, Inc. on behalf of The American Society of Plastic Surgeons.)

Context: Estrogens play an essential role in reproduction. Their action is mediated by nuclear α and β receptors (ER) and by membrane receptors. Only 3 females and 2 males, from 3 families, with a loss of ERα function have been reported to date., Objective: We describe here a new family, in which 2 sisters display endocrine and ovarian defects of different severities despite carrying the same homozygous rare variant of ESR1., Methods: A 36-year-old woman from a consanguineous Jordanian family presented with primary amenorrhea and no breast development, with high plasma levels of 17β-estradiol (E2), follicle-stimulating hormone and luteinizing hormone, and enlarged multifollicular ovaries, strongly suggesting estrogen resistance. Her 18-year-old sister did not enter puberty and had moderately high levels of E2, high plasma gonadotropin levels, and normal ovaries., Results: Genetic analysis identified a homozygous variant of ESR1 leading to the replacement of a highly conserved glutamic acid with a valine (ERα-E385V). The transient expression of ERα-E385V in HEK293A and MDA-MB231 cells revealed highly impaired ERE-dependent transcriptional activation by E2. The analysis of the KISS1 promoter activity revealed that the E385V substitution induced a ligand independent activation of ERα. Immunofluorescence analysis showed that less ERα-E385V than ERα-WT was translocated into the nucleus in the presence of E2., Conclusion: These 2 new cases are remarkable given the difference in the severity of their ovarian and hormonal phenotypes. This phenotypic discrepancy may be due to a mechanism partially compensating for the ERα loss of function., (© The Author(s) 2022. Published by Oxford University Press on behalf of the Endocrine Society. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Background: Immediate tissue expander (TE) breast reconstruction is reported to have the highest rate of postoperative infection among reconstructive modalities. The risk of infection is higher among patients treated at safety-net hospitals., Objectives: The goal of this study was to identify significant contributing factors to the elevated infection risk at our major safety-net institution., Methods: A retrospective chart review was conducted on all TE-based reconstruction patients with a diagnosis of postoperative infection between 2015 and 2019. Preoperative, perioperative, and postoperative risk factors for infection were determined and compared across patient and procedure demographics., Results: Two hundred forty-three patients, for a total of 412 breast reconstructions, were included in our study. Significant preoperative selection factors were identified to contribute to the elevated risk of infection, including the following: older age, higher BMI, and diabetes. Significant intraoperative and postoperative contributing factors included greater mastectomy weight, larger TE's and intraoperative fill volume, and longer drain duration. Doxycycline treatment for infected patients resulted in a significantly higher rate of resolution., Conclusions: Safety-net hospital population patients undergoing TE breast reconstruction are at higher risk for postoperative infection. Personal and procedural risk factors are identified. Balancing the benefits of immediate breast reconstruction with TEs with the elevated risk of postoperative infection remains challenging. Implementation of more stringent eligibility criteria may help mitigate the risk of infection., (© 2022 The Aesthetic Society.)

Background: The type of content that influences plastic and reconstructive surgery (PRS) residency program selection and attracts applicants is continually changing and not clearly understood. Further, the COVID-19 pandemic has had a major yet undetermined impact on residency selection., Objectives: The purpose of this study was to determine the type of PRS social media (SM) content that drives prospective applicants' interest in a residency program, and the degree of SM influence on applicants, especially in the context of COVID-19., Methods: Prospective PRS residency applicants were surveyed anonymously., Results: An average of 60% of respondents reported that PRS SM content influenced their perception of a program. Fifty-eight percent reported that resident lifestyle content made them more interested in a program. Separately, 32% reported that resident lifestyle content influenced them to rank a program higher. Seventy-two percent of respondents claimed SM content did not make them lose interest in a program. Rarely posting, outdated content, and lack of engagement were cited as factors for loss of interest in a program. A majority of respondents (53%) reported wanting to see more resident life and culture content on SM. Of the existing PRS SM content, respondents were most interested in resident lifestyle, followed by clinical and program-specific content., Conclusions: The COVID-19 pandemic amplified the importance of SM PRS residency selection. Resident lifestyle content was consistently indicated as more likely to make respondents gain interest in a program, rank a program higher, and as the most desired content. PRS programs will benefit from highlighting resident camaraderie, quality of life, hobbies, and lifestyle to attract applicants., (© 2021 The Aesthetic Society. Reprints and permission: journals.permissions@oup.com.)

Background: The incidence of invasive pneumococcal disease (IPD) varies depending on a number of factors, including vaccine uptake, in both children and adults, the geographic location, and local serotype prevalence. There are limited data about the burden of Streptococcus pneumoniae (Spn), serotype distribution, and clinical characteristics of adults hospitalized due to IPD in Colombia. The objectives of this study included assessment of Spn serotype distribution, clinical characteristics, mortality, ICU admission, and the need for mechanical ventilation., Methods: This was an observational, retrospective, a citywide study conducted between 2012 and 2019 in Bogotá, Colombia. We analyzed reported positive cases of IPD from 55 hospitals in a governmental pneumococcal surveillance program. Pneumococcal strains were isolated in each hospital and typified in a centralized laboratory. This is a descriptive study stratified by age and subtypes of IPD obtained through the analysis of medical records., Results: A total of 310 patients with IPD were included, of whom 45.5% were female. The leading cause of IPD was pneumonia (60%, 186/310), followed by meningitis. The most frequent serotypes isolated were 19A (13.87%, 43/310) and 3 (11.94%, 37/310). The overall hospital mortality rate was 30.3% (94/310). Moreover, 52.6% (163/310 patients) were admitted to the ICU, 45.5% (141/310) required invasive mechanical ventilation and 5.1% (16/310) non-invasive mechanical ventilation., Conclusion: Pneumococcal pneumonia is the most prevalent cause of IPD, with serotypes 19A and 3 being the leading cause of IPD in Colombian adults. Mortality due to IPD in adults continues to be very high., (© 2021. The Author(s).)

Purpose: Hip fractures are a worldwide health issue primarily for older patients, conditioning major morbidity and mortality. An experienced multidisciplinary team is essential to manage surgery and peri-operative implications, to enable rapid functional and cognitive recovery. Delirium is a recognizable problem associated with negative outcomes. Our study aims to determine the influence of pre-operative delirium in the incidence of post-operative delirium, and to evaluate the association between other known peri-operative risk factors with both conditions., Methods: A single-center, retrospective cohort study, conducted at a Level II trauma center over a 14-month period, included 241 patients with 65 years of age or older submitted to hip fracture surgery. Peri-operative data were gathered regarding baseline characteristics (sociodemographic, functional and cognitive status), intra-operative events (anesthesia technique, surgery duration, blood loss) and post-operative outcomes (delirium occurrence)., Results: Statistical analysis evidenced a female (75.5%) and elderly population (83.9 ± 7.8 years old) with significant comorbidities (cognitive impairment in 51.9%, ASA ≥ III in 79.7%, mean CIRS-G 8.83 ± 4.69) that underwent surgical fracture repair, mostly under 4 h (96.3%) and under regional anesthesia (63.1%). Pre- and post-operative delirium incidence was 18.3% and 12.9%, respectively, displaying increased presence according to cognitive impairment severity., Conclusion: Post-operative delirium was almost inexistent when it was absent pre-operatively. Moreover, pre-operative cognitive status was associated with the development of pre- and post-operative delirium. Careful cognitive assessment, implementation of preventive strategies and avoidance of peri-operative pro-delirium factors are crucial for comprehensive geriatric care., (© 2021. European Geriatric Medicine Society.)

Background & Aim: Recurrence of hepatocellular carcinoma (HCC) after liver transplantation (LT) has a poor prognosis, and the adjusted effect of different treatments on post-recurrence survival (PRS) has not been well defined. This study aims to evaluate prognostic and predictive variables associated with PRS., Methods: This Latin American multicenter retrospective cohort study included HCC patients who underwent LT between the years 2005-2018. We evaluated the effect of baseline characteristics at time of HCC recurrence diagnosis and PRS (Cox regression analysis). Early recurrences were those occurring within 12 months of LT. To evaluate the adjusted treatment effect for HCC recurrence, a propensity score matching analysis was performed to assess the probability of having received any specific treatment for recurrence., Results: From a total of 1085 transplanted HCC patients, the cumulative incidence of recurrence was 16.6% (CI 13.5-20.3), with median time to recurrence of 13.0 months (IQR 6.0-26.0). Factors independently associated with PRS were early recurrence (47.6%), treatment with sorafenib and surgery/trans-arterial chemoembolization (TACE). Patients who underwent any treatment presented "early recurrences" less frequently, and more extrahepatic metastasis. This unbalanced distribution was included in the propensity score matching, with correct calibration and discrimination (receiving operator curve of 0.81 [CI 0.72;0.88]). After matching, the adjusted effect on PRS for any treatment was HR of 0.2 (0.10;0.33); P < .0001, for sorafenib therapy HR of 0.4 (0.27;0.77); P = .003, and for surgery/TACE HR of 0.4 (0.18;0.78); P = .009., Conclusion: Although early recurrence was associated with worse outcome, even in this population, systemic or locoregional treatments were associated with better PRS., (© 2020 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Background:  Well-designed studies assessing the treatment outcome of brain arteriovenous malformations (AVMs) are infrequent and have not consistently included all of the available treatment modalities, making their results not completely generalizable. Moreover, the predictors of poor outcome are not well defined., Methods:  We performed an observational retrospective study of AVM patients. We included patients with clinical, radiologic, and outcome data, with a minimum follow-up of 1 year. Neurologic outcome was documented using the modified Rankin Scale (mRS) at the AVM diagnosis and 30 days after the treatment., Results:  There were 117 patients, with equal male/female proportion. The mean follow-up time was 51 months. Treatment distribution in the Spetzler-Martin grades I-III was as follows: 52 (54.6%) surgery, 31 (32.35%) radiosurgery, 2 (0.02%) embolization, and 11 (12%) conservative follow-up. Treatment distribution in Spetzler-Martin grades IV and V was as follows: 4 (20%) surgery, 7 (35%) radiosurgery, and 10 (45%) conservative follow-up. Poor neurologic outcome (mRS ≥ 3) was significantly associated with poor clinical status at diagnosis (Glasgow Coma Scale [GCS] score< 14; odds ratio [OR]: 0.20; 95% confidence interval [CI]: 0.001-0.396; p  = 0.010). The rupture of the AVM was associated with poor neurologic outcome. The Lawton-Young Supplementary scale (LYSS) proved to be the most effective in predicting poor outcome. The existence of seizures, treatment-related complications, and conservative treatment was associated with the worsening of the mRS score, whereas the existence of hemorrhage was associated with the likelihood of disability., Conclusion:  Our results suggest that poor neurologic status at diagnosis, AVM rupture, and conservative treatment were associated with worse outcome. Hemorrhage as initial presentation is related to disability, not with mRS worsening. The LYSS appeared to be the best method to predict outcome., Competing Interests: None declared., (Thieme. All rights reserved.)

Purpose: Practicing geriatric medicine is a challenging task since it involves working together with other medical doctors while coordinating a multidisciplinary team. Global Europe Initiative (GEI) group within the European Geriatric Medicine Society gathers geriatricians from different regions where geriatrics is underrepresented or still developing to promote initiatives for the advancement of geriatric medicine within these countries., Methods: Here we present a first effort to describe several aspects that affect practicing geriatric medicine in five different countries: Greece, Portugal, Russia, Turkey, and Tunisia., Results: We can notice discrepancies between countries concerning all dimensions of geriatrics (recognition, training, educational and professional standards, academic representation, working context)., Conclusions: These differences correspond to the specificities of each country and set the frame where geriatric medicine is going to be developed across Europe. EuGMS with GEI group can provide useful support.

This study aimed to compare liver transplantation (LT) outcomes and evaluate the potential rise in numbers of LT candidates with hepatocellular carcinoma (HCC) of different allocation policies in a high waitlist mortality region. Three policies were applied in two Latin American cohorts (1085 HCC transplanted patients and 917 listed patients for HCC): (i) Milan criteria with expansion according to UCSF downstaging (UCSF-DS), (ii) the AFP score, and (iii) restrictive policy or Double Eligibility Criteria (DEC; within Milan + AFP score ≤2). Increase in HCC patient numbers was evaluated in an Argentinian prospective validation set (INCUCAI; NCT03775863). Expansion criteria in policy A showed that UCSF-DS [28.4% (CI 12.8-56.2)] or "all-comers" [32.9% (CI 11.9-71.3)] had higher 5-year recurrence rates compared to Milan, with 10.9% increase in HCC patients for LT. The policy B showed lower recurrence rates for AFP scores ≤2 points, even expanding beyond Milan criteria, with a 3.3% increase. Patients within DEC had lower 5-year recurrence rates compared with those beyond DEC [13.3% (CI 10.1-17.3) vs 24.2% (CI 17.4-33.1; P = 0.0006], without significant HCC expansion. In conclusion, although the application of a stricter policy may optimize the selection process, this restrictive policy may lead to ethical concerns in organ allocation (NCT03775863)., (© 2020 Steunstichting ESOT. Published by John Wiley & Sons Ltd.)

The antigenic peptides processed by β-cells and presented through surface HLA class I molecules are poorly characterized. Each HLA variant (e.g., the most common being HLA-A2 and HLA-A3) carries some peptide-binding specificity. Hence, features that, despite these specificities, remain shared across variants may reveal factors favoring β-cell immunogenicity. Building on our previous description of the HLA-A2/A3 peptidome of β-cells, we analyzed the HLA-A3-restricted peptides targeted by circulating CD8 + T cells. Several peptides were recognized by CD8 + T cells within a narrow frequency (1-50/10 6 ), which was similar in donors with and without type 1 diabetes and harbored variable effector/memory fractions. These epitopes could be classified as conventional peptides or neoepitopes, generated either via peptide cis -splicing or mRNA splicing (e.g., secretogranin-5 [SCG5]-009). As reported for HLA-A2-restricted peptides, several epitopes originated from β-cell granule proteins (e.g., SCG3, SCG5, and urocortin-3). Similarly, H-2K d -restricted CD8 + T cells recognizing the murine orthologs of SCG5, urocortin-3, and proconvertase-2 infiltrated the islets of NOD mice and transferred diabetes into NOD/ scid recipients. The finding of granule proteins targeted in both humans and NOD mice supports their disease relevance and identifies the insulin granule as a rich source of epitopes, possibly reflecting its impaired processing in type 1 diabetes., (© 2020 by the American Diabetes Association.)

Purpose: To investigate the status of preoperative anterior pituitary function in patients undergoing pituitary adenoma (PA) resection and to identify factors associated with preoperative anterior pituitary dysfunction (APD)., Methods: Patients with functioning and nonfunctioning PAs who underwent pituitary adenoma resection for first time, from January 2009 to December 2019 were analyzed., Results: Total sample included 232 patients; 123 (53.2%) females, mean age at diagnosis was 53.3 years. Sixty-three percent presented as nonfunctioning PAs and 37.1% as functioning PAs. Eighty-eight percent were macroadenomas and 34.9% had cavernous sinus invasion. APD was demonstrated in 36.2% (n = 84) of the patients. The FSH/LH deficit was the most frequent anterior pituitary deficit (31.9%); followed by ACTH (18.1%); TSH (16.4%) and GH (13.8%). We identified as independent risk factors of APD, male sex (OR = 6.1, 95% CI = 3.3-11.0); age (OR = 1.03 for each year, 95% CI = 1.01-1.04), diabetes mellitus (OR = 3.5, 95% CI = 1.63-7.69), pituitary apoplexy presentation (OR = 4.3, 95% CI = 1.3-14.5) and tumor size (OR = 1.06 for each mm, 95% CI = 1.04-1.09). Nonfunctioning PAs (NFPA) had higher risk of APD than functioning PAs (FPA) (OR = 2.8 (95% CI = 1.5-5.0), but these differences disappeared after adjusted by tumor size (OR adjusted by tumor size = 1.7, 95% CI = 0.9-3.3). The tumor size with the highest diagnostic accuracy to predict hypopituitarism was 22 mm (sensitivity of 61.9% and specificity of 70.1%)., Conclusion: More than one third of PAs candidates for surgery had APD. The male sex, diabetes, an older age, pituitary apoplexy, and larger PAs were risk factors of APD. Hence, in these patients, the hormonal study should be prioritized and the need for dynamic tests must be carefully assessed.

Introduction: Glioblastoma (GBM) treatment starts in most patients with surgery, either resection surgery or biopsy, to reach a histology diagnose. Multidisciplinar team, including specialists in brain tumors diagnose and treatment, must make an individualize assessment to get the maximum benefit of the available treatments., Material and Methods: Experts in each GBM treatment field have briefly described it based in their experience and the reviewed of the literature., Results: Each area has been summarized and the consensus of the brain tumor group has been included at the end., Conclusions: GBM are aggressive tumors with a dismal prognosis, however accurate treatments can improve overall survival and quality of life. Neurosurgeons must know treatment options, indications and risks to participate actively in the decision making and to offer the best surgical treatment in every case., (Copyright © 2020 Sociedad Española de Neurocirugía. Publicado por Elsevier España, S.L.U. All rights reserved.)

Brain machine interfaces (BMIs), introduced into the daily lives of individuals with injuries or disorders of the nervous system such as spinal cord injury, stroke, or amyotrophic lateral sclerosis, can improve the quality of life. BMIs rely on the capability of microelectrode arrays to monitor the activity of large populations of neurons. However, maintaining a stable, chronic electrode-tissue interface that can record neuronal activity with a high signal-to-noise ratio is a key challenge that has limited the translation of such technologies. An electrode implant injury leads to a chronic foreign body response that is well-characterized and shown to affect the electrode-tissue interface stability. Several strategies have been applied to modulate the immune response, including the application of immunomodulatory drugs applied both systemically and locally. While the use of passive drug release at the site of injury has been exploited to minimize neuroinflammation, this strategy has all but failed as a bolus of anti-inflammatory drugs is released at predetermined times that are often inconsistent with the ongoing innate inflammatory process. Common strategies do not focus on the proper anchorage of soft hydrogel scaffolds on electrode surfaces, which often results in delamination of the porous network from electrodes. In this study, we developed a microwire platform that features a robust yet soft biocompatible hydrogel coating, enabling long-lasting drug release via formation of drug aggregates and dismantlement of hydrophilic biodegradable three-dimensional polymer networks. Facile surface chemistry is developed to functionalize polyimide-coated electrodes with the covalently anchored porous hydrogel network bearing large numbers of highly biodegradable ester groups. Exponential long-lasting drug release is achieved using such hydrogels. We show that the initial state of dexamethasone (Dex) used to formulate the hydrogel precursor solution plays a cardinal role in engineering hydrophilic networks that enable a sustained and long-lasting release of the anti-inflammatory agent. Furthermore, utilization of a high loading ratio that exceeds the solubility of Dex leads to the encapsulation of Dex aggregates that regulate the release of this anti-inflammatory agent. To validate the anti-inflammatory effect of the hydrogel-functionalized Dex-loaded microwires, an in vivo preliminary study was performed in adult male rats ( n = 10) for the acute time points of 48 h and 7 days post implant. Quantitative real-time polymerase chain reaction (qRT-PCR) was used to assess the mRNA expression of certain inflammatory-related genes. In general, a decrease in fold-change expression was observed for all genes tested for Dex-loaded wires compared with controls (functionalized but no drug). The engineering of hybrid microwires enables a sustained release of the anti-inflammatory agent over extended periods of time, thus paving the way to fabricate neuroprosthetic devices capable of attenuating the foreign body response.

Background: Glioblastoma (GBM) is one of the most aggressive and vascularized brain tumors in adults, with a median survival of 20.9 months. In newly diagnosed and recurrent GBM, bevacizumab demonstrated an increase in progression-free survival, but not in overall survival., Methods: We conducted an in silico analysis of VEGF expression, in a cohort of 1082 glioma patients. Then, to determine whether appropriate bevacizumab dose adjustment could increase the anti-angiogenic response, we used in vitro and in vivo GBM models. Additionally, we analyzed VEGFA expression in tissue, serum, and plasma in a cohort of GBM patients before and during bevacizumab treatment., Results: We identified that 20% of primary GBM did not express VEGFA suggesting that these patients would probably not respond to bevacizumab therapy as we proved in vitro and in vivo. We found that a specific dose of bevacizumab calculated based on VEGFA expression levels increases the response to treatment in cell culture and serum samples from mice bearing GBM tumors. Additionally, in a cohort of GBM patients, we observed a correlation of VEGFA levels in serum, but not in plasma, with bevacizumab treatment performance., Conclusions: Our data suggest that bevacizumab dose adjustment could improve clinical outcomes in Glioblastoma treatment.

This study compared the ability of pulsed-field gel electrophoresis (PFGE), flaA small variable region (SVR) sequencing, analysis of the clustered regularly interspaced short palindromic repeats locus by high resolution melting analysis (CRISPR-HRMA), and multilocus sequence typing (MLST) for typing 111 Campylobacter jejuni strains isolated from diverse sources during 20 years in Brazil. For this, we used previous results obtained by PFGE and flaA-SVR sequencing from our research group and performed CRISPR-HRMA and MLST typing for the first time. Furthermore, the discrimination index (DI) of each method was accessed. The DI for PFGE, flaA-SVR sequencing, CRISPR-HRMA, and MLST was 0.980, 0.932, 0.868, and 0.931, respectively. By PFGE and flaA-SVR sequencing, some strains from clinical and non-clinical sources and from humans and animals presented ≥ 80% similarity. Similarly, some strains from different origins presented the same ST and CRISPR-HRMA types. In conclusion, despite the different DI values, all assays provided the same epidemiological information suggesting that a potential transmission may have occurred between C. jejuni from clinical and non-clinical sources and from animals and humans in Brazil. Furthermore it was demonstrated the suitability of PFGE that should be used preferably together with MLST and/or flaA-SVR sequencing for typing C. jejuni strains.

Purpose: Approximately 25% of older inpatients have an indwelling urinary catheter (IUC), 45-54% unnecessarily. This study aims to describe the prevalence, indications, and complications of IUC use in Portuguese older inpatients., Methods: Multicentric, cross-sectional, observational study conducted in Portuguese internal medicine wards (UriCath)., Results: Of a total of 3135 inpatients from 39 hospitals, we included 628 patients with 65 years old or more using an IUC, mean age 82.0 ± 7.5. Prevalence of IUC use was 20.0%. The average Barthel Index was 44.0 ± 37.3 and Charlson comorbidity Index was 7.0 ± 2.8. The main reasons for IUC use were: urinary output monitoring (47.5%), urinary retention (22.5%), and pressure ulcers (11.0%). The IUC removal was attempted in 9.1% and 24.7% developed a complication., Conclusion: IUC use among older inpatients is prevalent and often inappropriate. Clinical awareness and development guidelines for restricted use of IUC are essential to reduce morbimortality and healthcare costs.

The association between direct-acting antivirals (DAAs) and hepatocellular carcinoma (HCC) wait-list progression or its recurrence following liver transplantation (LT) remains uncertain. We evaluated the impact of DAAs on HCC wait-list progression and post-LT recurrence. This Latin American multicenter retrospective cohort study included HCC patients listed for LT between 2012 and 2018. Patients were grouped according to etiology of liver disease: hepatitis C virus (HCV) negative, HCV+ never treated with DAAs, and HCV+ treated with DAAs either before or after transplantation. Multivariate competing risks models were conducted for both HCC wait-list progression adjusted by a propensity score matching (pre-LT DAA effect) and for post-LT HCC recurrence (pre- or post-LT DAA effect). From 994 included patients, 50.6% were HCV-, 32.9% were HCV+ never treated with DAAs, and 16.5% were HCV+ treated with DAAs either before (n = 66) or after LT (n = 98). Patients treated with DAAs before LT presented similar cumulative incidence of wait-list tumor progression when compared with those patients who were HCV+ without DAAs (26.2% versus 26.9%; P = 0.47) and a similar HCC-related dropout rate (12.1% [95% CI, 0.4%-8.1%] versus 12.9% [95% CI, 3.8%-27.2%]), adjusted for baseline tumor burden, alpha-fetoprotein values, HCC diagnosis after listing, bridging therapies, and by the probability of having received or not received DAAs through propensity score matching (subhazard ratio [SHR], 0.9; 95% CI, 0.6-1.6; P = 0.95). A lower incidence of posttransplant HCC recurrence among HCV+ patients who were treated with pre- or post-LT DAAs was observed (SHR, 0.7%; 95% CI, 0.2%-4.0%). However, this effect was confounded by the time to DAA initiation after LT. In conclusion, in this multicenter cohort, HCV treatment with DAAs did not appear to be associated with an increased wait-list tumor progression and HCC recurrence after LT., (Copyright © 2020 by the American Association for the Study of Liver Diseases.)

Background: the European Union of Medical Specialists (UEMS-GMS) recommendations for training in Geriatric Medicine were published in 1993. The practice of Geriatric Medicine has developed considerably since then and it has therefore become necessary to update these recommendations., Methods: under the auspices of the UEMS-GMS, the European Geriatric Medicine Society (EuGMS) and the European Academy of Medicine of Ageing (EAMA), a group of experts, representing all member states of the respective bodies developed a new framework for education and training of specialists in Geriatric Medicine using a modified Delphi technique. Thirty-two expert panel members from 30 different countries participated in the process comprising three Delphi rounds for consensus. The process was led by five facilitators., Results: the final recommendations include four different domains: 'General Considerations' on the structure and aim of the syllabus as well as quality indicators for training (6 sub-items), 'Knowledge in patient care' (36 sub-items), 'Additional Skills and Attitude required for a Geriatrician' (9 sub-items) and a domain on 'Assessment of postgraduate education: which items are important for the transnational comparison process' (1 item)., Conclusion: the current publication describes the development of the new recommendations endorsed by UEMS-GMS, EuGMS and EAMA as minimum training requirements to become a geriatrician at specialist level in EU member states., (© The Author(s) (2019). Published by Oxford University Press on behalf of the British Geriatrics Society.)

Autoimmune/autoinflammatory syndrome induced by adjuvants (ASIA) is a new entity in which exposure to an adjuvant triggers an aberrant autoimmune response. Metallosis is a rare condition characterized by the deposition and build-up of metal debris in the soft tissues of the body associated with metal-on-metal (MOM) prosthetic devices. It can present with local/systemic symptoms and signs due to a chronic inflammatory host response. The authors present the case of a 51-year-old woman with a 6-month history of systemic complaints due to intoxication with metal ions from hip metallosis. This case highlights the importance of follow-up and continuous monitoring of patients with a hip prosthesis. As this is a rare condition, a patient presenting with unspecific symptoms such as ASIA syndrome induced by metallosis requires a high level of clinical suspicion as the removal of the adjuvant can resolve the condition., Learning Points: Asia syndrome is a new entity in which exposure to an adjuvant triggers an aberrant autoimmune response.Metallosis is an uncommon condition with local and systemic presentation.A high level of suspicion and close monitoring is needed in patients with vague systemic complaints., Competing Interests: Conflicts of Interests: The Authors declare that there are no competing interests.

Although CD8 + T-cell-mediated autoimmune β cell destruction occurs in type 1 diabetes (T1D), the target epitopes processed and presented by β cells are unknown. To identify them, we combined peptidomics and transcriptomics strategies. Inflammatory cytokines increased peptide presentation in vitro, paralleling upregulation of human leukocyte antigen (HLA) class I expression. Peptide sources featured several insulin granule proteins and all known β cell antigens, barring islet-specific glucose-6-phosphatase catalytic subunit-related protein. Preproinsulin yielded HLA-A2-restricted epitopes previously described. Secretogranin V and its mRNA splice isoform SCG5-009, proconvertase-2, urocortin-3, the insulin gene enhancer protein ISL-1, and an islet amyloid polypeptide transpeptidation product emerged as antigens processed into HLA-A2-restricted epitopes, which, as those already described, were recognized by circulating naive CD8 + T cells in T1D and healthy donors and by pancreas-infiltrating cells in T1D donors. This peptidome opens new avenues to understand antigen processing by β cells and for the development of T cell biomarkers and tolerogenic vaccination strategies., (Copyright © 2018 Elsevier Inc. All rights reserved.)

The dispersion of pollutants and proliferation of antibiotic resistant bacteria in the aquatic environment are an emerging health concern worldwide. In this sense, it is essential to develop new technologies to increase the quality of wastewater treatment, which is spread throughout the environment. The present study has demonstrated evidence of the existence of antibiotic and mercury-resistant bacteria in the aquatic environment. The application of heterogeneous photocatalysis with UVA/TiO 2 P25 slurry (200 mg L -1 ), UVA/TiO 2 -immobilized, and UVA/TiO 2 -immobilized/H 2 O 2 were evaluated for the simultaneous elimination of a mixture of contaminants of emerging concern (acetamiprid (ACP), imazalil (IMZ) and bisphenol A (BPA)) and inactivation of antibiotic and mercury-resistant bacteria (Pseudomonas aeruginosa and Bacillus subtilis). UVA/TiO 2 -immobilized/H 2 O 2 increased the inactivation and elimination of the contaminants. After the combined treatment, the mixture of BPA, IMZ and ACP decreased 62%, 21% and <5%, respectively, after 300 min at 13.10 kJ L -1 of accumulated UV energy. The Pseudomonas aeruginosa strain was inactivated after 120 min using 5.24 kJ L -1 of accumulated UV energy, whereas the Bacillus subtilis strain was shown to be extremely resistant, with a capacity to develop mechanisms to avoid the oxidation process., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

Objectives: Chlamydia trachomatis (CT) , Neisseria gonorrhoeae (NG) and Trichomonas vaginalis (TV) are curable, mostly asymptomatic, STIs that cause adverse maternal and perinatal outcomes. Most countries do not test for those infections during antenatal care. We implemented a CT, NG and TV testing and treatment programme in an antenatal clinic in Gaborone, Botswana., Methods: We conducted a prospective study in the antenatal clinic at Princess Marina Hospital in Gaborone, Botswana. We offered pregnant women who were 18 years or older and less than 35 weeks of gestation, CT, NG and TV testing using self-collected vaginal swabs. Testing was conducted using a GeneXpert® CT/NG and TV system. Those who tested positive were given directly observed antibiotic therapy and asked to return for a test of cure. We determined the prevalence of infections, uptake of treatment and proportion cured. The relationships between positive STI test and participant characteristics were assessed., Results: We enrolled 400 pregnant women. Fifty-four (13.5%) tested positive for CT, NG and/or TV: 31 (8%) for CT, 5 (1.3%) for NG and 21 (5%) for TV. Among those who tested positive, 74% (40) received same-day, in person results and treatment. Among those who received delayed results (6), 67% (4) were treated. Statistical comparisons showed that being unmarried and HIV infected were positively association CT, NG and/or TV infection. Self-reported STI symptoms were not associated with CT, NG and/or TV infection., Conclusion: The prevalence of CT, NG and/or TV was high, particularly among women with HIV infection. Among women with CT, NG and/or TV infection, those who received same-day results were more likely to be treated than those who received delayed results. More research is needed on the costs and benefits of integrating highly sensitive and specific STI testing into antenatal care in Southern Africa., Competing Interests: Competing interests: None declared., (© Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2018. All rights reserved. No commercial use is permitted unless otherwise expressly granted.)

Background: Onchocerciasis is a chronic parasitic infection originally endemic in 13 discrete regional foci distributed among six countries of Latin America (Brazil, Colombia, Ecuador, Guatemala, Mexico and Venezuela). In Colombia, this disease was discovered in 1965 in the Pacific Coast of the country. The National Onchocerciasis Elimination Program was established in 1993 with the aim of eliminating disease morbidity and infection transmission. In 2013, the World Health Organization (WHO) verified Colombia as free of onchocerciasis, becoming the first country in the world to reach such a goal. This report provides the empirical evidence of the elimination of Onchocerca volvulus transmission by Simulium exiguum (s.l.) after 12 years of 6-monthly mass drug administration of Mectizan® (ivermectin) to all the eligible residents living in this endemic area., Methods: From 1996 onwards, a biannual community-based mass ivermectin administration programme was implemented, complemented by health education and community participation. In-depth parasitological, serological and entomological surveys were conducted periodically between 1998 and 2007 to evaluate the impact of ivermectin treatment according to the 2001 WHO guidelines. When the interruption of parasite transmission was demonstrated, the drug distribution ceased and a three-year post-treatment surveillance (PTS) period (2008-2010) was initiated., Results: After 23 rounds of treatment, parasitological and ophthalmological assessments showed absence of microfilariae in skin and anterior chamber of the eyes. Serological tests proved lack of antibodies against O. volvulus in children under 10 years-old. A total of 10,500 S. exiguum flies tested by PCR had no L3 infection (infectivity rate = 0.0095%; 95% CI: 0.0029-0.049) during 2004, indicating interruption of parasite transmission. However, biannual ivermectin treatments continued until 2007 followed by a 3-year PTS period at the end of which 13,481 flies were analyzed and no infective flies were found (infectivity rate = 0%; 95% CI: 0.0-0.014)., Conclusions: These results fulfilled the WHO criteria for onchocerciasis elimination. Consequently, in 2013 Colombia was verified as free of onchocerciasis, demonstrating that elimination of this neglected tropical disease is an achievable goal and paving the way for an elimination agenda to be followed by other endemic countries in Latin America and Africa.

Background: Etiological treatment of Chagas disease in chronic asymptomatic patients is still in debate and the adverse effects of traditional drugs are one of the main concerns in clinical practice. This study evaluated retrospectively the safety profile of benznidazole (BZN) and identified predictive factors for definite treatment interruption and development of severe reactions in adult patients treated with BZN in Colombia., Methods: Retrospective follow-up study conducted by review of medical records of adults with chronic Chagas disease treated with BZN in Colombia. A parametric survival analysis based on a generalized gamma distribution was used for assessing risk factors for treatment interruption. A multinomial logistic regression model was used to estimate the probability of severe adverse drug reactions (ADRs). Statistical associations were expressed as time ratios (TR) and adjusted odds ratios (aOR) respectively., Results: In total 224 adults patients treated with BZN were included; 172 (76.8%) completed the standard therapy (60 days of treatment), 205 (91.5%) presented ADRs and 52 cases (23.2%) required treatment interruption. The predominant symptoms were: rash (37.9%), itching (33.7%), epigastric pain (26.4%), abdominal bloating (24.2%) and nausea (22.1%). ADRs were mild (57.4%), moderate (35.5%) and severe (7.3%). Time to treatment interruption was significantly shorter when using doses of BZN ≥ 6 mg/kg/day (TR 0.55; 95% CI 0.39-0.76), presenting severe ADRs (TR 0.12; 95% CI: 0.07-0.19) and eosinophilia (TR 0.68; 95% CI: 0.49-0.94). Female sex (aOR 3.98; 95% CI 1.56-10.16), dose of BZN ≥ 6 mg/kg/day (aOR 1.41; 95% CI 1.17-1.70) and presence of > 3 ADRs (aOR 6.47; 95% CI 1.24-34.34) were considered as risk factors for developing severe ADRs., Conclusions: Dose, severity of ADRs, eosinophilia and female sex were the main predictors for treatment interruption or severe ADRs. The potential implications of these findings are discussed.

The aim of this analytical study is to develop an improved multi-residue methodology of high sensitivity and expanded scope for pesticide residue analysis in honeybee wax combs. The method was validated for 160 pesticide residues (including acaricides, insecticides, fungicides and herbicides) gas chromatography amenable and covering a wide variety of polarity and chemical structure. This method of analysis applied gas chromatography coupled to a triple quadrupole mass spectrometer for the quantitative analysis of pesticide residues. The extraction procedure applied was based QuEChERs method allowing acceptable recoveries for most of the pesticides (98%), within the range 60-120% with an associated precision (RSD) <20%, at concentration levels of MQL of 10µgkg -1 for all pesticides with the exception of 3,5-dichloroaniline and chlordane (20µgkg -1 ). The expanded uncertainty of the results was ±35% on average (coverage factor k=2 for a confidence level of 95%). The chromatographic multi-residue method was applied to determine levels of pesticide residues in 50 honeybee wax comb samples randomly collected from different apiaries in Spain. A total of 32 pesticide residues (14 insecticides/acaricides, 10 insecticides, 6 fungicides and 2 herbicides) were detected in the samples. The highest pesticide concentrations were found for those with insecticide-acaricide activity like acrinathrin, chlorfenvinphos, coumaphos and fluvalinate-tau, some of them are mainly applied in apiculture for controlling the honeybee parasite Varroa destructor. The total load of pesticide residues ranged from 69 to 1000µgkg -1 for 40% of the analysed samples, 22% contained pesticide residues in the ranges of 1000-2000µgkg -1 , 24% between 2000 and 5000µgkg -1 and 14% of the samples contained residues between 5000 and 9557µgkg -1 ., (Copyright © 2016 Elsevier B.V. All rights reserved.)

Tumor-cell-secreted extracellular vesicles (EVs) can cross the disrupted blood-brain barrier (BBB) into the bloodstream. However, in certain gliomas, the BBB remains intact, which might limit EVs release. To evaluate the ability of tumor-derived EVs to cross the BBB, we used an orthotopic xenotransplant mouse model of human glioma-cancer stem cells featuring an intact BBB. We demonstrated that all types of tumor cells-derived EVs-apoptotic bodies, shedding microvesicles and exosomes-cross the intact BBB and can be detected in the peripheral blood, which provides a minimally invasive method for their detection compared to liquid biopsies obtained from cerebrospinal fluid (CSF). Furthermore, these EVs can be readily distinguished from total murine EVs, since they carry human-specific DNA sequences relevant for GBM biology. In a small cohort of glioma patients, we finally demonstrated that peripheral blood EVs cargo can be successfully used to detect the presence of IDH1G395A, an essential biomarker in the current management of human glioma.

Introduction and Objective: Spinal muscular atrophy (SMA) is an autosomal recessive motor neuron disorder. SMA is caused by homozygous loss of the SMN1 gene and retention of the SMN2 gene resulting in reduced levels of full length SMN protein that are insufficient for motor neuron function. Various treatments that restore levels of SMN are currently in clinical trials and biomarkers are needed to determine the response to treatment. Here, we sought to investigate in SMA mice a set of plasma analytes, previously identified in patients with SMA to correlate with motor function. The goal was to determine whether levels of plasma markers were altered in the SMNΔ7 mouse model of SMA and whether postnatal SMN restoration resulted in normalization of the biomarkers., Methods: SMNΔ7 and control mice were treated with antisense oligonucleotides (ASO) targeting ISS-N1 to increase SMN protein from SMN2 or scramble ASO (sham treatment) via intracerebroventricular injection on postnatal day 1 (P1). Brain, spinal cord, quadriceps muscle, and liver were analyzed for SMN protein levels at P12 and P90. Ten plasma biomarkers (a subset of biomarkers in the SMA-MAP panel available for analysis in mice) were analyzed in plasma obtained at P12, P30, and P90., Results: Of the eight plasma biomarkers assessed, 5 were significantly changed in sham treated SMNΔ7 mice compared to control mice and were normalized in SMNΔ7 mice treated with ASO., Conclusion: This study defines a subset of the SMA-MAP plasma biomarker panel that is abnormal in the most commonly used mouse model of SMA. Furthermore, some of these markers are responsive to postnatal SMN restoration. These findings support continued clinical development of these potential prognostic and pharmacodynamic biomarkers., Competing Interests: PZ and ST are employees of PharmOptima, Inc. KC and SP are employees of the Spinal Muscular Atrophy Foundation. KVH and DK were employees of the Spinal Muscular Atrophy Foundation at the time of this research. This does not alter the authors' adherence to PLOS ONE policies on sharing data and materials.

Background & Aims: The French alpha-fetoprotein (AFP) model has recently shown superior results compared to Milan criteria (MC) for prediction of hepatocellular carcinoma (HCC) recurrence after liver transplantation (LT) in European populations. The aim of this study was to explore the predictive capacity of the AFP model for HCC recurrence in a Latin-American cohort., Methods: Three hundred twenty-seven patients with HCC were included from a total of 2018 patients transplanted at 15 centres. Serum AFP and imaging data were both recorded at listing. Predictability was assessed by the Net Reclassification Improvement (NRI) method., Results: Overall, 82 and 79% of the patients were within MC and the AFP model respectively. NRI showed a superior predictability of the AFP model against MC. Patients with an AFP score >2 points had higher risk of recurrence at 5 years Hazard Ratio (HR) of 3.15 (P = 0.0001) and lower patient survival (HR = 1.51; P = 0.03). Among patients exceeding MC, a score ≤2 points identified a subgroup of patients with lower recurrence (5% vs 42%; P = 0.013) and higher survival rates (84% vs 45%; P = 0.038). In cases treated with bridging procedures, following restaging, a score >2 points identified a higher recurrence (HR 2.2, P = 0.12) and lower survival rate (HR 2.25, P = 0.03). A comparative analysis between HBV and non-HBV patients showed that the AFP model performed better in non-HBV patients., Conclusions: The AFP model could be useful in Latin-American countries to better select patients for LT in subgroups presenting with extended criteria. However, particular attention should be focused on patients with HBV., (© 2016 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

A new and efficient method based on the simple metalating reagent Fe(CO)5 has been developed for the straightforward synthesis of well defined cyclometalled PCP iron carbonyl pincer complexes. The reaction proceeds cleanly under mild conditions at 30 °C and UV irradiation. Four hydride pincer complexes are synthesized and fully characterized as well as an intermediate dinuclear species. The new iron complexes are active and selective catalytic precursors for the dehydrogenative borylation of styrene with HBpin.

Objectives: Calcifying pseudoneoplasms of the neuraxis (CAPNON) are rare lesions occurring anywhere in the central nervous system (CNS). Since their description, only 55 cases have been reported. We present the largest series reviewing their imaging features, histology and potential origins., Patients and Methods: four patients with histopathologically verified CAPNON are presented. Subsequently, we review all reports published with respect to study type, number of patients, clinical presentation, anatomical area (intracranial, spinal, or both), radiological features, therapy, histopathologic features, duration of follow-up, complications, and outcome. Moreover, current management of CNS CAPNON are discussed. Autopsy patients were excluded., Results: Four patients with histopathologically verified diagnosis of CAPNON are presented between 46-73 years-old. Three of them were located in the spinal cord (levels C3, D2, and L2) and one intracranial (left atrium). The spine ones were diagnosed due to radicular pain, paraparesis and numbness in lower limb, the intracranial because of intense headache. The differential diagnosis included cavernous malformation, in the case of the lumbar CAPNON this suspicion put back the surgery six months. All cases were surgically treated with complete resection. No recurrence showed at the 12-month follow-up. A total of retrospective 30 articles were selected: 10 case series (33.33%) and 20 reports of single cases (66.66%). The 30 articles and our additional cases added up to a total of 27 patients with spinal CAPNON and 32 patients with intracranial CAPNON. All patients were treated surgically. A follow-up, conducted in 48 patients, showed no signs of recurrence in 46 of the 48., Conclusions: Calcifying pseudoneoplasms are rare benign lesions of yet unknown origin. They should be taken into consideration in the differential diagnosis of calcified lesions because an inaccurate diagnosis can result in potentially harmful and unnecessary therapies, as prognosis for these lesions is generally favorable., (Copyright © 2016 Elsevier B.V. All rights reserved.)

Background: Respiratory syncytial virus (RSV) is an important cause of lower respiratory tract infection, hospitalisation and death in adults., Methods: Based on evidence regarding the impact of RSV on adult populations at risk for severe infection and the efficacy and safety of RSV vaccines, the Portuguese Society of Pulmonology, the Portuguese Association of General and Family Medicine, the Portuguese Society of Cardiology, the Portuguese Society of Infectious Diseases and Clinical Microbiology, the Portuguese Society of Endocrinology, Diabetes and Metabolism, and the Portuguese Society of Internal Medicine endorses this position paper with recommendations to prevent RSV-associated disease and its complications in adults through vaccination., Conclusion: The RSV vaccine is recommended for people aged ≥50 years with risk factors (chronic obstructive pulmonary disease, asthma, heart failure, coronary artery disease, diabetes, chronic kidney disease, chronic liver disease, immunocompromise, frailty, dementia, and residence in a nursing home) and all persons aged ≥60 years. If it cannot be made available to this population, then the vaccine should be prioritised for individuals aged ≥75 years and those aged ≥50 years with risk factors. The vaccine should preferably be given between September and November and can be co-administered with the influenza vaccine. Ongoing studies on RSV vaccines may justify extending these recommendations in the future.

A classical formulation of the quantum multichromophoric theory of resonance energy transfer is developed on the basis of classical electrodynamics. The theory allows for the identification of a variety of processes of different order in the interactions that contribute to the energy transfer in molecular aggregates with intracoupling in donors and acceptor chromophores. Enhanced rates in multichromophoric resonance energy transfer are shown to be well described by this theory. Specifically, in a coupling configuration between N&#95;{A} acceptors and N&#95;{D} donors, the theory correctly predicts an enhancement of the energy transfer rate dependent on the total number of donor-acceptor pairs. As an example, the theory, applied to the transfer rate in light harvesting II, gives results in excellent agreement with experiment. Finally, it is explicitly shown that as long as linear response theory holds, the classical multichromophoric theory formally coincides with the quantum formulation.

Introduction: There are no reports describing polymorphisms in target genes of anti- Toxoplasma drugs in South American isolates., Objective: This study sought to perform cloning and sequencing of the dihydrofolate reductase ( dhfr ) and dihydropteroate-synthase ( dhps ) genes of the reference Rh strain and two Colombian isolates of Toxoplasma gondii ., Materials and Methods: Two isolates were obtained from the cerebrospinal fluid of HIV-infected patients with cerebral toxoplasmosis. A DNA extraction technique and PCR assay for the dhfr and dhps genes were standardized, and the products of amplification were cloned into Escherichia coli and sequenced., Results: One polymorphism (A « G) was found at position 235 of exon 2 in the dhps gene. In addition, two polymorphisms (G « C) at positions 259 and 260 and one polymorphism (T « G) at position 371 within exon 4 of the dhps gene were detected. In this last exon, a bioinformatic analysis revealed a non-synonymous polymorphism in the coding region that could lead to the substitution of Glu (CAA or CAG) for His (encoded by codons AAU or AAC). A structural model of the T. gondii DHPS protein was calculated, and the results revealed modifications in secondary structure due to mutations., Conclusions: The methods described in this study can be used as a tool to search for polymorphisms in samples from patients with different clinical manifestations of toxoplasmosis and to examine their relationship with the therapeutic response.

Introduction: Eight Giardia duodenalis genotypes (A-H) have been described to date. Genotypes A and B have been isolated from humans and a wide range of mammals; however, genotypes C-H have shown greater host specificity., Objective: Identifying G. duodenalis genotypes from cysts in faeces obtained from children attending the Instituto Colombiano de Bienestar Familiar (ICBF) day care centres and from dogs in Ibagué by PCR-RFLP targeting both the b -giardin and glutamate dehydrogenase genes., Materials and Methods: Cysts from G. duodenalis positive samples were concentrated, DNA was extracted and the b -giardin and glutamate dehydrogenase genes were analysed by PCR-RFLP. The MHOM/CO/04/G40 strain was used as positive control (this was obtained from the Grupo de Parasitología at the Instituto Nacional de Salud )., Results: Of the total human samples, 11/23 (48%) were genotyped as A and 12/23 (52%) as B; PCR-RFLP revealed that four canine samples were genotypes C and D, these being host-specific., Conclusions: Only genotypes associated with human infection (AII, BIII and BIV) were found in the children and host-specific genotypes were observed in canines (C and D). No interaction could be established between animal and human transmission cycles due to the small canine sample size and as the former did not come into contact with children attending ICBF day-care centres.

Objective: Preclinical therapies that restore survival motor neuron (SMN) protein levels can dramatically extend survival in spinal muscular atrophy (SMA) mouse models. Biomarkers are needed to effectively translate these promising therapies to clinical trials. Our objective was to investigate electrophysiological biomarkers of compound muscle action potential (CMAP), motor unit number estimation (MUNE) and electromyography (EMG) using an SMA mouse model., Methods: Sciatic CMAP, MUNE, and EMG were obtained in SMNΔ7 mice at ages 3-13 days and at 21 days in mice with SMN selectively reduced in motor neurons ( ChAT Cre ). To investigate these measures as biomarkers of treatment response, measurements were obtained in SMNΔ7 mice treated with antisense oligonucleotide (ASO) or gene therapy., Results: CMAP was significantly reduced in SMNΔ7 mice at days 6-13 (p<0.01), and MUNE was reduced at days 7-13 (p<0.01). Fibrillations were present on EMG in SMNΔ7 mice but not controls (p=0.02). Similar findings were seen at 21 days in ChAT Cre mice. MUNE in ASO-treated SMNΔ7 mice were similar to controls at day 12 and 30. CMAP reduction persisted in ASO-treated SMNΔ7 mice at day 12 but was corrected at day 30. Similarly, CMAP and MUNE responses were corrected with gene therapy to restore SMN., Interpretation: These studies confirm features of preserved neuromuscular function in the early postnatal period and subsequent motor unit loss in SMNΔ7 mice. SMN restoring therapies result in preserved MUNE and gradual repair of CMAP responses. This provides preclinical evidence for the utilization of CMAP and MUNE as biomarkers in future SMA clinical trials.

The identification of atrial fibrillation (AF) substrates is needed to improve ablation therapy guided by electrograms, although mechanisms that sustain AF are not fully understood. Detection of complex fractionated atrial electrograms (CFAE) is used for this purpose. Nonetheless, efficacy of this method is inadequate in the case of chronic AF. Recent hypothesis proposes the rotors as fibrillatory substrate. Novel approaches seek to relate CFAE with rotor; nevertheless, such methods are not able to identify the associated substrate. Furthermore, the patterns that characterize CFAE generated by rotors remain unknown. Thus, tracking of rotors is an unsolved issue. In this paper, we propose a non-supervised method to find patterns associated with fibrillatory substrates in chronic AF. We extracted two features based on local activation wave detection and one feature based on non-linear dynamics. Gaussian mixture model-based clustering was used to discriminate CFAE patterns. Resulting clusters are visualized in an electroanatomic map. We assessed the proposed method in a real database labeled according to the level of fractionation and in a simulated episode of chronic AF in which a rotor was detected. Our results indicate that the method proposed can separate different levels of fractionation in CFAE, and provide evidence that clustering can be used to locate the vortex of the rotors. Provided approach can support ablation therapy procedures by means of CFAE patterns discrimination.

On the basis of previous studies suggesting that vascular endothelial growth factor (VEGF) could protect motor neurons from degeneration, adeno-associated virus vectors (serotypes 1 and 9) encoding VEGF (AAV.vegf) were administered in a limb-expression 1 (LIX1)-deficient cat-a large animal model of lower motor neuron disease-using three different delivery routes to the central nervous system. AAV.vegf vectors were injected into the motor cortex via intracerebral administration, into the cisterna magna, or intravenously in young adult cats. Intracerebral injections resulted in detectable transgene DNA and transcripts throughout the spinal cord, confirming anterograde transport of AAV via the corticospinal pathway. However, such strategy led to low levels of VEGF expression in the spinal cord. Similar AAV doses injected intravenously resulted also in poor spinal cord transduction. In contrast, intracisternal delivery of AAV exhibited long-term transduction and high levels of VEGF expression in the entire spinal cord, yet with no detectable therapeutic clinical benefit in LIX1-deficient animals. Altogether, we demonstrate (i) that intracisternal delivery is an effective AAV delivery route resulting in high transduction of the entire spinal cord, associated with little to no off-target gene expression, and (ii) that in a LIX1-deficient cat model, however, VEGF expressed at high levels in the spinal cord has no beneficial impact on the disease course.

We have recently demonstrated the remarkable efficiency of self-complementary (sc) AAV9 vectors for central nervous system (CNS) gene transfer following intravenous delivery in mice and larger animals. Here, we investigated whether gene delivery to motor neurons (MNs) could also be achieved via intramuscular (i.m.) scAAV9 injection and subsequent retrograde transport along the MNs axons. Unexpectedly, we found that a single injection of scAAV9 into the adult mouse gastrocnemius (GA) mediated widespread MN transduction along the whole spinal cord, without limitation to the MNs connected to the injected muscle. Spinal cord astrocytes and peripheral organs were also transduced, indicating vector spread from the injected muscle to both the CNS and the periphery through release into the blood circulation. Moreover, we showed that i.m. injection of scAAV9 vectors expressing "survival of motor neuron" (Smn) in spinal muscular atrophy (SMA) mice mediated high survival motor neuron (SMN) expression levels at both the CNS and the periphery, and increased the median lifespan from 12 days to 163 days. These findings represent to date the longest extent in survival obtained in SMA mice following i.m. viral vector gene delivery, and might generate a renewed interest in the use of i.m. adeno-associated viruses (AAV) delivery for the development of gene therapy strategies for MN diseases.

A new megastigmane derivative, (6R,9S)-6'-(4"-hydroxybenzoyl)-roseoside (1) and two known compounds, the biflavoneagathisflavone (2) and 4-hydroxybenzoic acid (3) were isolated and purified from leaves and stems of Ouratea polyantha Engl. Agathisflavone was isolated in a single high-speed countercurrent chromatography run, while the megastigmane was purified in two steps, by using a combination of high-speed countercurrent chromatography and analytical column chromatography. All structures were elucidated on the basis of spectral evidence and comparison with literature data. Compound 1 was characterized by [alpha]D20, UV-Vis, IR, MS, 1H NMR, 13C NMR, HMQC, HMBC, COSY and NOESY. Compounds 1 and 2 showed an inhibitory effect of 63.6 and 13.7% on the G-6-Pase intact microsomes, respectively.

Objective: Evaluating the effect of ivermectin on soil-transmitted helminthes (STH) infection frequency in a Colombian population included in the Onchocerciasis Elimination Program for the Americas (OEPA)., Methods: This was an impact evaluation study which adopted a longitudinal approach using the population of Naicioná (1996) as baseline for comparison to people from the same population as controls (2008). The cross-sectional approach involved comparing the reference population of Naicioná (2008) to the population of Dos Quebradas (2008) used as controls. Fecal samples were processed by a modified Ritchie-Frick method., Results: Ascaris lumbricoides was the most frequently found parasite in Naicioná (60/121; 49.6 %: 37.8-63.895%CI) and in Dos Quebradas (36/76; 47.4 %: 33.2-65.6 95 % CI). Ivermectin's main effect on the population aged over 5 years was a decreased risk of Trichiuris trichiura infection in both longitudinal assessment (86 % reduction: 74-93 95 % CI) and cross-sectional assessment (63 %:24-82 95 % CI). A 93 % reduction (45-99 95 % CI) in Strongyloides stercoralis frequency was found in longitudinal assessment, compared to 85 % in cross-sectional assessment (-031-99 95 % CI)., Conclusions: Ivermectin use in the OEPA is not sufficient for STH morbidity control. Integrated programs including education and basic sanitation are required.