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The increasing demand for precise neuromodulation necessitates advancements in techniques to achieve higher spatial resolution. Magnetic stimulation, offering low signal attenuation and minimal tissue damage, plays a significant role in neuromodulation. Conventional transcranial magnetic stimulation (TMS), though noninvasive, lacks the spatial resolution and neuron selectivity required for spatially precise neuromodulation. To address these limitations, the next generation of magnetic neurostimulation technologies aims to achieve submillimeter‐resolution and selective neuromodulation with high temporal resolution. Invasive and nanoinvasive magnetic neurostimulation are two next‐generation approaches: invasive methods use implantable microcoils, while nanoinvasive methods use magnetic nanoparticles (MNPs) to achieve high spatial and temporal resolution of magnetic neuromodulation. This review will introduce the working principles, technical details, coil designs, and potential future developments of these approaches from an engineering perspective. Furthermore, the review will discuss state‐of‐the‐art microfabrication in depth due to its irreplaceable role in realizing next‐generation magnetic neuromodulation. In addition to reviewing magnetic neuromodulation, this review will cover through‐silicon vias (TSV), surface micromachining, photolithography, direct writing, and other fabrication technologies, supported by case studies, providing a framework for the integration of magnetic neuromodulation and microelectronics technologies. [ABSTRACT FROM AUTHOR]

Oxidative stress (OS) is a ubiquitous process for protecting against microorganisms' challenges. This review maps the most used methods for obtaining samples and analysing reactive oxygen species levels in apical periodontitis, following the PRISMA Extension for Scoping Reviews and is registered in Open Science Framework ([https://doi.org/10.17605/OSF.IO/D5U76]). A systematic search was conducted in electronic databases MEDLINE (PubMed), Embase, Scopus, Web of Science, LILACS, SciElo, OATD and DANS up to 17 July 2023. A total of 18 studies were included, with periapical tissue being the most common sample. Twenty‐eight different oxidative stress markers were identified, with inducible nitric oxide synthase being the most prevalent. The use of diverse biomarkers for oxidative stress assessment lacks specificity in identifying particular OS species for evaluating apical periodontitis and potential systemic effects. Studies are necessary to compare results obtained from less invasive methods (such as saliva and crevicular fluid) with those from periapical lesion samples. [ABSTRACT FROM AUTHOR]

Background and Aim: Primary sclerosing cholangitis (PSC) has been shown to recur after liver transplantation (LT). Some studies have identified certain clinical and laboratory variables associated with an increased risk for recurrent PSC (rPSC) in Caucasians. Furthermore, de novo cholangiocarcinoma (CCA) has been reported anecdotally in patients with rPSC. This study aims to assess the prevalence of rPSC, identify its associated risk factors, and investigate the occurrence of de novo CCA in a highly admixed population from Brazil. Methods: All patients submitted to LT for PSC enrolled in the Brazilian Cholestasis Study Group database were retrospectively reviewed for the occurrence of rPSC and de novo CCA. Results: Ninety‐six (58 males, mean age 32 ± 13 years) patients with PSC underwent LT. After 90 (39–154) months of follow‐up (FU), rPSC was observed in 29 (30%) subjects. There were no significant associations between rPSC and age, gender, concurrent or de novo inflammatory bowel disease, MELD score at the time of LT or allograft rejection. The only factor associated with an increased risk of disease recurrence was time after LT. Although survival was decreased in patients who developed rPSC, this difference was not significant. Only one female patient developed de novo CCA after rPSC, 11 years after LT. Conclusions: Recurrent PSC was observed in one‐third of PSC LT patients in Brazil and was associated with longer time after LT. Despite its frequency, rPSC was not associated with a higher risk of graft loss or a significant reduction in posttransplant survival. [ABSTRACT FROM AUTHOR]

The chemical vapor deposition of silicon on a patterned silicon substrate leads to the formation of 3D microcrystals, which, due to their inclined top facets and high aspect ratio, produce a light‐trapping effect enhancing the optical absorption in the near‐infrared (NIR). In this work, it is demonstrated that Si microcrystals can form the building blocks of a new class of NIR sensitive photodetectors operating in a linear or avalanche regime. Microcrystal‐based devices are designed by coupling a 2D kinetic‐growth model with a Poisson drift‐diffusion solver and fabricated by combining electron beam lithography and low‐energy plasma‐enhanced chemical vapor deposition (LEPECVD). The optoelectronic properties of microcrystal‐based p–i–n photodiodes are investigated both theoretically and experimentally by means of finite‐difference time‐domain (FDTD) simulations and responsivity measurements. At 1000 nm wavelength, the responsivity of microcrystal‐based devices is six times higher than that of an equivalent mesa diode. Moreover, the photocurrent gains of Si microcrystals operating as an avalanche photodiode (APD), at the same wavelength, reaches 2 × 104 demonstrating the potentialities of substrate patterning, combined with epitaxial growth, for amplified photodetection applications. [ABSTRACT FROM AUTHOR]

Summary: UMG1 is a unique epitope of CD43, not expressed by normal cells and tissues of haematopoietic and non‐haematopoietic origin, except thymocytes and a minority (<5%) of peripheral blood T lymphocytes. By immunohistochemistry analysis of tissue microarray and pathology slides, we found high UMG1 expression in 20%–24% of diffuse large B‐cell lymphomas (DLBCLs), including highly aggressive BCL2high and CD20low cases. UMG1 membrane expression was also found in DLBCL bone marrow‐infiltrating cells and established cell lines. Targeting UMG1 with a novel asymmetric UMG1/CD3ε‐bispecific T‐cell engager (BTCE) induced redirected cytotoxicity against DLBCL cells and was synergistic with lenalidomide. We conclude that UMG1/CD3ε‐BTCE is a promising therapeutic for DLBCLs. [ABSTRACT FROM AUTHOR]

Background: The impact of survivorship care plans (SCPs) on the proximal and distal outcomes of adult and childhood cancer survivors, and parent proxies, is unclear. This study aimed to determine the relationship between SCP receipt and these outcomes. Methods: A cross‐sectional survey of adult and childhood cancer survivors (and parent proxies for survivors aged younger than 16 years) across Australia and New Zealand was conducted. Multivariate regression models were fitted to measure the impact of SCP receipt on proximal (unmet information needs and propensity to engage with, and attend, cancer‐related follow‐up care) and distal outcomes (quality of life and satisfaction with cancer‐related follow‐up care) with control for cancer history and sociodemographic factors. Results: Of 1123 respondents, 499 were adult cancer survivors and 624 were childhood cancer survivors (including 222 parent proxies). We found that SCP receipt was predictive of greater attendance at, and awareness of, cancer‐related follow‐up care (adult: odds ratio [OR], 2.46; 95% CI, 1.18–5.12; OR, 2.38; 95% CI, 1.07–5.29; child/parent: OR, 2.61; 95% CI, 1.63–4.17; OR, 1.63; 95% CI, 1.06–2.50; respectively). SCP receipt also predicted fewer unmet information needs related to "follow‐up care required" and "possible late effects" (adult: OR, 0.44; 95% CI, 0.20–0.96; OR, 0.29; 95% CI, 0.13–0.64; child/parent: OR, 0.46; 95% CI, 0.30–0.72; OR, 0.57; 95% CI, 0.38–0.85; respectively). In terms of distal outcomes, SCP receipt predicted a better global quality of life for adult cancer survivors (β, 0.08; 95% CI, −0.01–7.93), proxy‐reported health‐related quality of life (β, 0.15; 95% CI, 0.44–7.12), and satisfaction with follow‐up care for childhood cancer survivors (OR, 2.93; 95% CI, 1.64–5.23). Conclusions: Previous studies have shown little impact of SCPs on distal end points. Results suggest that SCPs may be beneficial to cancer survivors' proximal and distal outcomes. This study found that survivorship care plans may be beneficial to both adult and childhood cancer survivors' distal and proximal outcomes. [ABSTRACT FROM AUTHOR]

Objective: National Cancer Control Plans (NCCPs) are high‐level policy documents that prioritise actions to be taken to improve cancer control activities. As the number of cancer survivors grows globally, there is an urgent need to assess whether and how psychosocial care across the cancer care continuum is included in NCCPs. This review aimed to ascertain the extent to which NCCPs referenced psycho‐oncology care for cancer survivors in the post‐treatment phase. Methods: NCCPs were obtained from the International Cancer Control Partnership (ICCP) portal (in November 2021) and reviewed in two phases. In Phase 1, all available NCCPs were screened to determine whether they mentioned psycho‐oncology or survivorship. In Phase 2, reviewers extracted data from the NCCPs identified in Phase 1 on the degree that each plan articulated objectives/goals to improve psychosocial care in the post‐treatment survivorship phase. Results: We screened 237 NCCPs. Of these, initial potential reference to psycho‐oncology and survivorship content were identified in 97 plans (41%). In Phase 1, 57/97 (59%) had reference to psycho‐oncology or survivorship content within defined criteria. In Phase 2, 27/97 (28%) had little mention of psycho‐oncology specifically in survivorship, 47/97 (48%) had some (general or brief) mention, and the remaining 23/97 (24%) had substantial content/specific sections and clearly articulated goals and/or objectives. Common goals for improving psychosocial care in the post‐treatment period included building capacity of healthcare professionals, implementing rehabilitation models, and increasing the utilisation of community services. Conclusions: Most NCCPs did not reference psycho‐oncology and only one‐quarter contained clear objectives specifically in the post‐treatment survivorship phase. [ABSTRACT FROM AUTHOR]

Spondylocostal dysostosis (SCD), a condition characterized by multiple segmentation defects of the vertebrae and rib malformations, is caused by bi‐allelic variants in one of the genes involved in the Notch signaling pathway that tunes the "segmentation clock" of somitogenesis: DLL3, HES7, LFNG, MESP2, RIPPLY2, and TBX6. To date, seven individuals with LFNG variants have been reported in the literature. In this study we describe two newborns and one fetus with SCD, who were found by trio‐based exome sequencing (trio‐ES) to carry homozygous (c.822‐5C>T) or compound heterozygous (c.[863dup];[1063G>A]) and (c.[521G>T];[890T>G]) variants in LFNG. Notably, the c.822‐5C>T change, affecting the polypyrimidine tract of intron 5, is the first non‐coding variant reported in LFNG. This study further refines the clinical and molecular features of spondylocostal dysostosis 3 and adds to the numerous investigations supporting the usefulness of trio‐ES approach in prenatal and neonatal settings. [ABSTRACT FROM AUTHOR]

Water buffalo (Bubalus bubalis) has a prominent position in the livestock industry worldwide but still suffers from limited knowledge on the mechanisms regulating the immune against infections, including brucellosis (BRC), one of the most significant neglected zoonotic diseases of livestock. Seventy‐three buffalo were recruited for the study. Thirty‐five were naturally infected with Brucella spp. The aims of the study were to (i) verify the cross‐reactivity of 16 monoclonal antibodies (mAbs) developed against human, bovine, and ovine antigens; (ii) evaluate lymphocyte subset alterations in BRC positive buffalo; (iii) evaluate the use of the canonical discriminant analysis (CDA), with flow cytometric data, to discriminate BRC positive from negative animals. A new set of eight mAbs (anti CD3e, CD16, CD18, CD45R0, CD79a; CD172a) were shown to cross‐react with water buffalo orthologous molecules. BRC positive animals presented a significant (p < 0.0001) decrease in the percentage of PBMC (29.5 vs. 40.3), total, T and B lymphocytes (23.0 vs. 35.5, 19.2 vs. 28.9, 2.6 vs. 5.7, respectively). In contrast, they showed an increase in percentage of granulocytes (65.2 vs. 55.1; p < 0.0001) and B lymphocytes CD21neg (22.9 vs. 16.1; p = 0.0067), a higher T/B lymphocyte ratio (10.3 vs. 6.4; p = 0.0011) and CD3+/CD21+ (14.7 vs. 8.3; p = 0.0005) ratio. The CDA, applied to 33 different flow cytometric traits, allowed the discrimination of all BRC positive from negative buffalo. Although this is a preliminary study, our results show that flow cytometry can be used in a wide range of applications in livestock diseases, including in support of uncertain BRC diagnoses. [ABSTRACT FROM AUTHOR]

Background: An increasing number of children diagnosed with both low‐ and high‐risk neuroblastoma are surviving. Yet, treatment can be intensive and often multimodal, especially for high‐risk neuroblastoma, resulting in significant long‐term health problems. We aimed to describe neuroblastoma survivors' pediatric hospitalizations, readmissions, and their associated costs. Method: We conducted a population‐based study of all children (<18 years) residing in New South Wales (NSW), Australia, and hospitalized with a recorded diagnosis of neuroblastoma during 2001–2020. We used linked NSW Admitted Patient Data Collection and death registration data to examine the frequency, length of stay, and readmissions following the first admission when neuroblastoma was diagnosed (i.e., the index admission), and the associated hospitalization costs by age and timing postindex admission discharge. Results: In total, 300 children (64% aged <3 years) were hospitalized for neuroblastoma over the study period. The median number of readmissions and length of stay within 2 years postdischarge were 17 (interquartile range IQR: 5.5–25) and 45.5 (IQR: 10–125) days, and median cost per child was AUD$124,058 (IQR $34,217–$264,627). Following discharge from the index admission, there were 7088 readmissions (median: 20 per child, IQR: 7–29). Fifty‐eight percent of readmissions occurred within 1‐year postdischarge, primarily due to fever, nausea, abdominal pain, and respiratory conditions. Conclusion: The burden of health problems requiring hospitalization among neuroblastoma survivors results in significant associated healthcare costs, warranting further efforts to optimize health care for neuroblastoma survivors that focuses on early intervention and long‐term monitoring. [ABSTRACT FROM AUTHOR]

This article discusses a study that aims to demonstrate the scientific validity of a novel cell-based non-invasive prenatal testing (cbNIPT) method for detecting fetal copy number variants (CNVs) using single cell sequencing of circulating extravillous trophoblasts (cEVTs). The study enrolled 1388 high-risk pregnancies and found a screen positive rate of 18.9% for aneuploidies and 11.2% for pCNVs. The results showed that cbNIPT was able to detect pCNVs <1 Mb in size, which is below the resolution of cell-free DNA screening. The authors conclude that analyzing cEVTs from maternal blood could significantly reduce the residual risk for pCNVs in early gestational weeks. [Extracted from the article]

Grapevine (Vitis vinifera L.) is the most widely cultivated fruit crop worldwide, contributing substantially to rural economies. The production cycle and productivity depend on seasonal cues and can range from a strongly deciduous habit in cool‐temperate climates to evergreen in subtropical and tropical climates. The influence of the different seasonal conditions on the dynamics of the perennating bud, including the degree of growth and metabolic quiescence, cell cycle status and internal tissue oxygen status between different climatic zones is largely unknown. This knowledge is important for adapting to changing climate conditions and for crop expansion to wider regions. This study investigated the growth and metabolic physiology of the perennating bud of commercially grown cv. Flame Seedless table grapes from Mediterranean and subtropical climate in Western Australia, from summer until late winter. Climate data were obtained, showing differences in minimum (night) temperature between the two climates, reflected by differences in calculated chilling units. Bud dormancy increased during autumn of both climates;however, the onset and depth of dormancy of buds from the subtropical region were attenuated relative to the Mediterranean condition. Stark contrasts were also observed in metabolism. The respiration of subtropical‐grown buds increased over fivefold during late autumn and winter, while that of Mediterranean‐grown buds increased less than twofold. This was also reflected in less desiccation of the subtropical‐grown buds, and an apparently greater degree of hypoxia within the bud during late winter, prior to bud burst. Collectively, these data show pronounced differences in growth and metabolic physiology of commercially grown table grapes, which provide a foundation for investigating the influence of differing climate and seasonality on the growth and productivity of table grapes and how these may be managed through breeding and agronomy. [ABSTRACT FROM AUTHOR]

Yield losses due to nutrient deficiency are estimated as the primary cause of the yield gap worldwide. Understanding how plant roots perceive external nutrient status and elaborate morphological adaptations in response to it is necessary to develop reliable strategies to increase crop yield. In the last decade, reactive oxygen species (ROS) were shown to be key players of the mechanisms underlying root responses to nutrient limitation. ROS contribute in multiple ways to shape the root system in response to nutritional cues, both as direct effectors acting on cell wall architecture and as second messengers in signalling pathways. Here, we review the mutual interconnections existing between perception and signalling of the most common forms of the major macronutrients (nitrogen, phosphorus and potassium), and ROS in shaping plant root system architecture. We discuss recent advances in dissecting the integration of these elements and their impact on morphological traits of the root system, highlighting the functional ductility of ROS and enzymes implied in ROS metabolism, such as class III peroxidases. Summary statement: Reactive oxygen species (ROS) are major regulators of root development and root plasticity in response to stress, by acting both as direct effectors by affecting the cell wall and as signalling molecules involved in signalling pathways. Class III peroxidases, as well as their upstream activator (e.g., UPBEAT1) or enzymes producing its substrates (e.g., NADPH oxidases), play a major role in controlling ROS pattern and thus their functionality in either cell wall stiffening or loosening. Recent advances are uncovering the importance of such functions in the case of nutrient stress, and attribute to ROS a pivotal role in determining root phenotype. [ABSTRACT FROM AUTHOR]

This study aims to compare the accelerometer‐measured daily patterns of PA and sedentary behavior among participants with and without prevalent/incident depressive symptoms. We used data from 5582 individuals in The Maastricht Study (59.9 ± 8.6 years, 50.3% women). Daily patterns of sedentary time, light‐intensity physical activity (LiPA), moderate‐to‐vigorous physical activity (MVPA), and sit‐to‐stand transitions were objectively measured at baseline with the activPAL3 activity monitor. Depressive symptoms were assessed using the 9‐item Patient Health Questionnaire, both at baseline and annually (median follow‐up: 5.1 years). General linear models were used to compare patterns of physical activity and sedentary behavior between those with and without prevalent/incident depressive symptoms. Participants with prevalent depressive symptoms had significantly more sedentary time (18.6 min/day) and lower LiPA (26.8 min/day) and MVPA (4.8 min/day) than participants without depressive symptoms. Considering the daily patterns, participants with prevalent depressive symptoms had significantly more sedentary time early in the afternoon (12:00–18:00), early evening (18:00–21:00), and during the night (00:00–03:00), less time in LiPA in all periods between 09:00–21.00 and less MVPA in the morning (09:00:12:00), early afternoon (12:00–15:00), and evening (18:00–21:00), than those without. Similar differences in activity and sedentary behavior patterns between those and without incident depressive symptoms were observed albeit the differences were smaller. Overall, we did not find specific time slots particularly associated with both prevalent and incident depressive symptoms. These findings may indicate that less sedentary time and more intense PA can be important targets for the prevention of depression irrespective of the timing of the day. [ABSTRACT FROM AUTHOR]

Summary: Haberlea rhodopensis is a resurrection plant that can tolerate extreme and prolonged periods of desiccation with a rapid restoration of physiological function upon rehydration. Specialized mechanisms are required to minimize cellular damage during desiccation and to maintain integrity for rapid recovery following rehydration.In this study we used respiratory activity measurements, electron microscopy, transcript, protein and blue native‐PAGE analysis to investigate mitochondrial activity and biogenesis in fresh, desiccated and rehydrated detached H. rhodopensis leaves.We demonstrate that unlike photosynthesis, mitochondrial respiration was almost immediately activated to levels of fresh tissue upon rehydration. The abundance of transcripts and proteins involved in mitochondrial respiration and biogenesis were at comparable levels in fresh, desiccated and rehydrated tissues. Blue native‐PAGE analysis revealed fully assembled and equally abundant OXPHOS complexes in mitochondria isolated from fresh, desiccated and rehydrated detached leaves. We observed a high abundance of alternative respiratory components which correlates with the observed high uncoupled respiration capacity in desiccated tissue.Our study reveals that during desiccation of vascular H. rhodopensis tissue, mitochondrial composition is conserved and maintained at a functional state allowing for an almost immediate activation to full capacity upon rehydration. Mitochondria‐specific mechanisms were activated during desiccation which probably play a role in maintaining tolerance. [ABSTRACT FROM AUTHOR]

Objective: The COVID-19 pandemic changed the time-dependent cardiac arrest network. This study aims to understand whether the rescue standards of CPR and out-of-hospital cardiac arrest (OHCA) were handled differently during pandemic compared to the previous year.Methods: Data for the years 2019 and 2020 were provided by the records of the Lombardy office of the Regional Agency for Emergency and Urgency (AREU). We analysed where the cardiac arrest occurred, when CPR started and whether the bystanders used PAD.Results: During 2020, there was a reduction in CPRs performed by bystanders (OR = 0.936 [CI95% 0.882-0.993], P = 0.029) and in the return of spontaneous circulation (ROSC) (OR = 0.621 [CI95% 0.563- 0.685], P < 0.0001), while there was no significant reduction in the use of PAD. Analysing only March, the period of the first wave in Lombardy, the comparison shows a reduction in bystanders CPRs (OR = 0.727 [CI95% 0.602- 0.877], P = 0.0008), use of PAD (OR = 0.441 [CI95% 0.272-0.716], P = 0.0009) and in ROSC (OR = 0.179 [CI95% 0.124-0.257], P < 0.0001). These phenomena could be influenced by the different setting in which the OHCAs occurred; in fact, those that occurred in public places with a mandatory PAD were strongly reduced (OR = 0.49 [CI95% , 0.44-0.55], P < 0.0001).Conclusions: COVID-19 had a profound impact on the time-dependant OHCA network. During the first pandemic wave, CPR and PAD used by bystanders decreased. The different context in which OHCAs occurred may partially explain these differences. [ABSTRACT FROM AUTHOR]

The present study aimed to investigate the personal well‐being and family distress of Italian caregivers during the lockdown. Five hundred sixty‐five family caregivers and 638 age‐ and sex‐matched noncaregivers completed a web‐based survey. The following scales were administered to all participants: General Health Questionnaire‐12 items (GHQ‐12), Insomnia Severity Index (ISI), Brief Resilient Coping Scale (BRCS), and Family Distress Index (FDI). Caregivers were also asked to provide information about their family members with disabilities. Individual and family distress, as well as insomnia, were significantly higher in caregivers than controls. Contrariwise, caregivers reported lower resilience levels. Multiple linear regression showed that distress was higher in caregivers living in Central and Southern Italy. Individual well‐being was negatively predicted by low independence measured by the activities of daily living (ADL). Family distress was higher in households of psychiatric patients. Finally, low resilience levels appeared as the strongest predictors of both individual and family distress. The lockdown caused severe distress among caregivers and families of people with disabilities. Support networks for people with disabilities and their families are fundamental to prevent severe consequences from a psychological, social, and economical point of view. [ABSTRACT FROM AUTHOR]

Introduction: Two‐dimensional strain echocardiography (2D‐SE) is a reliable method for measuring deformation of the left ventricle. Aim of the study: Aim of the study was to determine changes in 2D‐SE parameters over time collected during dipyridamole stress echo‐cardiography (dipy‐stress) and prognosis of patients with non‐diagnostic dipy‐stress results. Methods: In the first phase of the study, assessment of a prospective enrolled population with a non‐diagnostic dipy‐stress test result was conducted, checking through coronary CT angiography (CCTA) the presence of coronary artery disease (CAD). In the follow‐up phase, an echocardiographic re‐evaluation and outcome analysis during a mean follow‐up of 78 months was carried out. Results: In the first phase, Global Circumferential Strain (GCS) values were similar in the CCTA positive and CCTA negative groups at rest and after stress. For Global Longitudinal Strain (GLS), there was a significant reduction (p <.0001) in the CCTA positive group compared to the CCTA negative group. After 78 ± 9 months none of the enrolled patients experimented cardiac events. Values of GCS, both at rest and after stress, did not differ statistically comparing follow‐up values with baseline ones. No statistically significant changes were seen in the same analysis for GLS rest and stress values, between baseline and follow‐up in the two groups. Conclusions: Performing 2D‐SE during dipy‐stress can detect mild CAD that conventional stress‐tests miss. Patients with mild coronary stenosis may have a favorable mid‐term prognosis, but efforts should be made to investigate the decrease trend in GLS, at rest and after stress, reported in this patient group. [ABSTRACT FROM AUTHOR]

Autism spectrum disorder (ASD) is a heterogeneous neurodevelopment disorder resulting from different etiological factors, both genetic and/or environmental. These factors can lead to abnormal neuronal development on dendrite and synaptic function at the central nervous system. Recent studies have shown that a subset of ASD patients display increased circulation levels of the tyrosine metabolite, p‐cresol, related to chronic intestinal disorders because of dysbiosis of the intestinal microbiota. In particular, abnormal presence of intestinal Clostridium sp. has been linked to high levels of p‐cresol in ASD children younger than 8 years. However, the role of p‐cresol during development of the central nervous system is unknown. Here, we evaluated in vitro the effect of p‐cresol on neurite outgrowth in N2a and PC12 cell lines and dendritic morphology, synaptic density, neuronal activity, and calcium responses in primary rat hippocampal neurons. p‐cresol inhibits neural differentiation and neurites outgrowth in N2a and PC12 neuronal cell lines. In hippocampal neuronal cultures, Sholl's analysis shows a decrease in the dendritic arborization of neurons treated with p‐cresol. Synaptic density analyzed with the synaptic markers Piccolo and Shank2 is diminished in hippocampal neurons treated with p‐cresol. Electrically evoked intracellular calcium rise was drastically, but reversely, blocked by p‐cresol, whereas that spontaneous neuronal activity was severely affected by early addition of the metabolite. These findings show that p‐cresol alters dendrite development, synaptogenesis, and synapse function of neurons in culture, therefore, neuronal alterations occurring in ASD children may be related to this metabolite and dysbiosis of the intestinal microbiota. [ABSTRACT FROM AUTHOR]

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Porocarcinoma is a rare type of skin cancer that develops from the intraepidermal ductal part of eccrine sweat glands. It can arise de novo or from poroma ground with high potential for locoregional metastatic spread, morbidity, and mortality. It mostly occurs in elderly patients. [ABSTRACT FROM AUTHOR]

Understanding mechanisms of coexistence is a central topic in ecology. Mathematical analysis of models of competition between two identical species moving at different rates of symmetric diffusion in heterogeneous environments show that the slower mover excludes the faster one. The models have not been tested empirically and lack inclusions of a component of directed movement toward favourable areas. To address these gaps, we extended previous theory by explicitly including exploitable resource dynamics and directed movement. We tested the mathematical results experimentally using laboratory populations of the nematode worm, Caenorhabditis elegans. Our results not only support the previous theory that the species diffusing at a slower rate prevails in heterogeneous environments but also reveal that moderate levels of a directed movement component on top of the diffusive movement allow species to coexist. Our results broaden the theory of species coexistence in heterogeneous space and provide empirical confirmation of the mathematical predictions. [ABSTRACT FROM AUTHOR]

Longitudinal and high‐dimensional measurements have become increasingly common in biomedical research. However, methods to predict survival outcomes using covariates that are both longitudinal and high‐dimensional are currently missing. In this article, we propose penalized regression calibration (PRC), a method that can be employed to predict survival in such situations. PRC comprises three modeling steps: First, the trajectories described by the longitudinal predictors are flexibly modeled through the specification of multivariate mixed effects models. Second, subject‐specific summaries of the longitudinal trajectories are derived from the fitted mixed models. Third, the time to event outcome is predicted using the subject‐specific summaries as covariates in a penalized Cox model. To ensure a proper internal validation of the fitted PRC models, we furthermore develop a cluster bootstrap optimism correction procedure that allows to correct for the optimistic bias of apparent measures of predictiveness. PRC and the CBOCP are implemented in the R package pencal, available from CRAN. After studying the behavior of PRC via simulations, we conclude by illustrating an application of PRC to data from an observational study that involved patients affected by Duchenne muscular dystrophy, where the goal is predict time to loss of ambulation using longitudinal blood biomarkers. [ABSTRACT FROM AUTHOR]

SUMMARY: Autophagy is a conserved catabolic process that plays an essential role under nutrient starvation conditions and influences different developmental processes. We observed that seedlings of autophagy mutants (atg2, atg5, atg7, and atg9) germinated in the dark showed delayed chloroplast development following illumination. The delayed chloroplast development was characterized by a decrease in photosynthetic and chlorophyll biosynthetic proteins, lower chlorophyll content, reduced chloroplast size, and increased levels of proteins involved in lipid biosynthesis. Confirming the biological impact of these differences, photosynthetic performance was impaired in autophagy mutants 12 h post‐illumination. We observed that while gene expression for photosynthetic machinery during de‐etiolation was largely unaffected in atg mutants, several genes involved in photosystem assembly were transcriptionally downregulated. We also investigated if the delayed chloroplast development could be explained by lower lipid import to the chloroplast or lower triglyceride (TAG) turnover. We observed that the limitations in the chloroplast lipid import imposed by trigalactosyldiacylglycerol1 are unlikely to explain the delay in chloroplast development. However, we found that lower TAG mobility in the triacylglycerol lipase mutant sugardependent1 significantly affected de‐etiolation. Moreover, we showed that lower levels of carbon resources exacerbated the slow greening phenotype whereas higher levels of carbon resources had an opposite effect. This work suggests a lack of autophagy machinery limits chloroplast development during de‐etiolation, and this is exacerbated by limited lipid turnover (lipophagy) that physically or energetically restrains chloroplast development. Significance Statement: Autophagy is a catabolic process that plays an essential role during different developmental processes. We show that lack of autophagy machinery limits chloroplast development during de‐etiolation, and this is exacerbated by limited lipid turnover (lipophagy) that physically or energetically restrains chloroplast development. [ABSTRACT FROM AUTHOR]

Purpose: To explore Italian psychiatrists' attitudes toward the off‐label use of second generation antipsychotics (SGAs) in patients with substance use disorder and psychotic symptoms. Design and Methods: A sample of 300 Italian psychiatrists associated with the Italian Society of Neuropsychopharmacology was randomly selected to complete a survey about the off‐label prescription of SGAs. Findings: Oral aripiprazole (32.7%), olanzapine (30.2%), and quetiapine (25.2%) were considered "appropriate." Long‐acting antipsychoticss were generally considered "inappropriate." Practice Implications: Our findings reflect a substantial level of uncertainty and a lack of coherent clinical guidance within the realm of dual diagnosis treatment. Therefore, they emphasize the need to develop specific guidelines to improve the management of pharmacotherapy among this population. [ABSTRACT FROM AUTHOR]

In CMML, neoplastic monocytes can be distinguished based on their immunophenotype. Supportive care myeloid growth factors in concomitant extranodal non‐Hodgkin Lymphoma are safe. [ABSTRACT FROM AUTHOR]

The anterolateral ligament (ALL) has been suggested as an important secondary knee restrain on the dynamic laxity in anterior cruciate ligament- (ACL-) deficient knees. Nevertheless, its kinematical contribution to the pivot-shift (PS) phenomenon has not been clearly and objectively defined, and noninvasive sensor technology could give a crucial contribution in this direction. The aim of the present study was to quantify in vitro the PS phenomenon in order to investigate the differences between an ACL-deficient knee and an ACL+ALL-deficient knee. Ten fresh-frozen paired human cadaveric knees (n = 20) were included in this controlled laboratory study. Intact, ACL-deficient, and ACL+ALL-deficient knees were subjected to a manual PS test quantified by a noninvasive triaxial accelerometer (KiRA, OrthoKey). Kinematic data (i.e., posterior acceleration of the tibial lateral compartment) were recorded and compared among the three statuses. Pairwise Student's t -test was used to compare the single groups (p < 0.05). Intact knees, ACL-deficient knees, and ACL+ALL-deficient knees showed an acceleration of 5.3 ± 2.1 m/s2, 6.3 ± 2.3 m/s2, and 7.8 ± 2.1 m/s2, respectively. Combined sectioning of ACL and ALL resulted in a statistically significant acceleration increase compared to both the intact state (p < 0.01) and the ACL-deficient state (p < 0.01). The acceleration increase determined by isolated ACL resection compared to the intact state was not statistically significant (p > 0.05). The ALL sectioning increased the rotatory laxity during the PS after ACL sectioning as measured through a user-friendly, noninvasive triaxial accelerometer. [ABSTRACT FROM AUTHOR]

The efficacy of hydroxychloroquine (HCQ) in treating SARS-CoV-2 infection is harshly debated, with observational and experimental studies reporting contrasting results. To clarify the role of HCQ in Covid-19 patients, we carried out a retrospective observational study of 4,396 unselected patients hospitalized for Covid-19 in Italy (February–May 2020). Patients' characteristics were collected at entry, including age, sex, obesity, smoking status, blood parameters, history of diabetes, cancer, cardiovascular and chronic pulmonary diseases, and medications in use. These were used to identify subtypes of patients with similar characteristics through hierarchical clustering based on Gower distance. Using multivariable Cox regressions, these clusters were then tested for association with mortality and modification of effect by treatment with HCQ. We identified two clusters, one of 3,913 younger patients with lower circulating inflammation levels and better renal function, and one of 483 generally older and more comorbid subjects, more prevalently men and smokers. The latter group was at increased death risk adjusted by HCQ (HR[CI95%] = 3.80[3.08-4.67]), while HCQ showed an independent inverse association (0.51[0.43-0.61]), as well as a significant influence of cluster∗HCQ interaction (p < 0.001). This was driven by a differential association of HCQ with mortality between the high (0.89[0.65-1.22]) and the low risk cluster (0.46[0.39-0.54]). These effects survived adjustments for additional medications in use and were concordant with associations with disease severity and outcome. These findings suggest a particularly beneficial effect of HCQ within low risk Covid-19 patients and may contribute to clarifying the current controversy on HCQ efficacy in Covid-19 treatment. [ABSTRACT FROM AUTHOR]

Cardiovascular diseases (CVDs) are the leading cause of death globally and the number of cardiovascular patients, which is estimated to be over 30 million in 2018, represent a challenging issue for the healthcare systems worldwide. Therefore, the identification of novel molecular targets to develop new treatments is an ongoing challenge for the scientific community. In this context, sphingolipids (SLs) have been progressively recognized as potent bioactive compounds that play crucial roles in the modulation of several key biological processes, such as proliferation, differentiation, and apoptosis. Furthermore, SLs involvement in cardiac physiology and pathophysiology attracted much attention, since these molecules could be crucial in the development of CVDs. Among SLs, ceramide and sphingosine‐1‐phosphate (S1P) represent the most studied bioactive lipid mediators, which are characterized by opposing activities in the regulation of the fate of cardiac cells. In particular, maintaining the balance of the so‐called ceramide/S1P rheostat emerged as an important novel therapeutical target to counteract CVDs. Thus, this review aims at critically summarizing the current knowledge about the antithetic roles of ceramide and S1P in cardiomyocytes dysfunctions, highlighting how the modulation of their metabolism through specific molecules, such as myriocin and FTY720, could represent a novel and interesting therapeutic approach to improve the management of CVDs. [ABSTRACT FROM AUTHOR]

Drought is the main cause of productivity losses in soybean plants, triggering physiological and biochemical responses, stomatal closure being essential to prevent water losses and thus mitigate the negative effects of drought. Abscisic acid (ABA) is the main molecule involved in stomatal closure under drought conditions along with nitric oxide (•NO). However, the role of •NO in this process is not yet fully understood and contrasting findings about its role have been reported. Most of the assays in the literature have been carried out under in vitro conditions using •NO donors or scavengers, but little is known about the effects of endogenously produced •NO under drought conditions. This study is aimed to determine the pattern of endogenous •NO accumulation from the establishment of water stress and how this relates to stomatal closure and other biochemical and physiological responses. The analysis of soybean plant responses to drought revealed no correlation between whole-leaf •NO accumulation and typical water-deficit stress markers. Moreover, •NO accumulation did not explain oxidative damage induced by drought. However, endogenous •NO content correlated with the early stomatal closure. Analysis of stomatal behavior and endogenous •NO content in guard cells through epidermal peel technique showed a stomatal population with high variation in stomatal opening and •NO content under the initial stages of water stress, even when ABA responses are activated. Our data suggest that upon early stress perception, soybean plants respond by accumulating •NO in the guard cells to inhibit stomatal closure, potentially through the inhibition of ABA responses. [ABSTRACT FROM AUTHOR]

DMD is a rare disorder characterized by progressive muscle degeneration and premature death. Therapy development is delayed by difficulties to monitor efficacy non‐invasively in clinical trials. In this study, we used RNA‐sequencing to describe the pathophysiological changes in skeletal muscle of 3 dystrophic mouse models. We show how dystrophic changes in muscle are reflected in blood by analyzing paired muscle and blood samples. Analysis of repeated blood measurements followed the dystrophic signature at five equally spaced time points over a period of seven months. Treatment with two antisense drugs harboring different levels of dystrophin recovery identified genes associated with safety and efficacy. Evaluation of the blood gene expression in a cohort of DMD patients enabled the comparison between preclinical models and patients, and the identification of genes associated with physical performance, treatment with corticosteroids and body measures. The presented results provide evidence that blood RNA‐sequencing can serve as a tool to evaluate disease progression in dystrophic mice and patients, as well as to monitor response to (dystrophin‐restoring) therapies in preclinical drug development and in clinical trials. Synopsis: This study explored the potential of RNA‐sequencing of peripheral blood to track non‐invasively disease progression and response to treatment in dystrophic mice and in patients affected by Duchenne Muscular Dystrophy (DMD). The analysis of paired muscle and blood samples from healthy and dystrophic mice led to the identification of a large number of genes that are differentially expressed in muscle and showed that the muscle signature is partly reflected in blood.Treatment with two different antisense drugs, that yield different levels of dystrophin restoration, led to the identification of 14 genes whose expression in blood is associated with the safety and efficacy of treatment with antisense nucleotide drugs.The study of gene expression in patients affected by DMD showed the presence of a strong disease signature in blood.Comparison of the results on blood gene expression in mice and humans led to the identification of 688 genes that are differentially expressed both in dystrophic mice and in DMD patients. [ABSTRACT FROM AUTHOR]

Background: Improved outcome in tobacco smoking patients with non‐small cell lung cancer (NSCLC) following immunotherapy has previously been reported. However, little is known regarding this association during first‐line immunotherapy in patients with high PD‐L1 expression. In this study we compared clinical outcomes according to the smoking status of two large multicenter cohorts. Methods: We compared clinical outcomes according to the smoking status (never smokers vs. current/former smokers) of two retrospective multicenter cohorts of metastatic NSCLC patients, treated with first‐line pembrolizumab and platinum‐based chemotherapy. Results: A total of 962 NSCLC patients with PD‐L1 expression ≥50% who received first‐line pembrolizumab and 462 NSCLC patients who received first‐line platinum‐based chemotherapy were included in the study. Never smokers were confirmed to have a significantly higher risk of disease progression (hazard ratio [HR] = 1.49 [95% CI: 1.15–1.92], p = 0.0022) and death (HR = 1.38 [95% CI: 1.02–1.87], p = 0.0348) within the pembrolizumab cohort. On the contrary, a nonsignificant trend towards a reduced risk of disease progression (HR = 0.74 [95% CI: 0.52–1.05], p = 0.1003) and death (HR = 0.67 [95% CI: 0.45–1.01], p = 0.0593) were reported for never smokers within the chemotherapy cohort. After a random case–control matching, 424 patients from both cohorts were paired. Within the matched pembrolizumab cohort, never smokers had a significantly shorter progression‐free survival (PFS) (HR = 1.68 [95% CI: 1.17–2.40], p = 0.0045) and a nonsignificant trend towards a shortened overall survival (OS) (HR = 1.32 [95% CI: 0.84–2.07], p = 0.2205). On the contrary, never smokers had a significantly longer PFS (HR = 0.68 [95% CI: 0.49–0.95], p = 0.0255) and OS (HR = 0.66 [95% CI: 0.45–0.97], p = 0,0356) compared to current/former smoker patients within the matched chemotherapy cohort. On pooled multivariable analysis, the interaction term between smoking status and treatment modality was concordantly statistically significant with respect to ORR (p = 0.0074), PFS (p = 0.0001) and OS (p = 0.0020), confirming the significantly different impact of smoking status across the two cohorts. Conclusions: Among metastatic NSCLC patients with PD‐L1 expression ≥50% receiving first‐line pembrolizumab, current/former smokers experienced improved PFS and OS. On the contrary, worse outcomes were reported among current/former smokers receiving first‐line chemotherapy. [ABSTRACT FROM AUTHOR]

Maximizing participation in cancer research is important to improve the validity and generalizability of research findings. We conducted a four‐arm randomized controlled trial to test the impact of a novel video invitation on participant response. We invited childhood cancer survivors and parents of survivors <16 years to complete questionnaires. We compared response rates to an invitation letter (control) vs receiving the letter plus a video invitation on a flash drive presented by a childhood cancer survivor, a pediatric oncologist or a researcher. We explored factors associated with viewing the video and examined the impact of enclosing the USB on study costs. Overall 54% (634/1176) of questionnaires were returned. Participants who received a video invitation on a USB were more likely to return the questionnaire than those who did not (58% vs 47%, P <.001). Participation rate did not significantly differ by video presenter. Forty‐seven percent of participants who received a USB reported watching the video, of whom 48% reported that the video influenced their decision to participate. Participants with a lower income (OR = 0.43, 95% CI = 0.25‐0.74, P =.002) were more likely to report watching the video. Participants who received a video invitation required significantly fewer reminder calls than those who only received a written invitation (mean = 1.6 vs 1.1 calls, P <.001), resulting in a 25% recruitment cost‐saving for the study. Adding a USB with a video study invitation to recruitment packages is a cost‐effective way of improving study participation. This is important in an era of declining study participation and underrepresentation of vulnerable populations in research. What's new? High rates of patient participation in cancer research are critical to ensuring that data collected by clinical studies is relevant, reliable, and unbiased. Various recruitment strategies have been developed to improve participation rates, including video invitations. Here, the impact on study participation rates of a USB‐based video invitation sent via mail was examined among childhood cancer survivors who were asked to complete and return a questionnaire. Analyses show that participants who received a video invitation were more likely to return questionnaires than patients who received written information only. The findings offer insight into a cost‐effective approach for maximizing participant recruitment. [ABSTRACT FROM AUTHOR]

Automated monitoring approaches offer an avenue to unlocking large‐scale insight into how ecosystems respond to human pressures. However, since data collection and data analyses are often treated independently, there are currently no open‐source examples of end‐to‐end, real‐time ecological monitoring networks.Here, we present the complete implementation of an autonomous acoustic monitoring network deployed in the tropical rainforests of Borneo. Real‐time audio is uploaded remotely from the field, indexed by a central database, and delivered via an API to a public‐facing website.We provide the open‐source code and design of our monitoring devices, the central web2py database, and the ReactJS website. Furthermore, we demonstrate an extension of this infrastructure to deliver real‐time analyses of the eco‐acoustic data.By detailing a fully functional, open source, and extensively tested design, our work will accelerate the rate at which fully autonomous monitoring networks mature from technological curiosities, and towards genuinely impactful tools in ecology. [ABSTRACT FROM AUTHOR]

In this paper, we analyze the problem of public debt‐to‐GDP stability in the Eurozone. We suggest that a feasible solution might be the realization of a market‐financed, growth‐enhancing investment program, which would be particularly welcome because of the positive short‐ and long‐term repercussions it would have on GDP growth and the stabilizing effects on interest rates. Some simulations allow us to quantify these effects. The consequences of the COVID‐19 pandemic further reinforce our policy implications in terms of public debt sustainability. [ABSTRACT FROM AUTHOR]

Background: Malignant pleural mesothelioma (MPM) is a rare cancer with a poor prognosis. Centralization of rare cancer in dedicated centers is recommended to ensure expertise, multidisciplinarity and access to innovation. In Italy, expert centers for MPM have not been identified in all regions. We aimed to describe the treatment patterns among MPM patients across different Italian regions and to identify factors associated with the treatment patterns across the regions. Methods: We performed an observational study on a random sample of 2026 MPM patients diagnosed in 2003–2008. We included 26 population‐based registries covering 70% of the Italian population. To identify factors associated with treatment patterns, across the different regions, we fitted a multinomial logistic regression model adjusted by age, sex, stage, histology and hospital with thoracic surgical department. Results: MPM patients mostly received chemotherapy alone (41%) or no cancer‐directed therapy (36%) especially the older patients. The first course of treatment for MPM patients differed across regions. Patients from Piedmont, Liguria and Campania were more likely to receive no cancer‐directed therapy; those living in Tuscany and Sicily were more likely to get surgery; patients from Marche and Lazio were more likely to receive chemotherapy. These differences were not explained by age, sex, stage, histology and availability of a thoracic surgery department. Conclusions: There is limited expertise available and lack of a network able to maximize the expertise available may contribute to explaining the results of our study. Our findings support the need to ensure the appropriate care of all MPM patients in reorganizing the health care services. Key points: Significant findings of the study: MPM patients mostly received chemotherapy alone or no cancer‐directed therapy especially the older patients. The first course of treatment for MPM patients differed across Italian regions. What this study adds: Differences in MPM clinical management are not explained by the age, stage, histology nor by the availability of a thoracic surgery department. Limited expertise for MPM contribute to explaining the unequal access to appropriate care for MPM patients in Italy. [ABSTRACT FROM AUTHOR]

The entanglement between primary metabolism regulation and stress responses is a puzzling and fascinating theme in plant sciences. Among the major metabolites found in plants, γ‐aminobutyric acid (GABA) fulfils important roles in connecting C and N metabolic fluxes through the GABA shunt. Activation of GABA metabolism is known since long to occur in plant tissues following biotic stresses, where GABA appears to have substantially different modes of action towards different categories of pathogens and pests. While it can harm insects thanks to its inhibitory effect on the neuronal transmission, its capacity to modulate the hypersensitive response in attacked host cells was proven to be crucial for host defences in several pathosystems. In this review, we discuss how plants can employ GABA's versatility to effectively deal with all the major biotic stressors, and how GABA can shape plant immune responses against pathogens by modulating reactive oxygen species balance in invaded plant tissues. Finally, we discuss the connections between GABA and other stress‐related amino acids such as BABA (β‐aminobutyric acid), glutamate and proline. Recent research on γ‐aminobutyric acid (GABA) in plants highlighted a variety of functions concerning biotic stress responses including its interference with quorum sensing, the enhancement of plant endurance and toxicity to herbivorous. Connections of GABA metabolism with other stress‐related amino acids provide further indirect modes of action during the setup of immune responses. [ABSTRACT FROM AUTHOR]

Background: Autologous hematopoietic stem cell transplant (HSCT) recipients are not uniformly considered as "high risk" enough to receive fluoroquinolone (FQ) prophylaxis. The risks versus benefits of FQ prophylaxis in autologous HSCT require further investigation. Methods: A retrospective chart review of patients > 19 years old who received an autologous HSCT at Nebraska Medicine analyzed two time periods (period 1: no prophylaxis [2013‐2015] versus period 2: levofloxacin prophylaxis [2015‐2016]) to characterize the clinical impact of levofloxacin prophylaxis on autologous HSCT recipients. Results: A total of 224 autologous HSCT were screened with 214 included. Febrile neutropenia (FN) developed in 101/113 (89%) versus 60/101 (59%) patients in the no prophylaxis (NPx) versus prophylaxis (Px) group (P <.01). Time to onset of FN was a median 6 versus 7 days (P =.01), and total bloodstream infections (BSI) were 33/113 (29%) versus 7/101 (7%) (P <.01) in NPx and Px groups, respectively. Gram‐negative BSI were absent in the Px group. Viridans group streptococci were the most common Gram‐positive BSI overall, with FQ‐resistance more common in Px recipients. Rates of Clostridium difficile infections, length of hospital stay, or death at 100 days post‐HSCT did not differ between the groups. Conclusion: Fluoroquinolone prophylaxis introduced into autologous HSCT care at our institution in 2015 resulted in prevention of Gram‐negative BSI, decreased rates of FN, microbiologically documented infections, and a delay in time to onset of FN compared with the prior NPx. FQ prophylaxis in autologous HSCT recipients should be evaluated per individual institution. [ABSTRACT FROM AUTHOR]

Background: Duchenne muscular dystrophy (DMD) is a fatal disease for which no cure is available. Clinical trials have shown to be largely underpowered due to inter‐individual variability and noisy outcome measures. The availability of biomarkers able to anticipate clinical benefit is highly needed to improve clinical trial design and facilitate drug development. Methods: In this study, we aimed to appraise the value of protein biomarkers to predict prognosis and monitor disease progression or treatment outcome in patients affected by DMD. We collected clinical data and 303 blood samples from 157 DMD patients in three clinical centres; 78 patients contributed multiple blood samples over time, with a median follow‐up time of 2 years. We employed linear mixed models to identify biomarkers that are associated with disease progression, wheelchair dependency, and treatment with corticosteroids and performed survival analysis to find biomarkers whose levels are associated with time to loss of ambulation. Results: Our analysis led to the identification of 21 proteins whose levels significantly decrease with age and nine proteins whose levels significantly increase. Seven of these proteins are also differentially expressed in non‐ambulant patients, and three proteins are differentially expressed in patients treated with glucocorticosteroids. Treatment with corticosteroids was found to partly counteract the effect of disease progression on two biomarkers, namely, malate dehydrogenase 2 (MDH2, P = 0.0003) and ankyrin repeat domain 2 (P = 0.0005); however, patients treated with corticosteroids experienced a further reduction on collagen 1 serum levels (P = 0.0003), especially following administration of deflazacort. A time to event analysis allowed to further support the use of MDH2 as a prognostic biomarker as it was associated with an increased risk of wheelchair dependence (P = 0.0003). The obtained data support the prospective evaluation of the identified biomarkers in natural history and clinical trials as exploratory biomarkers. Conclusions: We identified a number of serum biomarkers associated with disease progression, loss of ambulation, and treatment with corticosteroids. The identified biomarkers are promising candidate prognostic and surrogate biomarkers, which may support drug developers if confirmed in prospective studies. The serum levels of MDH2 are of particular interest, as they correlate with disease stage and response to treatment with corticosteroids, and are also associated with the risk of wheelchair dependency and pulmonary function. [ABSTRACT FROM AUTHOR]

Introduction: Worldwide, life expectancy, and aging-related disorders as mild cognitive impairment (MCI) and Alzheimer disease (AD) are increasing, having a rising impact on patients' quality of life and caregivers' distress. Telemedicine offers many possibilities, such as remote diagnosing and monitoring of patients.Objective: The purpose of this study is to provide a narrative synthesis of the literature about the implementation of telemedicine for diagnosis, treatment, and follow-up of patients with AD and MCI and their caregivers.Methods: A systematic literature review was conducted on MEDLINE, EMBASE, and the Cochrane Library databases up to September 2018. MCI or AD diagnoses were the conditions of interest. We excluded other dementias.Results: Fifty-six articles met inclusion criteria. We identified two main categories: diagnosis group (DG) and follow-up/interventional group (FIG). Fifteen articles suggested how to make a remote or earlier diagnosis: four were case-control accuracy studies, nine were paired comparative accuracy studies, and two were prospective single-arm accuracy studies. Among these, four focused on MCI, six on AD, and five on both. Forty one focused on supporting patients during the stages of the disease (28 articles), patient's caregivers (nine articles), or both (four articles).Conclusions: The rising use of telemedicine could actively improve AD and MCI patients' lives, reduce caregivers' burden, and facilitate an early diagnosis if patients live in remote places. However, as some studies report, it is relevant to take into account the emotional impact of telemedicine on patients and not only on the effectiveness. [ABSTRACT FROM AUTHOR]

An implementation of smoothing splines is proposed to reduce orientation noise in electron backscatter diffraction (EBSD) data, and subsequently estimate more accurate geometrically necessary dislocation (GND) densities. The local linear adaptation of smoothing splines (LLASS) filter has two advantages over classical implementations of smoothing splines: (1) it allows for an intuitive calibration of the fitting versus smoothing trade‐off and (2) it can be applied directly and in the same manner to both square and hexagonal grids, and to 2D as well as to 3D EBSD data sets. Furthermore, the LLASS filter calculates the filtered orientation gradient, which is actually at the core of the method and which is subsequently used to calculate the GND density. The LLASS filter is applied on a simulated low‐misorientation‐angle boundary corrupted by artificial orientation noise (on a square grid), and on experimental EBSD data of a compressed Ni‐base superalloy (acquired on a square grid) and of a dual austenitic/martensitic steel (acquired on an hexagonal grid). The LLASS filter leads to lower GND density values as compared to raw EBSD data sets, as a result of orientation noise being reduced, while preserving true GND structures. In addition, the results are compared with those of filters available in the MTEX toolbox. [ABSTRACT FROM AUTHOR]

Immunotherapy, and in particular immune-checkpoints blockade therapy (ICB), represents a new pillar in cancer therapy. Antibodies targeting Cytotoxic T-Lymphocyte Antigen 4 (CTLA-4) and Programmed Death 1 (PD-1)/Programmed Death Ligand-1 (PD-L1) demonstrated a relevant clinical value in a large number of solid tumors, leading to an improvement of progression free survival and overall survival in comparison to standard chemotherapy. However, across different solid malignancies, the immune-checkpoints inhibitors efficacy is limited to a relative small number of patients and, for this reason, the identification of positive or negative predictive biomarkers represents an urgent need. Despite the expression of PD-L1 was largely investigated in various malignancies, (i.e., melanoma, head and neck malignancies, urothelial and renal carcinoma, metastatic colorectal cancer, and pancreatic cancer) as a biomarker for ICB treatment-patients selection, it showed an important, but still imperfect, role as positive predictor of response only in nonsmall cell lung cancer (NSCLC). Importantly, other tumor and/or microenvironments related characteristics are currently under clinical evaluation, in combination or in substitution of PD–L1 expression. In particular, tumor-infiltrating immune cells, gene expression analysis, mismatch- repair deficiency, and tumor mutational landscape may play a central role in predicting clinical benefits of CTLA-4 and/or PD-1/PD-L1 checkpoint inhibitors. In this review, we will focus on the clinical evaluation of emerging biomarkers and how these may improve the naïve vision of a single- feature patients-based selection. [ABSTRACT FROM AUTHOR]