Search

Background and purpose Some studies have shown that air pollution, often assessed by thin particulate matter with diameter below 2.5 µg/m3 (PM2.5), may contribute to severe COVID‐19 courses, as well as play a role in the onset and evolution of multiple sclerosis (MS). However, the impact of air pollution on COVID‐19 has never been explored specifically amongst patients with MS (PwMS). This retrospective observational study aims to explore associations between PM2.5 and COVID‐19 severity amongst PwMS. Methods Data were retrieved from an Italian web‐based platform (MuSC‐19) which includes PwMS with COVID‐19. PM2.5 2016–2018 average concentrations were provided by the Copernicus Atmospheric Monitoring Service. Italian patients inserted in the platform from 15 January 2020 to 9 April 2021 with a COVID‐19 positive test were included. Ordered logistic regression models were used to study associations between PM2.5 and COVID‐19 severity. Results In all, 1087 patients, of whom 13% required hospitalization and 2% were admitted to an intensive care unit or died, were included. Based on the multivariate analysis, higher concentrations of PM2.5 increased the risk of worse COVID‐19 course (odds ratio 1.90; p = 0.009). Conclusions Even if several other factors explain the unfavourable course of COVID‐19 in PwMS, the role of air pollutants must be considered and further investigated., Air pollution, often assessed by particulate matter with diameter below 2.5 µg/m3, may contribute to severe COVID‐19 courses. 1087 patients were included, of whom 13% required hospitalization and 2% were admitted to an intensive care unit or died. Even if several other factors explain the unfavourable course of COVID‐19 in patients with multiple sclerosis, the role of air pollutants must be considered and further investigated.

Martinez-Cava, A, Hernandez-Belmonte, A, Courel-Ibanez, J, Moran-Navarro, R, Gonzalez-Badillo, JJ, and Pallares, JG. Bench press at full range of motion produces greater neuromuscular adaptations than partial executions after prolonged resistance training. J Strength Cond Res XX(X): 000-000, 2019-Training at a particular range of motion (ROM) produces specific neuromuscular adaptations. However, the effects of full and partial ROM in one of the most common upper-limb exercises such as the bench press (BP) remain controversial. In this study, 50 recreationally to highly resistance trained men were randomly assigned to 1 of 4 training groups: full bench press (BPFULL), two-thirds bench press (BP2/3), and one-third bench press (BP1/3) and control (training cessation). Experimental groups completed a 10-week velocity-based resistance training program using the same relative load (linear periodization, 60-80% 1 repetition maximum [1RM]), only differing in the ROM trained. Individual ROM for each BP variation was determined in the familiarization and subsequently replicated in every lift during training and testing sessions. Neuromuscular adaptations were evaluated by 1RM strength and mean propulsive velocity (MPV). The BPFULL group obtained the best results for the 3 BP variations (effect size [ES] = 0.52-1.96); in turn, partial BP produced smaller improvements as the ROM decreased (BP2/3: ES = 0.29-0.78; BP1/3: ES = -0.01 to 0.66). After 10-week of training cessation, the control group declined in all neuromuscular parameters (ES = 0.86-0.92) except in MPV against low loads. Based on these findings, the BPFULL stands as the most effective exercise to maximize neuromuscular improvements in recreational and well-trained athletes compared with partial ROM variations.

AIM: To determine predictive indicators for dental health management of patients with different abilities, according to a new screening protocol. MATERIALS AND METHODS: This was an observational, analytical, retrospective, cross-sectional study. The sample consisted of all patients with different abilities, diagnosed with autism, Down syndrome, cognitive deficit, cerebral palsy and others, who received care between 1999 and 2019 at the Oral Health Service of the Centro Ann Sullivan del Peru and met the inclusion criteria. Data were obtained from the clinical histories to determine the predictive indicators for managing dental care in these patients. A multivariate statistical analysis was performed using binary logistic regression test. The research project was evaluated by the Research Project Reviewing Committee and then referred to the Human Ethics Committee from a university, securing the relevant approvals. RESULTS: Of the 589 cases evaluated, mean age was 14.5 years, 67.9% were male; systemic diagnosis of different abilities was autism in 62%, the most frequent treatment was caries (52.1%); and final management of these patients was conscious in 96.4% of the cases. With regard to type of classification and horizon, 67.1% of the cases corresponded to classification A, with 35.95% of these in horizon I. With regard to diagnosis of different abilities, autism presented 40.2% of the cases in classification A and horizon I. A predictive equation of 97.1% probability of whether or not sedation was used was obtained. Regression analysis showed that this model has high sensitivity (100%) and low specificity (15%). CONCLUSION: Results show that the type of management for dental care was conscious in nearly all the cases dealt with. This was significantly influenced by the Classification and Horizon Screening Protocol indicator, which established the best predictive model for whether or not to use sedation. The model adequately classifies patients who do not require sedation.

Raspberry is a source of dietary fibre and phenolic compounds, which are metabolised by the gut microbiota, resulting in the production of short chain fatty acids (SCFAs) and phenolic catabolites; but the formation of these compounds depends on the microbiota composition. The aim of this study was to investigate whether the raspberry and its fractions (phenolic extract, total and insoluble dietary fibre) affect the microbial activity depending on the body weight condition. For this, in vitro fermentations of raspberry fractions were carried out using faeces from normal-weight (NW) and overweight volunteers (OW) during 48 h, and phenolic catabolites and SCFAs were analysed at 0, 6, 24 and 48 h. The whole raspberry and the phenolic extract produced greater quantities of urolithins and total SCFAs when compared with fibre fractions, reaching the highest amount between 24 and 48 h. The body weight condition was an important factor, since faeces from NW led to greater production of urolithins from non-extractable phenolic compounds bound to fibre fractions, whereas in OW the urolithins production was higher from the fractions with more extractable polyphenols. In summary, the whole raspberry has been shown to have a prebiotic effect, mainly due to its phenolic compounds content rather than its fibre content.

Most bacteria are protected from environmental offenses by a cell wall consisting of strong yet elastic peptidoglycan. The cell wall is essential for preserving bacterial morphology and viability, and thus the enzymes involved in the production and turnover of peptidoglycan have become preferred targets for many of our most successful antibiotics. In the past decades, Vibrio cholerae, the gram-negative pathogen causing the diarrheal disease cholera, has become a major model for understanding cell wall genetics, biochemistry, and physiology. More than 100 articles have shed light on novel cell wall genetic determinants, regulatory links, and adaptive mechanisms. Here we provide the first comprehensive review of V. cholerae’s cell wall biology and genetics. Special emphasis is placed on the similarities and differences with Escherichia coli, the paradigm for understanding cell wall metabolism and chemical structure in gram-negative bacteria.

BackgroundSARS-CoV-2 coronavirus, an emerging Betacoronavirus, is the causative agent of the severe acute respiratory distress syndrome outbreak in 2019 (COVID-19). Currently, there are neither specific and selective antiviral drugs for the treatment nor vaccines to prevent contagion. Here we propose a bioinformatic approach in order to test in silico the efficacy of existing drugs for COVID-19. ResultsIn the first step of our study we identified, through a gene expression analysis, several drugs that could act on the biological pathways altered in COVID-19. In the second step, we performed a docking simulation in order to test the properties of the identified drugs to target the 3CL main protease of SARS-CoV-2. The drugs that showed higher binding affinity are bardoxolone (-8.78 kcal/ mol), Irinotecan (-8.40 kcal/mol) and Pyrotinib (-8.40 kcal/mol). Molecular dynamics simulations were carried out on the three selected drugs to validate the stability and interactions of the complexes. Among other promising drugs we found also AZD-8055, Olaparib, Tyrphostin AG 879, Topotecan Hydrochloride, MP-412, S-222611, Allitinib, 7-Ethyl-10-Hydroxy-Camptothecin, and Falnidamol. ConclusionsWe suggested some drugs that could efficient in COVID-19. However further studies are suggested to confirm the affinity of these drugs with 3CL main protease of SARS-CoV-2.

In this multi-center study, we provide a systematic evaluation of the clinical variability associated with paroxysmal sympathetic hyperactivity (PSH) in patients with acquired brain injury (ABI) to determine how these signs can impact outcomes. A total of 156 ABI patients with a disorder of consciousness (DoC) were admitted to neurorehabilitation subacute units (intensive rehabilitation unit; IRU) and evaluated at baseline (T0), after 4 months from event (T1), and at discharge (T2). The outcome measure was the Glasgow Outcome Scale-Extended, whereas age, sex, etiology, Coma Recovery Scale-Revised (CRS-r), Rancho Los Amigos Scale (RLAS), Early Rehabilitation Barthel Index (ERBI), PSH-Assessment Measure (PSH-AM) scores and other clinical features were considered as predictive factors. A machine learning (ML) approach was used to identify the best predictive model of clinical outcomes. The etiology was predominantly vascular (50.8%), followed by traumatic (36.2%). At admission, prevalence of PSH was 31.3%, which decreased to 16.6% and 4.4% at T1 and T2, respectively. At T2, 2.8% were dead and 61.1% had a full recovery of consciousness, whereas 36.1% remained in VS or MCS. A support vector machine (SVM)-based ML approach provides the best model with 82% accuracy in predicting outcomes. Analysis of variable importance shows that the most important clinical factors influencing the outcome are the PSH-AM scores measured at T0 and T1, together with neurological diagnosis, CRS-r, and RLAS scores measured at T0. This joint multi-center effort provides a comprehensive picture of the clinical impact of PSH signs in ABI patients, demonstrating its predictive value in comparison with other well-known clinical measurements.

Triple negative breast cancer (TNBC) accounts for about a fifth of all breast cancers and includes a diverse group of cancers. The heterogeneity of TNBC and the lack of target receptors on the cell surface make it difficult to develop specific therapeutic treatments. These aspects cause the high negative prognosis of patients with this type of tumor. The analysis of the molecular profiles of TNBC samples has allowed a better characterization of this tumor, supporting the search for new reliable diagnostic markers. To this end, we have developed a bioinformatic approach to integrate networks of genes differentially expressed in basal breast cancer compared to healthy tissues, with miRNAs able to regulate their expression. We studied the role of these miRNAs in TNBC subtype cell lines. We therefore identified two miRNAs, namely miR-135b and miR-365, with a central role in regulating the altered functional pathways in basal breast cancer. These two miRNAs are differentially expressed in human TNBC immunohistochemistry-selected tissues, and their modulation has been shown to play a role in the proliferation of tumor control and its migratory and invasive capacity in TNBC subtype cell lines. From the perspective of personalized medicine, we managed to modulate the expression of the two miRNAs in organotypic cultures, suggesting their possible use as diagnostic and therapeutic molecules. miR-135b and miR-365 have a key role in TNBC, controlling proliferation and invasion. Their detection could be helpful in TNBC diagnosis, while their modulation could become a new therapeutic tool for TNBC.

Coronavirus disease 2019 (COVID-19) is a contagious infectious disease caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). It manifests with variable clinical pictures ranging from asymptomatic to mild or uncomplicated illness to severe disease with possible multi-organ involvement, with respiratory and vascular systems being the most often affected. Since COVID-19 can affect patients with autoimmune rheumatic conditions, the concomitant presence of two diseases may have clinical characteristics whose knowledge may help facilitate clinical management. This review discusses the data available in the literature on COVID-19 in systemic lupus erythematosus (SLE) patients.

Objective: This study was undertaken to assess the impact of immunosuppressive and immunomodulatory therapies on the severity of coronavirus disease 2019 (COVID-19) in people with multiple sclerosis (PwMS). Methods: We retrospectively collected data of PwMS with suspected or confirmed COVID-19. All the patients had complete follow-up to death or recovery. Severe COVID-19 was defined by a 3-level variable: mild disease not requiring hospitalization versus pneumonia or hospitalization versus intensive care unit (ICU) admission or death. We evaluated baseline characteristics and MS therapies associated with severe COVID-19 by multivariate and propensity score (PS)-weighted ordinal logistic models. Sensitivity analyses were run to confirm the results. Results: Of 844 PwMS with suspected (n = 565) or confirmed (n = 279) COVID-19, 13 (1.54%) died; 11 of them were in a progressive MS phase, and 8 were without any therapy. Thirty-eight (4.5%) were admitted to an ICU; 99 (11.7%) had radiologically documented pneumonia; 96 (11.4%) were hospitalized. After adjusting for region, age, sex, progressive MS course, Expanded Disability Status Scale, disease duration, body mass index, comorbidities, and recent methylprednisolone use, therapy with an anti-CD20 agent (ocrelizumab or rituximab) was significantly associated (odds ratio [OR] = 2.37, 95% confidence interval [CI] = 1.18–4.74, p = 0.015) with increased risk of severe COVID-19. Recent use (

Background Patients affected by coxarthrosis may be treated surgically with total hip arthroplasty (THA). During the surgical intervention, the hip joint capsule can be completely removed, performing a capsulectomy. Otherwise it's possible to perform a capsulotomy, which allows for capsular conservation. Since there is no scientific evidence demonstrating the superiority of one method over the other, the choice whether to remove or conserve the capsule is at the surgeon's discretion and both procedures are actually accepted. The purpose of our study is to evaluate the differences in functional activities and proprioception in patients who underwent THA and capsulotomy with capsular conservation versus patients who underwent THA with capsulectomy. Methods In order to compare the two surgical techniques of capsulotomy with capsular conservation and capsulectomy, we created a randomized, controlled, double-blind, single-centre, non-pharmacological, interventional, superiority, parallel-group trial. The primary outcome of our study is evaluated using the HOOS scale (Hip disability and Osteoarthritis Outcome Score). Secondary outcomes are: the proprioceptive sensitivity, the postoperative bleeding, the surgical time, the active range of motion, and the ability to walk, sit and stand. The proprioception study is carried out through active and passive repositioning tests. THA is performed through the minimally invasive direct anterior approach. The evaluation tests are carried out in the 15 days preceding the intervention (T0), at 50-day post-operative (T1), and finally at three months after surgery (T2). Discussion Considering that the hip joint capsule is innervated by proprioceptive nerve endings, while the psuedocapsule that replaces the native capsule following a THA with capsulectomy doesn't have any active neurophysiological role, we hypothesize that capsulotomy with capsular conservation at the time of primary THA may lead to better proprioception and therefore better functional recovery. Trial registration ClinicalTrials.gov identifier: NCT02749058. Date of registration: 04/21/2016.

During homeostasis, interactions between tolerogenic dendritic cells (DCs), self-reactive T cells, and T regulatory cells (Tregs) contribute to maintaining mammalian immune tolerance. In response to infection, immunogenic DCs promote the generation of proinflammatory effector T cell subsets. When complex homeostatic mechanisms maintaining the balance between regulatory and effector functions become impaired, autoimmune diseases can develop. We discuss some of the newest advances on the mechanisms of physiopathologic homeostasis that can be employed to develop strategies to restore a dysregulated immune equilibrium. Some of these designs are based on selectively activating regulators of immunity and inflammation instead of broadly suppressing these processes. Promising approaches include the use of nanoparticles (NPs) to restore Treg control over self-reactive cells, aiming to achieve long-term disease remission, and potentially to prevent autoimmunity in susceptible individuals.

In vitro maturation (IVM) is an assisted reproduction technique with reduced hormone-related side-effects. Several attempts to implement IVM in routine practice have failed, primarily due to its relatively low efficiency compared with conventional in vitro fertilization (IVF). Recently, capacitation (CAPA)-IVM—a novel two-step IVM method—has improved the embryology outcomes through synchronizing the oocyte nuclear and cytoplasmic maturation. However, the efficiency gap between CAPA-IVM and conventional IVF is still noticeable especially in the numerical production of good quality embryos. Considering the importance of glucose for oocyte competence, its metabolization is studied within both in vivo and CAPA-IVM matured mouse cumulus-oocyte-complexes (COCs) through direct measurements in both cellular compartments, from transcriptional and translational perspectives, to reveal metabolic shortcomings within the CAPA-IVM COCs. These results confirmed that within in vivo COC, cumulus cells (CCs) are highly glycolytic, whereas oocytes, with low glycolytic activity, are deviating their glucose towards pentose phosphate pathway. No significant differences were observed in the CAPA-IVM oocytes compared with their in vivo counterparts. However, their CCs exhibited a precocious increase of glycolytic activity during the pre-maturation culture step and activity was decreased during the IVM step. Here, specific alterations in mouse COC glucose metabolism due to CAPA-IVM culture were characterized using direct measurements for the first time. Present data show that, while CAPA-IVM CCs are able to utilize glucose, their ability to support oocytes during final maturation is impaired. Future CAPA-IVM optimization strategies could focus on adjusting culture media energy substrate concentrations and/or implementing co-culture strategies.Summary sentence Pre-maturation culture conditions for immature oocytes from small antral follicles affect glycolytic activity and antioxidant defense capacity in mouse CCs during IVM.

Pesticides present in water resources can cause adverse health effects even in low concentrations, due to their bio-accumulative character. Therefore, the challenge for drinking water production increases, due to the limitations of conventional water treatment technologies in the removal of small molecular weight dissolved compounds. This work aimed to provide technical and scientific support for the selection of pulverized activated carbon - PACs, granular activated carbon - GACs, and carbon nanotubes - CNT concerning atrazine - ATZ, simazine - SMZ, and diuron - DIU adsorption for application in water treatment plants, considering two forms of application commercial product - CP and analytical standard - SD. These forms of application were tested aiming to verify the influence of the purity of the products used in experiments on the adsorption efficiency. It was possible to verify the adsorption efficiencies were not guided only by the characteristics of the adsorptive materials used, and that the selection should not be carried out only based on the, specific superficial area - BET size and distribution of specific pore volume. The isotherms demonstrated that the parameter Kf associated with the results of the selection experiment can be considered an alternative technical tool of simple application and sufficient for this purpose. Also, the capacity of activated carbons - ACs and nanomaterials - NMs were affected by the application of the compounds, highlighting the importance of using commercial product - CP in scientific research and technical investigations.

Hypertrophic cardiomyopathy (HCM) and Long QT Syndrome (LQTS) are inherited diseases characterized by a wide genetic heterogeneity. Based on the separate incidence of these pathologies and on the absence of linkage, the occurrence of both diseases in the same individual has an incidence of about 1/250000. We describe a rare case report of a 24 years-old patient with maternal familiarity for type 1 LQTS (mother carrier of KCNQ1 c.1781G>A) and paternal familiarity for HCM (father carrier of TNNI3 c.592C>G mutation) who inherited both gene mutations and was diagnosed with HCM and LQTS later in adolescence, after clinical and genetic evaluations.

Novel poly(vinyl alcohol)/chondroitin sulfate (PVA/CS) composite hydrogels containing hydroxyapatite (HA) or Sr-doped HA (HASr) particles were synthesized by a freeze/thaw method and characterized aiming towards biomedical applications. HA and HASr were synthesized by a wet-precipitation method and added to the composite hydrogels in fractions up to 15 wt%. Physical-chemical characterizations of particles and hydrogels included scanning electron microscopy, energy-dispersive spectroscopy, Fourier-transform infrared spectroscopy, X-ray diffraction, thermogravimetry, porosity, compressive strength/elastic modulus, swelling degree, and cell viability. Particles were irregular in shape and appeared to have narrow size variation. The thermal behavior of composite hydrogels was altered compared to the control (bare) hydrogel. All hydrogels exhibited high porosity. HA/HASr particles reduced total porosity without reducing pore size. The mechanical strength was improved as the fraction of HA or HASr was increased. HASr particles led to a faster water uptake but did not interfere with the total hydrogel swelling capacity. In cell viability essay, increased cell growth (above 120%) was observed in all groups including the control hydrogel, suggesting a bioactive effect. In conclusion, PVA/CS hydrogels containing HA or HASr particles were successfully synthesized and showed promising morphological, mechanical, and swelling properties, which are particularly required for scaffolding.

Resumen Objetivos El punto de corte utilizado del CYFRA 21-1 como marcador tumoral influye considerablemente en su utilidad diagnóstica y pronóstica. El objetivo de este estudio es establecer un punto de corte óptimo de CYFRA 21-1 que tenga validez diagnóstica, determinado con la tecnología Lumipulse® en pacientes con sospecha de cáncer. El objetivo secundario de este estudio es determinar si los niveles de CYFRA 21-1 tienen valor pronóstico. Métodos Se llevó a cabo un estudio retrospectivo en una muestra compuesta por 284 pacientes con sospecha de enfermedad maligna procedentes de seis hospitales de Madrid. El punto de corte se obtuvo mediante la curva ROC y el test de Youden. La validez diagnóstica se evaluó de acuerdo con la sensibilidad, especificidad, valores predictivos y ratios de probabilidad. El valor pronóstico de CYFRA 21-1 se determinó por medio de la regresión logística múltiple. Se confirmaron un total de 32 casos de cáncer. Resultados El punto de corte más óptimo fue 3,15 ng/mL. Este punto de corte mostró mejor especifidad, de 93,63% (89,66–96,16; IC 95%), Valor Predictivo Positivo (44,54–75,38; IC 95%) y Razón de Probabilidad Positiva 12,65 (7,64–20,95; IC 95%) que el punto de corte recomendado por Fujirebio® (1,8 ng/mL); con una especifidad de 73,71% (67,72–78,95; IC 95%), Valor Predictivo Positivo: 29,79% (21,02–40,23; IC 95%) y una Razón de Probabilidad Positiva de 3,43 (2,71–4,35; IC 95%), mejorando la precisión diagnóstica actual. En el análisis multivariante, se confirmó que los niveles elevados de CYFRA 21-1 (>3,15 ng/mL) son un factor pronóstico desfavorable. Conclusiones El mejor punto de corte obtenido para CYFRA 21-1 fue de 3,15 ng/mL en pacientes con sospecha de cáncer. Este nuevo punto de corte reduce la tasa de falsos positivos y mejora la eficacia diagnóstica de CYFRA 21-1 como marcador tumoral, así como su asociación con la mortalidad.

Objectives Chosen cutoff for cytokeratin 19 fragment antigen (CYFRA 21-1) as a tumor biomarker considerably influences its diagnostic and prognostic usefulness. The aim of the present study is to determine an optimal cutoff value for diagnostic validity of CYFRA 21-1 by Lumipulse ® technology in patients with suspected cancer and also to determine if CYFRA 21-1 levels provide prognostic value. Methods A consecutive 284 patients suggestive of malignant disease from six hospitals of Madrid were enrolled in a retrospective design. Optimal CYFRA 21-1 cutoff value was obtained by receiver operating characteristic curve and Youden test. The diagnostic validity was evaluated according to sensitivity, specificity, predictive values and likelihood ratios. The prognostic value of CYFRA 21-1 was checked using multiple logistic regression. Thirty-two diagnostic cancers were confirmed. Results The most optimal cutoff was 3.15 ng/mL. This cutoff showed a better specificity 93.63% (95% confidence interval [CI], 89.66–96.16), positive predictive value 60.98% (95% CI, 44.54–75.38) and positive likelihood ratio 12.65 (95% CI, 7.64–20.95) than the cutoff recommended by Fujirebio® (1.8 ng/mL) (specificity: 73.71% [95% CI, 67.72–78.95], positive predictive value: 29.79% [95% CI, 21.02–40.23] and positive likelihood ratio 3.43 [95% CI, 2.71–4.35]), improving the current diagnostic accuracy. In multivariate analysis, elevated levels of CYFRA 21-1 (>3.15 ng/mL) was confirmed as an unfavorable prognostic factor. Conclusions The best cutoff for CYFRA 21-1 obtained was 3.15 ng/mL in patients with suspected cancer. This new cutoff decreases the false positive rate and improves the diagnostic efficacy of CYFRA 21-1 as a tumor marker as well as its association with death events.

Automatic control of physiological variables is one of the most active areas in biomedical engineering. This paper is centered in the prediction of the analgesic variables evolution in patients undergoing surgery. The proposal is based on the use of hybrid intelligent modelling methods. The study considers the Analgesia Nociception Index (ANI) to assess the pain in the patient and remifentanil as intravenous analgesic. The model proposed is able to make a one-step-ahead prediction of the remifentanil dose corresponding to the current state of the patient. The input information is the previous remifentanil dose, the ANI variable and the electromyogram signal. Modelling techniques used are Artificial Neural Networks and Support Vector machines for Regression combined with clustering methods. Both training and validation were done with a real dataset from different patients. Results obtained show the potential of this methodology to calculate the drug dose corresponding to a given analgesic state of the patient.

Background Prostatic artery embolization (PAE) is a minimally invasive technique for the management of symptomatic benign prostatic hyperplasia (BPH) relieving the lower urinary tract symptoms in patients. Various embolic agents have been tested in animal models and subsequently used in human patients. The purpose of this study was to evaluate the technical feasibility, effectiveness, and safety of PAE with polyethylene glycol microspheres in a canine spontaneous BPH model. Results Five adult male Beagle dogs (4.78 ± 1.11 years) were diagnosed by tranrectal ultrasonography of spontaneous BPH (prostate volume > 18 ml) and underwent PAE with polyethylene glycol microspheres (400 ± 75 μm). PAE procedures were performed successfully in all dogs. After PAE, all dogs were inspected for potential procedure-related complications during 1 month of follow-up. No major complications were observed any animal. Follow-up angiography was performed in each animal at 1 month of follow-up. Recanalization was demonstrated in all the embolized prostatic arteries or main branches at the end of the study. Magnetic Resonance Imaging (MRI) evaluations were performed immediately before PAE as baseline data, and 1 week, 2 weeks and 1 month after PAE. MRI study showed that the prostate shrank substantially with ischemic necrosis in each dog. There was a significant reduction in the mean prostate volume at 2 weeks and 1 month compared with the baseline data, from 19.95 ± 1.89 mL to 13.14 ± 2.33 and 9.35 ± 2.69 mL (p Conclusions The findings of the present study support that PAE with the use of polyethylene glycol microspheres is a safe and feasible procedure that may induce a significant shrinkage of prostate due to the local ischemia and secondary glandular atrophy. Early recanalization of target arteries remains to be further addressed in both laboratory investigation and clinical practice.

The purpose of this study was threefold: i) to analyse the load-velocity relationship of the shoulder press (SP) exercise, ii) to investigate the stability (intra-individual variability) of this load-velocity relationship for athletes with different relative strength levels, and after a 10-week velocity-based resistance training (VBT), and iii) to describe the velocity-time pattern of the SP: first peak velocity [V max1 ], minimum velocity [V min ], and second peak velocity [V max2 ]. This study involves a cross-sectional (T1, n = 48 subjects with low, medium and high strength levels) and longitudinal (T2, n = 24 subjects randomly selected from T1 sample) design. In T1, subjects completed a progressive loading test up to the 1RM in the SP exercise. The barbell mean, peak and mean propulsive velocities (MV, PV and MPV) were monitored. In T2, subjects repeated the loading test after 10 weeks of VBT. There were very close relationships between the %1RM and velocity attained in the three velocity outcomes (T1, R2 : MV = 0.970; MPV = 0.969; PV = 0.954), being even stronger at the individual level (T1, R2 = 0.973–0.997). The MPV attained at the 1RM (~0.19 m·s-1) was consistent among different strength levels. Despite the fact that 1RM increased ~17.5% after the VBT programme, average MPV along the load-velocity relationship remained unaltered between T1 and T2 (0.69 ± 0.06 vs. 0.70 ± 0.06 m·s-1). Lastly, the three key parameters of the velocity-time curve were detected from loads > 74.9% 1RM at 14.3% (V max1 ), 46.1% (V min ), and 88.7% (V max2 ) of the concentric phase. These results may serve as a practical guideline to effectively implement the velocity-based method in the SP exercise.

Objetivos: Conhecer o processo de implementação da lista de verificação de cirurgia segura e Analisar o processo de implementação da lista de verificação de cirurgia segura em centro cirúrgico de um hospital federal, através da matriz SWOT. Métodos: Trata-se de um estudo descritivo e exploratório, com abordagem quanti-qualitativa. Os dados foram obtidos através de um questionário, com amostra de 56 participantes. O cenário foi o centro cirúrgico de um Hospital Federal situado no Município do Rio de Janeiro. Resultados: O processo de implementação da lista ainda não está implantado de forma sistemática e consistente; constatou-se a necessidade de implementação da lista em todos os procedimentos cirúrgicos, onde destaca-se as responsabilidades dos líderes e gestores na adoção de processo para cirurgia segura. Considerações finais: Foi evidenciada a importância atribuída à implementação da lista de verificação de cirurgia segura, considerada como estratégia para melhoria da segurança do paciente e minimização de erros.

This article analyzes the research on cryptocurrency and blockchain technology and the alternate banking system, led by giants like Bitcoin and Ethereum, and its potential utility for the millions of migrants living in working around the globe, who send nearly half a trillion dollars through various formal and informal channels to family and friends in their home countries. While research on migrant remittances is well established and has been examined from many different lenses, including economic, political, financial, sociological and entrepreneurial, there are few studies to date that examine how the growing crypto-blockchain channel can impact remittance flows, as a lower cost alternative to MoneyGram and Western Union, which have high transaction costs, and also considering that many migrants do not have formal bank accounts, eliminating formal bank transfers, and also that many migrants hold a vulnerable legal status, and may avoid formal money transfer channels. This article is exploratory in nature and identifies the work that has been done to date on this topic, and identifies potential future research in the area.

Autoimmune diseases are disorders of immune regulation where the mechanisms responsible for self-tolerance break down and pathologic T cells overcome the protective effects of T regulatory cells (Tregs) that normally control them. The result can be the initiation of chronic inflammatory diseases. Systemic lupus erythematosus (SLE) and other autoimmune diseases are generally treated with pharmacologic or biological agents that have broad suppressive effects. These agents can halt disease progression, yet rarely cure while carrying serious adverse side effects. Recently, nanoparticles have been engineered to correct homeostatic regulatory defects and regenerate therapeutic antigen-specific Tregs. Some approaches have used nanoparticles targeted to antigen presenting cells to switch their support from pathogenic T cells to protective Tregs. Others have used nanoparticles targeted directly to T cells for the induction and expansion of CD4+ and CD8+ Tregs. Some of these T cell targeted nanoparticles have been formulated to act as tolerogenic artificial antigen presenting cells. This article discusses the properties of these various nanoparticle formulations and the strategies to use them in the treatment of autoimmune diseases. The restoration and maintenance of Treg predominance over effector cells should promote long-term autoimmune disease remission and ultimately prevent them in susceptible individuals.

Artificial antigen-presenting cells (aAPCs) are synthetic versions of naturally occurring antigen-presenting cells (APCs) that, similar to natural APCs, promote efficient T effector cell responses in vitro. This report describes a method to produce acellular tolerogenic aAPCs made of biodegradable poly lactic-co-glycolic acid (PLGA) nanoparticles (NPs) and encapsulating IL-2 and TGF-β for a paracrine release to T cells. We document that these aAPCs can induce both human CD4+ and CD8+ T cells to become FoxP3+ T regulatory cells (Tregs). The aAPC NP-expanded human Tregs are functional in vitro and can modulate systemic autoimmunity in vivo in humanized NSG mice. These findings establish a proof-of-concept to use PLGA NPs as aAPCs for the induction of human Tregs in vitro and in vivo, highlighting the immunotherapeutic potential of this targeted approach to repair IL-2 and/or TGF-β defects documented in certain autoimmune diseases such as systemic lupus erythematosus.

This review summarizes the pleiotropic functions of leptin, whose capability to regulate both energy homeostasis and inflammation has unveiled the biological determinants of human obesity and the interconnection among dysmetabolic conditions, the onset of autoimmune diseases, and cancer in more affluent countries., The discovery of the archetypal adipocytokine leptin and how it regulates energy homeostasis have represented breakthroughs in our understanding of the endocrine function of the adipose tissue and the biological determinants of human obesity. Investigations on leptin have also been instrumental in identifying physio-pathological connections between metabolic regulation and multiple immunological functions. For example, the description of the promoting activities of leptin on inflammation and cell proliferation have recognized the detrimental effects of leptin in connecting dysmetabolic conditions with cancer and with onset and/or progression of autoimmune disease. Here we review the multiple biological functions and complex framework of operations of leptin, discussing why and how the pleiotropic activities of this adipocytokine still pose major hurdles in the development of effective leptin-based therapeutic opportunities for different clinical conditions.

Objectives: To determine the time to reverse transcription-polymerase chain reaction (RT-PCR) negativity after the first positive RT-PCR test, factors associated with longer time to RT-PCR negativity, proportion of children seroconverting after proven severe acute respiratory syndrome coronavirus 2 infection, and factors associated with the lack of seroconversion. Study design: The Epidemiological Study of Coronavirus in Children of the Spanish Society of Pediatrics is a multicenter study conducted in Spanish children to assess the characteristics of coronavirus disease 2019. In a subset of patients, 3 serial RT-PCR tests on nasopharyngeal swab specimens were performed after the first RT-PCR test, and immunoglobulin G serology for severe acute respiratory syndrome coronavirus 2 antibodies was performed in the acute and follow-up (

Breast cancer is a heterogeneous disease classified into four main subtypes with different clinical outcomes, such as patient survival, prognosis, and relapse. Current genetic tests for the differential diagnosis of BC subtypes showed a poor reproducibility. Therefore, an early and correct diagnosis of molecular subtypes is one of the challenges in the clinic. In the present study, we identified differentially expressed genes, long non-coding RNAs and RNA binding proteins for each BC subtype from a public dataset applying bioinformatics algorithms. In addition, we investigated their interactions and we proposed interacting biomarkers as potential signature specific for each BC subtype. We found a network of only 2 RBPs (RBM20 and PCDH20) and 2 genes (HOXB3 and RASSF7) for luminal A, a network of 21 RBPs and 53 genes for luminal B, a HER2-specific network of 14 RBPs and 30 genes, and a network of 54 RBPs and 302 genes for basal BC. We validated the signature considering their expression levels on an independent dataset evaluating their ability to classify the different molecular subtypes with a machine learning approach. Overall, we achieved good performances of classification with an accuracy >0.80. In addition, we found some interesting novel prognostic biomarkers such as RASSF7 for luminal A, DCTPP1 for luminal B, DHRS11, KLC3, NAGS, and TMEM98 for HER2, and ABHD14A and ADSSL1 for basal. The findings could provide preliminary evidence to identify putative new prognostic biomarkers and therapeutic targets for individual breast cancer subtypes. The research leading to these results has been supported by European Research Council grant agreements RIBOMYLOME (309545) and ASTRA (855923), and the European Union’s Horizon 2020 research and innovation programme grant agreements IASIS (727658), DeepRNA (793135), and INFORE (825080). We would like to thank for the financial support the project Grant SysBioNet, Italian Roadmap Research Infrastructures 2012.

Gram-negative bacteria resist external stresses due to cell envelope rigidity, which is provided by two membranes and a peptidoglycan layer. The outer membrane (OM) surface contains lipopolysaccharide (LPS; contains O-antigen) or lipooligosaccharide (LOS). LPS/LOS are essential in most Gram-negative bacteria and may contribute to cellular rigidity. Acinetobacter baumannii is a useful tool for testing these hypotheses as it can survive without LOS. Previously, our group found that strains with naturally high levels of penicillin binding protein 1A (PBP1A) could not become LOS deficient unless the gene encoding it was deleted, highlighting the relevance of peptidoglycan biosynthesis and suggesting that high PBP1A levels were toxic during LOS deficiency. Transposon sequencing and follow-up analysis found that axial peptidoglycan synthesis by the elongasome and a peptidoglycan recycling enzyme, ElsL, were vital in LOS-deficient cells. The toxicity of high PBP1A levels during LOS deficiency was clarified to be due to a negative impact on elongasome function. Our data suggest that during LOS deficiency, the strength of the peptidoglycan specifically imparted by elongasome synthesis becomes essential, supporting that the OM and peptidoglycan contribute to cell rigidity. IMPORTANCE Gram-negative bacteria have a multilayered cell envelope with a layer of cross-linked polymers (peptidoglycan) sandwiched between two membranes. Peptidoglycan was long thought to exclusively provide rigidity to the cell providing mechanical strength. Recently, the most outer membrane of the cell was also proposed to contribute to rigidity due to properties of a unique molecule called lipopolysaccharide (LPS). LPS is located on the cell surface in the outer membrane and is typically required for growth. By using Acinetobacter baumannii, a Gram-negative bacterium that can grow without LPS, we found that key features of the peptidoglycan structure also become essential. This finding supports that both the outer membrane and peptidoglycan contribute to cell rigidity.

Patients recovering from COVID-19 commonly report persistence of dyspnea, exertional fatigue, and difficulties in carrying out their daily activities. However, the nature of these symptoms is still unknown. The purpose of the study was to identify limiting causes of cardiopulmonary origin for the performance of physical exercise in post-COVID-19 condition that could explain the symptomatic persistence of dyspnea or fatigue-related symptoms. Thirty-two non-hospitalized patients with post-COVID-19 condition (i.e., still presenting a chronic symptomatic phase lasting &gt, 90 days since debut of symptoms that lasted for at least 2 months and cannot be explained by an alternative diagnosis) completed a clinical examination including echocardiography, submaximal and maximal cardiorespiratory fitness tests (Ekblom-Bak and Bruce’s protocols), and a battery of validated questionnaires about fatigue and exercise intolerance. Four participants (12.5%) reported an abnormal cardiac response to exercise during the submaximal test, which aroused suspicion of the presence of chronotropic incompetence. All of them were confirmed with a positive diagnosis maximal exercise test after cardiology screening, even with a comprehensive clinical examination, resting ECG, and echocardiogram, without other findings. No statistical differences were found in any physiological variables or questionnaire values, between patients with positive and negative diagnoses. Chronotropic incompetence and other autonomic disorders may appear in patients with mild forms of COVID-19 presentation and may persist in the long term, being responsible for exercise intolerance after resolution of acute infection. Clinicians should be aware that chronotropic incompetence and other autonomic disorders may be a complication of COVID-19 and should consider appropriate diagnostic and therapeutic interventions in these patients, especially when early exercise-related fatigability is reported.

Background: The MuSC-19 project is an Italian cohort study open to international partners that collects data on multiple sclerosis (MS) patients with COVID-19. During the second wave of the pandemic, serological tests became routinely available. Objective: To evaluate the seroprevalence of anti-SARS-CoV-2 antibodies according to the use of disease-modifying therapy (DMT) in a subset of patients included in the MuSC-19 data set who had undergone a serological test. Methods: We evaluated the association between positive serological test results and time elapsed since infection onset, age, sex, Expanded Disability Status Scale score, comorbidities and DMT exposure using a multivariable logistic model. Results: Data were collected from 423 patients (345 from Italy, 61 from Turkey and 17 from Brazil) with a serological test performed during follow-up. Overall, 325 out of 423 tested patients (76.8%) had a positive serological test. At multivariate analysis, therapy with anti-CD20 was significantly associated with a reduced probability of developing antibodies after COVID-19 (odds ratio (OR) = 0.20, p = 0.002). Conclusion: Patients with MS maintain the capacity to develop humoral immune response against SARS-COV-2, although to a lesser extent when treated with anti-CD20 drugs. Overall, our results are reassuring with respect to the possibility to achieve sufficient immunization with vaccination.

Background: It is unclear how multiple sclerosis (MS) affects the severity of Covid-19. Methods: Hospitalization, Intensive Care Unit (ICU) admission and death after Covid-19 diagnosis of 1362 MS patients were compared to the age and sex-matched Italian population in a retrospective observational case-cohort study with population-based control. The observed vs the expected events were compared in the whole MS cohort and in different subgroups (higher-risk: EDSS>3 or at least one comorbidity, lower-risk: EDSS

We recently reported that the treatment with nanoparticles (NPs) loaded with tolerogenic cytokines suppressed the manifestations of lupus-like disease induced by the transfer of donor CD4+ T cells from DBA/2 mice into (C57BL/6 × DBA/2)F1 (BDF1) mice. Although the protective effects were ascribed to the induction of adaptive CD4+ and CD8+ T regulatory cells, the results suggested that another population of immune cells could be involved. Here we report that NK cells critically contribute to the protection from lupus-like disease conferred by NPs to BDF1 mice, and that this effect is TGF-β-dependent.

Background Systemic lupus erythematosus (SLE) is a chronic autoimmune disease characterized by the presence of autoantibodies to multiple self-antigens, including heat shock proteins (HSP). Because of the increased expression of HSP90 and abnormal immune responses to it in SLE, we investigated whether an HSP90 DNA vaccine could modulate the development and clinical manifestations of SLE in lupus-prone mice. Methods (NZB x NZW)F1 (NZB/W) mice were vaccinated with DNA constructs encoding HSP90 or control plasmids or vehicle. The mice were then monitored for survival, circulating anti-dsDNA autoantibodies, and immune phenotypes. Renal disease was evaluated by immunohistochemistry and by the measurement of proteinuria. Results Vaccination with HSP90 DNA reduced lupus disease manifestations and prolonged the survival of NZB/W mice. The protective effects of the HSP90 DNA vaccine associated with the induction of tolerogenic dendritic cells (DCs) and an expansion of T regulatory cells (Tregs). Conclusions The beneficial effects of DNA vaccination with HSP90 in murine SLE support the possibility of HSP90-based therapeutic modalities of intervention in SLE.

To understand neutrophil impairment in the progression from MGUS through active MM, we investigated the function of mature, high-density neutrophils (HDNs), isolated from peripheral blood. In 7 MM, 3 MGUS and 3 healthy subjects by gene expression profile, we identified a total of 551 upregulated and 343 downregulated genes in MM-HDN, involved in chemokine signaling pathway and FC-gamma receptor mediated phagocytosis conveying in the activation of STAT proteins. In a series of 60 newly diagnosed MM and 30 MGUS patients, by flow-cytometry we found that HDN from MM, and to a lesser extend MGUS, had an up-regulation of the inducible FcγRI (also known as CD64) and a down-regulation of the constitutive FcγRIIIa (also known as CD16) together with a reduced phagocytic activity and oxidative burst, associated to increased immune-suppression that could be reverted by arginase inhibitors in co-culture with lymphocytes. In 43 consecutive newly-diagnosed MM patients, who received first-line treatment based on bortezomib, thalidomide and dexamethasone, high CD64 could identify at diagnosis patients with inferior median overall survival (39.5 versus 86.7 months, p = 0.04). Thus, HDNs are significantly different among healthy, MGUS and MM subjects. In both MGUS and MM neutrophils may play a role in supporting both the increased susceptibility to infection and the immunological dysfunction that leads to tumor progression.

Supplemental Digital Content is available in the text., Background and Purpose— Autoimmune responses can occur when antigens from the central nervous system are presented to lymphocytes in the periphery or central nervous system in several neurological diseases. However, whether autoimmune responses emerge after brain ischemia and their impact on clinical outcomes remains controversial. We hypothesized that brain ischemia facilitates the genesis of autoimmunity and aggravates ischemic brain injury. Methods— Using a mouse strain that harbors a transgenic T-cell receptor to a central nervous system antigen, MOG35-55 (myelin oligodendrocyte glycoprotein) epitope (2D2), we determined the anatomic location and involvement of antigen-presenting cells in the development of T-cell reactivity after brain ischemia and how T-cell reactivity impacts stroke outcome. Transient middle cerebral artery occlusion and photothrombotic stroke models were used in this study. We also quantified the presence and status of T cells from brain slices of ischemic patients. Results— By coupling transfer of labeled MOG35-55-specific (2D2) T cells with tetramer tracking, we show an expansion in reactivity of 2D2 T cells to MOG91-108 and MOG103-125 in transient middle cerebral artery occlusion and photothrombotic stroke models. This reactivity and T-cell activation first occur locally in the brain after ischemia. Also, microglia act as antigen-presenting cells that effectively present MOG antigens, and depletion of microglia ablates expansion of 2D2 reactive T cells. Notably, the adoptive transfer of neuroantigen-experienced 2D2 T cells exacerbates Th1/Th17 responses and brain injury. Finally, T-cell activation and MOG-specific T cells are present in the brain of patients with ischemic stroke. Conclusions— Our findings suggest that brain ischemia activates and diversifies T-cell responses locally, which exacerbates ischemic brain injury.

The Unit (COU) of Microbiology and Virology of Sandro Pertini Hospital began monitoring the immune response on a cohort of healthcare operators who received the Pfizer/BioNTech BNT162b2 vaccine. Three different tests for the detection of antibodies against SARS-CoV-2 were used showing 100% of seroconversion after 28 days from the first dose.

Introduction/Background* Mutations in BRCA-genes have been identified as predisposing to hereditary breast and ovarian cancers. Little is known about how ovarian cancer risks differs across different BRCA mutation type. The purpose of our study is to identify the correlation between specific type of BRCA mutations and (1) age of onset of high-grade serous ovarian cancer (HGSOC) and (2) patients’ survival. Methodology Retrospective multicentric series of newly diagnosed HGSOC-patients with FIGO Stage III-IV, assessed for germline (g)BRCA status. BRCA gene mutations were classified into 5 groups: deletion, insertion, no-sense, missense and splicing. Result(s)* A total of 214 patients were included in the analysis. 143 (67.1%) had a gBRCA1-pathogenic variant (PV) and 71 (33.1%) had a gBRCA2-PV. Overall, the mean age of onset was 54.75 years (10.9 SD) with a difference of around 4 years between patients having BRCA 1 and BRCA2 mutations (53yrs, SD 10.9 vs. 57.2yrs, SD 10.5; p=0.018). The most frequent mutation found was deletion (42.9%). Patients with no-sense mutation (18.2%) had the youngest age of onset, both in BRCA1 and BRCA2 subgroups, with an earlier occurrence of around 6 and 4 years respectively (BRCA1 group: 48.8yrs, SD 9.7 vs.54.7yrs, SD10.9; p=0.008) (BRCA2 group 53.0yrs SD 5.5 vs. 57.9yrs SD 10.9; p=0.04). Women with insertion (18.7%) had the oldest age of onset, both in BRCA 1 (57.7yrs, SD 11.7 vs. 52.2yrs, SD10.6; p=0.028) and BRCA2 (59.6yrs SD 10.1 vs. 56.6yrs SD 10.6) subgroups (p=ns) (table 1). No statistically significant difference in overall survival was found among the 5 groups examined (figure 1). Conclusion* Our study highlights for the first time that different types of BRCA mutations could indicate a different age for OC onset. If confirmed in larger series, it might have a relevant clinical impact, leading to a more tailored approach for risk-reducing surgery strategies for OC prevention. Moreover, as we initially include only advanced stages in our analysis, further investigation on the time of onset of early BRCA mutated OC is currently ongoing.

Objetivo: analisar o desempenho dos discentes submetidos a treinamento sobre a atuação do enfermeiro no processo hemoterápico, em comparação com os que não receberam treinamento. Método: Trata-se de uma pesquisa exploratória, de abordagem quantitativa. Para a coleta de dados, utilizou-se um questionário estruturado com discentes de graduação em enfermagem do último ano de curso e submetido a análise estatística descritiva. Resultados: os alunos que participaram do treinamento obtiveram maiores resultados positivos do que aqueles que não participaram, salientando a importância de investir na abordagem do tema durante a graduação em enfermagem, especialmente nos estágios supervisionados, reforçando os conhecimentos adquiridos, alcançando os níveis máximos para qualidade assistencial. Conclusão: Através dos resultados obtidos, evidenciou-se a necessidade de maior ênfase sobre a temática no decorrer da finalização do curso, de modo a garantir uma assistência segura.

The hospital-acquired pathogen Acinetobacter baumannii possesses a complex cell envelope that is key to its multidrug resistance and virulence. The bacterium, however, lacks many canonical enzymes that build the envelope in model organisms. Instead, A. baumannii contains a number of poorly annotated proteins that may allow alternative mechanisms of envelope biogenesis. We demonstrated previously that one of these unusual proteins, ElsL, is required for cell elongation and for withstanding antibiotics that attack the septal cell wall. Curiously, ElsL is composed of a leaderless YkuD-family domain usually found in secreted, cell-wall-modifying L,D-transpeptidases (LDTs). Here, we show that, rather than being an LDT, ElsL is actually a new class of cytoplasmic L,D-carboxypeptidase (LDC) that provides a critical step in cell-wall recycling previously thought to be missing from A. baumannii. Absence of ElsL impairs cell wall integrity, elongation, and intrinsic resistance due to buildup of murein tetrapeptide precursors, toxicity of which is bypassed by preventing muropeptide recycling. Multiple pathways in the cell become sites of vulnerability when ElsL is inactivated, including L,D-crosslink formation, cell division, and outer membrane lipid homoeostasis, reflecting its pleiotropic influence on cell envelope physiology. We thus reveal a novel class of cell-wall-recycling LDC critical to growth and homeostasis of A. baumannii and likely many other bacteria.ImportanceTo grow efficiently, resist antibiotics, and control the immune response, bacteria recycle parts of their cell wall. A key step in the typical recycling pathway is the reuse of cell wall peptides by an enzyme known as an LDC. Acinetobacter baumannii, an “urgent-threat” pathogen causing drug-resistant sepsis in hospitals, was previously thought to lack this enzymatic activity due to absence of a known LDC homolog. Here, we show that A. baumannii possesses this activity in the form of an enzyme class not previously associated with cell wall recycling. Absence of this protein intoxicates and weakens the A. baumannii cell envelope in multiple ways due to the accumulation of dead-end intermediates. Several other organisms of importance to health and disease encode homologs of the A. baumannii enzyme. This work thus reveals an unappreciated mechanism of cell wall recycling, manipulation of which may contribute to enhanced treatments targeting the bacterial envelope.

Purpose Lafora disease is a genetic neurodegenerative metabolic disorder caused by insoluble polyglucosan aggregate accumulation throughout the central nervous system and body. The retina is an accessible neural tissue, which may offer alternative methods to assess neurological diseases quickly and noninvasively. In this way, noninvasive imaging may provide a means to characterize neurodegenerative disease, which enables earlier identification and diagnosis of disease and the ability to monitor disease progression. In this study, we sought to characterize the retina of individuals with Lafora disease using non-invasive retinal imaging. Methods One eye of three individuals with genetically confirmed Lafora disease were imaged with optical coherence tomography (OCT) and adaptive optics scanning light ophthalmoscopy (AOSLO). When possible, OCT volume and line scans were acquired to assess total retinal thickness, ganglion cell-inner plexiform layer thickness, and outer nuclear layer + Henle fiber layer thickness. OCT angiography (OCTA) scans were acquired in one subject at the macula and optic nerve head (ONH). AOSLO was used to characterize the photoreceptor mosaic and examine the retinal nerve fiber layer (RNFL). Results Two subjects with previous seizure activity demonstrated reduced retinal thickness, while one subject with no apparent symptoms had normal retinal thickness. All other clinical measures, as well as parafoveal cone density, were within normal range. Nummular reflectivity at the level of the RNFL was observed using AOSLO in the macula and near the ONH in all three subjects. Conclusions This multimodal retinal imaging approach allowed us to observe a number of retinal structural features in all three individuals. Most notably, AOSLO revealed nummular reflectivity within the inner retina of each subject. This phenotype has not been reported previously and may represent a characteristic change produced by the neurodegenerative process.

Introduction: Given that the success of vaccines against coronavirus disease 2019 (COVID-19) relies on herd immunity, identifying patients at risk for vaccine hesitancy is imperative—particularly for those at high risk for severe COVID-19 (i.e., minorities and patients with neurological disorders). Methods: Among patients from a large neuroscience institute in Hawaii, vaccine hesitancy was investigated in relation to over 30 sociodemographic variables and medical comorbidities, via a telephone quality improvement survey conducted between 23 January 2021 and 13 February 2021. Results: Vaccine willingness (n = 363) was 81.3%. Univariate analysis identified that the odds of vaccine acceptance reduced for patients who do not regard COVID-19 as a severe illness, are of younger age, have a lower Charlson Comorbidity Index, use illicit drugs, or carry Medicaid insurance. Multivariable logistic regression identified the best predictors of vaccine hesitancy to be: social media use to obtain COVID-19 information, concerns regarding vaccine safety, self-perception of a preexisting medical condition contraindicated with vaccination, not having received the annual influenza vaccine, having some high school education only, being a current smoker, and not having a prior cerebrovascular accident. Unique amongst males, a conservative political view strongly predicted vaccine hesitancy. Specifically for Asians, a higher body mass index, while for Native Hawaiians and other Pacific Islanders (NHPI), a positive depression screen, both reduced the odds of vaccine acceptance. Conclusion: Upon identifying the variables associated with vaccine hesitancy amongst patients with neurological disorders, our clinic is now able to efficiently provide ancillary COVID-19 education to sub-populations at risk for vaccine hesitancy. While our results may be limited to the sub-population of patients with neurological disorders, the findings nonetheless provide valuable insight to understanding vaccine hesitancy.

The peptidoglycan cell wall is a predominant defining structure of bacteria, determining cell shape and supporting survival in diverse conditions. As a single, macromolecular sacculus enveloping the bacterial cell during growth and division, peptidoglycan is necessarily a dynamic structure that requires highly regulated synthesis of new material, remodeling, and turnover, or autolysis, of old material. Despite ubiquitous clinical exploitation of peptidoglycan synthesis as an antibiotic target, much remains unknown about how bacteria modulate synthetic and autolytic processes. Here, we couple bacterial genetics in Vibrio cholerae with compositional analysis of soluble pools of peptidoglycan turnover products to uncover a critical role for a widely misunderstood class of autolytic enzymes, the lytic transglycosylases (LTGs). We demonstrate that LTG activity is specifically required for vegetative growth. The vast majority of LTGs, however, are dispensable for growth, and defects that are ultimately lethal accumulate due to generally inadequate LTG activity, rather than the absence of specific individual enzymes. Consistent with this, we found that a heterologously expressed E. coli LTG, MltE, is capable of sustaining V. cholerae growth in the absence of endogenous LTGs. Lastly, we demonstrate that soluble, uncrosslinked, endopeptidase-dependent peptidoglycan chains accumulate in the WT, and, to a higher degree, in LTG mutants, and that LTG mutants are hyper-susceptible to the production of diverse periplasmic polymers. Collectively, our results suggest that a key function of LTGs is to prevent toxic crowding of the periplasm with synthesis-derived PG fragments. Contrary to prevailing models, our data further suggest that this process can be temporally separate from peptidoglycan synthesis.

Human epidermal growth factor receptor 2 (HER2) is overexpressed/amplified in one third of breast cancers (BCs), and is associated with the poorer prognosis and the higher metastatic potential in BC. Emerging evidences highlight the role of microRNAs (miRNAs) in the regulation of several cellular processes, including BC. Methods: Here we identified, by in silico approach, a group of three miRNAs with central biological role (high degree centrality) in HER2+ BC. We validated their dysregulation in HER2+ BC and we analysed their functional role by in vitro approaches on selected cell lines and by in vivo experiments in an animal model. Results: We found that their expression is dysregulated in both HER2+ BC cell lines and human samples. Focusing our study on the only upregulated miRNA, miR-429, we discovered that it acts as an oncogene and its upregulation is required for HER2+ cell proliferation. It controls the metastatic potential of HER2+ BC subtype by regulating migration and invasion of the cell. Conclusions: In HER2+ BC oncogenic miR-429 is able to regulate HIF1α pathway by directly targeting VHL mRNA, a molecule important for the degradation of HIF1α. The overexpression of miR-429, observed in HER2+ BC, causes increased proliferation and migration of the BC cells. More important, silencing miR-429 succeeds in delaying tumor growth, thus miR-429 could be proposed as a therapeutic probe in HER2+ BC tumors.

We evaluated the results obtained from the treatment of 88 intraarticular hyaluronic acid injections in haemophilic arthropathy according to the parameters of pain, function, health and radiographic evaluation. In 58 joints there was an improvement in the conditions preceding the treatments, in 20 the joint disease was stabilised, in 10 the treatment was ineffective and 9 of these were subsequently operated. 36 patients repeated the cycle at a distance. No adverse effects. Haemophilic arthropathy in its mild or moderate forms of joint damage can be effectively treated with viscosupplementation.

Introduction: Neuromyelitis optica spectrum disorders (NMOSD) are autoimmune diseases of the central nervous system mainly involving the optic nerves and spinal cord. Many advances have been made i...

Purpose To examine vision-related quality of life in patients with diabetic macular edema (DME) treated with intravitreal aflibercept (EYLEA, Regeneron Pharmaceuticals, Inc, Tarrytown, NY). Design AQUA was a multicenter, open-label, single-arm, phase 4 study. Participants Adults 18 years of age or older with type 1 or 2 diabetes mellitus and DME. Methods Patients received intravitreal aflibercept 2 mg every 8 weeks for 52 weeks, after 5 initial doses every 4 weeks. Main Outcome Measures The primary outcome was the change in 25-item National Eye Institute Visual Function Questionnaire (NEI VFQ-25) total score from baseline to week 52. Secondary outcomes included the change in NEI VFQ-25 near and distant activities subscale scores, best-corrected visual acuity (BCVA; Early Treatment Diabetic Retinopathy Study [ETDRS] letters), and central retinal thickness (CRT) from baseline to week 52. Change in NEI VFQ-25 score at week 52 for better-seeing eyes (BSEs) and worse-seeing eyes (WSEs) also was evaluated. Results A total of 553 patients comprised the full analysis set, and 560 patients comprised the safety analysis set. At baseline, the mean NEI VFQ-25 total score was 70.12, mean BCVA was 61.5 ETDRS letters, and mean CRT was 464.81 μm. A mean of 8.8 injections were administered over 52 weeks. At week 52, the mean improvement from baseline in the NEI VFQ-25 total score was +6.11 (standard deviation [SD], 11.46); the corresponding improvements in near and distant activities were +11.37 (SD, 18.01) and +7.33 (SD, 17.32), respectively. Similarly, improvements in patients whose BSE and WSE were treated were 7.74 (SD, 13.59) and 5.48 (SD, 9.70), respectively. At week 52, mean change in BCVA was +10.0 ETDRS letters (SD, 8.0 ETDRS letters), and mean change in CRT was –175.38 μm (SD, 132.62 μm). Overall, 53.6% of patients reported treatment-emergent adverse events (TEAEs), of whom 26.8% experienced an ocular TEAE in the study eye. The most common serious ocular TEAE was endophthalmitis (0.5% [n = 3]). Five deaths (0.9%) were reported, but were not considered treatment related. Conclusions Intravitreal aflibercept was associated with clinically meaningful improvements in NEI VFQ-25 total score over 52 weeks in patients with DME; these were even more pronounced for near than for distant activities. Adverse events were consistent with the known safety profile of intravitreal aflibercept.