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To address the current pandemic, multiple studies have focused on the development of new mHealth apps to help in curbing the number of infections, these applications aim to accelerate the identification and self-isolation of people exposed to SARS-CoV-2, the coronavirus known to cause COVID-19, by being in close contact with infected individuals. The main objectives of this paper are: (1) Analyze the current status of COVID-19 apps available on the main virtual stores: Google Play Store and App Store for Spain, and (2) Propose a novel mobile application that allows interaction and doctor-patient follow-up without the need for real-time consultations (face-to-face or telephone). In this research, a search for eHealth and telemedicine apps related to Covid-19 was performed in the main online stores: Google Play Store and App Store, until May 2021. Keywords were entered into the search engines of the online stores and relevant apps were selected for study using a PRISMA methodology. For the design and implementation of the proposed app named COVINFO, the main weaknesses of the apps studied were taken into account in order to propose a novel and useful app for healthcare systems. The search yielded a total of 50 apps, of which 24 were relevant to this study, of which 23 are free and 54% are available for Android and iOS operating systems (OS). The proposed app has been developed for mobile devices with Android OS being compatible with Android 4.4 and higher. This app enables doctor-patient interaction and constant monitoring of the patient's progress without the need for calls, chats or face-to-face consultation in real time. This work addresses design and development of an application for the transmission of the user's symptoms to his regular doctor, based on the fact that only 16.6% of existing applications have this functionality. The COVINFO app offers a novel service: asynchronous doctor-patient communication, as well as constant monitoring of the patient's condition and evolution. This app makes it possible to better manage the time of healthcare personnel and avoid overcrowding in hospitals, with the aim of preventing the collapse of healthcare systems and the spread of the coronavirus., (© 2022. The Author(s).)

Collecting entomopathogenic fungi associated with mosquitoes and studies on their activity against mosquito developmental stages will improve the understanding of their potential as agents to control important mosquito vectors. Twenty-one strains of entomopathogenic fungi affecting mosquitoes in Central Brazil were studied: 7 of Beauveria bassiana, 7 of Metarhizium humberi, 3 of M. anisopliae, 2 of Cordyceps sp. and one each of Akanthomyces saksenae and Simplicillium lamellicola. These fungi were isolated from field-collected mosquito adults (3 strains) or larvae (a single strain); the other 17 strains were isolated from laboratory-reared Aedes aegypti sentinel larvae set out in partially immersed cages placed in diverse small- to middle-sized aquatic mosquito habitats in or close to areas with secondary tropical forest. The frequent recovery of normally soil-borne Metarhizium spp. and B. bassiana from aquatic habitats is notable. Our laboratory findings indicated that M. anisopliae IP 429 and IP 438 and M. humberi IP 421 and IP 478 were highly active against immature stages and, together with M. anisopliae IP 432, also against adults. These strains appear to be the most promising candidates to develop effective control strategies targeting the different developmental stages of A. aegypti, the most important vector of viral diseases in humans in the tropics., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Background: CGAR, a Phase 3b open-label study, evaluated the long-term safety of galcanezumab in patients with cluster headache who completed one of two Phase 3 double-blind studies in chronic or episodic cluster headache., Methods: Patients (N = 164) received galcanezumab 300 mg subcutaneously up to once a month. Primary endpoint was safety, as assessed by treatment-emergent adverse events, serious adverse events, and suicidality. Other endpoints included discontinuation rates, immunogenicity, efficacy as assessed by the Patient Global Impression of Improvement, and health values., Results: At baseline, mean (standard deviation) age was 48.3 (9.8) years, 75.0% were men, and 85.4% were white. Treatment-emergent adverse events (n = 119 [72.6%]) were mostly mild-to-moderate, with nasopharyngitis the most commonly reported (22.0%). One of 18 serious adverse events was judged as treatment related (constipation). Two patients (1.2%) reported suicidal ideation. Five patients (3.1%) discontinued due to an adverse event. Eight patients were treatment-emergent anti-drug antibody positive, two of whom were not treatment-emergent anti-drug antibody positive in the parent studies. On the Patient Global Impression of Improvement, ≥81% reported their cluster headache status as very much, much, or a little better at Months 1, 6, and 12. Health value scores generally improved from baseline., Conclusions: In this open-label study, galcanezumab was generally well tolerated and improved patient-reported cluster headache status. Trial registration number: NCT02797951; https://clinicaltrials.gov/ct2/show/NCT02797951.

Aedes aegypti (Linnaeus, 1762) is an important vector of arboviruses in the tropics and subtropics. New control strategies based on natural enemies such as entomopathogenic fungi are of utmost importance, and the present study reports the first isolation of Clonostachys spp. (Hypocreales: Bionectriaceae) from mosquitoes and their activity against A. aegypti. Entomopathogenic fungi were surveyed in central Brazil using A. aegypti larvae as sentinels and, also, a CDC light trap. Clonostachys eriocamporesii R.H. Perera & K.D. Hyde, 2020 (IP 440) and Clonostachys byssicola Schroers, 2001 (IP 461) were identified by sequence analysis of the nuclear ribosomal internal transcribed spacer gene, and tested against eggs, larvae, and adults. Both strains were highly active against A. aegypti third instar larvae, with mortalities ≥ 80% at 10 7 conidia/mL after 5 days but distinctly less active against eggs and adults. This is the first report of both C. eriocamporesii and C. byssicola as naturally occurring pathogens affecting mosquitoes, and IP 440 appears to be a promising control agent against aquatic stages of A. aegypti., (© 2022. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

A Gram-stain-positive, moderately halophilic, aerobic, endospore-forming, rod-shaped bacterium, designated strain DP4-553-S T , was isolated from hypersaline sediment collected from the Dalangtan Playa in the Qaidam Basin, Northwest PR China. Growth occurred within 0-21.6% (w/v) NaCl (optimum 7.2%) at pH 5.5-9.0 (optimum pH 7.0) and at 4-45 °C (optimum 37 °C). Phylogeny based on 16S rRNA gene sequences indicated that strain DP4-553-S T belonged to the genus Sediminibacillus , with high 16S rRNA gene sequence similarity to Sediminibacillus halophilus EN8d T (99.5 %), Sediminibacillus terrae JSM 102062 T (99.4 %), Virgibacillus senegalensis SK-1 T (99.3 %) and Sediminibacillus albus NHBX5 T (98.3 %). The G+C content of the chromosomal DNA was 43.6 mol %. The average amino acid identity, average nucleotide identity and digital DNA-DNA hybridization values between strain DP4-553-S T and the four close type strains were 71.2-93.3, 74.0-90.5 and 20.0-41.4 %, respectively. The whole genomic analysis showed that strain DP4-553-S T constituted a different taxon separated from the recognized Sediminibacillus species. The major cellular fatty acids were anteiso-C 15 : 0 , anteiso-C 17 : 0 , iso-C 16 : 0 , C 16 : 0 and iso-C 15 : 0 . The type strain contained cell-wall peptidoglycan based on diaminopimelic acid and possessed menaquinone-7 as the major respiratory isoprenoid quinone. The polar lipid pattern consisted of diphosphatidylglycerol, phosphatidylglycerol, four unidentified glycolipids, phosphatidylcholine, aminophospholipid, aminolipid and seven unidentified phospholipids. The combined data from phenotypic and genotypic studies demonstrated that strain DP4-553-S T represents a novel species of the genus Sediminibacillus , for which the name Sediminibacillus dalangtanensis sp. nov. is proposed, the type strain is DP4-553-S T (=MCCC 1K03838 T = KCTC 43250 T ).

Although urban greening is universally recognized as an essential part of sustainable and climate-responsive cities, a growing literature on green gentrification argues that new green infrastructure, and greenspace in particular, can contribute to gentrification, thus creating social and racial inequalities in access to the benefits of greenspace and further environmental and climate injustice. In response to limited quantitative evidence documenting the temporal relationship between new greenspaces and gentrification across entire cities, let alone across various international contexts, we employ a spatially weighted Bayesian model to test the green gentrification hypothesis across 28 cities in 9 countries in North America and Europe. Here we show a strong positive and relevant relationship for at least one decade between greening in the 1990s-2000s and gentrification that occurred between 2000-2016 in 17 of the 28 cities. Our results also determine whether greening plays a "lead", "integrated", or "subsidiary" role in explaining gentrification., (© 2022. The Author(s).)

Occupational stress, as a negative facet, is a pervasive problem with significant implications for organizations, employees, welfare systems and health. The implementation of measurement tools that can capture the different organizational dimensions that determine stress in workers is part of the stress management and troubleshooting strategy that every company must manage daily. The aim of the present study was to adapt and validate the 25-item version of the ILO-WHO stress scale by Ivancevich and Matteson in the context of the Canary Islands of Spain. The tool assesses specific organizational dimensions of work-related stress determinants: organizational climate and structure, leader influence, cohesion, territory, technology and group support. An exploratory factor analysis (EFA) on a sample of 1510 Canary Islands workers was carried out. The results indicate that the job stress scale revealed adequate psychometric properties, construct validity and internal consistency (Cronbach's alpha = 0.972), and it can be profitably used to measure stress. At the end of the paper, theoretical and practical implications are discussed.

Objectives: The Patient-Reported Outcome Measurement Information System (PROMIS) Preference score (PROPr) can be used to assess health state utility (HSU) and estimate quality-adjusted life-years in cost-effectiveness analyses. It is based on item response theory and promises to overcome limitations of existing HSU scores such as ceiling effects. The PROPr contains 7 PROMIS domains: cognitive abilities, depression, fatigue, pain, physical function, sleep disturbance, and ability to participate in social roles and activities. We aimed to compare the PROPr with the 5-level EQ-5D (EQ-5D-5L) in terms of psychometric properties using data from 3 countries., Methods: We collected PROMIS-29 profile and EQ-5D-5L data from 3 general population samples (United Kingdom = 1509, France = 1501, Germany = 1502). Given that cognition is not assessed by the PROMIS-29, it was predicted by the recommended linear regression model. We compared the convergent validity, known-groups construct validity, and ceiling and floor effects of the PROPr and EQ-5D-5L., Results: The mean PROPr (0.48, 0.53, 0.48; P<.01) and EQ-5D-5L scores (0.82, 0.85, 0.83; P<.01) showed significant differences of similar magnitudes (d = 0.34; d = 0.32; d = 0.35; P<.01) across all samples. The differences were invariant to sex, income, occupation, education, and most conditions but not for age. The Pearson correlation coefficients between both scores were r = 0.74, r = 0.69, and r = 0.72. PROPr's ceiling and floor effects both were minor to moderate. The EQ-5D-5L's ceiling (floor) effects were major (negligible)., Conclusions: Both the EQ-5D-5L and the PROPr assessed by the PROMIS-29 show high validity. The PROPr yields considerably lower HSU values than the EQ-5D-5L. Consequences for quality-adjusted life-year measurements should be investigated in future research., (Copyright © 2021. Published by Elsevier Inc.)

Objective: To provide a review of challenges in clinical trials for the preventive treatment of cluster headache (CH) and highlight considerations for future studies., Background: Current guidelines for preventive treatment of CH are largely based on off-label therapies supported by a limited number of small randomized controlled trials. Guidelines for clinical trial design for CH treatments from the International Headache Society were last issued in 1995., Methods/results: Randomized controlled clinical trials were identified in the European and/or United States clinical trial registries with a search term of "cluster headache," and manually reviewed. Cumulatively, there were 27 unique placebo-controlled prevention trials for episodic and/or chronic CH, of which 12 were either ongoing, not yet recruiting, or the status was unknown. Of the remaining 15 trials, 5 were terminated early and 7 of the 10 completed trials enrolled fewer patients than planned or did not report the planned sample size. A systematic search of PubMed was also utilized to identify published manuscripts reporting results from placebo-controlled preventive trials of CH. This search yielded 16 publications, of which 7 were registered. Through critical review of trial data and published manuscripts, challenges and complexities encountered in clinical trials for the preventive treatment of CH were identified. For example, the excruciating pain associated with CH demands a suitably limited baseline duration, rapid treatment efficacy onset, and poses a specific issue regarding duration of investigational treatment period and length of exposure to placebo. In episodic CH, spontaneous remission as part of natural history, and the unpredictability and irregularity of cluster periods across patients present additional key challenges., Conclusions: Optimal CH trial design should balance sound methodology to demonstrate efficacy of a potential treatment with patient needs and the natural history of the disease, including unique outcome measures and endpoint timings for chronic versus episodic CH., (© 2022 Eli Lilly and Company. Headache: The Journal of Head and Face Pain published by Wiley Periodicals LLC on behalf of American Headache Society.)

Prostate cancer is a global cancer burden and considerable effort has been made through the years to identify biomarkers for the disease. Approximately a decade ago, the potential of analysing extracellular vesicles in liquid biopsies started to be envisaged. This was the beginning of a new exciting area of research investigating the rich molecular treasure found in extracellular vesicles to identify biomarkers for a variety of diseases. Vesicles released from prostate cancer cells and cells of the tumour microenvironment carry molecular information about the disease that can be analysed in several biological fluids. Numerous studies document the interest of researchers in this field of research. However, methodological issues such as the isolation of vesicles have been challenging. Remarkably, novel technologies, including those based on nanotechnology, show promise for the further development and clinical use of extracellular vesicles as liquid biomarkers. Development of biomarkers is a long and complicated process, and there are still not many biomarkers based on extracellular vesicles in clinical use. However, the knowledge acquired during the last decade constitutes a solid basis for the future development of liquid biopsy tests for prostate cancer. These are urgently needed to bring prostate cancer treatment to the next level in precision medicine., (© 2021. The Author(s).)

Background: Increasing participation in the Australian National Bowel Cancer Screening Program (NBCSP) is the most efficient and cost-effective way of reducing mortality associated with colorectal cancer by detecting and treating early-stage disease. Currently, only 44% of Australians aged 50-74 years complete the NBCSP. This efficacy trial aims to test whether this SMS intervention is an effective method for increasing participation in the NBCSP. Furthermore, a process evaluation will explore the barriers and facilitators to sending the SMS from general practice., Methods: We will recruit 20 general practices in the western region of Victoria, Australia to participate in a cluster randomised controlled trial. General practices will be randomly allocated with a 1:1 ratio to either a control or intervention group. Established general practice software will be used to identify patients aged 50 to 60 years old who are due to receive a NBCSP kit in the next month. The SMS intervention includes GP endorsement and links to narrative messages about the benefits of and instructions on how to complete the NBCSP kit. It will be sent from intervention general practices to eligible patients prior to receiving the NBCSP kit. We require 1400 eligible patients to provide 80% power with a two-sided 5% significance level to detect a 10% increase in CRC screening participation in the intervention group compared to the control group. Our primary outcome is the difference in the proportion of eligible patients who completed a faecal occult blood test (FOBT) between the intervention and control group for up to 12 months after the SMS was sent, as recorded in their electronic medical record (EMR). A process evaluation using interview data collected from general practice staff (GP, practice managers, nurses) and patients will explore the feasibility and acceptability of sending and receiving a SMS to prompt completing a NBCSP kit., Discussion: This efficacy trial will provide initial trial evidence of the utility of an SMS narrative intervention to increase participation in the NBCSP. The results will inform decisions about the need for and design of a larger, multi-state trial of this SMS intervention to determine its cost-effectiveness and future implementation., Trial Registration: Australian New Zealand Clinical Trials Registry ACTRN12620001020976 . Registered on 17 October 2020., (© 2022. The Author(s).)

Introduction: Therapeutic advances have increased the survival of non-small-cell lung cancer (NSCLC) patients as well as the lifetime risk of being diagnosed with brain metastases (BM). Although BM have historically been associated with poor prognosis, it is unclear whether they remain a strong predictor of reduced survival. This study aimed to evaluate the prognostic value of BM and the utility of the Lung-molGPA., Methods: This single-center retrospective database analysis included 1,393 NSCLC patients with newly diagnosed BM who registered at the Instituto Nacional de Cancerología of Mexico (INCan) from 2010 to 2020. The Kaplan-Meier method and log-rank test were used for the survival analysis. Survival times were calculated from the date of NSCLC diagnosis (OS), or BM diagnosis, to the date of death or last follow-up. Cox proportional-hazards models were used to calculate the hazard ratio (HR) for death and the significance of the parameters evaluated., Results: Out of 1,058 patients who underwent genetic testing for epidermal growth factor receptor (EGFR) mutations and/or anaplastic lymphoma kinase (ALK) rearrangements, 650 had a positive tumor mutational/rearrangement status (543 had EGFR mutations, 104 had ALK rearrangements, and 3 had both EGFR and ALK alterations). Median OS did not differ between patients with BM and without BM (17.7 months [95% CI, 15.4-19.0] vs. 16.6 months [95% CI, 14.3-19.0]; p = 0.362). In contrast, the presence of BM was associated with worse OS in patients with a negative tumor mutational status (HR: 1.225 [95% CI, 1.041-1.443]; p = 0.015), who did not receive TKI therapy (HR: 1.269 [95% CI, 1.082-1.488]; p = 0.003), or with non-adenocarcinoma histology (HR: 1.582 [95% CI, 1.118-2.238]; p = 0.01). The median survival after BM diagnosis was 4.27, 6.96, 14.68, and 18.89 months for adenocarcinoma patients with Lung-molGPA scores 0-1, 1.5-2, 2.5-3, and 3.5-4, respectively (p < 0.0001). For non-adenocarcinoma patients with Lung-molGPA scores 0-1, 1.5-2, and 2.5-3, the corresponding estimates were 0.95, 2.89, and 9.39 months, respectively (p < 0.0001)., Conclusions: These results show that the prognosis of NSCLC patients with BM is no longer uniformly poor and should be individually assessed. Furthermore, the validity of the Lung-molGPA was confirmed in an independent population from a different geographical region., (© 2022 S. Karger AG, Basel.)

Latin America has been particularly hard hit by the COVID-19 syndemic, including the associated economic fallout that has threatened the livelihoods of most families. Social protection platforms and policies should have a crucial role in safeguarding individual and family wellbeing; however, the response has been insufficient to address the scale of the crisis. In this Viewpoint, we focus on two policy challenges of the COVID-19 syndemic: rapidly and effectively providing financial support to the many families that lost livelihoods, and responding to and mitigating the increased risk of intimate partner violence (IPV). We argue that building programmatic linkages between social protection platforms, particularly cash transfers, and IPV prevention, mitigation, and response services, creates synergies that can promote freedom from both poverty and violence., Competing Interests: Declaration of interests All authors declare no competing interests., (Copyright © 2022 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY-NC-ND 4.0 license. Published by Elsevier Ltd.. All rights reserved.)

Objective: The objective of the study was to assess the tolerability and safety of galcanezumab in patients with chronic cluster headache (CH) with up to 15 months of treatment., Background: Chronic CH is a highly debilitating disease with a substantial and unmet medical need., Methods: Patients were randomized to receive placebo or galcanezumab (300 mg) monthly for 12 weeks, followed by an optional 52-week open-label extension and 16-week posttreatment follow-up (washout). This is a secondary analysis and long-term follow-up of a previously conducted clinical trial. The safety analysis included patients who received galcanezumab at any time during the study. Outcomes included adverse events (AEs), discontinuations, laboratory values, vital signs, electrocardiograms (ECGs), and suicidality ratings., Results: A total of 233 patients received at least one galcanezumab dose. The mean exposure was 341 days. Galcanezumab-treated patients were mostly male (n = 169/233; 72.5%) with a mean age of 44.9 (±10.9) years. Treatment-emergent adverse events (TEAEs) were reported by 185 patients (n = 185/233; 79.4%), 23 patients (n = 23/233; 9.9%) reported serious adverse events (SAEs), and 18 patients (n = 18/233; 7.7%) discontinued due to AEs. The SAE CH was reported by three patients. The most common TEAEs (>10%) were nasopharyngitis (n = 41/233; 17.6%) and injection site pain (n = 33/233; 14.2%). 27.5% of patients (n = 64/233) had TEAEs related to injection sites. Likely hypersensitivity events, including injection site rash, injection site urticaria, and injection site hypersensitivity were reported (n = 14/233; 6.0%). There were past histories of suicidal ideation (n = 55/237; 23.2%) and suicidal behavior (n = 9/236; 3.8%). During the study, 15 patients (n = 15/230; 6.5%), seven with previous history, reported suicidal ideation. One patient had a nonfatal suicide attempt during the open-label extension and an aborted attempt during the washout. There were no new safety findings compared with the placebo-controlled treatment period in laboratory values, vital signs, or ECGs., Conclusions: Galcanezumab 300 mg monthly had a favorable tolerability and safety profile in patients with chronic CH with up to 15 months of treatment., (© 2021 Eli Lilly and Company. Headache: The Journal of Head and Face Pain published by Wiley Periodicals LLC on behalf of American Headache Society.)

Currently available anti-viral drugs may be useful in reducing the viral load but are not providing the necessary physiological effects to reduce the SARS-CoV-2 complications efficiently. Treatments that provide better clinical outcomes are urgently needed. Vitamin C (ascorbic acid, AA) is an essential nutrient with many biological roles that have been proven to play an important part in immune function; it serves as an antioxidant, an anti-viral, and exerts anti-thrombotic effects among many other physiological benefits. Research has proven that AA at pharmacological doses can be beneficial to patients with acute respiratory distress syndrome (ARDS) and other respiratory illnesses, including sepsis. In addition, High-Dose Intravenous Vitamin C (HDIVC) has proven to be effective in patients with different viral diseases, such as influenza, chikungunya, Zika, and dengue. Moreover, HDIVC has been demonstrated to be very safe. Regarding COVID-19, vitamin C can suppress the cytokine storm, reduce thrombotic complications, and diminish alveolar and vascular damage, among other benefits. Due to these reasons, the use of HDIVC should be seriously considered in complicated COVID-19 patients. In this article, we will emphasize vitamin C's multiple roles in the most prominent pathophysiological processes presented by the COVID-19 disease.

Entomopathogenic fungi can achieve important innovative outcomes for integrated mosquito control especially of Aedes aegypti, the key vector of arboviruses to humans in the tropics and subtropics. This study sought to design and to develop a simple dissemination device to attract and to infect gravid A. aegypti adults with a granular formulation of the ascomycete Metarhizium humberi IP 46, and to validate this device in the laboratory as well as in semi-field and field conditions. Hydrogel (polyacrylamide potassium polyacrylate) was confirmed to be a suitable substitute for water used in the device that attracted gravid females under field conditions. Females laid eggs on black polyethylene terephthalate carpet fixed in the device that also proved to be a suitable substrate for a granular formulation of fungal microsclerotia and/or conidia. The plastic device (29.5 cm high) was divided into a lower closed compartment with a water reservoir and an upper, laterally open but covered compartment with continuously hydrated gel and the fungal formulation attached to the carpet. The uppermost compartment permitted free circulation of mosquito adults. The device attracted both male and female A. aegypti. The fungal formulations of IP 46 propagules tested in the device were effective against adults in laboratory, semi-field, and field settings. Findings in the laboratory, semi-field, and especially in field conditions strengthen the value and utility of this innovative device for focal applications of a mycoinsecticide against this important mosquito vector.Key points• Low-cost and simple disseminating device for focal control of Aedes aegypti.• Granulized Metarhizium humberi IP 46 and hydrogel yield extended control.• Findings in field tests strengthen benefit of the device for focal application., (© 2021. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Hematopoietic cells transplants are technically complex and expensive imposing a huge burden on health care systems, especially those in developing countries and regions. In 2017 > 4500 transplants were done in 13 Latin American countries with established transplant programmes. We interrogated data on transplant rate, cost, funding source, hospital type, Gini coefficient and the United Nations Development Programme Inequality-Adjusted Human Development Index to determine co-variates associated with transplant development. Transplant rates varied almost 30-fold between the 13 countries from 345 in Uruguay to 12 in Venezuela with a regional transplant rate 7-8-fold lower compared with the US and EU. We found significant correlations between higher transplant cost, public funding, transplants in private hospitals with transplant rate. Low cost per transplant regardless of payor and transplants done in public hospitals were associated with low transplant rates. In contrast, high cost per transplant funded by the government and transplants done in private hospitals were associated with high transplant rates. Surprisingly, we found transplant rates were higher when transplants cost more, when they were done in private for-profit hospitals and payed for with public funds. These data give insights how to increase transplant rates in Latin America and other developing regions., (© 2021. The Author(s), under exclusive licence to Springer Nature Limited.)

An approach for reducing toxicity and enhancing therapeutic potential of supramolecular polyamine phosphate nanoparticles (PANs) through PEGylation of polyamines before their assembly into nanoparticles is presented here. It is shown that the number of polyethylene glycol (PEG) chains for polyamine largely influence physico-chemical properties of PANs and their biological endpoints. Poly(allylamine hydrochloride) (PAH) are functionalized through carbodiimide chemistry with three ratios of PEG molecules per PAH chain: 0.1, 1, and 10. PEGylated PAH is then assembled into PANs by exposing the polymer to phosphate buffer solution. PANs decrease size and surface charge with increasing PEG ratios as evidenced by dynamic light scattering and zeta potential measurements, with the ten PEG/PAH ratio PANs having practically zero charge. Small angle X-ray scattering (SAXS) proves that PEG chains form a shell around a polyamine core, which is responsible for the screening of positive charges. MTT experiments show that the screening of amine groups decreases nanoparticle toxicity, with the lowest toxicity for the 10 PEG/PAH ratio. Fluorescence correlation spectroscopy (FCS) proves less interaction with proteins for PEGylated PANs. Positron emission tomography (PET) imaging of 18 F labelled PANs shows longer circulation time in healthy mice for PEGylated PANs than non-PEGylated ones., (© 2021 Wiley-VCH GmbH.)

SARS-CoV-2 is the virus responsible for the COVID-19 pandemic. This disease is beginning to be better understood in terms of its other, non-respiratory, clinical manifestations. Over the course of months caring for patients infected by the virus, clinical and laboratory changes have been identified that have prompted researchers to debate the potential that SARS-CoV-2 has to trigger an exacerbated immune response that is capable of changing endothelial homeostasis through both direct and indirect mechanisms. With the intention of contributing to this debate, a review was conducted of the possible mechanisms that could trigger these phenomena in patients with COVID-19. It is important to understand the pathophysiology of the immunological mechanisms related to this disease in order to understand the potential endothelial damage that COVID-19 can provoke., Competing Interests: Conflicts of interest: No conflicts of interest declared concerning the publication of this article., (Copyright© 2021 The authors.)

Background: Acute occlusion of the posterior sagittal sinus may lead to dramatic increase in intracranial pressure (ICP), refractory to standard treatment. Hybrid vascular bypass of cranial venous outflow into the internal jugular vein (IJV) has seldom been described for this in recent neurosurgical literature., Objective: To describe creation of a novel vascular bypass shunt from the superior sagittal sinus (SSS) to internal jugular vein (IJV) utilizing a covered stent-Dacron graft construct for control of refractory ICP., Methods: We illustrate a patient with refractory ICP increases after acute sinus ligation that was performed to halt torrential bleeding from intraoperative injury. A temporary shunt was created that successfully controlled ICP. From the promising results of the temporary shunt, we utilized a prosthetic hybrid bypass graft to function as a shunt from the sagittal sinus to IJV. Yet the associated anticoagulation led to complications and a poor outcome., Results: Rapid and sustained ICP reduction can be expected after sagittal sinus-to-jugular bypass shunt placement in acute sinus occlusion. Details of the surgical technique are described. Heparin anticoagulation, while imperative, is also associated with worrisome complications., Conclusion: Acute occlusion of posterior third of sagittal sinus carries a very malignant clinical course. Intractable intracranial hypertension from acute sinus occlusion may be effectively treated with a SSS-IJV bypass shunt. A covered stent construct provides an effective vascular bypass conduit. However, the anticoagulation risk can lead to fatal outcomes. The neurosurgeon must always strive for primary repair of an injured sinus., (© 2021. The Author(s), under exclusive licence to Springer-Verlag GmbH Austria, part of Springer Nature.)

Background: The development of secondary resistance (SR) in metastatic colorectal cancer (mCRC) treated with anti-epidermal growth factor receptor (anti-EGFR) antibodies is not fully understood at the molecular level. Here we tested in vivo selection of anti-EGFR SR tumors in CRC patient-derived xenograft (PDX) models as a strategy for a molecular dissection of SR mechanisms., Methods: We analyzed 21 KRAS, NRAS, BRAF, and PI3K wildtype CRC patient-derived xenograft (PDX) models for their anti-EGFR sensitivity. Furthermore, 31 anti-EGFR SR tumors were generated via chronic in vivo treatment with cetuximab. A multi-omics approach was employed to address molecular primary and secondary resistance mechanisms. Gene set enrichment analyses were used to uncover SR pathways. Targeted therapy of SR PDX models was applied to validate selected SR pathways., Results: In vivo anti-EGFR SR could be established with high efficiency. Chronic anti-EGFR treatment of CRC PDX tumors induced parallel evolution of multiple resistant lesions with independent molecular SR mechanisms. Mutations in driver genes explained SR development in a subgroup of CRC PDX models, only. Transcriptional reprogramming inducing anti-EGFR SR was discovered as a common mechanism in CRC PDX models frequently leading to RAS signaling pathway activation. We identified cAMP and STAT3 signaling activation, as well as paracrine and autocrine signaling via growth factors as novel anti-EGFR secondary resistance mechanisms. Secondary resistant xenograft tumors could successfully be treated by addressing identified transcriptional changes by tailored targeted therapies., Conclusions: Our study demonstrates that SR PDX tumors provide a unique platform to study molecular SR mechanisms and allow testing of multiple treatments for efficient targeting of SR mechanisms, not possible in the patient. Importantly, it suggests that the development of anti-EGFR tolerant cells via transcriptional reprogramming as a cause of anti-EGFR SR in CRC is likely more prevalent than previously anticipated. It emphasizes the need for analyses of SR tumor tissues at a multi-omics level for a comprehensive molecular understanding of anti-EGFR SR in CRC., (© 2021. The Author(s).)

Background: Australian guidelines recommend that all people aged 50-70 years old actively consider taking daily low-dose aspirin (100-300 mg per day) for 2.5 to 5 years to reduce their risk of colorectal cancer (CRC). Despite the change of national CRC prevention guidelines, there has been no active implementation of the guidelines into clinical practice. We aim to test the efficacy of a health consultation and decision aid, using a novel expected frequency tree (EFT) to present the benefits and harms of low dose aspirin prior to a general practice consultation with patients aged 50-70 years, on informed decision-making and uptake of aspirin., Methods: Approximately five to seven general practices in Victoria, Australia, will be recruited to participate. Patients 50-70 years old, attending an appointment with their general practitioner (GP) for any reason, will be invited to participate in the trial. Two hundred fifty-eight eligible participants will be randomly allocated 1:1 to intervention or active control arms using a computer-generated allocation sequence stratified by general practice, sex, and mode of trial delivery (face-to-face or teletrial). There are two co-primary outcomes: informed decision-making at 1-month post randomisation, measured by the Multi-dimensional Measure of Informed Choice (MMIC), and self-reported daily use of aspirin at 6 months. Secondary outcomes include decisional conflict at 1-month and other behavioural changes to reduce CRC risk at both time points., Discussion: This trial will test the efficacy of novel methods for implementing national guidelines to support informed decision-making about taking aspirin in 50-70-year-olds to reduce the risk of CRC and other chronic diseases., Trial Registration: The Australian New Zealand Clinical Trials Registry (ANZCTR) ACTRN12620001003965 . Registered on 10 October 2020., (© 2021. The Author(s).)

Background: In recent years, transperineal biopsies gained popularity for prostate cancer diagnosis; lower infective complications and improved sampling of the prostate are the main advantages of this technique. One question that remains unclear is whether an initial transperineal biopsy confers a lower risk for rebiopsy compared with the transrectal approach., Methods: Six hundred seventy-one men were prospectively followed after an initial negative prostate biopsy for a median period of 49.50 (IQR: 37.62-61.17) months. Rebiopsy rate was analyzed attending to first biopsy approach (transrectal versus transperineal systematic) and clinical variables., Results: Diagnostic rate was similar for transrectal and transperineal systematic biopsies. Targeted biopsies outperformed any systematic approach, and transperineal targeted in particular was superior to transrectal targeted. Rebiopsy rates were 15.4% and 5.26% for the transrectal and transperineal systematic groups, respectively. Prostate-specific antigen density and type of first biopsy were identified as rebiopsy predictors., Conclusion: Men undergoing transperineal systematic biopsies had a three times lower rate of rebiopsy over the study period compared with the traditional transrectal approach. This advantage could be added to the already described potential benefits of transperineal biopsies. Targeted biopsies had lower rebiopsy rate over the study period. Further innovations that decreased the cost of transperineal biopsies could favor this approach in the future., Competing Interests: All authors have no conflict of interest to declare., (© 2020 Asian Pacific Prostate Society. Published by Elsevier B.V.)

Rheumatoid arthritis (RA) is a debilitating autoimmune disease with grave physical, emotional and socioeconomic consequences. Despite advances in targeted biologic and pharmacologic interventions that have recently come to market, many patients with RA continue to have inadequate response to therapies, or intolerable side effects, with resultant progression of their disease. In this review, we detail multiple biomolecular pathways involved in RA disease pathogenesis to elucidate and highlight pathways that have been therapeutic targets in managing this systemic autoimmune disease. Here we present an up-to-date accounting of both emerging and approved pharmacological treatments for RA, detailing their discovery, mechanisms of action, efficacy, and limitations. Finally, we turn to the emerging fields of bioengineering and cell therapy to illuminate possible future targeted therapeutic options that combine material and biological sciences for localized therapeutic action with the potential to greatly reduce side effects seen in systemically applied treatment modalities., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Shams, Martinez, Dawson, Flores, Gabriel, Garcia, Guevara, Murray, Pacifici, Vargas, Voelker, Hell and Ashouri.)

The impact of ambient relative humidity (RH) on conidial production of Metarhizium humberi IP 46 microsclerotia (MS) formulated in pellets or granules was investigated, and a promising granular formulation was tested against Aedes aegypti adults to confirm its efficacy. Microcrystalline cellulose (MC) and diatomaceous earth (DE) or a combination of vermiculite (VE), DE and silicon dioxide (SD) were tested as carriers in granular formulations containing MS. A range of 93-96.5% RH was critical for fungal development, and at least 96.5-98.5% RH was required for high conidial production on pellets or granules. Conidial production was clearly higher on pellets and granules prepared with VE than MC as the main carrier. VE granules containing MS were highly active against A. aegypti adults. Most mosquitoes were killed within 6 days after treatment regardless of the exposure time of adults to the formulation (1 min-24 h) or ambient humidity (75 or >98%). Production of conidia on dead adults varied between 7.3 × 10 6 and 2.2 × 10 7 conidia/individual, when exposed to MS granules for 12 h and 1 min, respectively. Granular formulations containing VE as the main carrier and MS as the active ingredient of M. humberi have strong potential for use against A. aegypti. KEY POINTS: • High conidial production on granular microsclerotial formulations at >96.5% RH • Vermiculite is more appropriate as a carrier than microcrystalline cellulose • Granules with IP 46 microsclerotia are highly active against Aedes aegypti adults.

Introduction and Objectives: Instability is a frequent symptom after whiplash (WL) with alterations in postural control in chronic phases. The main objective of our study was to evaluate if there were objective alterations in postural control in the acute phases after a WL, as well as to determine the presence or absence of oculomotor alterations in early phases., Material and Methods: A posturographic study was carried out using the NedSVE/IBV system, as well as an oculomotor assessment, in a sample of 44 patients with WL in the first 24h after the accident., Results: More than half of the patients had a global assessment below normal. The predominant sensory pattern was vestibular. The main parameters of the Romberg test (total displacement, swept area, average speed, anteroposterior and mediolateral displacement and anteroposterior force) increased following the sequence Romberg open eyes, Romberg foam rubber open eyes, Romberg closed eyes, and Romberg foam rubber closed eyes. Concerning the comparison with normality and using the reference values of the Institute of Biomechanics of Valencia, the data from the WL patients showed significant differences in all the parameters analysed, except for gait assessment and the mediolateral directional rhythmic control., Conclusions: Our data confirm that patients in the acute phase of WL have worse postural control than non-injured persons. The results suggest that patients with WL have greater visual dependence. Only a minority of patients had oculomotor abnormalities during early examination., (Copyright © 2020 Sociedad Española de Rehabilitación y Medicina Física. Publicado por Elsevier España, S.L.U. All rights reserved.)

A number of devices can now provide mechanical circulatory support (MCS) to patients with acute cardiogenic shock (CS) and chronic end-stage heart failure (HF). Women differ from men in pathophysiology and natural history of CS and HF, and are usually sicker at admission. Current evidence suggests that women benefit as much as men, if not more, from both temporary and durable MCS for appropriate indications. Yet, women have been under-represented in clinical trials of MCS devices. Limited evidence suggests that women benefit more from temporary MCS in CS associated with acute myocardial infarction. However, in patients with durable left ventricular assist devices (LVADs), women are more likely to experience thromboembolic events and right HF. This review aims to study available evidence and determine areas for further research on gender differences in (a) use of temporary MCS for CS and (b) use of durable LVADs. Use of MCS in conditions specific to, or more common in women (pregnancy, takotsubo cardiomyopathy, peripartum cardiomyopathy, and spontaneous coronary artery dissection) is also discussed., (Copyright © 2020. Published by Elsevier Ltd.)

Objective: To characterize the pediatric patients presenting at the two pediatric centers in Bogotá, with first isolate urine culture of community-acquired extended-spectrum b-lactamase (ESBL)-producing enterobacteriaceae., Methods: Review of microbiological data of children between January, 2012 and December, 2018, obtained using the WHONET software., Results: A total of 2657 Escherichia coli, Klebsiella spp and Proteus mirabilis - positive urine cultures were obtained within a 6-year period; data of 132 patients were finally selected. Frequency of ESBL-producing bacteria infections in community-acquired urinary tract infections (UTI) was 5%: 123 E. coli (93.2%), 7 K. pneumoniae (5.2%), 1 K. oxytoca (0.8%), and 1 P. mirabilis (0.8%)., Conclusion: A predominance of female sex, preschool children, and lower tract urinary infections were found, as well as a low frequency of comorbidities. Adequate sensitivity to amikacin and nitrofurantoin was found in this study.

In the basin of Mekong, over 70 million people rely on unimproved surface water for their domestic requirements. Surface water is often contaminated with fecal matter and yet little information exists on the underlying mechanisms of fecal contamination in tropical conditions at large watershed scales. Our objectives were to (1) investigate the seasonality of fecal contamination using Escherichia coli as fecal indicator bacteria (FIB), and (2) establish links between the fecal contamination in stream water and its controlling factors (hydrology and land use). We present the results of (1) a sampling campaign at the outlet of 19 catchments across Lao PDR, in both the dry and the rainy seasons of 2016, and (2) a 10-day interval monitoring conducted in 2017 and 2018 at three point locations of three rivers (Nam Ou, Nam Suang, and Mekong) in northern Lao PDR. Our results show the presence of fecal contamination at most of the sampled sites, with a seasonality characterized by higher and extreme E. coli concentrations occurring during the rainy season. The highest E. coli concentrations, strongly correlated with total suspended sediment concentrations, were measured in catchments dominated by unstocked forest areas, especially in mountainous northern Lao PDR and in Vientiane province.

Background: Few trials have evaluated the utility of liquid biopsies to detect epidermal growth factor receptor mutations (EGFRm) at the time of response evaluation and its association with the clinical characteristics and outcomes of non-small-cell lung cancer (NSCLC) patients., Objective: This study aimed to evaluate, in a real-world clinical setting, the prevalence of plasma EGFRm and its association with the clinical characteristics, response and survival outcomes of NSCLC patients under treatment with EGFR-tyrosine kinase inhibitors (EGFR-TKIs)., Methods: This observational study enrolled advanced or metastatic NSCLC patients, with confirmed tumor EGFRm, receiving treatment with first- or second-generation EGFR-TKIs. Blood samples for the detection of plasma EGFRm were collected at the time of response evaluation and processed using the Target Selector™ assay. The main outcomes were the detection rate of plasma EGFRm, median Progression-Free Survival (PFS) and Overall Survival (OS) according to plasma EGFR mutational status., Results: Of 84 patients, 50 (59.5%) had an EGFRm detected in plasma. After a median follow-up of 21.1 months, 63 patients (75%) had disease progression. The detection rate of plasma EGFRm was significantly higher in patients with disease progression than in patients with partial response or stable disease (68.3% versus 33.3%; P< 0.01). PFS and OS were significantly longer in patients without plasma EGFRm than among patients with plasma EGFRm (14.3 months [95% CI, 9.25-19.39] vs 11.0 months [95% CI, 8.61-13.46]; P= 0.034) and (67.8 months [95% CI, 39.80-95.94] vs 32.0 months [95% CI, 17.12-46.93]; P= 0.006), respectively. A positive finding in LB was associated with the presence of ⩾ 3 more metastatic sites (P= 0.028), elevated serum carcinoembryonic (CEA) at disease progression (P= 0.015), and an increase in CEA with respect to baseline levels (P= 0.038)., Conclusions: In NSCLC patients receiving EGFR-TKIs, the detection of plasma EGFRm at the time of tumor response evaluation is associated with poor clinical outcomes.

The search for sustainability in the Supply Chain (SC) is one of the tasks that most concerns business leaders in all manufacturing sectors because of the importance that the Supply Chain has as a transversal tool and due to the leading role that it has been playing lately. Of all the manufacturing sectors, this study focuses on the aerospace, shipbuilding, and automotive sectors identified as transport. The present study carries out a descriptive review of existing publications in these three sectors in relation to the sustainability of the Supply Chain in its 4.0 adaptation as an update in matters that are in constant evolution. Among the results obtained, Lean practices are common to the three sectors, as well as different technologies focused on sustainability. Furthermore, the results show that the automotive sector is the one that makes the greatest contribution in this sense through collaborative programs that can be very useful to the other two sectors, thus benefiting from the consequent applicable advantages. Meanwhile, the Aerospace and Shipbuilding sectors do not seem to be working on promoting a sustainable culture in the management of the Supply Chain or on including training programs for their personnel in matters related to Industry 4.0.

Background: Sexual dimorphism in the hypothalamic pituitary adrenal (HPA) axis can influence sex-specific patterns of response to stressors. While a host of findings exist on sex differences in stress-induced activity of the HPA axis and associated mechanisms in rodents, less is known about the intricacies of sex differences in stress responsivity in humans. Accordingly, the overall aim of the present study was to investigate psychological variables that may account for differences in the cortisol stress response between men and women., Methods: Eighty-six participants filled out self-report measures of anxiety (STA-Y), aggression (BPAQ), and happiness (SHS). We then exposed all participants to a one-minute Cold Pressor Test (CPT) that was maintained between 3-5° C. Cortisol and pain ratings were assessed. We focused on the 20-minute time point for cortisol since that is when cortisol is near its peak post-stress., Results: Women reported higher pain ratings compared to men. Women also showed a positive relationship between pain ratings and cortisol. Aggression was significantly related to cortisol levels in men, but not in women. Similarly, trait anxiety was positively related to cortisol levels in men, but not in women. Happiness was unrelated to cortisol levels in women and men. Follow-up regressions were conducted separately for men and women. A significant model was found for cortisol in men only with trait anxiety, aggression, and the interaction between trait anxiety and aggression., Conclusions: The current study builds on previous reports by showing that aggression and anxiety differentially influence the cortisol response to an acute stress in men and women.

Multiple myeloma (MM) is a plasma cell neoplasm characterized by destructive bony lesions, anemia, and renal impairment. Access to effective therapy is limited globally. We report the rates and utilization of hematopoietic cell transplantation (HCT) globally from 2006-2015 to better characterize access to HCT for patients with MM. This was an analysis of a retrospective survey of Worldwide Network of Blood and Marrow Transplant sites, conducted annually between 2006-2015. Incidence estimates were from the Global Burden of Disease study. Outcome measures included total number of autologous and allogeneic HCTs by world regions, and percentage of newly diagnosed MM patients who underwent HCT, calculated by the number of transplants per region in calendar year/gross annual incidence of MM per region. From 2006 to 2015, the number of autologous HCT performed worldwide for MM increased by 107%. Utilization of autologous HCT was highest in Northern America and European regions, increasing from 13% to 24% in Northern America, and an increase from 15% to 22% in Europe. In contrast, the utilization of autologous HCT was lower in the Africa/Mediterranean region, with utilization only changing from 1.8% in 2006 to 4% in 2015. The number of first allogeneic HCT performed globally for MM declined after a peak in 2012 by -3% since 2006. Autologous HCT utilization for MM has increased worldwide in high-income regions but remains poorly utilized in Africa and the East Mediterranean. More work is needed to improve access to HCT for MM patients, especially in low to middle income countries. © 2020 American Society for Transplantation and Cellular Therapy. Published by Elsevier Inc., (Copyright © 2020 American Society for Transplantation and Cellular Therapy. Published by Elsevier Inc. All rights reserved.)

Background: Human implantation is a complex process requiring synchrony between a healthy embryo and a functionally competent or receptive endometrium. In order to assess endometrial receptivity in Assisted Reproductive Technology (ART) cycles serial evaluation of endometrial volumetric analysis may have a predictive value on a positive outcome., Methods: Serial 3D transvaginal ultrasound performed in women on ART cycle to evaluate embryo implantation predictors. Prospective case control study of 169 subjects were assessed. Endometrial pattern, thickness, volume and adjusted endometrial volume (ratio between endometrial volume and uterine volume) was performed to all subjects on a continuous process from baseline, during controlled ovarian stimulation, trigger day with human chorionic gonadotropin hormone (hCG) and at embryo transfer day., Results: Demographics and ART procedures and scores, was similar between the two groups. Endometrial morphology also showed no difference between the two groups. Endometrial volume and adjusted endometrial volume was significantly higher in the positive group as soon as day 6 of ovarian controlled stimulation., Conclusions: Serial 3D endometrial volume and adjusted endometrial volumes provides a predicting clinical tool enhancing elective embryo transfers in fresh ART cycle. Thus providing a non-invasive continuous technique for endometrial receptivity assessment that reflects endometrial changes during ART procedures.

Internet of Things (IoT) technology is increasingly pervasive in all aspects of our life and its usage is anticipated to significantly increase in future Smart Cities to support their myriad of revolutionary applications. This paper introduces a new architecture that can support several IoT-enabled smart home use cases, with a specified level of security and privacy preservation. The security threats that may target such an architecture are highlighted along with the cryptographic algorithms that can prevent them. An experimental study is performed to provide more insights about the suitability of several lightweight cryptographic algorithms for use in securing the constrained IoT devices used in the proposed architecture. The obtained results showed that many modern lightweight symmetric cryptography algorithms, as CLEFIA and TRIVIUM, are optimized for hardware implementations and can consume up to 10 times more energy than the legacy techniques when they are implemented in software. Moreover, the experiments results highlight that CLEFIA significantly outperforms TRIVIUM under all of the investigated test cases, and the latter performs 100 times worse than the legacy cryptographic algorithms tested.

Pancreatic duct ligation (PDL) in the murine model has been described as an exocrine pancreatic atrophy-inducing procedure. However, its influence has scarcely been described on premalignant lesions. This study describes the histological changes of premalignant lesions and the gene expression in a well-defined model of pancreatic ductal adenocarcinoma by PDL. Selective ligation of the splenic lobe of the pancreas was performed in Ptf1a-Cre (+/ki) ; K-ras LSLG12Vgeo (+/ki) mice (PDL-Kras mice). Three experimental groups were evaluated: PDL group, controls and shams. The presence and number of premalignant lesions (PanIN 1-3 and Atypical Flat Lesions-AFL) in proximal (PP) and distal (DP) pancreas were studied for each group over time. Microarray analysis was performed to find differentially expressed genes (DEG) between PP and PD. Clinical human specimens after pancreaticoduodenectomy with ductal occlusion were also evaluated. PDL-Kras mice showed an intense pattern of atrophy in DP which was shrunk to a minimal portion of tissue. Mice in control and sham groups had a 7 and 10-time increase respectively of risk of high-grade PanIN 2 and 3 and AFL in their DP than PDL-Kras mice. Furthermore, PDL-Kras mice had significantly less PanIN 1 and 2 and AFL lesions in DP compared to PP. We identified 38 DEGs comparing PP and PD. Among them, several mapped to protein secretion and digestion while others such as Nupr1 have been previously associated with PanIN and PDAC. PDL in Ptf1a-Cre (+/ki) ; K-ras LSLG12Vgeo (+/ki) mice induces a decrease in the presence of premalignant lesions in the ligated DP. This could be a potential line of research of interest in some cancerous risk patients.

The development of high-complexity geometry parts is one of the main goals of additive manufacturing technology. However, the failure of printed structures and the joining of different parts to create complex assemblies represents a real challenge in the research of efficient and sustainability techniques for the permanent assembly of polymers. Laser welding processes have been used as a single-step method to join metals for years. Nowadays, the growing trend in the use of thermoplastics for additive manufacturing has led to the need to adapt this technique to materials with a very specific nature and which are more sensitive to thermal effects. In addition, the possibility of transmitting the laser beam through transparent polymer layers allows to us focus the energy supply on internal sections of the assembled components. In this research, an infrared laser marking system was used to join two different samples of polylactic acid manufactured by fused deposited modeling technology. In order to increase the effectiveness of the bonding process, a transparent and a dark sample have been used as assembly material, focusing the laser beam on the interface area of the two parts. By means of tensile tests, dimensional measurement and the use of optical microscopy techniques, a basis was established that links the supplied energy by laser to the joining performance.

Background: Our objective was to identify possible associations between clinical and laboratory variables and the risk of developing acute kidney injury (AKI) in severely injured patients admitted to the intensive care unit (ICU) for whom creatine kinase (CK) levels were available., Methods: For this retrospective observational study, we analyzed adult trauma patients admitted to the ICU from 2011 to 2015 at Fundación Valle del Lili (FVL) University Hospital. Our primary outcome was the incidence of AKI. Multivariate regression analysis was used to assess risk factors for this outcome., Results: A total of 315 patients were included. The trauma mechanisms were blunt (n = 130), penetrating (n = 66) and blast (n = 44) trauma. The median (interquartile range, IQR) of injury severity score (ISS) was 21 (16-29). AKI developed in 75 patients (23.8%). Multivariate regression analysis revealed that the thoracic abbreviated injury scale (AIS) value (median (IQR) in the AKI group: 3 (0-4)), Acute Physiology and Chronic Health Evaluation (APACHE II) score (median (IQR) in the AKI group: 18 (10-27)), CK greater than 5000 U/L, lactic acid concentration at admission, and dobutamine administration were independently associated with AKI., Conclusion: We found that age, APACHE II score, thoracic trauma, lactic acidosis, and dobutamine administration were independently associated with AKI. Trauma surgeons need to be aware of the increased odds of AKI if one of these factors is identified during the evaluation and treatment of injured patients.

Telomere length measured in leukocyte (LTL) has been found to be associated with the risk of developing several cancer types, including myeloproliferative neoplasms (MPNs). LTL is genetically determined by, at least, 11 SNPs previously shown to influence LTL. Their combination in a score has been used as a genetic instrument to measure LTL and evaluate the causative association between LTL and the risk of several cancer types. We tested, for the first time, the "teloscore" in 480 MPN patients and 909 healthy controls in a European multi-center case-control study. We found an increased risk to develop MPNs with longer genetically determined telomeres (OR = 1.82, 95% CI 1.24-2.68, P = 2.21 × 10 -3 , comparing the highest with the lowest quintile of the teloscore distribution). Analyzing the SNPs individually we confirm the association between TERT-rs2736100-C allele and increased risk of developing MPNs and we report a novel association of the OBFC1-rs9420907-C variant with higher MPN risk (OR allelic  = 1.43; 95% CI 1.15-1.77; P = 1.35 × 10 -3 ). Consistently with the results obtained with the teloscore, both risk alleles are also associated with longer LTL. In conclusion, our results suggest that genetically determined longer telomeres could be a risk marker for MPN development.

Background: Switching between antiarrhythmic drugs is timed to minimize arrhythmia recurrence and adverse reactions. Dronedarone and amiodarone have similar electrophysiological profiles; however, little is known about the optimal timing of switching, given the long half-life of amiodarone., Methods: The ARTEMIS atrial fibrillation (AF) Loading and Long-term studies evaluated switching patients with paroxysmal/persistent AF from amiodarone to dronedarone. Patients were randomized based on the timing of the switch: immediate, after a 2-week, or after a 4-week washout of amiodarone. Patients who did not convert to sinus rhythm after amiodarone loading underwent electrical cardioversion. The primary objectives were, for the Loading study, to evaluate recurrence of AF ≤60 days; and for the Long-term study, to profile the pharmacokinetics of dronedarone and its metabolite according to different timings of dronedarone initiation., Results: In ARTEMIS AF Loading, 176 were randomized (planned 768) after a 28 ± 2 days load of oral amiodarone. Atrial fibrillation recurrence trended less in the immediate switch versus 4-week washout group (hazard ratio [HR] = 0.65 [97.5% CI: 0.34-1.23]; P = .14) and in the 2-week washout versus the 4-week washout group (HR = 0.75 [97.5% CI: 0.41-1.37]; P = .32). In ARTEMIS AF Long-term, 108 patients were randomized (planned 105). Pharmacokinetic analyses (n = 97) showed no significant differences for dronedarone/SR35021 exposures in the 3 groups., Conclusion: The trial was terminated early due to poor recruitment and so our findings are limited by low numbers. However, immediate switching from amiodarone to dronedarone appeared to be well tolerated and safe.

Objective: Solitary fibrous tumors (SFT) are rare, locally aggressive, mesenchymal neoplasms that pose both diagnostic and operative challenges. In this review of the literature, data were collected from all previously described sellar and suprasellar SFTs to date, with special attention paid to presenting symptoms, surgical technique performed, recurrence status, and adjuvant radiotherapy or chemotherapy, among others., Methods: A review of prior sellar and suprasellar SFTs was performed. Eleven cases of SFTs in the sellar and suprasellar regions were identified. We considered age and sex, along with case-specific information, such as presenting symptoms, surgical approach taken, number of resections, recurrence information, and adjuvant therapy., Results: All cases including ours presented with visual deficits, ranging from blurry vision to complete bilateral visual loss. Endocrine hormonal abnormalities occurred in nearly all patients (90%.) Craniotomy was performed more often than endonasal transsphenoidal resection of tumors, 42% versus 33%, respectively., Conclusions: SFTs are slow-growing fibroblastic mesenchymal neoplasms that comprise <2% of all intracranial tumors. They are even more infrequently found in the sellar/suprasellar region, with our case being the 12th reported case of such and the first only to use supraorbital craniotomy as a resection strategy. Multimodal therapy consisting of safe gross total resection, radiosurgery, and/or chemotherapy provides the best possible results for these rare and locally aggressive entities., (Published by Elsevier Inc.)

Background: This analysis characterizes the immunogenicity profile of galcanezumab, a humanized monoclonal antibody that selectively binds calcitonin gene-related peptide and inhibits its activity, in phase 3 migraine trials., Methods: Immunogenicity data were analyzed from baseline and double-blind, placebo-controlled phases of the 3-month chronic migraine study REGAIN, the 6-month episodic migraine studies EVOLVE-1 and EVOLVE-2, and from baseline and open-label phases of the 12-month chronic and episodic migraine Study CGAJ. The incidence of baseline antidrug antibodies, treatment-emergent antidrug antibodies, neutralizing antidrug antibodies, and the effect of antidrug antibody titer on pharmacokinetics and pharmacodynamics were assessed. The relationship between antidrug antibody status and efficacy was explored using average change in monthly migraine headache days. Safety analyses assessed the potential relationship between treatment-emergent antidrug antibodies and hypersensitivity events or adverse events related to injection sites., Findings: Across studies, 5.9-11.2% of patients had baseline antidrug antibodies. The incidence of treatment-emergent antidrug antibodies was 2.6-12.4% in the galcanezumab group and 0.5-1.7% in the placebo group. The majority of treatment-emergent antidrug antibodies were detected approximately 3-6 months after first study drug dose. Overall, the observed antidrug antibody titer did not impact galcanezumab concentrations, calcitonin gene-related peptide concentrations, or galcanezumab efficacy. There was no evidence that hypersensitivity events or adverse events related to injection sites were mediated by treatment-emergent antidrug antibodies., Interpretation: These data showed that immunogenicity did not impact galcanezumab concentrations, calcitonin gene-related peptide concentrations, or the efficacy and hypersensitivity profile of galcanezumab in patients with migraine.

Objective: To report efficacy and safety of galcanezumab in adults with chronic cluster headache., Background: Galcanezumab is a humanized monoclonal antibody that binds to calcitonin gene-related peptide and inhibits its biological activity., Methods: This study comprised a prospective baseline period, a 12-week double-blind, placebo-controlled treatment period, and a 52-week open-label period. Up to six protocol-specified concomitant preventive medications were allowed if patients were on a stable dose for 2 months prior to the prospective baseline period. Patients were randomized 1:1 to monthly subcutaneous galcanezumab (300 mg) or placebo. The primary endpoint was overall mean change from baseline in weekly attack frequency with galcanezumab compared to placebo. Key secondary endpoints were ≥50% response rate and percentage of patients meeting sustained response. Results from the double-blind treatment period are reported., Results: A total of 237 patients were randomized and treated (120 placebo; 117 galcanezumab). At baseline, the mean age was 45 years and 63% were using ≥1 preventive drug. The primary endpoint was not met; mean change in weekly attack frequency was -4.6 placebo versus -5.4 galcanezumab ( p  = 0.334). Key secondary endpoints also were not met. Injection site-related treatment-emergent adverse events were more common in the galcanezumab than the placebo group, with significantly more injection site erythema., Conclusion: Treatment with galcanezumab 300 mg did not achieve its primary and key secondary endpoints. This study underscores the potential distinct biology of cCH as well as the significant unmet need for safe, effective, and well-tolerated preventive treatment. The safety profile of galcanezumab in cCH is consistent with that observed in trials of episodic CH and migraine., Trial Registration: NCT02438826; https://www.clinicaltrials.gov/ct2/show/NCT02438826.

Infection of an endoventricular patch used for left ventricular aneurysm repair with formation of cardiocutaneous fistula is a rare but potentially serious complication. We report an adult patient who developed a cardiocutaneous fistula 1 year after repair of a third left ventricular aneurysm. The patient was successfully treated with a redo operation using a bovine pericardial patch with omental flap coverage. He is alive and well 10 years later., (Copyright © 2020 The Society of Thoracic Surgeons. Published by Elsevier Inc. All rights reserved.)

The aim of this study was to evaluate the potential of pulsed electric fields (PEF) to improve the extraction of the lipid-soluble astaxanthin from fresh biomass of a wild-type (CECT 11028) and mutant (ATCC 74219) Xanthophyllomyces dendrorhous strain using ethanol as solvent. Inactivation and propidium uptake studies revealed that inactivation is a good index for estimated the proportion of irreversible permeabilized cells when inactivation is higher than 70% in the two strains. Ethanol was ineffective for extracting carotenoids from the PEF-treated cells (20 kV/cm, 135 μs) of the two strains. However, after aqueous incubation of PEF-treated X. dendrorhous ATCC 74219 cells for 12 h, up to 2.4 ± 0.05 mg/g dried weight (d.w.) of carotenoids were extracted in ethanol. From total carotenoid extracted, around 84% corresponded to all-trans astaxanthin. The detection and quantification of esterase activity in the supernatant and the relationship between the percentage of esterase activity quantified and the amount of carotenoids extracted indicate that the extraction of astaxanthin was mediated by enzymatic esterase activity triggered by PEF during incubation. On the other hand, the formation of a large lipid globule into the cytoplasm of PEF-treated X. dendrorhous CECT 11028 cells during aqueous incubation prevented carotenoid extraction. The process developed in this investigation represents a more sustainable and greener method that those previously used for extracting astaxanthin from yeast., (Copyright © 2020 Aguilar-Machado, Delso, Martinez, Morales-Oyervides, Montañez and Raso.)