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Amyotrophic lateral sclerosis (ALS) is a clinically heterogeneous disease, with chameleon presentations and several mimics. Considering the poor prognosis of ALS, their precise and timely identification is pivotal. Affection of the cervical spine represents one potential source of ALS mimics that should never be missed, since it is potentially treatable. We hereby present 5 cases initially diagnosed as ALS but eventually found to have different kinds of cervical spine affection, from a common compressive myelopathy to a rare space-occupying cystic fluid collection.

Objectives To assess the prevalence of delirium (DEL) among older patients living at home and periodically visited by their General Practitioners (GPs). Design Observational study. Setting In Italy, programmed home visits by the GPs are regularly scheduled for their vulnerable and frail patients who are often on poly-drug regimens and suffering from dementia. Participants N = 102 patients among those receiving programmed home visits by n = 6 GP based in the Brianza area (Lombardy). Measurements Patients were screened for delirium with the Italian version of the 4AT, with a score ≥ 4 considered as a positive indicator for DEL. The Charlson Comorbidity Index (CCI), the Short Physical Performance Battery (SPPB), the presence of dementia, and benzodiazepine (BZD) use were recorded. Results DEL+ was detected in almost half of the recruited sample (44.1%), and it was clearly associated with increased comorbidity and decreased motor abilities. Pre-existing dementia was documented in most of DEL+ patients (71.1%), while this was the case for only a minority of DEL- (5.2%, p vs. 22.8%, p Conclusions DEL prevalence as detected by GP during programmed home visits is surprisingly high, and related to motor impairment, comorbidities (among which dementia), and BZD use. DEL prompt recognition should be one of the goals of GP-programmed home visits, since this treatable and preventable condition is associated to an elevated burden of frailty and risk of death.

Background: The phase 3 GIMEMA-MMY-3006 trial, which compared bortezomib, thalidomide, and dexamethasone (VTD) combination therapy with thalidomide and dexamethasone (TD) as induction therapy before and consolidation therapy after double autologous haematopoietic stem-cell transplantation (HSCT) for newly diagnosed multiple myeloma, showed the superiority of the triplet regimen over the doublet in terms of increased complete response rate and improved progression-free survival. We report the results from the final analysis of the study. Methods: In this randomised, open-label, phase 3 study, patients aged 18–65 years with previously untreated symptomatic multiple myeloma and a Karnofsky Performance Status of 60% or higher were enrolled at 73 centres in Italy. Patients were randomised (1:1) by a web-based system to receive three 21-day cycles of thalidomide (100 mg daily orally for the first 14 days and 200 mg daily thereafter) plus dexamethasone (total 320 mg per cycle; 40 mg on days 1–2, 4–5, 8–9, and 11–12 in the VTD regimen, and 40 mg on days 1–4 and 9–12 in the TD regimen), either alone (TD group) or with bortezomib (1·3 mg/m2 intravenously on days 1, 4, 8, and 11; VTD group). After double autologous HSCT, patients received two 35-day cycles of either the VTD or TD regimen, according to random assignment, as consolidation therapy. The primary outcome was the rate of complete response and near complete response after induction (already reported). In this updated analysis we assessed long-term progression-free survival and overall survival (secondary endpoints of the study) with an extended 10-year median follow-up, and analysed the variables influencing survival. Analysis was by intention to treat. The study is registered with ClinicalTrials.gov, NCT01134484. Findings: Between May 10, 2006, and April 30, 2008, 480 patients were enrolled and randomly assigned to receive VTD (241 patients) or TD (239 patients). Six patients withdrew consent before start of treatment. 236 (99 [42%] women) in the VTD group and 238 (102 [43%] women) in the TD group were included in the intention-to-treat analysis. The data cutoff date for this analysis was May 31, 2018. Median follow-up for surviving patients was 124·1 months (IQR 117·2–131·7). The 10-year progression-free survival estimate for patients in the VTD group was 34% (95% CI 28–41) compared with 17% (13–23) for the TD group (hazard ratio [HR] 0·62 [95% CI 0·50–0·77]; p

Objectives: Evidences from either small series or spontaneous reporting are accumulating that SARS-CoV-2 involves the Nervous Systems. The aim of this study is to provide an extensive overview on the major neurological complications in a large cohort of COVID-19 patients. Methods: Retrospective, observational analysis on all COVID-19 patients admitted from February 23rd to April 30th, 2020 to ASST Papa Giovanni XXIII, Bergamo, Italy for whom a neurological consultation/neurophysiological assessment/neuroradiologic investigation was requested. Each identified neurologic complication was then classified into main neurologic categories. Results: Of 1760 COVID-19 patients, 137 presented neurologic manifestations that manifested after COVID-19 symptoms in 98 pts and was the presenting symptom in 39. Neurological manifestations were classified as: (a) cerebrovascular disease [53 pts (38.7%)] including 37 ischemic and 11 haemorrhagic strokes, 4 transient ischemic attacks, 1 cerebral venous thrombosis; (b) peripheral nervous system diseases [31 (22.6%)] including 17 Guillain–Barrè syndromes; (c) altered mental status [49 (35.8%)] including one necrotizing encephalitis and 2 cases with RT-PCR detection of SARS-Cov-2 RNA in CSF; (d) miscellaneous disorders, among whom 2 patients with myelopathy associated with Ab anti-SARS-CoV-2 in CSF. Patients with peripheral nervous system involvement had more frequently severe ARDS compared to patients with cerebrovascular disease (87.1% vs 42%; difference = 45.1% 95% CI 42.0–48.2; χ2= 14.306; p < 0.0002) and with altered mental status (87.1% vs 55.6%; difference = 31.5% 95% CI 27.5–37.5%; χ2= 7.055; p < 0.01). Conclusion: This study confirms that involvement of nervous system is common in SARS-CoV-2 infection and offers clinicians useful information for prevention and prompt identification in order to set the adequate therapeutic strategies.

A 49-year-old man was admitted in the Psychiatric Unit of our Hospital due to an acute episode of severe agitation and persecutory ideas forcing the wife to bring him to the Emergency Department (ED). His medical history was marked by a couple of similar accesses to the ED with acute agitation in the recent past. In addition, his wife reported in the last 2 years an inclination to retirement and depressive mood and a continuous decline in mood with apathy and inertia and deficits in episodic memory, with increasing forgetfulness despite maintaining good work functioning. Quite surprisingly, she added that the patient had started to follow a strict fruitarian diet with a highly predominant consumption of just apples. He did neither smoke nor drink alcohol. Notwithstanding, oral olanzapine (15 mg / day) was started with improvement of agitation; however, the patient showed a gradual cognitive worsening with disorientation and executive dysfunction.

Background Childhood overweight and obesity are a global concern, with prevalence rising dramatically over the last decades. The condition is caused by an increase in energy intake and reduction of physical activity, leading to excessive fat accumulation, followed by systemic chronic inflammation and altered function of immune cell responses. This study aimed at providing new insights regarding sex-specificity on the inflammatory response to obesity in the young patient. Design Forty-three Brazilian obese adolescents (Female = 22 and Male=21, BMI (body mass index) Z-score average = 2.78 ± 0.51) and forty-nine eutrophic adolescents (Female = 24 and Male = 25, BMI Z-score average = −0.35 ± 0.88) were enrolled in the study. Anthropometrical analyses and blood cell counts were carried out. Using Luminex®xMAP™ technology, circulating serum cytokines, chemokines, and inflammatory biomarkers were analyzed. Two-way ANOVA test, Tukey’s test, and Spearman’s correlation coefficient were employed, with a significance threshold set at p Results We identified increased levels of serum amyloid A (SAA), platelets, and leukocytes solely in male obese patients. We found a noteworthy sex-dependent pattern in regard to inflammatory response: obese boys showed higher TNFβ, IL15, and IL2 and lower IL10 and IL13, while obese girls showed increased TNFα, CCL3, CCL4, and IP10 content in the circulation. BMI Z-score was significantly linearly correlated with neutrophils, leukocytes, platelets, SAA, TNFα, CCL3, CCL4, IP10, and IL13 levels within the entire cohort (non-sex-dependent). Conclusions Our data support a complex relationship between adiposity, blood cell count, and circulating inflammatory cytokine content. High SAA levels suggest that this factor may play a critical role in local and systemic inflammation. In the eutrophic group, females presented a lower status of inflammation, as compared to males. Both obese boys and girls showed an increased inflammatory response in relation to eutrophic counterparts. Taken together, results point out to clear sex dimorphism in the inflammatory profile of obese adolescents.

Sarcomas are defined as a group of mesenchymal malignancies with over 100 heterogeneous subtypes. As a rare and difficult to diagnose entity, micrometastasis is already present at the time of diagnosis in many cases. Current treatment practice of sarcomas consists mainly of surgery, (neo)adjuvant chemo- and/or radiotherapy. Although the past decade has shown that particular genetic abnormalities can promote the development of sarcomas, such as translocations, gain-of-function mutations, amplifications or tumor suppressor gene losses, these insights have not led to established alternative treatment strategies so far. Novel therapeutic concepts with immunotherapy at its forefront have experienced some remarkable success in different solid tumors while their impact in sarcoma remains limited. In this review, the most common immunotherapy strategies in sarcomas, such as immune checkpoint inhibitors, targeted therapy and cytokine therapy are concisely discussed. The programmed cell death (PD)-1/PD-1L axis and apoptosis-inducing cytokines, such as TNF-related apoptosis-inducing ligand (TRAIL), have not yielded the same success like in other solid tumors. However, in certain sarcoma subtypes, e.g. liposarcoma or undifferentiated pleomorphic sarcoma, encouraging results in some cases when employing immune checkpoint inhibitors in combination with other treatment options were found. Moreover, newer strategies such as the targeted therapy against the ancient cytokine macrophage migration inhibitory factor (MIF) may represent an interesting approach worth investigation in the future.

The most recent international guidelines recommend the measurement of cardiac troponin I (cTnI) and cardiac troponin T (cTnT) using high-sensitivity methods (hs-cTn) for the detection of myocardial injury and the differential diagnosis of acute coronary syndromes. Myocardial injury is a prerequisite for the diagnosis of acute myocardial infarction, but also a distinct entity. The 2018 Fourth Universal Definition of Myocardial Infarction states that myocardial injury is detected when at least one value above the 99th percentile upper reference limit is measured in a patient with high-sensitivity methods for cTnI or cTnT. Not infrequently, increased hs-cTnT levels are reported in patients with congenital or chronic neuromuscular diseases, while the hs-cTnI values are often in the normal range. Furthermore, some discrepancies between the results of laboratory tests for the two troponins are occasionally found in individuals apparently free of cardiac diseases, and also in patients with cardiac diseases. In this review article, authors discuss the biochemical, pathophysiological and analytical mechanisms which may cause discrepancies between hs-cTnI and hs-cTnT test results.

Ovarian cancer is one of the deadliest malignancies among women. Approximately 75% of the patients with ovarian cancer are diagnosed with advanced disease that already has metastasis, particularly to the omentum. The omentum constitutes the ideal soil for ovarian cancer metastasis due to a complex intraperitoneal milieu that favors and supports the whole metastatic process. Adipose-derived stem/stromal cells (ADSCs) are part of this microenvironment and foster tumor progression via sustained paracrine secretion, including extracellular vesicles (EVs). Nonetheless, the preferential relationship between ADSCs, ADSC-derived EVs, and ovarian cancer cells could be exploited to use ADSCs and EVs as a vehicle for anti-cancer therapies. This review will analyze the strict relations between tumor progression, metastatic disease, and adipose tissue with its staminal components. In addition, we will describe the crosstalk and biologic relationship between ADSCs and tumor cells, the role of EVs in intercellular communication, the establishment of drug resistance, metastatic capacity, and ovarian cancer progression. We will analyze the new therapeutic opportunities in treating ovarian cancer offered by ADSCs and EVs as a vehicle for therapeutic molecules to target precisely tumor cells and limit the systemic adverse effects. Finally, we will discuss the limitations of these therapeutic approaches.

Resumo Objetivos Avaliar e comparar os resultados do tratamento cirúrgico das luxações acromioclaviculares (LACs) aguda e crônica, definindo o plano terapêutico mais eficaz. Métodos Estudo retrospectivo realizado com 30 pacientes operados entre 2011 e 2018 para LAC tipos III e V, separados de acordo com a classificação temporal em subgrupo agudo (< 3 semanas; subgrupo I) e subgrupo crônico (> 3 semanas; subgrupo II). Todos os pacientes foram submetidos a avaliação pós-cirúrgica com protocolo padronizado composto por dados epidemiológicos, funcionais e radiográficos. Resultados No subgrupo I, a pontuação na escala visual analógica (EVA) foi de 1,10, o escore de Constant-Murley foi de 92,3, e o escore da University of California at Los Angeles (UCLA) foi de 33,5. A distância coracoclavicular (CC) foi de 11,0 mm, e o aumento do espaço CC foi em média menor do que 8,9% em relação ao ombro contralateral. No subgrupo II, a EVA foi de 1,11, o escore de Constant-Murley foi de 94,2, e o da UCLA, 32,4. A distância CC foi de 13,8 mm, sendo o aumento do espaço CC de 22,9% em relação ao contralateral. Conclusão Apesar de não ter havido diferença significativa entre os quesitos avaliados, houve uma tendência de o subgrupo agudo apresentar distância CC (p = 0,098) e percentual de aumento da distância CC (p = 0,095) menor do que o subgrupo crônico. Assim, é interessante que o tratamento cirúrgico seja realizado nas primeiras três semanas após o trauma, para tentar evitar essa tendência. Nos casos em que não for possível realizar o tratamento na fase aguda, a técnica de Weaver Dunn modificada apresenta bons resultados clínicos e funcionais.

Introduction Conflicting results regarding the impact of left common pulmonary vein (LCPV) on clinical outcome of atrial fibrillation (AF) ablation with cryoballoon technology have been reported. Methods We systematically searched PubMed and Cochrane library for articles that compared the arrhythmia recurrence rate after cryoballoon ablation between patients with normal pattern PVs and patients with LCPV. Studies of first ablation for persistent and paroxysmal AF using the 28 mm Arctic Front Advance, Medtronic cryoballoon (CB-A) reporting clinical success rates at a mean follow-up of ≥12 months were included. Data were analyzed by applying a random effects model. Results A total of 5 studies with a total of 1178 patients met our predefined inclusion criteria. After a mean follow-up of 18.4 months, the overall success rate of CB-A ablation among patients with persistent and paroxysmal AF was 57%; in the LCPV group the success rate was 46% and in the normal anatomical pattern group it was 61%. No significant heterogeneity was noted among the studies (I2 = 35.8%; Q (df = 3) = 6.23 p-value = 0.18). Arrhythmia recurrence after CB-A ablation was not statistically significant between the two groups (LogOR 0.24; 95% CI [-0.16-0.63]; p-value = 0.23). No significant difference in PNI was observed between the two groups (p-value = 0.693). Conclusion The presence of LCPV does not affect the long-term outcome of paroxysmal and persistent atrial fibrillation ablation with 28 mm CB-A compared to normal left PVs pattern.

Background The oncolytic viruses have shown promising results for the treatment of multiple myeloma. However, the use of human viruses is limited by the patients’ antiviral immune response. In this study, we investigated an alternative oncolytic strategy using non-human pathogen viruses as the bovine viral diarrhea virus (BVDV) that were able to interact with CD46. Methods We treated several human myeloma cell lines and non-myeloma cell lines with BVDV to evaluate the expression of CD46 and to study the effect on cell viability by flow cytometry. The possible synergistic effect of bortezomib in combination with BVDV was also tested. Moreover, we infected the bone marrow mononuclear cells obtained from myeloma patients and we checked the BVDV effect on different cell populations, defined by CD138, CD14, CD3, CD19, and CD56 expression evaluated by flow cytometry. Finally, the in vivo BVDV effect was tested in NOD-SCID mice injected subcutaneously with myeloma cell lines. Results Human myeloma cells were selectively sensitive to BVDV treatment with an increase of cell death and, consequently, of apoptotic markers. Consistently, bone marrow mononuclear cells isolated from myeloma patients treated with BVDV, showed a significant selective decrease of the percentage of viable CD138+ cells. Interestingly, bortezomib pre-treatment significantly increased the cytotoxic effect of BVDV in myeloma cell lines with a synergistic effect. Finally, the in vitro data were confirmed in an in vivo myeloma mouse model showing that BVDV treatment significantly reduced the tumoral burden compared to the vehicle. Conclusions Overall, our data indicate, for the first time, a direct oncolytic effect of the BVDV in human myeloma cells suggesting its possible use as novel alternative anti-myeloma virotherapy strategy.

The negative association between obstructive sleep apnea (OSA) and adverse cardiovascular outcomes in patients undergoing percutaneous coronary intervention (PCI) is well documented. However, little is known about the influence of OSA on fibrinolytic therapy. The aim of this study was to evaluate the impact of severe OSA on pharmacoinvasive treatment in ST elevation myocardial infarction (STEMI) patients. We enrolled consecutive STEMI patients without previous vascular disease, heart failure, or OSA diagnosis. All patients underwent either a pharmacoinvasive therapy or primary PCI. Syntax score (SS) was calculated for all patients, and a full bedside polysomnography was performed in the first 72 h of admission. In-hospital events and 30 days readmissions were analyzed. The sample included 116 patients, 87 men. Patients with severe OSA were older (p = 0.01), had higher neck and abdominal circumferences (p

Objective: to identify scientific evidences available on the literature on nursing interventions on advanced mobile prehospital care for elderly people post-trauma. Method: an integrative review of literature on the databases PubMed, CINAHL, and LILACS, from 2012 to 2017. Results: a sample composed by 26 studies, grouped into six thematic categories: circulation with hemorrhage control (n=11); dysfunction, neurological state (n=7); airway with protection of the cervical spine (n=3); secondary evaluation (n=3); ventilation and breathing (n=1), and environment exposition/control (n=1). Conclusion: Despite having identified nursing interventions, there was no description of specific nursing interventions related to advanced mobile prehospital care for elderly people post-trauma. RESUMEN Objetivo: identificar las evidencias científicas disponibles en la literatura acerca de las intervenciones de enfermería durante la atención prehospitalaria móvil avanzada a ancianos postrauma. Método: revisión integrativa de la literatura en las bases de datos PubMed, CINAHL y LILACS, realizada en el período entre 2012 y 2017. Resultados: la muestra constó de 26 estudios, que fueron agrupados en seis ejes temáticos: Circulación con control de la hemorragia (n=11); Disfunción, estado neurológico (n=7); Vía aérea con protección de la columna cervical (n=3); Evaluación secundaria (n = 3); Ventilación y respiración (n=1); y Exposición/control del ambiente (n=1). Conclusión: en las intervenciones de enfermería identificadas, no se describían intervenciones específicas de enfermería relacionadas a la atención prehospitalaria móvil avanzada a ancianos postrauma. RESUMO Objetivo: identificar as evidências científicas disponíveis na literatura acerca das intervenções de enfermagem no atendimento pré-hospitalar móvel avançado para idosos pós-trauma. Método: revisão integrativa da literatura nas bases de dados PubMed, CINAHL e LILACS, no período de 2012 a 2017. Resultados: amostra composta por 26 estudos, agrupados em seis categorias temáticas: circulação com controle da hemorragia (n=11); disfunção, estado neurológico (n=7); via aérea com proteção da coluna cervical (n=3); avaliação secundária (n=3); ventilação e respiração (n=1) e exposição/controle do ambiente (n=1). Conclusão: apesar de terem sido identificadas intervenções de enfermagem, não houve descrição de intervenções específicas de enfermagem relacionadas ao atendimento pré-hospitalar móvel avançado de idosos pós-trauma.

Prostate cancer is the most frequent malignancy in the worldwide male population; it is also one of the most common among all the leading cancer-related death causes. In the last two decades, the therapeutic scenario of metastatic castration-resistant prostate cancer has been enriched by the use of chemotherapy and androgen receptor signaling inhibitors (ARSI) and, more recently, by immunotherapy and poly(ADP–ribose) polymerase (PARP) inhibitors. At the same time, several trials have shown the survival benefits related to the administration of novel ARSIs among patients with non-castration-resistant metastatic disease along with nonmetastatic castration-resistant cancer too. Consequently, the therapeutic course of this malignancy has been radically expanded, ensuring survival benefits never seen before. Among the more recently emerging agents, the so-called “antibody–drug conjugates” (ADCs) are noteworthy because of their clinical practice changing outcomes obtained in the management of other malignancies (including breast cancer). The ADCs are novel compounds consisting of cytotoxic agents (also known as the payload) linked to specific antibodies able to recognize antigens expressed over cancer cells’ surfaces. As for prostate cancer, researchers are focusing on STEAP1, TROP2, PSMA, CD46 and B7-H3 as optimal antigens which may be targeted by ADCs. In this paper, we review the pivotal trials that have currently changed the therapeutic approach to prostate cancer, both in the nonmetastatic castration-resistant and metastatic settings. Therefore, we focus on recently published and ongoing trials designed to investigate the clinical activity of ADCs against prostate malignancy, characterizing these agents. Lastly, we briefly discuss some ADCs-related issues with corresponding strategies to overwhelm them, along with future perspectives for these promising novel compounds.

Thrombotic complications are common in COVID-19 patients, but cerebral venous system involvement, timing after infection, optimal treatment, and long-term outcome are uncertain. We report a case of massive cerebral venous thrombosis and concomitant internal iliac vein thrombosis occurring in the late phase of paucisymptomatic COVID-19 infection. Mild respiratory symptoms, without fever, started 3 weeks before headache and acute neurological deficits. The patient had silent hypoxemia and typical COVID-19 associated interstitial pneumonia. Brain CT scan showed a left parietal hypodense lesion with associated sulcal subarachnoid hemorrhage. CT cerebral venography showed a massive cerebral venous thrombosis involving the right transverse sinus, the right jugular bulb, the superior sagittal sinus, the straight sinus, the vein of Galen, and both internal cerebral veins. Abdominal CT scan showed no malignancy but revealed an asymptomatic right internal iliac vein thrombosis. Both cerebral venous thrombosis and pelvic vein thrombosis were effectively treated with unfractionated heparin started on the day of admission, then shifted to low molecular weight heparin, with a favorable clinical course. Nasopharyngel swab, repeated twice, tested negative for SARS-CoV-2. Serological tests confirmed SARS-CoV-2 infection. Our case supports active surveillance and prevention of thrombotic complications associated with COVID-19, which may affect both peripheral and cerebral venous system. Early initiation of unfractionated heparin may lead to good neurologic outcome.

Background Selective bilateral lesions of the parietal–occipital lobes can lead to an uncommon and incompletely understood clinical entity, Balint’ syndrome, which consists of simultanagnosia, oculomotor apraxia, optic ataxia and difficulty in perceiving distances between objects. Case presentation We herein report a rare presentation of Balint’s syndrome in a 65-year-old woman suffering from stroke and SARS-CoV2 infection. Conclusion During SARS-CoV2 pandemic, Italian physicians were forced to work with less instrumental diagnostic resources, relying on their clinical knowledge mostly. The aim of this case report is to highlight the importance of performing a precise neurological evaluation, particularly during these challenging times: it might avoid incorrect diagnosis and favour the discovery of rare clinical diseases.

Inflammation and endothelial activation play a pivotal role in development and progression of diabetic retinopathy (DR), a vision-threatening complication of diabetes mellitus (DM) and the leading cause of blindness in the working age population. Easily accessible and validated biomarkers for DR early diagnosis and progression are required for use in clinical trials: here, we reviewed the available literature to understand the association of circulating levels of selected markers of inflammation and endothelial activation with the presence of nonproliferative and proliferative DR (NPDR and PDR) and investigate the relationship between their systemic and ocular levels. We additionally provide data synthesis and perform statistical analysis for interpretation of the collected evidence. CRP, IL-1β, IL-6, TNFα, sICAM1, and sVCAM1 circulating levels were increased in subjects with DM compared to healthy individuals. Moreover, TNFα and sVCAM1 showed increasing systemic levels with DR presence and severity; circulating CRP increased with the transition from no DR to NPDR, whereas IL-6 was increased in PDR compared to NDPR stages. The relationship between ocular and systemic concentrations of these proteins remained unclear due to the low number of studies with matched sampling. In conclusion, the available data supports the use of systemic biomarkers of inflammation and endothelial activation to identify DM status and DR severity. These systemic biomarkers are likely reflecting an overall state of inflammation and vascular activation in different tissues of the body, including the eyes. Prospective, longitudinal datasets are required to validate these biomarkers as predictors of early DR presence, of DR progression, or for disease monitoring.

In 2021 the scientific community’s efforts have been focused on solving the back-breaking challenge of the COVID-19 pandemic, but sexually transmitted infections (STI) are still one of the most common global health problems. Syphilis is a systemic disease caused by the spirochaete Treponema pallidum (TP) and is one of the oldest known diseases. Its incidence has increased in the last few years and syphilis still remains a contemporary plague that continues to afflict millions of people worldwide. Despite research improvements, syphilis pathogenesis is not completely clear; clinical presentation is very heterogeneous and the diagnosis can sometimes be difficult. Furthermore, few therapeutic options are available, and a vaccine has not been found yet. In this review, we describe the most recent evidence concerning the clinical manifestation, diagnosis, treatment and vaccine prospectives for this disease.

Background: Subcortical vascular dementia (sVAD) is considered the most frequent dementia in old population, and it is due to a small vessel disease. It has a very specific nosography, where the dominant factors are dysexecutive functions, depression, and apathy. Very few studies described visual hallucinations in sVAD, apart from in the final stages of it. Methods: This study recruited 577 patients with a diagnosis of sVAD associated with major ocular pathologies and 1118 patients with sVAD without any significant ocular pathology: Patients were followed up for 24 months. We studied the influence of ocular pathologies in precocious visual hallucinations, on behavior disorder (aggressiveness), and gait disorders (instability, fells). We registered the necessity of neuropsychiatric therapies, incidence of hospitalization, and institutionalization. Results: What emerges from our study is that the ocular comorbidities might change the behavior profile of dementia, provoking behavioral alterations, and the need for therapies with adverse effects. As far as old age is a complicated status of life, many factors can modify its development. The possible contribution of multiple biological events cannot be neglected, particularly the underlying influence of chronic diseases as well as the geriatric conditions, per se, might compromise the cognitive functions and the pathological conditions. Ocular pathology as a superimposing event in sVAD might worse the outcome. A correct and rapid identification of critical patients might be relevant for the dynamic life events in these patients and their caregiver

The pathophysiology of essential tremor (ET) is controversial and might be further elucidated by advanced neuroimaging. Focusing on homogenous ET patients diagnosed according to the 2018 consensus criteria, this study aimed to: (1) investigate whether task functional MRI (fMRI) can identify networks of activated and deactivated brain areas, (2) characterize morphometric and functional modulations, relative to healthy controls (HC). Ten ET patients and ten HC underwent fMRI while performing two motor tasks with their upper limb: (1) maintaining a posture (both groups); (2) simulating tremor (HC only). Activations/deactivations were obtained from General Linear Model and compared across groups/tasks. Voxel-based morphometry and linear regressions between clinical and fMRI data were also performed. Few cerebellar clusters of gray matter loss were found in ET. Conversely, widespread fMRI alterations were shown. Tremor in ET (task 1) was associated with extensive deactivations mainly involving the cerebellum, sensory-motor cortex, and basal ganglia compared to both tasks in HC, and was negatively correlated with clinical tremor scales. Homogeneous ET patients demonstrated deactivation patterns during tasks triggering tremor, encompassing a network of cortical and subcortical regions. Our results point towards a marked cerebellar involvement in ET pathophysiology and the presence of an impaired cerebello-thalamo-cortical tremor network.

Assessment of consciousness following severe brain-injury is challenging. Our hypothesis is that electroencephalography (EEG) can provide information on awareness, in terms of oscillatory activity and network task–related modifications, in people with disorders of consciousness. Similar results were obtained with neuroimaging techniques; we aim at demonstrating the use of EEG, which is low cost and routinely implemented, to the same goal. Nineteen-channel EEG was recorded in 7 persons with unresponsive wakefulness syndrome (UWS) and in 10 healthy subjects during the execution of active (attempted movement) and passive motor tasks as well as 2 mental imagery tasks. Event-related synchronization/desynchronization (ERS/ERD), coherence and network parameters were calculated in delta (1-4 Hz), theta (4-8 Hz), alpha1 (8-10 Hz), alpha2 (10-12 Hz), and beta (13-30 Hz) ranges. In UWS subjects, passive movement induced a weak alpha2 ERD over contralateral sensorimotor area. During motor imagery, ERD was detected over the frontal and motor contralateral brain areas; during spatial imagery, ERS in lower alpha band over the right temporo-parietal regions was missing. In UWS, functional connectivity provided evidence of network disruption and isolation of the motor areas, which cannot dialog with adjacent network nodes, likely suggesting a diffuse structural alteration. Our findings suggest that people with a clinical diagnosis of UWS were able to modulate their brain activity when prompted to perform movement tasks and thus suggest EEG as a potential tool to support diagnosis of disorders of consciousness.

Tumor burden is a complex microenvironment where different cell populations coexist and have intense cross-talk. Among them, a heterogeneous population of tumor cells with staminal features are grouped under the definition of cancer stem cells (CSCs). CSCs are also considered responsible for tumor progression, drug resistance, and disease relapse. Furthermore, CSCs secrete a wide variety of extracellular vesicles (EVs) with different cargos, including proteins, lipids, ssDNA, dsDNA, mRNA, siRNA, or miRNA. EVs are internalized by other cells, orienting the microenvironment toward a protumorigenic and prometastatic one. Given their importance in tumor growth and metastasis, EVs could be exploited as a new therapeutic target. The inhibition of biogenesis, release, or uptake of EVs could represent an efficacious strategy to impair the cross-talk between CSCs and other cells present in the tumor microenvironment. Moreover, natural or synthetic EVs could represent suitable carriers for drugs or bioactive molecules to target specific cell populations, including CSCs. This review will discuss the role of CSCs and EVs in tumor growth, progression, and metastasis and how they affect drug resistance and disease relapse. Furthermore, we will analyze the potential role of EVs as a target or vehicle of new therapies.

Despite effective treatments, cytomegalovirus (CMV) continues to have a significant impact on morbidity and mortality in allogeneic stem cell transplant (allo-SCT) recipients. This multicenter, retrospective, cohort study aimed to evaluate the reproducibility of the safety and efficacy of commercially available letermovir for CMV prophylaxis in a real-world setting. Endpoints were rates of clinically significant CMV infection (CSCI), defined as CMV disease or CMV viremia reactivation within day +100-+168. 204 adult CMV-seropositive allo-SCT recipients from 17 Italian centres (median age 52 years) were treated with LET 240 mg/day between day 0 and day +28. Overall, 28.9% of patients underwent a haploidentical, 32.4% a matched related, and 27.5% a matched unrelated donor (MUD) transplant. 65.7% were considered at high risk of CSCI and 65.2% had a CMV seropositive donor. Low to mild severe adverse events were observed in 40.7% of patients during treatment [gastrointestinal toxicity (36.3%) and skin rash (10.3%)]. Cumulative incidence of CSCI at day +100 and day +168 was 5.4% and 18.1%, respectively, whereas the Kaplan-Meier event rate was 5.8% (95% CI: 2.4-9.1) and 23.3% (95% CI: 16.3-29.7), respectively. Overall mortality was 6.4% at day +100 and 7.3% at day +168. This real-world experience confirms the efficacy and safety of CMV.

The ongoing COVID-19 pandemic is likely to have a profound impact on the lives of high-risk drug users and on the services responding to their needs in at least two important ways: first, through the restrictive measures introduced to mitigate the spread of the virus and, second, as a result of extensive economic downturn. Currently there is great uncertainty as to the future intensity and duration of the pandemic. In addition, the lessons we have been able to learn from previous economic downturns may be of limited applicability to the current situation, which differs in a number of significant respects. Experience nevertheless suggests that the potential consequences for drug users’ health and well-being may be severe. The ongoing uncertainty serves to underline the importance of close monitoring of the drug situation and preparing flexible and innovative solutions to be able to meet new challenges which may arise.

Introduction: Multiple myeloma (MM) is characterized by the high tendency to relapse and develop drug resistance. Areas covered: This review focused on the main novel targets identified to design drugs for the treatment of relapsing MM patients. CD38 and SLAMF7 are the main surface molecules leading to the development of monoclonal antibodies (mAbs) recently approved for the treatment of relapsing MM patients. B cell maturation antigen (BCMA) is a suitable target for antibody-drug conjugates, bispecific T cell engager mAbs and Chimeric Antigen Receptor (CAR)-T cells. Moreover, the programmed cell death protein 1 (PD)-1/PD-Ligand (PD-L1) expression profile by MM cells and their microenvironment and the use of immune checkpoints inhibitors in MM patients are reported. Finally, the role of histone deacetylase (HDAC), B cell lymphoma (BCL)-2 family proteins and the nuclear transport protein exportin 1 (XPO1) as novel targets are also underlined. The clinical results of the new inhibitors in relapsing MM patients are discussed. Expert opinion: CD38, SLAMF7, and BCMA are the main targets for different immunotherapeutic approaches. Selective inhibitors of HDAC6, BCL-2, and XPO1 are new promising compounds under clinical investigation in relapsing MM patients.

Multiple myeloma is the second most frequent hematological cancer after lymphoma and remains an incurable disease. The pervasive support provided by the bone marrow microenvironment to myeloma cells is crucial for their survival. Here, an unbiased assessment of receptor tyrosine kinases overexpressed in myeloma identified ROR2, a receptor for the WNT noncanonical pathway, as highly expressed in myeloma cells. Its ligand, WNT5A is the most abundant growth factor in the bone marrow of myeloma patients. ROR2 mediates myeloma cells interactions with the surrounding bone marrow and its depletion resulted in detachment of myeloma cells from their niche in an in vivo model, triggering apoptosis and thus markedly delaying disease progression. Using in vitro and ex vivo 3D-culture systems, ROR2 was shown to exert a pivotal role in the adhesion of cancer cells to the microenvironment. Genomic studies revealed that the pathways mostly deregulated by ROR2 overexpression were PI3K/AKT and mTOR. Treatment of cells with specific PI3K inhibitors already used in the clinic reduced myeloma cell adhesion to the bone marrow. Together, our findings support the view that ROR2 and its downstream targets represent a novel therapeutic strategy for the large subgroup of MM patients whose cancer cells show ROR2 overexpression.

The plasma membrane of cells has a complex architecture based on the bidimensional liquid-crystalline bilayer arrangement of phospho- and sphingolipids, which in turn embeds several proteins and is connected to the cytoskeleton. Several studies highlight the spatial membrane organization into more ordered (L o or lipid raft) and more disordered (L d ) domains. We here report on a fluorescent analog of the green fluorescent protein chromophore that, when conjugated to a phospholipid, enables the quantification of the L o and L d domains in living cells on account of its large fluorescence lifetime variation in the two phases. The domain composition is straightforwardly obtained by the phasor approach to confocal fluorescence lifetime imaging, a graphical method that does not require global fitting of the fluorescence decay in every spatial position of the sample. Our imaging strategy was applied to recover the domain composition in human oligodendrocytes at rest and under treatment with galactosylsphingosine (psychosine). Exogenous psychosine administration recapitulates many of the molecular fingerprints of a severe neurological disease, globoid cell leukodystrophy, better known as Krabbe disease. We found out that psychosine progressively destabilizes plasma membrane, as witnessed by a shrinking of the L o fraction. The unchanged levels of galactosyl ceramidase, i.e., the enzyme lacking in Krabbe disease, upon psychosine treatment suggest that psychosine alters the plasma membrane structure by direct physical effect, as also recently demonstrated in model membranes.

Autism spectrum disorder (ASD) is a neurodevelopmental condition associated with difficulties in the social, communicative, and behavioral domains. Most cases of ASD arise from an unknown etiologic process, but there are numerous risk factors, including comorbidities and maternal exposures. Although it is not part of the diagnostic criteria, hearing difficulties ranging from deafness to hyperacusis are present in the majority of persons with ASD. High-functioning children with ASD have been found to have significantly slower and asymmetric auditory brainstem reflexes. Additionally, histopathological studies of postmortem brainstems in decedents who had ASD have consistently revealed significantly fewer neurons in auditory nuclei compared with those in people who did not have ASD. The authors review the literature implicating auditory dysfunction in ASD along with results from human study participants and postmortem human brain tissue. Together, these results implicate significant structural and functional abnormalities in the auditory brainstem in ASD and support the utility of auditory testing to screen for ASD.

Multiple myeloma (MM) is characterized by an accumulation of malignant plasma cells (PCs) in the bone marrow (BM). The amplification of 1q21 is one of the most common cytogenetic abnormalities occurring in around 40% of de novo patients and 70% of relapsed/refractory MM. Patients with this unfavorable cytogenetic abnormality are considered to be high risk with a poor response to standard therapies. The gene(s) driving amplification of the 1q21 amplicon has not been fully studied. A number of clear candidates are under investigation, and some of them (IL6R, ILF2, MCL-1, CKS1B and BCL9) have been recently proposed to be potential drivers of this region. However, much remains to be learned about the biology of the genes driving the disease progression in MM patients with 1q21 amp. Understanding the mechanisms of these genes is important for the development of effective targeted therapeutic approaches to treat these patients for whom effective therapies are currently lacking. In this paper, we review the current knowledge about the pathological features, the mechanism of 1q21 amplification, and the signal pathway of the most relevant candidate genes that have been suggested as possible therapeutic targets for the 1q21 amplicon.

Made available in DSpace on 2021-06-25T11:18:15Z (GMT). No. of bitstreams: 0 Previous issue date: 2021-05-25 Universidade Estadual Paulista Glioblastoma (GBM) is the most lethal and frequent type of brain tumor, leading patients to death in approximately 14 months after diagnosis. GBM treatment consists in surgical removal followed by radio and chemotherapy. However, tumors commonly relapse and the treatment promotes only a slight increase in patient survival. Thus, uncovering the cellular mechanisms involved in GBM resistance is of utmost interest, and the use of cell lines has been shown to be an extremely important tool. In this work, the exploration of RNAseq data from different GBM cell lines revealed different expression signatures, distinctly correlated with the behavior of GBM cell lines regarding proliferation indexes and radio-resistance. U87MG and U138MG cells, which presented expressively reduced proliferation and increased radio-resistance, showed a particular expression signature encompassing enrichment in many extracellular matrix (ECM) and receptor genes. Contrasting, U251MG and T98G cells, that presented higher proliferation and sensibility to radiation, exhibited distinct signatures revealing consistent enrichments for DNA repair processes and although several genes from the ECM-receptor pathway showed up-regulation, enrichments for this pathway were not detected. The ECM-receptor is a master regulatory pathway that is known to impact several cellular processes including: survival, proliferation, migration, invasion, and DNA damage signaling and repair, corroborating the associations we found. Furthermore, searches to The Cancer Genome Atlas (TCGA) repository revealed prognostic correlations with glioma patients for the majority of genes highlighted in the signatures and led to the identification of 31 ECM-receptor genes individually correlated with radiation responsiveness. Interestingly, we observed an association between the number of upregulated genes and survivability greater than 5 years after diagnosis, where almost all the patients that presented 21 or more upregulated genes were deceased before 5 years. Altogether our findings suggest the clinical relevance of ECM-receptor genes signature found here for radiotherapy decision and as biomarkers of glioma prognosis. School of Pharmaceutical Sciences São Paulo State University (UNESP) Center for Cell-Based Therapy (CTC) Regional Blood Center of Ribeirão Preto Department of Genetics Ribeirão Preto Medical School University of São Paulo (USP) Radiation Oncology Branch National Cancer Institute National Institutes of Health (NIH) School of Pharmaceutical Sciences São Paulo State University (UNESP)

Non-syndromic intellectual disability (NS-ID or idiopathic) is a complex neurodevelopmental disorder that represents a global health issue. Although many efforts have been made to characterize it and distinguish it from syndromic intellectual disability (S-ID), the highly heterogeneous aspect of this disorder makes it difficult to understand its etiology. Long noncoding RNAs (lncRNAs) comprise a large group of transcripts that can act through various mechanisms and be involved in important neurodevelopmental processes. In this sense, comprehending the roles they play in this intricate context is a valuable way of getting new insights about how NS-ID can arise and develop. In this review, we attempt to bring together knowledge available in the literature about lncRNAs involved with molecular and cellular pathways already described in intellectual disability and neural function, to better understand their relevance in NS-ID and the regulatory complexity of this disorder.

Lung cancer is the leading cause of cancer deaths. Tumor heterogeneity, which hampers development of targeted therapies, was herein deconvoluted via single cell RNA sequencing in aggressive human adenocarcinomas (carrying Kras-mutations) and comparable murine model. We identified a tumor-specific, mutant-KRAS-associated subpopulation which is conserved in both human and murine lung cancer. We previously reported a key role for the oncogene BMI-1 in adenocarcinomas. We therefore investigated the effects of in vivo PTC596 treatment, which affects BMI-1 activity, in our murine model. Post-treatment, MRI analysis showed decreased tumor size, while single cell transcriptomics concomitantly detected near complete ablation of the mutant-KRAS-associated subpopulation, signifying the presence of a pharmacologically targetable, tumor-associated subpopulation. Our findings therefore hold promise for the development of a targeted therapy for KRAS-mutant adenocarcinomas., Maroni, Bassal, Krishnan et al. characterise human non-small cell lung cancer (NSCLC) carrying Kras-mutations by single-cell RNA sequencing. They identify a tumour-specific population that is conserved in mice and responds to the drug, PTC596, which is currently in clinical trials and may offer a potential avenue for treating aggressive NSCLC expressing mutated Kras.

Aim Ventricular fibrillation amplitude spectral area (AMSA) and end-tidal carbon dioxide (ETCO2) are predictors of shock success, understood as restoration of an organized rhythm, and return of spontaneous circulation (ROSC). However, little is known about their combined use. We aimed to assess the prediction accuracy when combined, and to clarify if they are correlated in out of hospital cardiac arrest' victims. Materials and Methods Records acquired by external defibrillators in out-of-hospital cardiac arrest patients of the Lombardia Cardiac Arrest registry were processed. The 1-min pre-shock ETCO2 median value (METCO2) was computed from the capnogram and AMSA (2–48 mV.Hz range) computed applying the Fast Fourier Transform to a 2-second pre-shock filtered ECG interval (0.5−30 Hz). Support Vector Machine (SVM) predictive models based on METCO2, AMSA and their combination were fit; results were given as the area under the curve (AUC) of the receiver operating characteristic (ROC) curves. Results We considered 112 patients with 391 shocks delivered. METCO2 and AMSA were predictors of shock success [AUC (IQR) of the ROC curve: 0.59 (0.56−0.62); 0.68 (0.65−0.72), respectively] and of ROSC [0.56 (0.53−0.59); 0.74 (0.71−0.78),]. Their combination in a SVM model increased the accuracy for predicting shock success [AUC (IQR) of the ROC curve: 0.71 (0.68−0.75)] and ROSC [0.77 (0.73−0.8)]. AMSA and METCO2 were significantly correlated only in patients who achieved ROSC (rho = 0.33 p = 0.03). Conclusions AMSA and ETCO2 predict shock success and ROSC after every shock, and their predictive power increases if combined. Notably, they were correlated only in patients who achieved ROSC.

We prospectively evaluated changes in cardiac and hepatic iron overload (IO) and in morpho-functional cardiac parameters and myocardial fibrosis by magnetic resonance imaging (MRI) in patients with low-risk and intermediate-1-risk myelodysplastic syndromes (MDS). Fifty patients enrolled in the Myocardial Iron Overload in MyElodysplastic Diseases (MIOMED) study were followed for 12 months. IO was quantified by the T2* technique and biventricular function parameters by cine images. Macroscopic myocardial fibrosis was detected by late gadolinium enhancement technique. Twenty-eight patients (71.89±8.46 years; 8 females) performed baseline and follow-up MRIs. Thirteen patients had baseline hepatic IO, with a higher frequency among transfusion-dependent patients. Out of the 15 patients with a baseline MRI liver iron concentration

The emergence SARS-CoV-2 in late 2019 and early 2020 has caused a pandemic of unprecedented proportions. Management of COVID-19 became emergent public health priorities, and the impact on other public health initiatives, such as expanded HIV screening and linkage to care, remain largely unknown. In this Single-Center retrospective observational study, we describe the characteristics and circumstance of the new HIV cases during 2020 compared to 2019. We observed a decrease of HIV diagnosis during this period. Interestingly, median age at HIV diagnosis decreased of one decade and percentage of female patients was higher. In addition, more patients received diagnosis during hospitalization and more AIDS-defining conditions, such as Pneumocystis pneumonia, were detected. We express our concern that HIV new diagnoses will increase as a result of people's inability to get tested or treated in this period. More efforts are needed to improve local screening programs both during and after COVID-19 pandemic.

BackgroundThe PD-1/PD-L1 axis has recently emerged as an immune checkpoint that controls antitumor immune responses also in hematological malignancies. However, the use of anti-PD-L1/PD-1 antibodies in multiple myeloma (MM) patients still remains debated, at least in part because of discordant literature data on PD-L1/PD-1 expression by MM cells and bone marrow (BM) microenvironment cells. The unmet need to identify patients which could benefit from this therapeutic approach prompts us to evaluate the BM expression profile of PD-L1/PD-1 axis across the different stages of the monoclonal gammopathies.MethodsThe PD-L1/PD-1 axis was evaluated by flow cytometry in the BM samples of a total cohort of 141 patients with monoclonal gammopathies including 24 patients with Monoclonal Gammopathy of Undetermined Significance (MGUS), 38 patients with smoldering MM (SMM), and 79 patients with active MM, including either newly diagnosed or relapsed-refractory patients. Then, data were correlated with the main immunological and clinical features of the patients.ResultsFirst, we did not find any significant difference between MM and SMM patients in terms of PD-L1/PD-1 expression, on both BM myeloid (CD14+) and lymphoid subsets. On the other hand, PD-L1 expression by CD138+ MM cells was higher in both SMM and MM as compared to MGUS patients. Second, the analysis on the total cohort of MM and SMM patients revealed that PD-L1 is expressed at higher level in CD14+CD16+ non-classical monocytes compared with classical CD14+CD16− cells, independently from the stage of disease. Moreover, PD-L1 expression on CD14+ cells was inversely correlated with BM serum levels of the anti-tumoral cytokine, IL-27. Interestingly, relapsed MM patients showed an inverted CD4+/CD8+ ratio along with high levels of pro-tumoral IL-6 and a positive correlation between %CD14+PD-L1+ and %CD8+PD-1+ cells as compared to both SMM and newly diagnosed MM patients suggesting a highly compromised immune-compartment with low amount of CD4+ effector cells.ConclusionsOur data indicate that SMM and active MM patients share a similar PD-L1/PD-1 BM immune profile, suggesting that SMM patients could be an interesting target for PD-L1/PD-1 inhibition therapy, in light of their less compromised and more responsive immune-compartment.

Simple Summary Despite the impressive clinical impact of programmed death-ligand 1 (PD-L1)/programmed cell death-1 (PD-1) blockade in solid tumors, the use of these checkpoint inhibitors in multiple myeloma (MM) still remains debated with unsatisfying clinically meaningful results. In this review we summarize the available literature data on the PD-L1/PD-1 expression profile, highlighting some discrepancies and providing a rationale for the combination with anti-CD38 antibodies, in light of the immunosuppressive effect of CD38-mediated adenosine production. Abstract The emerging role of the PD-1/PD-L1 axis in MM immune-microenvironment has been highlighted by several studies. However, discordant data have been reported on PD-1/PD-L1 distribution within the bone marrow (BM) microenvironment of patients with monoclonal gammopathies. In addition, the efficacy of PD-1/PD-L1 blockade as a therapeutic strategy to reverse myeloma immune suppression and inhibit myeloma cell survival still remains unknown. Recent data suggest that, among the potential mechanisms behind the lack of responsiveness or resistance to anti-PD-L1/PD-1 antibodies, the CD38 metabolic pathways involving the immune-suppressive factor, adenosine, could play an important role. This review summarizes the available data on PD-1/PD-L1 expression in patients with MM, reporting the main mechanisms of regulation of PD-1/PD-L1 axis. The possible link between the CD38 and PD-1/PD-L1 pathways is also reported, highlighting the rationale for the potential use of a combined therapeutic approach with CD38 blocking agents and anti-PD-1/PD-L1 antibodies in order to improve their anti-tumoral effect in MM patients.

The present study reports a case of left axillary nerve palsy following kneeling pushing phase using a birthing bar. The palsy eventually resolved; however,neuritis puerperalishas the potential to be highly disabling.

Objectives Left dorsolateral prefrontal cortex anodal transcranial direct current stimulation (tDCS) was applied in a group of patients with disorders of consciousness to determine the effects of modulation of spontaneous oscillatory brain activity. Methods 12 patients in an unresponsive wakefulness syndrome (UWS) and 12 in a minimally conscious state (MCS) underwent 2-weeks active and 2-weeks sham tDCS. Neurophysiological assessment was performed with EEG power spectra and coherence analysis directly before and after each session. Results An increase of power and coherence of the frontal and parietal alpha and beta frequency bands and significant clinical improvements were seen after the active tDCS in MCS patients. In contrast, UWS patients showed some local frontal changes in the slow frequencies. No treatment effect was observed after sham. Conclusions tDCS could induce changes in cortical EEG oscillations, modulating the travel of alpha and beta waves between anterior and posterior brain areas when some cognitive functions were preserved. This plays an important role in consciousness by integrating cognitive-emotional processing with the state of arousal. In unresponsive people, brain integration seems to be lost. Significance Our results further support the critical role of long-range fronto-parietal connections in consciousness and show the potential therapeutic utility of tDCS.

Background: Trans-catheter ablation of drug refractory atrial fibrillation (AF) is an effective and safe treatment to avoid arrhythmia recurrences. However, some patients may present anatomic variant making impossible an inferior venous approach. We report a case of pulmonary veins isolation (PVI) with cryoballoon technology via right internal jugular vein (RIJV) access. Methods: After the first trans catheter PVI attempt was failed due to inferior vena cava (IVC) hypoplasia, cryoballoon ablation with a 28-mm cryoballoon (AFAPRO - Medtronic CryoCath LP, Quebec, Canada) via superior venous access was performed. A quadripolar electrode was inserted in coronary sinus from left basilic vein. The right internal jugular vein was accessed with Seldinger technique and left atrial (LA) catheterization was performed via single trans-septal puncture (TP) under trans-esophageal echocardiographic (TOE) and fluoroscopy guidance using an SL2 (St. Jude Medical) trans-septal sheath with a BRK2 (St. Jude Medical) needle. All pulmonary veins (PVs) were engaged. Cryothermal energy was delivered after checking the correct occlusion and PVI was successfully obtained for all PVs. The procedure lasted 210 min, fluoroscopy time was 55 min. During the 16-month follow-up no sustained atrial arrhythmia recurrence was detected. Conclusion: PVI with cryoballoon technology in patients with hypoplasia of IVC can be safely and successfully performed using right internal jugular access.

At the time of writing, the number of confirmed COVID‐19 cases in Italy has dropped off to less than 150 cases per day. Now we can finally take a breath and think back on what we have experienced during the last months in our hospital Papa Giovanni XXIII in Bergamo, Lombardy, the epicentre of the Italian pandemic.

The monoclonal antibodies (mAbs) have significantly changed the treatment of multiple myeloma (MM) patients. However, despite their introduction, MM remains an incurable disease. The mAbs currently used for MM treatment were developed with different mechanisms of action able to target antigens, such as cluster of differentiation 38 (CD38) and SLAM family member 7 (SLAMF7) expressed by both, MM cells and the immune microenvironment cells. In this review, we focused on the mechanisms of action of the main mAbs approved for the therapy of MM, and on the possible novel approaches to improve MM cell killing by mAbs. Actually, the combination of anti-CD38 or anti-SLAMF7 mAbs with the immunomodulatory drugs significantly improved the clinical effect in MM patients. On the other hand, pre-clinical evidence indicates that different approaches may increase the efficacy of mAbs. The use of trans-retinoic acid, the cyclophosphamide or the combination of anti-CD47 and anti-CD137 mAbs have given the rationale to design these types of combinations therapies in MM patients in the future. In conclusion, a better understanding of the mechanism of action of the mAbs will allow us to develop novel therapeutic approaches to improve their response rate and to overcome their resistance in MM patients.

Background: The development of thrombotic coagulopathy is frequent in COVID-19 patients, but the timing after infection, cerebral venous system involvement, treatment and outcome are uncertain.Case Presentation: We report a case of massive cerebral venous thrombosis occurring in the late phase of COVID-19 infection. Mild respiratory symptoms, without fever, started three weeks before headache and acute neurological deficits. She had no dyspnea, although she was hypoxic and with typical COVID-19 associated interstitial pneumonia. Brain CT scan showed a left parietal hypodense lesion with associated sulcal subarachnoid haemorrhage. CT angiography showed a massive cerebral vein thrombosis. An asymptomatic concomitant right internal iliac vein thrombosis was found. Both cerebral venous thrombosis and deep venous thrombosis were effectively treated with unfractionated heparin started on the day of admission, then shifted to low molecular weight heparin, with a favorable clinical course. Nasopharyngel swab, repeated twice, tested negative for SARS-CoV-2. Serological tests confirmed SARS-CoV-2 infection. Conclusions: Our case supports active surveillance and prevention of thrombotic complications associated with COVID-19, which may affect both peripheral and cerebral venous system. Early initiation of unfractionated heparin may lead to good neurological outcome.

Background To date, there have not been any epidemiologic studies that have evaluated the association between swimming over a lifetime and knee health. Objective The study aimed to evaluate the relationship of a history of swimming with knee pain, radiographic knee OA (ROA), and symptomatic knee OA (SOA). Design Cross-sectional retrospective study. Setting Four academic centers in the United States. Participants Respondents to the historical physical activity survey within the Osteoarthritis Initiative with knee radiographs and symptom assessments. Methods In this retrospective study nested within the Osteoarthritis Initiative, researchers performed logistic regression with the predictor being swimming over a lifetime and over particular age ranges. Main outcome measurements Person-based definitions of frequent knee pain, ROA, and SOA. Results A total of 2637 participants were included, with a mean age of 64.3 years (SD 8.9), body mass index of 28.4 kg/m2 (SD 4.9), and 44.2% male. Over a lifetime, the adjusted prevalence measures for frequent knee pain, ROA, and SOA for any versus no history of swimming were 36.4% (33.4% - 39.5%) v. 39.9% (37.4% - 42.5%), 54.3% (51.0% - 57.6%) v. 61.1% (58.4% - 63.7%), and 21.9% (19.4% - 24.7%) v. 27.0% (24.7% - 29.4%) respectively. Conclusions This is the first epidemiologic study to indicate that swimming is potentially beneficial toward knee health, particularly when performed earlier in life (before age 35). Future prospective studies are needed to confirm these findings and to better scrutinize the associations in older age groups.

Cardiovascular diseases (CVD), including heart and pathological circulatory conditions, are the world’s leading cause of mortality and morbidity. Endothelial dysfunction involved in CVD pathogenesis is a trigger, or consequence, of oxidative stress and inflammation. Endothelial dysfunction is defined as a diminished production/availability of nitric oxide, with or without an imbalance between endothelium-derived contracting, and relaxing factors associated with a pro-inflammatory and prothrombotic status. Endothelial dysfunction-induced phenotypic changes include up-regulated expression of adhesion molecules and increased chemokine secretion, leukocyte adherence, cell permeability, low-density lipoprotein oxidation, platelet activation, and vascular smooth muscle cell proliferation and migration. Inflammation-induced oxidative stress results in an increased accumulation of reactive oxygen species (ROS), mainly derived from mitochondria. Excessive ROS production causes oxidation of macromolecules inducing cell apoptosis mediated by cytochrome-c release. Oxidation of mitochondrial cardiolipin loosens cytochrome-c binding, thus, favoring its cytosolic release and activation of the apoptotic cascade. Oxidative stress increases vascular permeability, promotes leukocyte adhesion, and induces alterations in endothelial signal transduction and redox-regulated transcription factors. Identification of new endothelial dysfunction-related oxidative stress markers represents a research goal for better prevention and therapy of CVD. New-generation therapeutic approaches based on carriers, gene therapy, cardiolipin stabilizer, and enzyme inhibitors have proved useful in clinical practice to counteract endothelial dysfunction. Experimental studies are in continuous development to discover new personalized treatments. Gene regulatory mechanisms, implicated in endothelial dysfunction, represent potential new targets for developing drugs able to prevent and counteract CVD-related endothelial dysfunction. Nevertheless, many challenges remain to overcome before these technologies and personalized therapeutic strategies can be used in CVD management.

Background Chikungunya (CHIKV) is an arbovirus transmitted mainly by Aedes aegypti females. CHIKV has been highlighted as the pathogen with the greatest impact due to the high morbidity caused by the infection. In 2016, Brazil experienced an outbreak that affected almost 272 000 people. Here, we performed a molecular characterization and phylogenetic analysis of the CHIKV circulating in 2016 in the state of Sergipe, Brazil. Methods A partial region of the E1 gene of 16 CHIKV-positive samples from Sergipe State was amplified and sequenced. Results All sequences belonged to the East-Central-South-African genotype and three point mutations were verified. Two of them were silent mutations and one was a non-synonymous mutation, which changed lysine to threonine at position 211 in the E1 protein. This mutation was present in 81.2% of the sequences, as well as in other five Brazilian sequences from previous studies. This study found that CHIKV strains circulating in Sergipe during the 2016 outbreak belonged to two different haplotypes. Conclusions The strains circulating in Sergipe are phylogenetically close to other Brazilian samples circulating in the northeast and southeast of the country, as well as viruses circulating during the same period in Haiti, indicating the rapid spread of these haplotypes.

Genomic analysis could contribute to a better understanding of the biological determinants of the evolution of multiple myeloma (MM) precursor disease and an improved definition of high-risk patients. To assess the feasibility and value of next-generation sequencing approaches in an asymptomatic setting, we performed a targeted gene mutation analysis and a genome-wide assessment of copy number alterations (CNAs) by ultra-low-pass whole genome sequencing (ULP-WGS) in six patients with monoclonal gammopathy of undetermined significance and 25 patients with smoldering MM (SMM). Our comprehensive genomic characterization highlighted heterogeneous but substantial values of the tumor fraction, especially in SMM, a rather high degree of genomic complexity, in terms of both mutations and CNAs, and inter-patient variability, a higher incidence of gene mutations and CNAs in SMM, confirming ongoing evolution, intraclonal heterogeneity, and instances of convergent evolution. ULP-WGS of these patients proved effective in revealing the marked genome-wide level of their CNAs, most of which are not routinely investigated. Finally, the analysis of our small SMM cohort suggested that chr(8p) deletions, the DNA tumor fraction, and the number of alterations may have clinical relevance in the progression to overt MM. Although validation in larger series is mandatory, these findings highlight the promising impact of genomic approaches in the clinical management of SMM.