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International audience; Background - Infective endocarditis (IE) is a common and serious complication in patients receiving chronic hemodialysis (HD). Objectives - This study sought to investigate whether there are significant differences in complications, cardiac surgery, relapses, and mortality between IE cases in HD and non-HD patients. Methods - Prospective cohort study (International Collaboration on Endocarditis databases, encompassing 7,715 IE episodes from 2000 to 2006 and from 2008 to 2012). Descriptive analysis of baseline characteristics, epidemiological and etiological features, complications and outcomes, and their comparison between HD and non-HD patients was performed. Risk factors for major embolic events, cardiac surgery, relapses, and in-hospital and 6-month mortality were investigated in HD-patients using multivariable logistic regression. Results - A total of 6,691 patients were included and 553 (8.3%) received HD. North America had a higher HD-IE proportion than the other regions. The predominant microorganism was Staphylococcus aureus (47.8%), followed by enterococci (15.4%). Both in-hospital and 6-month mortality were significantly higher in HD versus non-HD-IE patients (30.4% vs. 17% and 39.8% vs. 20.7%, respectively; p

Background Stroke is a leading cause of disability, injury, and death in elderly people and represents a major public health problem with substantial medical and economic consequences. The incidence of stroke rapidly increases with age, doubling for each decade after age 55 years. Gait impairment is one of the most important problems after stroke, and improving walking function is often a key component of any rehabilitation program. To achieve this goal, a robotic gait trainer seems to be promising. In fact, some studies underline the efficacy of robotic gait training based on end-effector technology, for different diseases, in particular in stroke patients. In this randomized controlled trial, we verify the efficacy of the robotic treatment in terms of improving the gait and reducing the risk of falling and its long-term effects. Methods In this single-blind randomized controlled trial, we will include 152 elderly subacute stroke patients divided in two groups to receive a traditional rehabilitation program or a robotic rehabilitation using G-EO system, an end-effector device for the gait rehabilitation, in addition to the traditional therapy. Twenty treatment sessions will be conducted, divided into 3 training sessions per week, for 7 weeks. The control group will perform traditional therapy sessions lasting 50 min. The technological intervention group, using the G-EO system, will carry out 30 min of traditional therapy and 20 min of treatment with a robotic system. The primary outcome of the study is the evaluation of the falling risk. Secondary outcomes are the assessment of the gait improvements and the fear of falling. Further evaluations, such as length and asymmetry of the step, walking and functional status, and acceptance of the technology, will be carried. Discussion The final goal of the present study is to propose a new approach and an innovative therapeutic plan in the post-stroke rehabilitation, focused on the use of a robotic device, in order to obtain the beneficial effects of this treatment. Trial registration ClinicalTrials.gov NCT04087083. Registered on September 12, 2019

PURPOSE. The purpose of this study was to investigate the effects of the extension of collateral vessels on the outcomes of eyes affected by central retinal vein occlusion (CRVO) and branch retinal vein occlusion (BRVO). METHODS. The study was designed as a cross-sectional case series. Patients affected by CRVO and BRVO were progressively recruited, along with an age- and sex-matched control group of healthy subjects. Structural optical coherence tomography (OCT) and OCT angiography (OCTA; 4.5 × 4.5 mm and 9.0 × 9.0 mm acquisitions) were performed on all participants in order to assess the relationship between the presence of collateral vessels and final anatomical outcomes - central macular thickness (CMT), foveal avascular zone - and functional outcomes - best corrected visual acuity (BCVA). RESULTS. Fifty-six eyes affected by CRVO and 47 eyes affected by BRVO were included. Baseline LogMAR BCVA was 0.41 ± 0.33 LogMAR in CRVO, and 0.39 ± 0.25 LogMAR in BRVO (P < 0.01), improving to 0.20 ± 0.26 LogMAR in CRVO (P < 0.01), and 0.19 ± 0.22 LogMAR in BRVO (P < 0.01). Baseline CMT was 511 ± 214 μm in CRVO and 482 ± 178 μm in BRVO (P > 0.05), decreasing to 328 ± 105 μm (P < 0.01) and 321 ± 78 μm in CRVO and BRVO, respectively (P < 0.01). Collateral vessels were detected in 16 of 56 eyes (29%) in CRVO and in 47 of 47 eyes (100%) in BRVO. Their extension was correlated with worse anatomic and visual outcomes. Remarkably, no correlation was found with peripheral capillary nonperfusion and vessel density impairment. CONCLUSIONS. The present study demonstrates that collateral vessel extension is associated with worse anatomic and functional outcomes in patients affected by CRVO and BRVO.

Major surgical societies advised using non-operative management of appendicitis and suggested against laparoscopy during the COVID-19 pandemic. The hypothesis is that a significant reduction in the number of emergent appendectomies was observed during the pandemic, restricted to complex cases. The study aimed to analyse emergent surgical appendectomies during pandemic on a national basis and compare it to the same period of the previous year. This is a multicentre, retrospective, observational study investigating the outcomes of patients undergoing emergent appendectomy in March–April 2019 vs March–April 2020. The primary outcome was the number of appendectomies performed, classified according to the American Association for the Surgery of Trauma (AAST) score. Secondary outcomes were the type of surgical technique employed (laparoscopic vs open) and the complication rates. One thousand five hundred forty one patients with acute appendicitis underwent surgery during the two study periods. 1337 (86.8%) patients met the inclusion criteria: 546 (40.8%) patients underwent surgery for acute appendicitis in 2020 and 791 (59.2%) in 2019. According to AAST, patients with complicated appendicitis operated in 2019 were 30.3% vs 39.9% in 2020 (p = 0.001). We observed an increase in the number of post-operative complications in 2020 (15.9%) compared to 2019 (9.6%) (p 24 h after admission (+ 58%), open surgery (+ 112%) and conversion to open surgery (+ 166%). In Italian hospitals, in March and April 2020, the number of appendectomies has drastically dropped. During the first pandemic wave, patients undergoing surgery were more frequently affected by more severe appendicitis than the previous year's timeframe and experienced a higher number of complications. Trial registration number and date: Research Registry ID 5789, May 7th, 2020

Trop-2 is a transmembrane signal transducer that can induce cancer growth. Using antibody targeting and N-terminal Edman degradation, we show here that Trop-2 undergoes cleavage in the first thyroglobulin domain loop of its extracellular region, between residues R87 and T88. Molecular modeling indicated that this cleavage induces a profound rearrangement of the Trop-2 structure, which suggested a deep impact on its biological function. No Trop-2 cleavage was detected in normal human tissues, whereas most tumors showed Trop-2 cleavage, including skin, ovary, colon, and breast cancers. Coimmunoprecipitation and mass spectrometry analysis revealed that ADAM10 physically interacts with Trop-2. Immunofluorescence/confocal time-lapse microscopy revealed that the two molecules broadly colocalize at the cell membrane. We show that ADAM10 inhibitors, siRNAs and shRNAs abolish the processing of Trop-2, which indicates that ADAM10 is an effector protease. Proteolysis of Trop-2 at R87-T88 triggered cancer cell growth both in vitro and in vivo. A corresponding role was shown for metastatic spreading of colon cancer, as the R87A-T88A Trop-2 mutant abolished xenotransplant metastatic dissemination. Activatory proteolysis of Trop-2 was recapitulated in primary human breast cancers. Together with the prognostic impact of Trop-2 and ADAM10 on cancers of the skin, ovary, colon, lung, and pancreas, these data indicate a driving role of this activatory cleavage of Trop-2 on malignant progression of tumors.

Background: Chronic kidney disease (CKD) is a common condition in older people and represents a global health issue since it increases the risk of associated comorbidities and all-cause mortality. Furthermore, older people with reduced renal function might be at higher risk for developing functional limitation and disability. Moreover, the current creatinine-based measures of renal function are influenced by several factors in older population. The aims of the CKD-3D project are to perform an observational study to expand the knowledge about CKD-disability relationship and to investigate the use of novel biomarkers of kidney function. Methods: An observational, multicenter, prospective cohort study will be conducted in 75 + old patients consecutively admitted to acute care wards of geriatric medicine at participating hospitals. The study planned to enroll 440 patients undergoing clinical and laboratory evaluations at baseline and after 12 months. Face-to-face follow-up at 6 months and telephone follow-up at 3 and 9 months will be carried out. Comprehensive Geriatric Assessment (CGA) and the measurement of Cystatin C, Beta-Trace Protein and Beta2-Microglobulin levels will be included. Discussion: This study will provide useful information to prevent CKD-related disability by collecting real-life data over 1-year period. The combined approach of CGA and the investigation of innovative existing biomarkers will make it possible to develop new recommendations and guidelines for a patient-centered approach. It is believed that such a study may lead to an improvement of knowledge on CKD in elderly patients and may also have implications in daily clinical practice and in decision-making process.

Monoclonal gammopathy of renal significance is a relatively new diagnosis that attributes kidney disease to damage caused by a monoclonal protein. There is growing recognition of this disease in patients previously diagnosed with monoclonal gammopathy of undetermined significance, as they increasingly develop clinically significant renal impairment requiring treatment. We outline a case of a patient presenting with worsening renal function, found to have a circulating monoclonal protein and ultimately diagnosed with a subtype of monoclonal gammopathy of renal significance referred to as immunotactoid glomerulopathy. Abbreviations: MGUS: Monoclonal gammopathy of undetermined significance; M-protein: Monoclonal protein; MM: Multiple myeloma; MGRS: Monoclonal gammopathy of renal significance; MGCS: Monoclonal gammopathy of clinical significance; CKD: Chronic kidney disease; C3 and C4: Complement 3 and complement 4, respectively; EF: Ejection fraction; CT: Computed tomography; IgG: Immunoglobulin G; GFR: Glomerular filtration rate; PET: Positron emission tomography; MRI: Magnetic Resonance Imaging.

The scenario of CKD in the older population is known to be very complex. Among community dwelling older people there is a broad range of different functional levels ranging from fitness and robustness to frailty or disability. Impaired physical function, frailty and disability, cognitive impairment, depression, vision and hearing impairment, malnutrition, and sarcopenia all contribute to worsen health outcomes and to increase the use of health care resources, thus challenging health care systems. The benefits of preventing/slowing the progression of CKD among these patients have the potential to impact different social and health domains, e.g. reducing the need for long-term care and the cost related to caregiving. Thus, early identification of CKD represents a relevant issue to be addressed in the older population.

Executive abilities are frequently impaired in patients with chronic obstructive pulmonary disease (COPD). We aimed at investigating the association between trail making test (TMT) and survival. Our series consisted of 68 stable COPD outpatients followed-up every 6 months for 52.6 ± 27.6 months. Enrolled patients underwent a baseline comprehensive neuropsychological assessment, including mini-mental state exam, attentional matrices, digit span, Rey auditory verbal learning, Rey-Osterrieth complex figure, copy drawing, tokens test, verbal fluency, category fluency, frontal assessment battery, Raven's progressive matrices, TMT-A, -B and -B-A. The association between neuropsychological deficits and overall mortality was investigated by Cox regression. During follow-up period, 41 patients (60.3%) died. After adjusting for potential confounders, TMT-B was significantly associated with mortality (HR = 2.42, 95% CI = 1.10-5.31), along with age (HR = 1.06, 95% CI = 1.0-1.13), overall comorbidity (HR = 1.29, 95% CI = 1.02-1.62) and use of noninvasive ventilation (HR = 2.16, 95% CI = 1.05-4.45). Defective TMT-B may be associated with long-term mortality in patients with stable COPD.

Purpose The aim of our study was to assess respiratory function at the time of clinical recovery and 6 weeks after discharge in patients surviving to COVID-19 pneumonia. Methods Our case series consisted of 13 patients with COVID-19 pneumonia. Results At the time of clinical recovery, FEV1 (2.07 ± 0.72 L) and FVC (2.25 ± 0.86 L) were lower compared to lower limit of normality (LLN) values (2.56 ± 0.53 L, p = 0.004, and 3.31 ± 0.65 L, p < 0.001, respectively), while FEV1/FVC (0.94 ± 0.07) was higher compared to upper limit of normality (ULN) values (0.89 ± 0.01, p = 0.029). After 6 weeks pulmonary function improved but FVC was still lower than ULN (2.87 ± 0.81, p = 0.014). Conclusion These findings suggest that COVID-19 pneumonia may result in clinically relevant alterations in pulmonary function tests, with a mainly restrictive pattern. Electronic supplementary material The online version of this article (10.1007/s15010-020-01474-9) contains supplementary material, which is available to authorized users.

We report a case of a fibromyalgia (FM) patient with an history of brain-cancer presenting signs and symptoms of gadolinium toxicity following repeated administrations of a macrocyclic contrast agent, Gadovist. In the present report, we provide evidence supporting the hypothesis of a causal relationship linking gadolinium deposition to a clinical manifestation of disease, namely fibromyalgia. We unravel a role for gadolinium in the still unknown etiology of fibromyalgia as a metal toxicity disorder. Contrast agents are routinely administered in a clinical context. It is thus possible that the patients are mistakenly believed to show complaint of their primary disease, whereas, in some instances, their symptoms are associated with gadolinium deposition. Keywords: Gadolinium deposition, Fibromyalgia syndrome, Chronic pain, Toxicity, Contrast agents, Magnetic resonance imaging

Background Resuscitation of septic patients regarding goals, monitoring aspects and therapy is highly variable. Our aim was to characterize cardiovascular and fluid management of sepsis in Argentina, a low and middle-income country (LMIC). Furthermore, we sought to test whether the utilization of dynamic tests of fluid responsiveness, as a guide for fluid therapy after initial resuscitation in patients with persistent or recurrent hypoperfusion, was associated with decreased mortality. Methods Secondary analysis of a national, multicenter prospective cohort study (n = 787) fulfilling Sepsis-3 definitions. Epidemiological characteristics, hemodynamic management data, type of fluids and vasopressors administered, physiological variables denoting hypoperfusion, use of tests of fluid responsiveness, and outcomes, were registered. Independent predictors of mortality were identified with logistic regression analysis. Results Initially, 584 of 787 patients (74%) had mean arterial pressure (MAP) 2 saturation (39%), central venous–arterial PCO2 difference (38%), MAP (31%), dynamic tests of fluid responsiveness (30%), capillary-refill time (28%), mottling (26%), central venous pressure (24%), cardiac index (13%) and/or pulmonary wedge pressure (3%). Independent predictors of mortality were SOFA and Charlson scores, lactate, requirement of mechanical ventilation, and utilization of dynamic tests of fluid responsiveness. Conclusions In this prospective observational study assessing the characteristics of resuscitation of septic patients in Argentina, a LMIC, the prevalent use of initial fluid bolus with normal saline and Ringer lactate and the use of norepinephrine as the most frequent vasopressor, reflect current worldwide practices. After initial resuscitation with 30 mL/kg of fluids and vasopressors, 413 patients developed persistent or recurrent hypoperfusion, which required further volume expansion. In this setting, the assessment of fluid responsiveness with dynamic tests to guide fluid resuscitation was independently associated with decreased mortality.

textabstractPurpose: Aortic stiffness (AS) is associated with cardiovascular events and all-cause mortality in the older population. AS might also influence the health-related quality of life (HRQOL) as a result of the negative effects of AS on cognitive and physical morbidity. We aimed to investigate the possible association between AS and HRQOL in people aged 75 years and over. Patients and Methods: This cross-sectional study was part of the SCOPE study, an international multicenter cohort observational study. The indicators for AS were aortic pulse wave velocity (aPWV) and central pulse pressure (cPP). HRQOL was assessed using the EQ-5D index and the EQ-5D visual analog scale (VAS). ANCOVA and multivariate regression models were used to investigate possible associations. Results: We included 280 Dutch participants of the SCOPE study. Median age was 79 years (IQR 76–83) and 42.1% were women. Participants reporting any problem on the EQ-5D index (n=214) had higher values of aPWV (12.6 vs 12.2 m/s, p = 0.024) than participants not experiencing any problem (n=66) and comparable values of cPP (44.4 vs 42.0 mmHg, p = 0.119). Estimates only slightly changed after adjustments. No association was found between indicators of AS and EQ-5D VAS. Conclusion: Aortic stiffness was associated with impaired quality of late life. This association could be mediated by subclinical vascular pathology affecting mental and physical health.

Introduction: Given the role of inflammation in the pathogenesis of diabetic macular edema (DME), the use of intravitreal corticosteroid agents can be a valid therapeutic alternative in the...

Aim To describe the methods and feasibility of the nutritional intervention carried out within the SPRINTT Randomized cotrolled trial. We also illustrate how nutrition interventionists identified participants at risk of malnutrition and the lessons learnt from the nutrition intervention. Findings SPRINTT nutrition intervention was well-received by the majority of the participants. It was mainly carried out using tailored nutrition counselling, but also other means of delivering the intervention were successfully used. Compared with a standard nutrition prescription, an individualized protocol to diagnose malnutrition and follow-up by tailored nutrition counselling helped achieve nutritional targets more effectively in spite of diversity of population in nutritional habits and in some cases reluctance to accept changes. Message The SPRINTT nutrition intervention was feasible and allowed flexibility to the varying needs and cultural differences of this heterogeneous population of frail, older Europeans. It may serve as a model to educate and improve nutrition among community-dwelling older people at risk of mobility limitations. Supplementary Information The online version contains supplementary material available at 10.1007/s41999-020-00438-4., Background The “Sarcopenia and Physical Frailty in Older People: Multicomponent Treatment Strategies” (SPRINTT) project sponsored a multi-center randomized controlled trial (RCT) with the objective to determine the effect of physical activity and nutrition intervention for prevention of mobility disability in community-dwelling frail older Europeans. We describe here the design and feasibility of the SPRINTT nutrition intervention, including techniques used by nutrition interventionists to identify those at risk of malnutrition and to carry out the nutrition intervention. Methods SPRINTT RCT recruited older adults (≥ 70 years) from 11 European countries. Eligible participants (n = 1517) had functional limitations measured with Short Physical Performance Battery (SPPB score 3–9) and low muscle mass as determined by DXA scans, but were able to walk 400 m without assistance within 15 min. Participants were followed up for up to 3 years. The nutrition intervention was carried out mainly by individual nutrition counseling. Nutrition goals included achieving a daily protein intake of 1.0–1.2 g/kg body weight, energy intake of 25–30 kcal/kg of body weight/day, and serum vitamin D concentration ≥ 75 mmol/L. Survey on the method strategies and feasibility of the nutrition intervention was sent to all nutrition interventionists of the 16 SPRINTT study sites. Results Nutrition interventionists from all study sites responded to the survey. All responders found that the SPRINTT nutrition intervention was feasible for the target population, and it was well received by the majority. The identification of participants at nutritional risk was accomplished by combining information from interviews, questionnaires, clinical and laboratory data. Although the nutrition intervention was mainly carried out using individual nutritional counselling, other assisting methods were used as appropriate. Conclusion The SPRINTT nutrition intervention was feasible and able to adapt flexibly to varying needs of this heterogeneous population. The procedures adopted to identify older adults at risk of malnutrition and to design the appropriate intervention may serve as a model to deliver nutrition intervention for community-dwelling older people with mobility limitations. Supplementary Information The online version contains supplementary material available at 10.1007/s41999-020-00438-4.

Retinal vein occlusion is the second most common retinal vascular pathology after diabetic retinopathy and a major cause of vision impairment. Nowadays, both central retinal vein occlusion (CRVO) and branch retinal vein occlusion (BRVO) can be well-managed by intravitreal treatments. However, considering the long-life expectance of the patients, few data are present in the literature about the very long-term outcome of CRVO and BRVO. The present study was an interventional, retrospective analysis of the morphological and functional long-term outcome of CRVO and BRVO patients, followed in an Italian referral center. We collected data from 313 eyes (178 CRVO eyes and 135 BRVO eyes). Mean follow-up was 45 ± 25 months (range 12–84 months). Both CRVO and BRVO eyes experience a significant visual acuity improvement secondary to anti-vascular endothelial growth factor/dexamethasone treatments (from 0.57 ± 0.25 to 0.41 ± 0.24 LogMAR in CRVO and from 0.53 ± 0.42 to 0.30 ± 0.41 LogMAR in BRVO, respectively) (p

Background The aim of our study was to identify independent predictors of functional decline in older nursing home (NH) residents, taking into account both resident and facility characteristics. Methods Longitudinal observational study involving 1,760 older (≥65 y) residents of NH participating in the SHELTER* study (57 NH in eight countries). All residents underwent a comprehensive geriatric assessment using the interRAI LTCF. Functional decline was defined as an increase of at least one point in the MDS Long Form ADL scale during a 1 year follow-up. Facility and country effects were taken into account. Results During the study period 891 (50.6%), NH residents experienced ADL decline. Residents experiencing ADL decline were older, had lower disability at baseline, were more frequently affected by severe dementia and by urinary incontinence, and used more antipsychotics. In the mixed-effect logistic regression model, factors independently associated with a higher risk of functional decline were dementia and urinary incontinence, whereas the presence of a geriatrician was a protective factor. Conclusions Both resident and facility characteristics are associated with the risk of functional decline in NH residents. Increasing the quality of healthcare by involving a geriatrician in residents’ care might be an important strategy to improve the outcome of this vulnerable population.

Simple Summary The dysregulation of Wnt pathways is involved in colorectal carcinogenesis. H2O2 differentially regulates the Wnt/β-Catenin pathway in colorectal cancer (CRC), but the molecular mechanisms remain unclear. Cellular stress might also stimulate APC protein production retaining some functions in N-terminus and lead to cancer progression. The effect of oxidative distress on Wnt/β-catenin signaling in the light of APC functions is unknown. We exposed starved HCT116, SW480 and SW620 CRC cell lines to H2O2-induced short-term oxidative stress. This treatment promoted the activation of β-Catenin and increased cytoplasmic APC. H2O2 regulated gene expression, related to cellular phenotype and stimulated both Wnt/β-Catenin-dependent and -independent signaling. These findings suggest that oxidative distress may influence APC functions in Wnt signaling and open up new perspectives to develop personalized therapeutic approaches for CRC. Abstract Colorectal cancer (CRC) is a multistep process that arises in the colic tissue microenvironment. Oxidative stress plays a role in mediating CRC cell survival and progression, as well as promoting resistance to therapies. CRC progression is associated with Wnt/β-Catenin signaling dysregulation and loss of proper APC functions. Cancer recurrence/relapse has been attributed to altered ROS levels, produced in a cancerous microenvironment. The effect of oxidative distress on Wnt/β-Catenin signaling in the light of APC functions is unclear. This study evaluated the effect of H2O2-induced short-term oxidative stress in HCT116, SW480 and SW620 cells with different phenotypes of APC and β-Catenin. The modulation and relationship of APC with characteristic molecules of Wnt/β-Catenin were assessed in gene and protein expression. Results indicated that CRC cells, even when deprived of growth factors, under acute oxidative distress conditions by H2O2 promote β-Catenin expression and modulate cytoplasmic APC protein. Furthermore, H2O2 induces differential gene expression depending on the cellular phenotype and leading to favor both Wnt/Catenin-dependent and -independent signaling. The exact mechanism by which oxidative distress can affect Wnt signaling functions will require further investigation to reveal new scenarios for the development of therapeutic approaches for CRC, in the light of the conserved functions of APC.

113 Background: Patients with hematologic malignancies are referred to palliative care less than patients with solid tumor malignancies. Clinical trials are underway at academic centers exploring early inpatient palliative care for patients newly diagnosed with AML receiving induction chemotherapy. Feasibility of such interventions have not been studied in a community setting. We structured a multi-faceted intervention for our community hematology and palliative team on the benefits of early palliative care in hematologic malignancies with the aim to increase utilization. Methods: In 2017, 24% of patients with AML admitted to Lancaster General Hospital for induction chemotherapy received an inpatient palliative consultation. Needs assessment performed on the hematology and palliative teams demonstrated a need for integration of palliative care into clinical pathways, automatic triggers for consultation, a need for increased education on AML, and creation of standard elements in inpatient consultations. Results: In the spring of 2018, we integrated palliative care into institutional AML clinical pathways such that all patients receive inpatient palliative consultation within 72 hours of admission. A consultation trigger was placed within the admission order set and is currently being incorporated into the chemotherapy treatment protocol. An educational program on AML was created and presented by the hematology team to the inpatient palliative team. This intervention included creation of minimum standards for inpatient palliative consultation including provider assessment within 72 hours of referral, two visits per week by a provider and a minimum of one visit by the interdisciplinary team during admission with a focus on symptom management, psychosocial assessments, and advanced care planning. Conclusions: We have demonstrated feasibility of creating standards for early palliative care intervention in AML patients with collaboration from the hematology and palliative teams. Next steps will include assessing whether these interventions increase uptake of palliative care utilization and specific patient outcomes.

We recently reported that activation of Trop-2 through its cleavage at R87-T88 by ADAMIO underlies Trop-2-driven progression of colon cancer. However, the mechanism of action and pathological impact of Trop-2 in metastatic diffusion remain unexplored. Through searches for molecular determinants of cancer metastasis, we identified TROP2 as unique in its up-regulation across independent colon cancer metastasis models. Overexpression of wild-type Trop-2 in KM12SM human colon cancer cells increased liver metastasis rates in vivo in immunosuppressed mice. Metastatic growth was further enhanced by a tail-less, activated Delta cytoTrop-2 mutant, indicating the Trop-2 tail as a pivotal inhibitory signaling element. In primary tumors and metastases, transcriptome analysis showed no down-regulation of CDH1 by transcription factors for epithelial-to-mesenchymal transition, thus suggesting that the pro-metastatic activity of Trop-2 is through alternative mechanisms. Trop-2 can tightly interact with ADAM10. Here, Trop-2 bound E-cadherin and stimulated ADAM10-mediated proteolytic cleavage of E-cadherin intracellular domain. This induced detachment of E-cadherin from beta-actin, and loss of cell-cell adhesion, acquisition of invasive capability, and membrane-driven activation of beta-catenin signaling, which were further enhanced by the Delta cytoTrop-2 mutant. This Trop-2/E-cadherin/beta-catenin program led to anti-apoptotic signaling, increased cell migration, and enhanced cancer-cell survival. In patients with colon cancer, activation of this Trop-2-centered program led to significantly reduced relapse-free and overall survival, indicating a major impact on progression to metastatic disease. Recently, the anti-Trop-2 mAb Sacituzumab govitecan-hziy was shown to be active against metastatic breast cancer. Our findings define the key relevance of Trop-2 as a target in metastatic colon cancer. Funding Agencies|grants of Fondazione of the Cassa di Risparmio della Provincia di Chieti; Compagnia di San PaoloCompagnia di San Paolo [2489IT]; Italian Ministry of Development [MI01_00424]; Region Abruzzo (POR FESR) [C78C14000100005]; Oncoxx Biotech (Italian Ministry of University and Research, Smart Cities and Communities) [SCN_00558]; Programma Per Giovani Ricercatori "Rita Levi Montalcini", Italian Ministry of University and Research [PGR12I7N1Z]

The enteric nervous system (ENS) is the third division of the autonomic autonomic nervous system and the largest collection of neurons outside the central nervous system (CNS). The ENS has been referred to as “the brain in the gut” or “the second brain of the human body” because of its highly integrated neural circuits controlling a vast repertoire of gut functions, including absorption/secretion, splanchnic blood vessels, some immunological aspects, intestinal epithelial barrier, and gastrointestinal (GI) motility. The latter function is the result of the ENS fine-tuning over smooth musculature, along with the contribution of other key cells, such as enteric glia (astrocyte like cells supporting and contributing to neuronal activity), interstitial cells of Cajal (the pacemaker cells of the GI tract involved in neuromuscular transmission), and enteroendocrine cells (releasing bioactive substances, which affect gut physiology). Any noxa insult perturbing the ENS complexity may determine a neuropathy with variable degree of neuro-muscular dysfunction. In this review, we aim to cover the most recent update on genetic mechanisms leading to enteric neuropathies ranging from Hirschsprung’s disease (characterized by lack of any enteric neurons in the gut wall) up to more generalized form of dysmotility such as chronic intestinal pseudo-obstruction (CIPO) with a significant reduction of enteric neurons. In this line, we will discuss the role of the RAD21 mutation, which we have demonstrated in a family whose affected members exhibited severe gut dysmotility. Other genes contributing to gut motility abnormalities will also be presented. In conclusion, the knowledge on the molecular mechanisms involved in enteric neuropathy may unveil strategies to better manage patients with neurogenic gut dysmotility and pave the way to targeted therapies.

Introduction Recently published data suggests that inflammatory heart disease (IHD) is far more prevalent in COVID-19 patients than initially expected. Specifically, there have been reports of greater than expected right ventricular (RV) involvement in the post COVID-19 recovery period. However, there are no published data comparing RV dysfunction in COVID-19 and non-COVID-19 patient cohorts with IHD. Purpose This study was designed to assess and compare the prevalence of RV hypokinesis in 2 patient cohorts: patients with COVID-19 related IHD and patients with non-COVID-19 related IHD, based on cardiac MRI findings (CMR). Methods An institutional cardiac imaging database was queried for all patients with IHD documented by CMR. Inflammatory heart disease was defined as pericarditis and/or myocarditis using the recently modified Lake Louise criteria, including T1 and T2 relaxation mapping. The prevalence of IHD was evaluated in 2 separate patient cohorts, subjects with COVID-19 related IHD and subjects with non-COVID-19 related IHD. Further assessment of these 2 patients cohorts included the presence of RV hypokinesis. A two-tailed Z-test was used for statistical comparison of the presence of IHD and the presence of RV hypokinesis in these 2 patient cohorts. Results 62 COVID patients and 6782 non-COVID patients were identified in the imaging database. 53 of the 62 COVID patients (85.5%) had evidence of IHD on CMR study. In contrast, 1273 of the 6782 patients (18.8%) had documented IHD detected by CMR. There was a statistically significant difference between the incidence of IHD in the 2 patient groups (p-value Conclusion These data suggest that the prevalence of IHD in COVID-19 patients is 4 times greater than in patients with a non-COVID etiology, based on CMR imaging findings. Furthermore, the occurrence of RV hypokinesis is 5 times greater in COVID-19 patients than in IHD patients with a non-COVID etiology, also based on CMR findings. These data suggest that CMR imaging is of value in detecting both IHD and RV dysfunction, which are often difficult to detect with other imaging modalities. Funding Acknowledgement Type of funding sources: None.

Introduction Intuitively, severity of symptoms usually correlates with severity of disease process or disease progression. In this regard, the ACC Sports and Exercise Cardiology Section proposed an algorithm for competitive athletes to assess and manage cardiac injury after COVID-19 infection based on initial symptoms. However, there are no published, evidence-based data to substantiate this approach. Purpose This study was designed to assess the correlation between symptoms at the time of initial diagnosis to post-COVID recovery cardiac symptoms and findings on a cardiac MRI study (CMR). It is hypothesized that the initial symptoms at the time of a positive COVID-19 test may not be reliable or sufficient in predicting the severity of post-COVID recovery symptoms or findings on CMR. Methods An institutional cardiac imaging database was queried for all patients with a positive COVID-19 PCR test, who subsequently underwent a CMR for post-COVID recovery cardiac symptoms. Severity of COVID-19 symptoms were assessed using a checklist of mild symptoms and more severe symptoms as defined by the Centers for Disease Control, Atlanta GA. Mild symptoms included: fever/chills, cough, fatigue, body aches, headache, loss of taste/smell, sore throat, congestion, and nausea vomiting diarrhea. More severe symptoms included: shortness of breath, chest pain, and confusion. For each patient, prevalence of these symptoms was assessed at the time of initial diagnosis, and then again post-COVID recovery, just prior to the time of CMR. Inflammatory heart disease (IHD) was defined as pericarditis and/or myocarditis using the recently modified Lake Louise criteria, including T1 and T2 relaxation mapping. Results 58 patients with a positive COVID-19 PCR test were identified, who subsequently underwent a CMR study for evaluation of cardiac symptoms. 36 patients (62%) had no symptoms at the time of initial diagnosis, while 7 patients (12%) had mild symptoms. Lastly, 15 patients (26%) had more severe symptoms at the time of initial diagnosis. All CMR studies were prompted by the subsequent development of shortness of breath or chest pain. Detection rates of IHD in these 3 groups of patients is delineated in Figure 1. A chi-squared test was used to assess any statistically significant differences in the CMR detection rate of IHD based on initial symptoms. There was no significant difference in the likelihood of IHD based on initial COVID symptoms (p-value=0.856). Conclusion Forty-three of 58 patients (74%) with no/mild symptoms at the time of initial COVID-19 diagnosis developed more severe post-COVID symptoms requiring CMR. In contrast, 15 of 58 patients (26%) with more severe symptoms at the time of initial COVID-19 diagnosis had persistence of these symptoms requiring CMR. These data suggest that the severity of symptoms on initial presentation with COVID-19 does not predict post-COVID recovery symptoms or CMR findings of inflammatory heart disease. Funding Acknowledgement Type of funding sources: None.

Background: Fluocinolone acetonide (FAc) implant represents a long-term strategy for the management of diabetic macular edema (DME). Because of the 3-year duration, the careful monitoring of the intraocular pressure (IOP) is necessary. The main aim of the study was to provide quantitative IOP cutoffs associated with the onset of IOP increases.Methods: The study was retrospectively conducted with 2-year of follow-up. We separately considered eyes with good IOP control (Group 1), eyes requiring IOP-lowering medications (Group 2) and eyes undergoing IOP-lowering surgery (Group 3). The statistical analysis assessed Delta% IOP changes over the 2-year follow-up. ROC analysis was performed to detect significant cutoffs associated with Group 2 and Group 3. IOP changes occurring after a previously administered dexamethasone (DEX) implant were also evaluated.Results: We included 48 eyes (48 patients), stratified as follows: Group 1 (25/48; 52%), Group 2 (19/48; 40%) and Group 3 (4/48; 8%). ROC analysis performed on IOP values detected 2-months later DEX implant showed a mean Delta IOP increase>24% significantly associated with IOP-lowering medications after FAc implant, whereas a mean Delta IOP increase>35% was significantly associated with IOP-lowering surgery after FAc implant. With respect to IOP changes occurred after FAc implant, our ROC analysis showed a mean Delta IOP increase>8% significantly associated with IOP-lowering medications, whereas a mean Delta IOP increase>15% was significantly associated with IOP-lowering surgery. DEX-related IOP changes showed 52% sensitivity and 100% specificity of FAc-related IOP increases.Conclusions: IOP changes provides clinically relevant cutoffs associated with the onset of FAc-related IOP increases.

The primary objective of this study was to assess whether the topical administration of two neuroprotective drugs (brimonidine and somatostatin) could prevent or arrest retinal neurodysfunction in patients with type 2 diabetes. For this purpose, adults aged between 45 and 75 years with a diabetes duration ≥5 years and an Early Treatment of Diabetic Retinopathy Study (ETDRS) level of ≤35 were randomly assigned to one of three arms: placebo, somatostatin, or brimonidine. The primary outcome was the change in implicit time (IT) assessed by multifocal electroretinography between baseline and at the end of follow-up (96 weeks). There were 449 eligible patients allocated to brimonidine (n = 152), somatostatin (n = 145), or placebo (n = 152). When the primary end point was evaluated in the whole population, we did not find any neuroprotective effect of brimonidine or somatostatin. However, in the subset of patients (34.7%) with preexisting retinal neurodysfunction, IT worsened in the placebo group (P < 0.001) but remained unchanged in the brimonidine and somatostatin groups. In conclusion, the topical administration of the selected neuroprotective agents appears useful in preventing the worsening of preexisting retinal neurodysfunction. This finding points to screening retinal neurodysfunction as a critical issue to identify a subset of patients in whom neuroprotective treatment might be of benefit.

The main aim of this study was to evaluate the ability of serum biomarkers to predict the worsening of retinal neurodysfunction in subjects with type 2 diabetes. For this purpose, we measured selected molecules (N-epsilon-carboxy methyl lysine (CML), laminin P1 (Lam-P1), and asymmetric dimethylarginine (ADMA)) in the serum of 341 participants of the EUROCONDOR study at baseline, 24, and 48 weeks. Retinal neurodysfunction was assessed by measuring implicit time (IT) using multifocal electroretinography, and structural changes were examined by spectral domain&ndash, optical coherence tomography. The values of IT at baseline were directly correlated with baseline serum concentrations of CML (r = 0.135, p = 0.013). Furthermore, in the placebo group, increase in CML concentration throughout follow-up correlated with the IT (r = 0.20, p = 0.03). Baseline serum levels of CML also correlated with macular retinal thickness (RT) (r = 0.231, p &lt, 0.001). Baseline Lam-P1 levels correlated with the increase of the RT at the end of follow-up in the placebo group (r = 0.22, p = 0.016). We provide evidence that CML may be a biomarker of both retinal neurodysfunction and RT, whereas Lam-P1 was associated with RT only. Therefore, circulating levels of these molecules could provide a complementary tool for monitoring the early changes of diabetic retinopathy (DR).

Purpose: To compare nonmydriatic montage widefield images with dilated fundus ophthalmoscopy for determining diabetic retinopathy (DR) severity. Materials and methods: In this prospective, observational, cross-sectional study, patients with a previous diagnosis of diabetes and without history of diabetes-associated ocular disease were screened for DR. Montage widefield imaging was obtained with a system that combines confocal technology with white-light emitting diode (LED) illumination (DRSplus, Centervue, Padua, Italy). Dilated fundus examination was performed by a retina specialist. Results: Thirty-seven eyes (20 patients, 8 females) were finally included in the analysis. Mean age of the patients enrolled was 58.0 ± 11.6years [range 31–80years]. The level of DR identified on montage widefield images agreed exactly with indirect ophthalmoscopy in 97.3% (36) of eyes and was within 1 step in 100% (37) of eyes. Cohen's kappa coefficient (κ) was 0.96, this suggesting an almost perfect agreement between the two modalities in DR screening. Nonmydriatic montage widefield imaging acquisition time was significantly shorter than that of dilated clinical examination (p = 0.010). Conclusion: Nonmydriatic montage widefield images were compared favorably with dilated fundus examination in defining DR severity; however, they are acquired more rapidly.

To compare the long-term functional and anatomical outcomes of cataract surgery with combined versus 1-month deferred intravitreal dexamethasone implant (DEX) in eyes with pre-existing diabetic macular edema (DME). Best-corrected visual acuity (BCVA) and central retinal thickness (CRT) were retrospectively evaluated in both groups before treatments, then 1, 4, 12 and 24 months after DEX. Forty eyes were analyzed, 20 in each group. BCVA disclosed comparable trends, increasing from similar starting values (p = 0.9913) to akin scores 1 month after DEX (p = 0.4229). After 4 months, it similarly reduced without significant variations within each group throughout the whole observation period. CRT was similar at the time of surgery (p = 0.6134) and was reduced by DEX injection in both samples, with a superior beneficial effect in the combined group after 1 month (p = 0.0010). At 4 months, CRT further elevated and remained overall stable in the long term without differences. By 12 months, 19 (95%) eyes received further injections: 1 (5%) fluocinolone, 3 (15%) received other DEX and fluocinolone, 13 (65%) ≥ 1 DEX only and 2 (10%) anti-VEGFs. During the second year, 6 additional eyes (from the 13 receiving DEX) switched to fluocinolone, reaching a total of 10 (50%). Similar results were observed in the deferred group. DEX implant performed at the time of surgery achieved the same long-term functional and anatomical outcomes compared to a 1-month injection deferral in treating eyes with pre-existing DME that should undergo cataract extraction.

Multimodal imaging of an impending retinal vein occlusion in an arteriovenous malformation associated with optic nerve drusen (OND) in a 16-year-old girl affected by Wyburn-Mason Syndrome. The authors seek to determine whether the association between the two entities has had an additive role in the acute retinal vascular event. [ Ophthalmic Surg Lasers Imaging Retina . 2020;51:418–419.]

Purpose The aim of this study was to assess respiratory function at the time of clinical recovery, 6 weeks, 6 months, and 12 months after discharge in patients surviving to COVID-19 pneumonia. Methods Our case series consisted of 13 hospitalized patients with COVID-19 pneumonia. Results Baseline pulmonary function tests were 55.7 ± 15.6 for FEV1%, 68.6 ± 16.0 for FVC%, and 1.2 ± 0.1 for FEV1/FVC%. Although pulmonary function showed a small improvement after 6 weeks, patients experienced a more significant improvement after 6 and 12 months in FEV1% (95.4 ± 13.7 and 107.2 ± 16.5, respectively; p

Summary Background Although COVID-19 has greatly affected many low-income and middle-income countries, detailed information about patients admitted to the intensive care unit (ICU) is still scarce. Our aim was to examine ventilation characteristics and outcomes in invasively ventilated patients with COVID-19 in Argentina, an upper middle-income country. Methods In this prospective, multicentre cohort study (SATICOVID), we enrolled patients aged 18 years or older with RT-PCR-confirmed COVID-19 who were on invasive mechanical ventilation and admitted to one of 63 ICUs in Argentina. Patient demographics and clinical, laboratory, and general management variables were collected on day 1 (ICU admission); physiological respiratory and ventilation variables were collected on days 1, 3, and 7. The primary outcome was all-cause in-hospital mortality. All patients were followed until death in hospital or hospital discharge, whichever occurred first. Secondary outcomes were ICU mortality, identification of independent predictors of mortality, duration of invasive mechanical ventilation, and patterns of change in physiological respiratory and mechanical ventilation variables. The study is registered with ClinicalTrials.gov, NCT04611269, and is complete. Findings Between March 20, 2020, and Oct 31, 2020, we enrolled 1909 invasively ventilated patients with COVID-19, with a median age of 62 years [IQR 52–70]. 1294 (67·8%) were men, hypertension and obesity were the main comorbidities, and 939 (49·2%) patients required vasopressors. Lung-protective ventilation was widely used and median duration of ventilation was 13 days (IQR 7–22). Median tidal volume was 6·1 mL/kg predicted bodyweight (IQR 6·0–7·0) on day 1, and the value increased significantly up to day 7; positive end-expiratory pressure was 10 cm H2O (8–12) on day 1, with a slight but significant decrease to day 7. Ratio of partial pressure of arterial oxygen (PaO2) to fractional inspired oxygen (FiO2) was 160 (IQR 111–218), respiratory system compliance 36 mL/cm H2O (29–44), driving pressure 12 cm H2O (10–14), and FiO2 0·60 (0·45–0·80) on day 1. Acute respiratory distress syndrome developed in 1672 (87·6%) of patients; 1176 (61·6%) received prone positioning. In-hospital mortality was 57·7% (1101/1909 patients) and ICU mortality was 57·0% (1088/1909 patients); 462 (43·8%) patients died of refractory hypoxaemia, frequently overlapping with septic shock (n=174). Cox regression identified age (hazard ratio 1·02 [95% CI 1·01–1·03]), Charlson score (1·16 [1·11–1·23]), endotracheal intubation outside of the ICU (ie, before ICU admission; 1·37 [1·10–1·71]), vasopressor use on day 1 (1·29 [1·07–1·55]), D-dimer concentration (1·02 [1·01–1·03]), PaO2/FiO2 on day 1 (0·998 [0·997–0·999]), arterial pH on day 1 (1·01 [1·00–1·01]), driving pressure on day 1 (1·05 [1·03–1·08]), acute kidney injury (1·66 [1·36–2·03]), and month of admission (1·10 [1·03–1·18]) as independent predictors of mortality. Interpretation In patients with COVID-19 who required invasive mechanical ventilation, lung-protective ventilation was widely used but mortality was high. Predictors of mortality in our study broadly agreed with those identified in studies of invasively ventilated patients in high-income countries. The sustained burden of COVID-19 on scarce health-care personnel might have contributed to high mortality over the course of our study in Argentina. These data might help to identify points for improvement in the management of patients in middle-income countries and elsewhere. Funding None. Translation For the Spanish translation of the Summary see Supplementary Materials section.

Anosognosia and impairment of insight are characteristic features of Alzheimer's disease (AD), which can lead to delays in appropriate medical care and significant family discord. The default mode network (DMN), a distributed but highly connected network of brain regions more active during rest than during task, is integrally involved in awareness. DMN dysfunction is common in AD, and disrupted communication between memory-related and self-related DMN networks is associated with anosognosia in AD patients. In addition, the temporoparietal junction (TPJ) is a key region of the "social brain" and also contributes to representations of the self. The exact classification of the TPJ within the DMN is unclear, though connections between the TPJ and DMN have been highlighted in multiple avenues of research. Here we discuss the relationship between the TPJ, DMN, and AD, as well as the potential involvement of the TPJ in anosognosia in AD. We review past and present findings to raise attention to the TPJ, with a specific emphasis on neuroimaging technologies which suggest a pivotal role of the TPJ within large-scale brain networks linked to anosognosia in AD.

Background Presently available medications and surgical treatments for Parkinson’s disease have limited effects on fine motor problems and often leave patients with significant fine motor disability. Standard of care occupational therapy (OT) yields low efficacy, potentially due to a lack of standard protocols. Neurologic music therapy (NMT) techniques, especially rhythmic auditory stimulation which relies on interaction between rhythm and movement, have shown to be effective in PD gait rehabilitation possibly through their reliance on neural pathways that are not affected by PD. Therapeutic instrumental music performance (TIMP) is one other NMT technique that holds promise but which mode of action and efficacy has not been investigated in PD yet. Methods One hundred PD participants will be randomly assigned to receive 15 sessions of either TIMP with rhythm or TIMP without rhythm, standard of care OT, or to be waitlisted (control) over 5 consecutive weeks. Brain oscillatory responses will be collected using magnetoencephalography during an auditory-motor task to understand the underlying mechanisms. The Grooved Pegboard, the UPDRS III finger tap, and the finger-thumb opposition will be assessed to investigate clinical changes related to fine motor function. This project will also serve to confirm or refute our pilot data findings suggesting NMT relies on compensatory brain networks utilized by the PD brain to bypass the dysfunctional basal ganglia. Discussion This study aims to use standardized TIMP and OT research protocols for investigating the neuronal pathways utilized by each intervention and possibly study their efficacy with respect to fine motor rehabilitation via a randomized control trial in the PD population. Trial registration ClinicalTrials.gov NCT03049033. Registered on September 29, 2020

Crescentic glomerulonephritis, also known as rapidly progressive glomerulonephritis, is a syndrome characterized by progressive and rapid deterioration of renal function over the course of weeks to months. Oliguria, hematuria, azotemia, and hypertension are characteristic features of this condition. Crescentic glomerulonephritis is further classified according to the staining pattern on immunofluorescence. In rare instances, a mixed pattern of injury is encountered as in the case of double antibody-positive rapidly progressive glomerulonephritis (RPGN). This case illustrates the challenge in treatment of double antibody-positive RPGN in an elderly female with no previous renal disease. The patient was found to be positive for anti-GBM antibody and MPO-ANCA. Treatment was initially targeted against MPO-ANCA as the biopsy was most consistent with this process; however, the patient failed to respond to treatment and was subsequently transitioned to oral cyclophosphamide directed against anti-GBM disease. In cases of doubly antibody-positive RPGN with anti-GBM disease and ANCA-associated vasculitis, initial treatment should focus on inducing remission of anti-GBM disease as double antibody-positive disease often presents with the aggressive morbidity and mortality seen in anti-GBM disease, and the chronic risk of relapse seen in ANCA-mediated vasculitis.

ObjectiveThis study aimed to determine the most appropriate cognitive and cerebrospinal fluid (CSF) biomarker setting to distinguish frontotemporal dementia (FTD) from Alzheimer’s disease (AD).MethodPatients with FTD, those with AD, and those without dementia were enrolled in this study. CSF amyloid-ß 42 (Aß42), total (t)-tau, and phosphorylated (p)-tau concentrations were determined by enzyme-linked immunosorbent assays. Cognition was evaluated by the Mini-Mental State Examination (MMSE) and its domain scores. The associations of CSF biomarkers with cognitive measures were examined using regression models and the diagnostic value of CSF biomarkers was determined by receiver operating characteristics curves.ResultsCSF Aß42 levels were lower, whereas t-tau/Aß42 and p-tau/Aß42 ratios were higher in patients with AD compared with those with FTD. Some MMSE domain scores were different in FTD and AD, but they did not improve the ability to distinguish between the two pathologies. Poor temporal orientation scores were associated with low Aß42 levels only in patients with FTD. The p-tau/Aß42 ratio reached sufficient levels of sensitivity and specificity to discriminate FTD with primary progressive aphasia from AD.ConclusionsThe ratio of CSF p-tau/Aß42 is a sensitive and specific biomarker for discriminating patients with primary progressive aphasia from those with AD.

Alzheimer's disease (AD) is a multifactorial condition in which, along with amyloid-β (Aβ) and tau-related pathology, the synergistic activity of co-morbidity factors promote the onset and progression of the disease. Epidemiological evidence indicates that glucose intolerance, deficits in insulin secretion, or type-2 diabetes mellitus (T2DM) participate in increasing cognitive impairment or dementia risk. Insulin plays a pivotal role in the process as the hormone critically regulates brain functioning. GLP-1, the glucagon-like peptide 1, facilitates insulin signaling, regulates glucose homeostasis, and modulates synaptic plasticity. Exenatide is a synthetic GLP-1 analog employed in T2DM. However, exenatide has also been shown to affect the signaling of the brain-derived neurotrophic factor (BDNF), synaptic plasticity, and cognitive performances in animal models. In this study, we tested whether exenatide exerts neuroprotection in a preclinical AD model set to mimic the clinical complexity of the human disease. We investigated the effects of exenatide treatment in 3xTg-AD mice challenged with a high-fat diet (HFD). Endpoints of the study were variations in systemic metabolism, insulin and neurotrophic signaling, neuroinflammation, Aβ and tau pathology, and cognitive performances. Results of the study indicate that exenatide reverts the adverse changes of BDNF signaling and the neuroinflammation status of 3xTg-AD mice undergoing HFD without affecting systemic metabolism or promoting changes in cognitive performances.

Background The very aggressive nature and low survival rate of pancreatic ductal adenocarcinoma (PDAC) dictates the necessity to find novel efficacious therapies. Recent evidence suggests that phosphoinositide 3-kinase (PI3K) and 3-phosphoinositide-dependent protein kinase 1 (PDK1) are key effectors of oncogenic KRAS in PDAC. Herein, we report the role and mechanism of action of PDK1, a protein kinase of the AGC family, in PDAC. Methods PDAC cell lines were treated with selective PDK1 inhibitors or transfected with specific PDK1-targeting siRNAs. In vitro and in vivo assays were performed to investigate the functional role of PDK1 in PDAC. Specifically, anchorage-dependent and anchorage-independent growth was assessed in PDAC cells upon inhibition or downregulation of PDK1. Detailed investigation of the effect of PDK1 inhibition/downregulation on specific signalling pathways was also performed by Western blotting analysis. A xenograft tumour mouse model was used to determine the effect of pharmacological inhibition of PDK1 on PDAC cells growth in vivo. Results Treatment with specific inhibitors of PDK1 impaired anchorage-dependent and anchorage-independent growth of pancreatic cancer cell lines, as well as pancreatic tumour growth in a xenograft model. Mechanistically, inhibition or downregulation of PDK1 resulted in reduced activation of the serum/glucocorticoid regulated kinase family member 3 and subsequent reduced phosphorylation of its target N-Myc downstream regulated 1. Additionally, we found that combination of sub-optimal concentrations of inhibitors selective for PDK1 and the class IB PI3K isoform p110γ inhibits pancreatic cancer cell growth and colonies formation more potently than each single treatment. Conclusions Our data indicate that PDK1 is a suitable target for therapeutic intervention in PDAC and support the clinical development of PDK1 inhibitors for PDAC. Electronic supplementary material The online version of this article (10.1186/s13046-019-1191-2) contains supplementary material, which is available to authorized users.

Publisher's version (útgefin grein), Background:The ongoing “Sarcopenia and Physical fRailty IN older people: multi-componenT Treatment stra-tegies (SPRINTT)” randomized controlled trial (RCT) is testing the efficacy of a multicomponent intervention inthe prevention of mobility disability in older adults with physical frailty & sarcopenia (PF&S). Here, we describethe procedures followed for PF&S case finding and screening of candidate participants for the SPRINTT RCT. Wealso illustrate the main demographic and clinical characteristics of eligible screenees.Methods:The identification of PF&S was based on the co-occurrence of three defining elements: (1) reducedphysical performance (defined as a score on the Short Physical Performance Battery between 3 and 9); (2) lowmuscle mass according to the criteria released by the Foundation for the National Institutes of Health; and (3)absence of mobility disability (defined as ability to complete the 400-m walk test in 15 min). SPRINTT wasadvertised through a variety of means. Site-specific case finding strategies were developed to accommodate thevariability across centers in catchment area characteristics and access to the target population. A quick “parti-cipant profiling” questionnaire was devised to facilitate PF&S case finding.Results:During approximately 22 months, 12,358 prescreening interviews were completed in 17 SPRINTT sitesresulting in 6710 clinic screening visits. Eventually, 1566 candidates were found to be eligible for participatingin the SPRINTT RCT. Eligible screenees showed substantial physical function impairment and comorbidityburden. In most centers, project advertisement through mass media was the most rewarding case findingstrategy.Conclusion:PF&S case finding in the community is a challenging, but feasible task. Although largely autonomousin daily life activities, older adults with PF&S suffer from significant functional impairment and comorbidity.This subset of the older population is therefore at high risk for disability and other negative health-relatedevents. Key strategies to consider for successfully intercepting at-risk older adults should focus on mass com-munication methods., The present work was funded by a grant from the InnovativeMedicines Initiative - Joint Undertaking (IMI-JU 115621). The workwas also partly supported by the nonprofit research foundation “CentroStudi Achille e Linda Lorenzon” and by intramural research grants fromthe Università Cattolica del Sacro Cuore (D3.2 2013 and D3.2 2015).The authors thank all the participants and the staff involved in thetrial for the enthusiastic participation and dedication.

Endogenous endophthalmitis (EE) is a potentially blinding ophthalmological emergency with poor visual prognosis requiring a high index of clinical suspicion to obtain a prompt diagnosis. The main factors associated with poor visual outcomes include the virulence of the causative organism and timing of intervention. Infective endocarditis can present with nonspecific ocular complaints and remains an important risk factor for developing EE. We report an unusual case of EE in a 78-year-old male caused by infective endocarditis secondary to Streptococcus viridans resulting in bioprosthetic aortic valve abscess with dehiscence.

HER-3 is becoming an attractive target for antibody–drug conjugate (ADC)-based therapy. Indeed, this receptor and its ligands are found to be overexpressed in several malignancies, and re-activation of its downstream signaling axis is known to play a critical role in modulating the sensitivity of targeted therapeutics in different tumors. In this study, we generated a novel ADC named EV20/NMS-P945 by coupling the anti-HER-3 antibody EV20 with a duocarmycin-like derivative, the thienoindole (TEI) NMS-P528, a DNA minor groove alkylating agent through a peptidic cleavable linker. This ADC showed target-dependent cytotoxic activity in vitro on several tumor cell lines and therapeutic activity in mouse xenograft tumor models, including those originating from pancreatic, prostatic, head and neck, gastric and ovarian cancer cells and melanoma. Pharmacokinetics and toxicological studies in monkeys demonstrated that this ADC possesses a favorable terminal half-life and stability and it is well tolerated. These data support further EV20/NMS-P945 clinical development as a therapeutic agent against HER-3-expressing malignancies.

Besides its metabolic and endocrine effects, growth hormone (GH)-releasing hormone (GHRH) is involved in the modulation of inflammation. Recently synthetized GHRH antagonist MIA-690 and MR-409, GHRH agonist, developed by us have shown potent pharmacological effects in various experimental paradigms. However, whether their administration modify resistance to chronic inflammatory stimuli in colon is still unknown. Ex vivo results demonstrated that MIA-690 and MR-409 inhibited production of pro-inflammatory and oxidative markers induced by lipopolysaccharide on isolated mouse colon specimens. In vivo, both MIA-690 and MR-409 have also been able to decrease the responsiveness to nociceptive stimulus, in hot plate test. Additionally, both peptides also induced a decreased sensitivity to acute and persistent inflammatory stimuli in male mice, in formalin test and dextran sodium sulfate (DSS)-induced colitis model, respectively. MIA-690 and MR-409 attenuate DSS-induced colitis with particular regard to clinical manifestations, histopathological damage and release of pro-inflammatory and oxidative markers in colon specimens. Respect to MR-409, MIA-690 showed higher efficacy in inhibiting prostaglandin (PG)E2, 8-iso-PGF2α and serotonin (5-HT) levels, as well as tumor necrosis factor (TNF)-α, interleukin (IL)-6 and nitric oxide synthase gene expression in colon specimens of DSS-induced colitis. Furthermore, MIA-690 decreased serum insulin-like growth factor (IGF)-1 levels in mice DSS-treated, respect to MR-409. Thus, our findings highlight the protective effects of MIA-690 and MR-409 on inflammation stimuli. The higher antinflammatory and antioxidant activities observed with MIA-690 could be related to decreased serum IGF-1 levels.

Anticholinergic burden (ACB) and anemia were found associated with an increased risk of death among older patients. Additionally, anticholinergic medications may contribute to the development of anemia. Therefore, we aimed at investigating the prognostic interplay of ACB and anemia among older patients discharged from hospital. Our series consisted of 783 patients enrolled in a multicenter observational study. The outcome of the study was 1 year mortality. ACB was assessed by an Anticholinergic Cognitive Burden score. Anemia was defined as hemoglobin &lt, 13 g/dL in men and &lt, 12 g/dL in women. The association between study variables and mortality was investigated by Cox regression analysis. After adjusting for several potential confounders, ACB score = 2 or more was significantly associated with the outcome in anemic patients (HR = 1.93, 95%CI = 1.13–3.40), but not non anemic patients (HR = 1.51, 95%CI = 0.65–3.48). An additive prognostic interaction between ACB and anemia was observed (p = 0.02). Anemia may represent a relevant effect modifier in the association between ACB and mortality.

B-cell prolymphocytic leukemia (B-PLL) is a rare leukemia characterized by rapidly increasing leukocytosis with splenomegaly and lymphadenopathy. Treatment strategies are largely based on studies of chronic lymphocytic leukemia (CLL). Antibodies against the cell surface protein CD20 are considered to be first-line therapy. A 76-year-old male with known CLL presented 2 weeks after starting chemoimmunotherapy for newly refractory CLL after failing ibrutinib therapy. White blood cell count was elevated at 226.7 × 103/µL. Fluorescent in situ hybridization analysis of a bone marrow specimen showed new development of complex cytogenetics. Flow cytometry revealed B cells appearing slightly dimmer on CD45 and brighter on CD20 compared with typical B-CLL suggestive of less mature lymphocyte forms. The patient was diagnosed with B-PLL and started on obinutuzumab and venetoclax with rapid normalization of white blood cells. This case recapitulates the challenges in diagnosing and treating B-PLL. Ibrutinib resistance is a growing area of study with several proposed mechanisms of acquired resistance. The pathogenesis of B-PLL is not completely understood, although mutations in MYC are presumed to play a role.

Hundreds of proteins/genes have been linked to the metastatic phenotype. However, consistent markers of tumour aggressiveness and metastatic potential in breast cancer patients were not identified, not even including proteomic analysis and large-scale genome sequencing.Metastasis-associated genes were predicted to include not only drivers of the metastatic phenotype, but also secondary events, together with adaptive, counterbalancing changes. Thus, to identify candidates with a required role in metastatic diffusion, we looked for genes that were concordantly dysregulated across orthogonal cancer metastasis settings. This led us to identify Trop-2 as uniquely upregulated and associated to metastasis in experimental models of breast cancer, as well as in other solid tumors. We identified functional inactivation of E-cadherin by Trop-2 as the main motor of metastatic diffusion of such metastatic systems. Trop-2 binding to E-cadherin inactivated its cell-cell adhesion function, through release from the cytoskeleton, for activation of β-catenin transcriptional activity. This led to anti-apoptotic signaling, increased cell migration capacity and enhanced cancer cell survival. We showed that this mechanism led to metastatic diffusion of xenotransplants growing in immunosuppressed mice. An E-cadherin-inactivation metastasis program was then shown to be recapitulated in breast cancer patients, as well as in other solid tumors, over 24 independent case series, encompassing 13,042 primary tumours. Aggressive triple-negative breast cancers were shown to be driven toward global relapse by Trop-2 overexpression, through E-cadherin inactivation and activation of β-catenin transcriptional activity. No disease recurrence was observed in control cases over +12 years of follow-up. These finding lead to a novel paradigm of a Trop-2-driven, E-cadherin-inactivation program as a main metastasis driver in solid tumors. This may open far-reaching perspectives in diagnostic procedures and anti-cancer therapies. Citation Format: Saverio Alberti, Marco Trerotola, Valeria Relli, Rossano Lattanzio, Martina Ceci, Khouloud Boujnah, Valeria Garbo, Antonino Moschella, Patrizia Querzoli, Massimo Pedriali, Laura Antolini, Emanuela Guerra. Trop-2 inactivation of E-cadherin drives triple negative breast cancer relapse [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr PD15-04.

(1) Background: Tuberculosis (TB) is one of the world’s top infectious killers, in fact every year 10 million people fall ill with TB and 1.5 million people die from TB. Vitamins have an important role in vital functions, due to their anti-oxidant, pro-oxidant, anti-inflammatory effects and to metabolic functions. The aim of this review is to discuss and summarize the evidence and still open questions regarding vitamin supplementation as a prophylactic measure in those who are at high risk of Mycobacterium tuberculosis (MTB) infection and active TB; (2) Methods: We conducted a search on PubMed, Scopus, Google Scholar, EMBASE, Cochrane Library and WHO websites starting from March 1950 to September 2021, in order to identify articles discussing the role of Vitamins A, B, C, D and E and Tuberculosis; (3) Results: Supplementation with multiple micronutrients (including zinc) rather than vitamin A alone may be more beneficial in TB. The WHO recommend Pyridoxine (vitamin B6) when high-dose isoniazid is administered. High concentrations of vitamin C sterilize drug-susceptible, MDR and extensively drug-resistant MTB cultures and prevent the emergence of drug persisters; Vitamin D suppresses the replication of mycobacterium in vitro while VE showed a promising role in TB management as a result of its connection with oxidative balance; (4) Conclusions: Our review suggests and encourages the use of vitamins in TB patients. In fact, their use may improve outcomes by helping both nutritionally and by interacting directly and/or indirectly with MTB. Several and more comprehensive trials are needed to reinforce these suggestions.

Aim To provide an updated overview of studies on under-prescription in older subjects, describing its prevalence, causes, consequences as well as potential interventions to reduce it. Findings Under-prescription is common in older patients and associated with negative clinical outcomes, such as higher risk of cardiovascular events, worsening disability, hospitalization and death. Promising interventions to correct it include the implementation of explicit under-prescription criteria, the use of comprehensive geriatric assessment by geriatricians, and the involvement of a clinical pharmacist. Message Further studies should be performed to provide a better understanding of under-prescription and to confirm the efficacy of corrective interventions. Under-prescription is defined as the omission of a medication that is indicated for the treatment of a condition or a disease, without any valid reason for not prescribing it. The aim of this review is to provide an updated overview of under-prescription, summarizing the available evidence concerning its prevalence, causes, consequences and potential interventions to reduce it. A PubMed search was performed, using the following keywords: under-prescription; under-treatment; prescribing omission; older adults; polypharmacy; cardiovascular drugs; osteoporosis; anticoagulant. The list of articles was evaluated by two authors who selected the most relevant of them. The reference lists of retrieved articles were screened for additional pertinent studies. Although several pharmacological therapies are safe and effective in older patients, under-prescription remains widespread in the older population, with a prevalence ranging from 22 to 70%. Several drugs are underused, including cardiovascular, oral anticoagulant and anti-osteoporotic drugs. Many factors are associated with under-prescription, e.g. multi-morbidity, polypharmacy, dementia, frailty, risk of adverse drug events, absence of specific clinical trials in older patients and economic factors. Under-prescription is associated with negative consequences, such as higher risk of cardiovascular events, worsening disability, hospitalization and death. The implementation of explicit criteria for under-prescription, the use of the comprehensive geriatric assessment by geriatricians, and the involvement of a clinical pharmacist seem to be promising options to reduce under-prescription. Under-prescription remains widespread in the older population. Further studies should be performed, to provide a better comprehension of this phenomenon and to confirm the efficacy of corrective interventions.