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Abstract Protein acetylation plays potential roles in regulating autophagy occurrence. However, it varies greatly between yeast and mammals, and has not been thoroughly investigated in other organisms. Here, we reported that the components of BmAtg8–PE ubiquitin-like system (BmAtg3, BmAtg4, BmAtg7, and BmAtg8) in Bombyx mori were localized in the nucleus under nutrient-rich conditions, whereas they were exported to the cytoplasm upon autophagy induction. RNAi of BmP300 and inhibition of BmP300 activity resulted in nucleo-cytoplasmic translocation of BmAtg3 and BmAtg8, as well as premature induction of autophagy in the absence of stimulus. Conversely, RNAi of BmHDAC1 and inhibition of class I/II HADCs activities led to the nuclear accumulation of BmAtg3 and BmAtg8. In addition, acetylation sites in Atg proteins of BmAtg8–PE ubiquitin-like system were identified by mass spectrometry, and acetylation-site mutations caused nucleo-cytoplasmic translocation of BmAtg3, BmAtg4, and BmAtg8 along with autophagy promotion. Similarly, the subcellular localization of human ATG4b is determined by acetylation modification. In general, BmP300-mediated acetylation sequesters the components of BmAtg8–PE ubiquitin-like system in the nucleus, thus leading to the autophagy inhibition. Oppositely, BmHDAC1-mediated deacetylation leads to the nucleo-cytoplasmic translocation of the components of BmAtg8–PE ubiquitin-like system and promotes autophagy. This process is evolutionarily conserved between insects and mammals.

The Cohort Study of Mobile Phone Use and Health (COSMOS) has repeatedly collected self-reported and operator-recorded data on mobile phone use. Assessing health effects using self-reported information is prone to measurement error, but operator data were available prospectively for only part of the study population and did not cover past mobile phone use. To optimize the available data and reduce bias, we evaluated different statistical approaches for constructing mobile phone exposure histories within COSMOS. We evaluated and compared the performance of 4 regression calibration (RC) methods (simple, direct, inverse, and generalized additive model for location, shape, and scale), complete-case analysis, and multiple imputation in a simulation study with a binary health outcome. We used self-reported and operator-recorded mobile phone call data collected at baseline (2007-2012) from participants in Denmark, Finland, the Netherlands, Sweden, and the United Kingdom. Parameter estimates obtained using simple, direct, and inverse RC methods were associated with less bias and lower mean squared error than those obtained with complete-case analysis or multiple imputation. We showed that RC methods resulted in more accurate estimation of the relationship between mobile phone use and health outcomes by combining self-reported data with objective operator-recorded data available for a subset of participants. [ABSTRACT FROM AUTHOR]

Background: Isolated rapid eye movement sleep behavioral disorder (iRBD) can precede neurodegenerative diseases. There is an urgent need for biomarkers to aid early intervention and neuroprotection. Objective: The aim is to assess quantitative motor, cognitive, and brain magnetic resonance imaging (MRI) characteristics in iRBD patients. Methods: Thirty‐eight polysomnography‐confirmed iRBD patients and 28 age‐ and sex‐matched healthy controls underwent clinical, cognitive, and motor functional evaluations, along with brain MRI. Motor tasks included nine‐hole peg test, five‐times‐sit‐to‐stand test, timed‐up‐and‐go test, and 4‐meter walking test with and without cognitive dual task. Quantitative spatiotemporal gait parameters were obtained using an optoelectronic system. Brain MRI analysis included functional connectivity (FC) of the main resting‐state networks, gray matter (GM) volume using voxel‐based morphometry, cortical thickness, and deep GM and brainstem volumes using FMRIB's Integrated Registration and Segmentation Tool and FreeSurfer. Results: iRBD patients relative to healthy subjects exhibited a poorer performance during the nine‐hole peg test and five‐times‐sit‐to‐stand test, and greater asymmetry of arm‐swing amplitude and stride length variability during dual‐task gait. Dual task significantly worsened the walking performance of iRBD patients more than healthy controls. iRBD patients exhibited nonmotor symptoms, and memory, abstract reasoning, and visuospatial deficits. iRBD patients exhibited decreased FC of pallidum and putamen within the basal ganglia network and occipital and temporal areas within the visuo‐associative network, and a reduced volume of the supramarginal gyrus. Brain functional alterations correlated with gait changes. Conclusions: Subtle motor and nonmotor alterations were identified in iRBD patients, alongside brain structural and functional MRI changes. These findings may represent early signs of neurodegeneration and contribute to the development of predictive models for progression to parkinsonism. © 2024 The Author(s). Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society. [ABSTRACT FROM AUTHOR]

Strategies to increase the anti-tumor efficacy of cytokine-induced killer cells (CIKs) include genetic modification with chimeric antigen receptors (CARs) or the addition of soluble T-cell engaging bispecific antibodies (BsAbs). Here, CIKs were modified using a transposon system integrating two distinct anti-CD19 CARs (CAR-MNZ and CAR-BG2) or combined with soluble CD3xCD19 BsAb blinatumomab (CIK + Blina). CAR-MNZ bearing the CD28-OX40-CD3ζ signaling modules, and CAR-BG2, designed on the Tisagenlecleucel CAR sequence (Kymriah®), carrying the 4-1BB and CD3ζ signaling elements, were employed. After transfection and CIK expansion, cells expressed CAR-CD19 to a similar extent (35.9% CAR-MNZ and 17.7% CAR-BG2). In vitro evaluations demonstrated robust proliferation and cytotoxicity (~50% cytotoxicity) of CARCIK-MNZ, CARCIK-BG2, and CIK + Blina against CD19+ target cells, suggesting similar efficacy. All effectors formed an increased number of synapses, activated NFAT and NFkB, and secreted IL-2 and IFN-ɣ upon encountering targets. CIK + Blina displayed strongest NFAT and IFN-ɣ induction, whereas CARCIK-BG2 demonstrated superior synapse formation. All the effectors have shown therapeutic activity in vivo against the CD19+ Daudi tumor model, with CARCIK cells showing a more durable response compared to CIK + Blina, likely due to the short half-life of Blina in this model. [ABSTRACT FROM AUTHOR]

The number of solid organ transplant recipients (SOTRs) is growing as a consequence of an increase in transplantations and longer survival; these patients, thus, frequently suffer various comorbidities and are subjected to the detrimental effects of immunosuppressive agents, which expose them to a higher risk of developing malignancies. These drugs also complicate the surgical treatment of neoplasms, as they can hinder wound healing, especially when associated with other unfavorable factors (e.g., previous radiotherapy, diabetes, etc.). We herein present our experience with a 74-year-old SOTR who underwent a radical extended parotidectomy and reconstruction with a submental island flap for a persistent cutaneous squamous carcinoma after radiotherapy; his complicated clinical course was characterized by incredibly slow wound healing. The current literature was reviewed to provide a succinct overview of the main difficulties of head and neck surgery in SOTRs. In particular, the immunosuppressive regimen can be tapered considering the individual risk and other elements should be carefully assessed, possibly prior to surgery, to prevent cumulative harm. New developments, including intraoperative monitoring of flap vascularization through indocyanine green fluorescence video-angiography and the prophylactic application of negative pressure wound therapy, when feasible, may be particularly beneficial for high-risk patients. [ABSTRACT FROM AUTHOR]

Background: This retrospective study contrasts the impact of the SARS-CoV-2 pandemic in Lombardy (Italy) and Israel, focusing on mortality, healthcare response, public health measures, and demographics. Methods: We analyzed SARS-CoV-2 data from Lombardy and Israel covering four viral waves. Data included infection rates, hospitalizations, and mortality. In Lombardy, healthcare data were collected from the administrative database of the Lombardy Welfare Directorate; in Israel, they were collected from Clalit Health Services and the Israeli Ministry of Health's COVID-19 database. Statistical analyses compared trends in infection rates, demographics, and mortality rates across the four viral waves by using logistic and linear regression models and adjusting for age, sex, and comorbidities. Results: Lombardy exhibited significantly higher SARS-CoV-2 infections and COVID-19 hospitalization rates during the first wave than Israel, with 71,558 cases over a population sample of ~10 million versus 5741 over a population sample of ~4.7 million in Israel. The majority of cases in Israel were managed at home, with 18 cases only (0.3%) requiring intensive care unit (ICU) hospitalization during the first wave, compared to 4104 (5.7%) cases in Lombardy. Israel's vaccination campaign began earlier, so that by the fourth wave, 439,545 (42.2%) people in Israel were fully vaccinated with three doses, compared to 214,542 (22.9%) in Lombardy. Mortality decreased over time in both sites, dropping from 103 cases (1.8%) to 1550 (0.1%) in Israel and from 13,372 (18.7%) to 4388 (0.3%) in Lombardy. Conclusions: Early public health interventions and vaccination were crucial in managing the SARS-CoV-2 impact. [ABSTRACT FROM AUTHOR]

Purpose: To estimate utility values associated with visual loss using EuroQol (EQ-5D) questionnaire, the impact of low-vision (LV) device use on utilities and the contribution of Instrumental Activities of Daily Living (IADL) score in patients attending vision rehabilitation (VR) services enrolled in the Italian Device & Aids Register (D.A.Re). Methods: This is a multicenter, prospective, cross-sectional study. D.A.Re. collects general and clinical information, vision-specific variables, use of electronic devices and quality of life questionnaires. Results: A total of 442 patients (75.0±16.6 years, 275 female) were included, 88 (19.9%) used specialised electronic LV devices, and 116 (26.2%) used smartphones and tablets. Users of smartphones and tablets were younger than non-users (67.5 vs. 77.6 years, p<0.001), but overall, their age ranged between 20 and 93. Stronger associations were found between vision-specific variables and IADL score compared to EQ-5D score. In multivariable age-adjusted models, the utility value of using smartphones and tablets on EQ-5D score was 0.12 (p<0.01), slightly larger than that of 1.0 logMAR difference (-0.09, p<0.01) or visual field damage within 10° of fixation (-0.10, p<0.01). Use of portable low-vision electronic devices and being employed or student (vs. retired) was also associated with better utility values (0.12 and 0.15, respectively, p<0.05). Conclusions: Visual loss is associated with loss of utilities in Italian patients attending VR services, whereas special-purpose electronic aids, and smartphone and tablet use are associated with better utility values. We found that IADL may be more sensitive to visual loss than EQ-5D and could be a valid health-related quality of life outcome in trials on VR. [ABSTRACT FROM AUTHOR]

Association between measurable residual disease (MRD) and survival outcomes in chronic lymphocytic leukemia (CLL) has often been reported. However, limited quantitative analyses over large datasets have been undertaken to establish the predictive power of MRD. Here, we provide a comprehensive assessment of published MRD data to explore the utility of MRD in the prediction of progression‐free survival (PFS). We undertook two independent analyses, which leveraged available published data to address two complimentary questions. In the first, data from eight clinical trials was modeled via a meta‐regression approach, showing that median PFS can be predicted from undetectable MRD rates at 3–6 months of post‐treatment. The resulting model can be used to predict the probability of technical success of a planned clinical trial in chemotherapy. In the second, we investigated the evidence for predicting PFS from competing MRD metrics, for example baseline value and instantaneous MRD value, via a joint modeling approach. Using data from four small studies, we found strong evidence that including MRD metrics in joint models improves predictions of PFS compared with not including them. This analysis suggests that incorporating MRD is likely to better inform individual progression predictions. It is therefore proposed that systematic MRD collection should be accompanied by modeling to generate algorithms that inform patients' progression. [ABSTRACT FROM AUTHOR]

Abstract Pregnancy has been associated with diagnosis or growth of meningiomas in several case reports, which has led to the hypothesis that pregnancy may be a risk factor for meningiomas. The aim of this study was to test this hypothesis in a large population-based cohort study. Women born in Sweden 1958–2000 (N = 2,204,126) were identified and matched with the Medical Birth Register and the Cancer Register. The expected number of meningioma cases and risk ratios were calculated for parous and nulliparous women and compared to the observed number of cases. Compared to parous women, meningiomas were more common among nulliparous (SIR = 1.73; 95% CI 1.52–1.95). The number of meningioma cases detected during pregnancy was lower than the expected (SIR = 0.40; 95% CI 0.20–0.72). Moreover, no increased risk was found in the first-year post-partum (SIR = 1.04; 95% CI 0.74–1.41). Contrary to our hypothesis, there was no increased risk for diagnosing a meningioma during pregnancy or 1-year post-partum. A lower detection rate during pregnancy, may reflect under-utilization of diagnostic procedures, but the actual number of meningiomas was homogenously lower among parous than nulliparous women throughout the study period, indicating that pregnancy is not a risk factor for meningioma.

The paper describes a mixed reality environment for testing highly automated vehicle functions. The proposed Scenario-inthe-Loop test system connects real-time computer simulation with real elements being applicable at automotive proving ground. The paper outlines necessary hardware and software requirements and proposes basic system architecture. The limitation and bottleneck of the system are also identified: latency of the wireless communication constraints the accuracy of the test system. However, the presented framework can contribute to efficient development, testing and validation of automated cars. The Scenario-In-The-Loop architecture has also been justified by real-world demonstration using an experimental 5G New Radio network technology.

The study of biodiversity is a fundamental step to develop conservation strategies. Reptile populations are immersed in a global crisis, due to anthropic disturbances. Almost the entire Pampa ecoregion in Argentina was modified for agricultural and livestock activities, the only remnants of mountain native grasslands in Buenos Aires province being the Tandilia and Ventania mountain systems. Ventania reptiles have been exhaustively researched in last years, while Tandilia counts with fewer studies. We presented an actualized reptiles list of the Tandilia Mountain System. We used five data sources to collect presence records: literature, fieldwork, museum collection, citizen science, and a online database. The composition of reptiles from the Tandilia Mountain range includes 26 species in 12 families. Due to the presence of several endemic reptiles, and the representativeness of more than half of the reptiles of Pampa Ecoregion, Tandilia would be useful to determine conservation priority areas to conserve the native grassland and their reptile fauna.

BackgroundConsiderable variability exists in international prevalence and incidence estimates of dementia. The accuracy of estimates of dementia in the oldest-old and the controversial question of whether dementia incidence and prevalence decline at very old age will be crucial for better understanding the dynamics between survival to extreme old age and the occurrence and risk for various types of dementia and comorbidities. International Centenarian Consortium - Dementia (ICC-Dementia) seeks to harmonise centenarian and near-centenarian studies internationally to describe the cognitive and functional profiles of exceptionally old individuals, and ascertain the trajectories of decline and thereby the age-standardised prevalence and incidence of dementia in this population. The primary goal of the ICC-Dementia is to establish a large and thorough heterogeneous sample that has the power to answer epidemiological questions that small, separate studies cannot. A secondary aim is to examine cohort-specific effects and differential survivorship into very old age. We hope to lay the foundation for further investigation into risk and protective factors for dementia and healthy exceptional brain ageing in centenarians across diverse ethnoracial and sociocultural groups.MethodsStudies focusing on individuals aged ≥95 years (approximately the oldest 1 percentile for men, oldest 5th percentile for women), with a minimum sample of 80 individuals, including assessment of cognition and functional status, are invited to participate. There are currently seventeen member or potential member studies from Asia, Europe, the Americas, and Oceania. Initial attempts at harmonising key variables are in progress.DiscussionGeneral challenges facing large, international consortia like ICC-Dementia include timely and effective communication among member studies, ethical and practical issues relating to human subject studies and data sharing, and the challenges related to data harmonisation. A specific challenge for ICC-Dementia relates to the concept and definition of'abnormal' in this exceptional group of individuals who are rarely free of physical, sensory and/or cognitive impairments.

Philodryas agassizii is an endangered snake of shrubland and grasslands well preserved in Argentina, Paraguay, Brazil, and Uruguay. In the southeastern area of its range, this snake was only found associated with highland grassland of the Tandilia and Ventania mountain systems, Argentina. In this work, we described six new records of Philodryas agassizii from the Tandilia Mountain System, which represent four new localities for the species. These records extend the known range of Philodryas agassizii in the Tandilia mountain system, 100 km from the closest previously known site.

Abstract Introduction Depression is a highly prevalent condition in the elderly, with a vast impact on quality of life, life expectancy, and medical outcomes. Selective serotonin reuptake inhibitors (SSRIs) are the most commonly prescribed agents in this condition and, although generally safe, tolerability issues cannot be overlooked. Vortioxetine is an antidepressant with a novel mechanism of action. Based on studies to date, it may have a promising tolerability profile in the elderly, as it does not adversely affect psychomotor or cognitive performance and does not alter cardiovascular and endocrine parameters. The present study aims to assess the tolerability profile of vortioxetine in comparison with the SSRIs considered as a single group in elderly participants with depression. The rate of participants withdrawing from treatment due to adverse events after 6 months of follow up will be the primary outcome. Methods and analysis This is a pragmatic, multicentre, open-label, parallel-group, superiority, randomized trial funded by the Italian Medicines Agency (AIFA - Agenzia Italiana del Farmaco). Thirteen Italian Community Psychiatric Services will consecutively enrol elderly participants suffering from an episode of major depression over a period of 12 months. Participants will be assessed at baseline and after 1, 3 and 6 months of follow up. At each time point, the following validated rating scales will be administered: Montgomery–Åsberg Depression Rating Scale (MADRS), Antidepressant Side-Effect Checklist (ASEC), EuroQual 5 Dimensions (EQ-5D), Short Blessed Test (SBT), and Charlson Age-Comorbidity Index (CACI). Outcome assessors and the statistician will be masked to treatment allocation. A total of 358 participants (179 in each group) will be enrolled. Ethics and dissemination This study will fully adhere to the ICH E6 Guideline for Good Clinical Practice. Participants’ data will be managed and safeguarded according to the European Data Protection Regulation 2016/679. An external Ethical Advisory Board will help guarantee high ethical standards. Trial registration Clinicaltrials.gov: NCT03779789 , Registered on 19 December 2018. Submitted on 19 December. EudraCT number: 2018–001444-66. Trial status Protocol version 1.5; 09/06/2018. Recruitment started In February 2019 and it is ongoing. It is expected to end approximately on 30 September 2021.

ObjectiveOur knowledge on the long-term consequences of COVID-19 is still scarce despite the clinical relevance of persisting syndrome. The aim of this study was to analyze patient-reported outcomes, including assessment by specific questionnaires of health impairment and symptoms.MethodsThis is a prospective, observational and multicenter cohort study coordinated by Fondazione IRCSS Ca' Granda Ospedale Maggiore Policlinico di Milano and Istituto di Ricerche Farmacologiche Mario Negri IRCCS including eight hospitals located in North and Central Italy. A telephone interview to assess rehospitalization, access to health care resources, general health status subjective evaluation, and symptoms was performed at 12 months after the discharge in patients admitted to hospital because of COVID-19 from February 2020 to the end of May 2020.ResultsAmong the 776 patients discharged alive, 44 (5.7%) died, 456 subjects (58.8%) completed the questionnaire and 276 (35.6%) were not reachable or refused to join the telephone interview. The mean age of the study population was 59.4 years (SD 14.1), 69.8% of individuals needed oxygen support during hospitalization and 10.4% were admitted to ICU. Overall, 91.7% of participants reported at least one symptom/sequela at 12 months. Exertional dyspnea (71.7%), fatigue (54.6%), and gastrointestinal symptoms (32.8%) were the most reported ones. Health issues after discharge including hospitalization or access to emergency room were described by 19.4% of subjects. Female and presence of comorbidities were independent predictors of whealth impairment and presence of ≥2 symptoms/sequelae after 12 months from hospitalization for COVID-19.ConclusionsPatient-reported symptoms and sequelae, principally dyspnea and fatigue, are found in most individuals even 12 months from COVID-19 hospitalization. Long-term follow-up based on patient-centered outcome can contribute to plan tailored interventions.

BackgroundPatients with end-stage renal disease are known to be particularly frail, and the cause is still widely seen as being directly related to specific factors in renal replacement therapy. However, a closer examination of the transitional phase from predialysis to long-term hemodialysis leads to controversial explanations, considering that the frailty process is already well-described in the early stages of renal insufficiency. This study aims to describe longitudinally and multifactorially changes in the period extending from the decision to start the replacement therapy through to the end of 2 years of hemodialysis. We hypothesized that frailty is pre-existent in the predialysis phase and does not worsen with the beginning of the replacement therapy. Between 2015 and 2018 we recruited 25 patients (72.3 ± 5.7 years old) in a predialysis program, with the expectation that replacement therapy would begin within the coming few months.MethodsThe patients underwent a baseline visit before starting hemodialysis, with 4 follow-up visits in the first 2 years of treatment. Health status, physical performance, cognitive functioning, hematology parameters, and adverse events were monitored during the study period.ResultsAt baseline, our sample had a high variability with patients ranging from extremely frail to very fit. In the 14 participants that did not drop out of the study, out of 32 clinical and functional measures, a statistically significant worsening was only observed in the Short Physical Performance Battery (SPPB) score (p < 0.01, F = 8.50) and the number of comorbidities (p = 0.01, F = 3.94). A careful analysis, however, reveals a quite stable situation in the first year of replacement therapy, for both frail and fit participants and a deterioration in the second year that in frail participants could lead to death.ConclusionOur results should stimulate a reassessment about the role of a predialysis program in reducing complications during the transitional phase, but also about frailty prevention programs once hemodialysis has begun, for both frail and fit patients, to maintain satisfactory health status.

BackgroundBirth defects have been consistently associated with elevated childhood cancer risks; however, the relationship between congenital heart disease (CHD) and childhood cancer remains conflicting. Considering the increasing patient population with CHD after improvements in their life expectancies, insights into this relationship are particularly compelling. Thus, we aimed to determine the relationship between CHD and cancer in Swedish children.Methods and findingsAll individuals registered in the Swedish Medical Birth Register (MBR) between 1973 and 2014 were included in this population-based cohort study (n = 4,178,722). Individuals with CHD (n = 66,892) were identified from the MBR and National Patient Register, whereas cancer diagnoses were retrieved from the Swedish Cancer Register. The relationship between CHD and childhood cancer (ConclusionsWe found associations between CHD and childhood lymphomas and hepatoblastomas not explained by a diagnosis of Down syndrome. Stronger associations were observed in complex CHD.

BACKGROUND. Chimeric antigen receptor (CAR) T cell immunotherapy has resulted in complete remission (CR) and durable response in highly refractory patients. However, logistical complexity and high costs of manufacturing autologous viral products limit CAR T cell availability. METHODS. We report the early results of a phase I/II trial in B cell acute lymphoblastic leukemia (B-ALL) patients relapsed after allogeneic hematopoietic stem cell transplantation (HSCT) using donor-derived CD19 CAR T cells generated with the Sleeping Beauty (SB) transposon and differentiated into cytokine-induced killer (CIK) cells. RESULTS. The cellular product was produced successfully for all patients from the donor peripheral blood (PB) and consisted mostly of [CD3.sup.+] lymphocytes with 43% CAR expression. Four pediatric and 9 adult patients were infused with a single dose of CAR T cells. Toxicities reported were 2 grade I and 1 grade II cytokine-release syndrome (CRS) cases at the highest dose in the absence of graft-versus-host disease (GVHD), neurotoxicity, or dose-limiting toxicities. Six out of 7 patients receiving the highest doses achieved CR and CR with incomplete blood count recovery (CRi) at day 28. Five out of 6 patients in CR were also minimal residual disease negative (MRD). Robust expansion was achieved in the majority of the patients. CAR T cells were measurable by transgene copy PCR up to 10 months. Integration site analysis showed a positive safety profile and highly polyclonal repertoire in vitro and at early time points after infusion. CONCLUSION. SB-engineered CAR T cells expand and persist in pediatric and adult B-ALL patients relapsed after HSCT. Antileukemic activity was achieved without severe toxicities. TRIAL REGISTRATION. ClinicalTrials.gov NCT03389035. FUNDING. This study was supported by grants from the Fondazione AIRC per la Ricerca sul Cancro (AIRC); Cancer Research UK (CRUK); the Fundacion Cientifica de la Asociacion Espanola Contra el Cancer (FC AECC); Ministero Della Salute; Fondazione Regionale per la Ricerca Biomedica (FRRB)., Introduction Substantial efforts over the past few years have led chimeric antigen receptor (CAR) T cell therapy to success in relapsed and refractory (r/r) B cell malignancies. The early concept [...]