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The characterization of gas-liquid flows involves the measurement or prediction of temperature, pressure and velocities, plus some quantities which describe the flow structure. Concerning the latter, the most used is the local void fraction, which in this work is accompanied by the flow complexity, another quantity which evaluates the number of interfaces passing through a point during the sampling interval. The cross-section averaged value of the flow complexity may be put into relation with the liquid velocity. In horizontal ducts, such correlation may assume a very simple potential form or a slightly more complex aspect if the effect of flow development along the duct is included. It can be also determined by detection of the phase density function at different heights on the vertical diameter of the duct cross-section alone. Therefore the liquid velocity and consequently gas velocity (via slip correlations) can be estimated by inline phase density measurements using local impedance probes. The paper presents the preliminary analyses to develop the correlation and the design of a multi-probe sensor to perform the measurements.

Ecological variation and anthropogenic landscape modification have had key roles in the diversification and extinction of mammals in Madagascar. Lemurs represent a radiation with more than 100 species, constituting roughly one-fifth of the primate order. Almost all species of lemurs are threatened with extinction, but little is known about their genetic diversity and demographic history. Here, we analyse high-coverage genome-wide resequencing data from 162 unique individuals comprising 50 species of Lemuriformes, including multiple individuals from most species. Genomic diversity varies widely across the infraorder and yet is broadly consistent among individuals within species. We show widespread introgression in multiple genera and generally high levels of genomic diversity likely resulting from allele sharing that occurred during periods of connectivity and fragmentation during climatic shifts. We find distinct patterns of demographic history in lemurs across the ecogeographic regions of Madagascar within the last million years. Within the past 2,000 years, lemurs underwent major declines in effective population size that corresponded to the timing of human population expansion in Madagascar. In multiple regions of the island, we identified chronological trajectories of inbreeding that are consistent across genera and species, suggesting localized effects of human activity. Our results show how the extraordinary diversity of these long-neglected, endangered primates has been influenced by ecological and anthropogenic factors., Competing Interests: Competing interests: L.F.K.K. and K.K.-H.F. are employees of Illumina as of the submission of the paper. The other authors declare no competing interests., (© 2024. The Author(s), under exclusive licence to Springer Nature Limited.)

Choledochal cysts (CCs) are cystic dilations of intrahepatic and/or extrahepatic bile ducts. Around 80% of CCs are diagnosed within the first decade of life. These complex clinical entities are extremely rare, especially in the Western population. CCs are frequently classified according to the Todani classification. CCs may be asymptomatic or present as acute pancreatitis and/or cholangitis, biliary obstruction, or malignancy. Therefore, the diagnosis relies primarily on abdominal imaging modalities, mainly magnetic resonance cholangiopancreatography. Management is tailored based on the cyst morphology and the patient's clinical characteristics, with surveillance, surgery, and interventional endoscopy being the most frequent management options. While the surgical approach is the most frequently employed, type III CCs (also known as choledochocele) are frequently managed endoscopically, and novel endoscopic, minimally invasive treatment options are rapidly emerging., Competing Interests: Declarations. Conflict of interest: The authors declare that they have no conflict of interest., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Endoscopic ultrasound-guided biliary drainage (EUS-BD) has dramatically spread and improved in the last two decades and is changing the paradigm of drainage in case of malignant biliary obstruction (MBO). EUS-BD can be achieved from different routes, including the common bile duct (choledochoduodenostomy), intrahepatic bile ducts (hepaticogastrostomy), and gallbladder as a rescue (cholecystogastrostomy/cholecystoduodenostomy). EUS-guided hepaticogastrostomy (EUS-HGS) is a valuable option for biliary drainage in MBO when ERCP fails or is not feasible. EUS-HGS has demonstrated high efficacy with a good rate of technical and clinical success. The safety profile is also overall favorable, although severe adverse events may occur in a significant proportion of patients. From a technical perspective, EUS-HGS is considered one of the most demanding procedures in biliopancreatic endoscopy, requiring multiple steps and high technical skills and experience. In this comprehensive review, technical tips and clinical outcomes of EUS-HGS are reviewed according to the latest evidence in the literature.

Background: Several randomized clinical trials comparing different bowel preparations (BP) have shown similar efficacy; however, there is a lack of real-world studies on this topic., Aims: This study aims to identify the most effective BP regimen in a real-world setting and any predictors of inadequate BP., Methods: A retrospective single-center study was conducted over 14 months at an academic hospital including outpatient colonoscopies in which adult patients did not teach on how to perform BP before colonoscopy. Colonoscopies with 1L-PEG, 2L-PEG and picosulphate mixtures were considered. A multivariable analysis for factors associated to poor BP was fitted., Results: Overall, 1779 patients (51 %F, 60±14) years were included. The 1L-PEG regimen provided a higher rate of BP adequacy at multivariate analysis (adjusted OR 2.30, 95 %CI 1.67-3.16,p < 0.001) and was associated with higher median Boston Bowel Preparation Scale score (p < 0.001), higher rate of right-colon cleansing (p < 0.001) and exam completion (p = 0.04). Furthermore, we identified male sex, history of constipation, active smoking, previous pelvic surgery, concomitant psychiatric/neurological or chronic kidney diseases as predictors of inadequate BP., Conclusions: This is the largest real-world study comparing 1L-PEG to other BP regimens. Our results suggest 1L-PEG provides better BP in a non-controlled setting, improving clinical practice quality and minimizing the need for repeated colonoscopies and saving healthcare resources., Competing Interests: Conflict of interest Authors declare no conflict of interests for this article., (Copyright © 2024 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

In the last few years, our understanding of disease molecular mechanisms underpinning ALS has advanced greatly, allowing the first steps in translating into clinical practice novel research findings, including gene therapy approaches. Similarly, the recent advent of assistive technologies has greatly improved the possibility of a more personalized approach to supportive and symptomatic care, in the context of an increasingly complex multidisciplinary line of actions, which remains the cornerstone of ALS management. Against this rapidly growing background, here we provide an comprehensive update on the most recent studies that have contributed towards our understanding of ALS pathogenesis, the latest results from clinical trials as well as the future directions for improving the clinical management of ALS patients., (© 2024. The Author(s).)

Background and Objectives : Serum alpha-fetoprotein (AFP) is a recognized affordable oncological marker in patients with hepatocellular carcinoma (HCC). However, AFP's prognostic role has been assessed mainly after specific treatments, and no unanimously recognized cut-offs have been identified. The aim of this study is to investigate the prognostic role of different basal AFP cut-offs on survival and HCC course. Materials and Methods : In this single-center, retrospective study, all patients newly diagnosed with HCC between January 2009 and December 2021 were prospectively enrolled. Only patients suitable for curative HCC treatments were included in the analyses. Patients were stratified according to AFP cut-offs of 20, 200, 400, and 1000 ng/mL, which were correlated with survival outcomes and clinical parameters. Results : A total of 266 patients were analyzed, with a median follow-up time of 41.5 months. Median overall survival (OS) of all cohort was 43 months. At the multivariate Cox-regression analysis, AFP value ≥ 1000 ng/mL correlated with impaired OS (1-year OS: 67% vs. 88%, 5-year OS: 1% vs. 43%; p = 0.005); other risk factors were tumor dimension ≥ 5 cm (HR 1.73; p = 0.002), Child-Pugh class B-C (HR 1.72; p = 0.002), BCLC stage A (vs. 0) (HR 2.4; p = 0.011), and malignant portal vein thrombosis (HR 2.57; p = 0.007). AFP ≥ 1000 ng/mL was also associated with a reduced recurrence-free survival (HR 2.0; p = 0.038), while starting from AFP ≥ 20 ng/mL, a correlation with development of HCC metastases over time (HR 3.5; p = 0.002) was seen. AFP values ≥ 20 ng/mL significantly correlated with tumor size and higher histological grading; starting from AFP values ≥ 400 ng/mL, a significant correlation with Child-Pugh class B-C and female gender was also observed. Conclusions : Basal AFP correlates with relevant outcomes in patients with HCC. It could help identify patients at a higher risk of worse prognosis who might benefit from personalized surveillance and treatment programs. Prospective studies are needed to confirm these results.

Background and Objectives: Amyotrophic lateral sclerosis associated with mutations in SOD1 (SOD1-ALS) might be susceptible to specific treatment. The aim of the study is to outline the clinical features of SOD1-ALS patients by comparing them to patients without ALS major gene variants and patients with variants in other major ALS genes. Defining SOD1-ALS phenotype may assist clinicians in identifying patients who should be prioritized for genetic testing., Methods: We performed an extensive literature research including original studies which reported the clinical features of SOD1-ALS and at least one of the following patient groups: C9ORF72 hexanucleotide repeat expansion (C9-ALS), TARDBP (TARDBP-ALS), FUS (FUS-ALS) or patients without a positive test for a major-ALS gene (N-ALS). A random effects meta-analytic model was applied to clinical data extracted encompassing sex, site and age of onset. To reconstruct individual patient survival data, the published Kaplan-Meier curves were digitized. Data were measured as odds ratio (OR) or standardized mean difference (SMD) as appropriate. Median survival was compared between groups., Results: Twenty studies met the inclusion criteria. We identified 721 SOD1-ALS, 470 C9-ALS, 183 TARDBP-ALS, 113 FUS-ALS and 2824 N-ALS. SOD1-ALS showed a higher rate of spinal onset compared with N-ALS and C9-ALS (OR = 4.85, 95% CI = 3.04-7.76; OR = 10.47, 95% CI = 4.32-27.87) and an earlier onset compared with N-ALS (SMD = - 0.45, 95% CI = - 0.72 to - 0.18). SOD1-ALS had a similar survival compared with N-ALS (p = 0.14), a longer survival compared with C9-ALS (p < 0.01) and FUS-ALS (p = 0.019) and a shorter survival compared with TARDBP-ALS (p < 0.01)., Discussion: This study indicates the presence of a specific SOD1-ALS phenotype. Insights in SOD1-ALS clinical features are important in genetic counseling, disease prognosis and support patients' stratification in clinical trials., (© 2023. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany.)

Background: Various reduction techniques exist to treat traumatic shoulder dislocation, but best management remains unclear., Aims: To investigate the reduction rate of traumatic anteroinferior shoulder dislocations using two sedation-free techniques and success rates of subgroups., Methods: A single-center study was performed analysing shoulder dislocations in a two-year period. Adult patients with anteroinferior shoulder dislocation were included. Two sedation-free reduction techniques were used: the Davos self-reduction technique and the Arlt-chair technique. Two attempts were performed before sedation. All patients gave informed consent to study participation., Results: The investigated 106 patients (106 shoulder dislocations) had a mean age of 48 ± 18 years (74% male patients). The majority occurred during winter sports (76%). The overall success rate for both sedation-free reduction techniques was 82% (87 reduced shoulders, two attempts). A significantly increased success rate was found in patients without greater tuberosity fracture (86% without vs. 68% with fracture, p  = 0.002) and for patients with repeated dislocation (93% vs. 80% for primary dislocation, p  = 0.004). Time for reduction was 5 minutes (Davos technique) and 1 minute (Arlt-chair-technique). Associated injuries were mostly Hill Sachs lesions (78%). There was no major complication and no new-onset sensory deficit., Conclusion: Davos and Arlt reduction techniques allowed sedation-free and fast treatment for anteroinferior shoulder dislocation during winter sports., Competing Interests: The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article., (© The Author(s) 2023.)

As research in automatically detecting bugs grows and produces new techniques, having suitable collections of programs with known bugs becomes crucial to reliably and meaningfully compare the effectiveness of these techniques. Most of the existing approaches rely on benchmarks collecting manually curated real-world bugs, or synthetic bugs seeded into real-world programs. Using real-world programs entails that extending the existing benchmarks or creating new ones remains a complex time-consuming task. In this paper, we propose a complementary approach that automatically generates programs with seeded bugs. Our technique, called HyperPUT, builds C programs from a "seed" bug by incrementally applying program transformations (introducing programming constructs such as conditionals, loops, etc.) until a program of the desired size is generated. In our experimental evaluation, we demonstrate how HyperPUT can generate buggy programs that can challenge in different ways the capabilities of modern bug-finding tools, and some of whose characteristics are comparable to those of bugs in existing benchmarks. These results suggest that HyperPUT can be a useful tool to support further research in bug-finding techniques-in particular their empirical evaluation., Competing Interests: Competing interestThe authors declare that they have no known competing interests that could have appeared to influence the work reported in this paper., (© The Author(s) 2024.)

Fungal periprosthetic joint infections (PJI) are difficult to treat, due to important biofilm formation and limited local penetration of systemically administered antifungals. Calcium sulphate (CaSO 4 ) might be a promising carrier to increase local concentration of antifungals. We hypothesized that local amphotericin B release from CaSO 4 is high enough to significantly contribute to treatment of fungal PJI. We report joint fluid and serum concentrations of amphotericin B after local application with CaSO 4 as an implanted resorbable carrier material as adjunct to standard surgical and systemic antifungal treatment in two cases of PJI with Candida spp. Maximal joint fluid amphotericin B concentration was 14.01 mg/L 5 days after the second local administration of liposomal amphotericin in Case One and 25.77 mg/L 14 days after the second local administration in Case Two. Concentrations higher than minimal inhibitory concentrations (MIC) could be measured for 21 days and 17 days after local administration in Case One and Two, respectively. In Case Two, serum concentration of amphotericin B was <0.01 mg/L 3 days after local administration of 450 mg liposomal amphotericin B. No local or systemic adverse reaction was observed. Fungal PJI was successfully eradicated in both cases with a follow-up of 12 months in Case One and 20 months in Case Two. Application of amphotericin B-loaded CaSO 4 was associated with joint fluid concentrations higher than minimal inhibitory concentrations for Candida spp. for approximately 3 weeks, with the advantage that the carrier material dissolves spontaneously and does not require secondary removal. Relapse of fungal infections did not occur in these two patients., (© 2022 The Authors. APMIS published by John Wiley & Sons Ltd on behalf of Scandinavian Societies for Pathology, Medical Microbiology and Immunology.)

Human-robot interaction is a rapidly developing field and robots have been taking more active roles in our daily lives. Patient care is one of the fields in which robots are becoming more present, especially for people with disabilities. People with neurodegenerative disorders might not consciously or voluntarily produce movements other than those involving the eyes or eyelids. In this context, Brain-Computer Interface (BCI) systems present an alternative way to communicate or interact with the external world. In order to improve the lives of people with disabilities, this paper presents a novel BCI to control an assistive robot with user's eye artifacts. In this study, eye artifacts that contaminate the electroencephalogram (EEG) signals are considered a valuable source of information thanks to their high signal-to-noise ratio and intentional generation. The proposed methodology detects eye artifacts from EEG signals through characteristic shapes that occur during the events. The lateral movements are distinguished by their ordered peak and valley formation and the opposite phase of the signals measured at F7 and F8 channels. This work, as far as the authors' knowledge, is the first method that used this behavior to detect lateral eye movements. For the blinks detection, a double-thresholding method is proposed by the authors to catch both weak blinks as well as regular ones, differentiating itself from the other algorithms in the literature that normally use only one threshold. Real-time detected events with their virtual time stamps are fed into a second algorithm, to further distinguish between double and quadruple blinks from single blinks occurrence frequency. After testing the algorithm offline and in realtime, the algorithm is implemented on the device. The created BCI was used to control an assistive robot through a graphical user interface. The validation experiments including 5 participants prove that the developed BCI is able to control the robot., (© 2023. Springer Nature Limited.)

Objectives: Differentiation between primary (PLS) and amyotrophic lateral sclerosis (ALS) entails relevant consequences for prognosis and management but is mostly unreliable at early stages. The objectives of the study are (1) to determine the features at onset that could help to differentiate between PLS and ALS, (2) to evaluate the diagnostic performance of an integrated serum biomarker panel, and (3) to identify the prognostic factors for patients presenting with upper motor neuron (UMN) syndrome., Methods: We selected and retrospectively analyzed the clinical data of patients presenting with UMN syndrome. At the first evaluation, when available, serum biomarkers were measured using ultrasensitive single molecule array., Results: The study population included 55 patients with PLS and 50 patients with ALS. Patients with PLS presented a longer time to first neurologic evaluation (PLS: 35.0 months, interquartile range [IQR] 17.0-38.0 months; ALS: 12.5 months, IQR 7.0-21.3 months; p < 0.01) and lower levels of neurofilament light chain (NfL) (PLS: 81.8 pg/mL, IQR 38.4-111.1 pg/mL; ALS: 155.9 pg/mL, IQR 85.1-366.4 pg/mL; p = 0.01). Two patients with PLS and 3 patients with ALS carried the C9orf72 expansion. NfL resulted an independent predictor of final diagnosis (odds ratio 1.01, 95% CI 1.00-1.02; p = 0.04) and an independent prognostic factor (hazard ratio 1.01, 95% CI 1.00-1.01; p < 0.01)., Discussion: NfL might help to differentiate patients with PLS from patients with ALS and to predict prognosis in patients with UMN syndrome., (© 2023 American Academy of Neurology.)

Background: Obesity is a chronic disease that impairs quality of life and leads to several comorbidities. When conservative therapies fail, bariatric surgical options such as Roux-en-Y gastric bypass (RYGB) and sleeve gastrectomy (SG) are the most effective therapies to induce persistent weight loss. Over the last two decades, bariatric endoscopy has become a valid alternative to surgery in specific settings. Primary bariatric endoscopic therapies: Restrictive gastric procedures, such as intragastric balloons (IGBs) and endoscopic gastroplasty, have been shown to be effective in inducing weight loss compared to diet modifications alone. Endoscopic gastroplasty is usually superior to IGBs in maintaining weight loss in the long-term period, whereas IGBs have an established role as a bridge-to-surgery approach in severely obese patients. IGBs in a minority of patients could be poorly tolerated and require early removal. More recently, novel endoscopic systems have been developed with the combined purpose of inducing weight loss and improving metabolic conditions. Duodenal mucosal resurfacing demonstrated efficacy in this field in its early trials: significant reduction from baseline of HbA1c values and a modest reduction of body weight were observed. Other endoscopic malabsorptive have been developed but need more evidence. For example, a pivotal trial on duodenojejunal bypasses was stopped due to the high rate of severe adverse events (hepatic abscesses). Optimization of these more recent malabsorptive endoscopic procedures could expand the plethora of bariatric patients that could be treated with the intention of improving their metabolic conditions. Revisional bariatric therapies: Weight regain may occur in up to one third of patients after bariatric surgery. Different endoscopic procedures are currently performed after both RYGB and SG in order to modulate post-surgical anatomy. The application of argon plasma coagulation associated with endoscopic full-thickness suturing systems (APC-TORe) and Re-EndoSleeve have shown to be the most effective endoscopic treatments after RYGB and SG, respectively. Both procedures are usually well tolerated and have a very low risk of stricture. However, APC-TORe may sometimes require more than one session to obtain adequate final results. The aim of this review is to explore all the currently available primary and revisional endoscopic bariatric therapies focusing on their efficacy and safety and their potential application in clinical practice.

Although inflammation appears to play a role in neurolymphomatosis (NL), the mechanisms leading to degeneration in the peripheral nervous system are poorly understood. The purpose of this exploratory study was to identify molecular pathways underlying NL pathogenesis, combining clinical and neuropathological investigation with gene expression (GE) studies. We characterized the clinical and pathological features of eight patients with NL. We further analysed GE changes in sural nerve biopsies obtained from a subgroup of NL patients (n=3) and thirteen patients with inflammatory neuropathies as neuropathic controls. Based on the neuropathic symptoms and signs, NL patients were classified into three forms of neuropathy: chronic symmetrical sensorimotor polyneuropathy (SMPN, n=3), multiple mononeuropathy (MN, n=4) and acute motor-sensory axonal neuropathy (AMSAN, n=1). Predominantly diffuse malignant cells infiltration of epineurium was present in chronic SMPN, whereas endoneurial perivascular cells invasion was observed in MN. In contrast, diffuse endoneurium malignant cells localization occurred in AMSAN. We identified alterations in the expression of 1266 genes, with 115 up-regulated and 1151 down-regulated genes, which were mainly associated with ribosomal proteins (RP) and olfactory receptors (OR) signaling pathways, respectively. Among the top up-regulated genes were actin alpha 1 skeletal muscle (ACTA1) and desmin (DES). Similarly, in NL nerves ACTA1, DES and several RPs were highly expressed, associated with endothelial cells and pericytes abnormalities. Peripheral nerve involvement may be due to conversion towards a more aggressive phenotype, potentially explaining the poor prognosis. The candidate genes reported in this study may be a source of clinical biomarkers for NL., Competing Interests: MF is Editor-in-Chief of the Journal of Neurology and Associate Editor of Neurological Sciences, received compensation for consulting services and/or speaking activities from Bayer, Biogen Idec, Merck-Serono, Novartis, Roche, Sanofi Genzyme, Takeda and Teva Pharmaceutical Industries, and receives research support from Biogen Idec, Merck-Serono, Novartis, Teva Pharmaceutical Industries, Roche, Italian Ministry of Health, Fondazione Italiana Sclerosi Multipla and ARiSLA (Fondazione Italiana di Ricerca per la SLA). The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Cerri, Gentile, Clarelli, Santoro, Falzone, Dina, Romano, Domi, Pozzi, Fazio, Podini, Sorosina, Carrera, Esposito, Riva, Briani, Cavallaro, Filippi and Quattrini.)

Objective: Mutations in the TARDBP gene are a rare cause of genetic motor neuron disease (MND). Morphologic MRI characteristics of MND patients carrying this mutation have been poorly described. Our objective was to investigate distinctive clinical and MRI features of a relatively large sample of MND patients carrying TARDBP mutations., Methods: Eleven MND patients carrying a TARDBP mutation were enrolled. Eleven patients with sporadic MND (sMND) and no genetic mutations were also selected and individually matched by age, sex, clinical presentation and disease severity, along with 22 healthy controls. Patients underwent clinical and cognitive evaluations, as well as 3D T1-weighted and diffusion tensor (DT) MRI on a 3 Tesla scanner. Gray matter (GM) atrophy was first investigated at a whole-brain level using voxel-based morphometry (VBM). GM volumes and DT MRI metrics of the main white matter (WM) tracts were also obtained. Clinical, cognitive and MRI features were compared between groups., Results: MND with TARDBP mutations was associated with all possible clinical phenotypes, including isolated upper/lower motor neuron involvement, with no predilection for bulbar or limb involvement at presentation. Greater impairment at naming tasks was found in TARDBP mutation carriers compared with sMND. VBM analysis showed significant atrophy of the right lateral parietal cortex in TARDBP patients, compared with controls. A distinctive reduction of GM volumes was found in the left precuneus and right angular gyrus of TARDBP patients compared to controls. WM microstructural damage of the corticospinal tract (CST) and inferior longitudinal fasciculi (ILF) was found in both sMND and TARDBP patients, compared with controls, although decreased fractional anisotropy of the right CST and increased axial diffusivity of the left ILF ( p = 0.017) was detected only in TARDBP mutation carriers., Conclusions: TARDBP patients showed a distinctive parietal pattern of cortical atrophy and greater damage of motor and extra-motor WM tracts compared with controls, which sMND patients matched for disease severity and clinical presentation were lacking. Our findings suggest that TDP-43 pathology due to TARDBP mutations may cause deeper morphologic alterations in both GM and WM., (Copyright © 2022 Spinelli, Ghirelli, Riva, Canu, Castelnovo, Domi, Pozzi, Carrera, Silani, Chiò, Filippi and Agosta.)

In the last decades, the continuous increase in the number of the vast cohort of chronic patients that constantly need medical assistance and supervision, and the widespread lack of therapist has brought to an increased interest in the role of medical technologies in rehabilitative programs and assistive scenarios. Current clinical evidence in rehabilitation demonstrates that there is an important and increasing demand for innovative therapeutic solutions to recover the hand functions to prevent patients to need assistance in performing daily life activities. This works describes the pathway from patent to TRL5 of a device to support hand grip actions and interaction with daily life objects. E-KIRO is based on the use of electromagnets, which are able to attach/detach interactive objects equipped with a ferromagnetic plate. Five end-users used the device and scored it with excellent usability based on the System Usability Scale.

Background and Purpose: This study was undertaken to determine the diagnostic and prognostic value of a panel of serum biomarkers and to correlate their concentrations with several clinical parameters in a large cohort of patients with amyotrophic lateral sclerosis (ALS)., Methods: One hundred forty-three consecutive patients with ALS and a control cohort consisting of 70 patients with other neurodegenerative disorders (DEG), 70 patients with ALS mimic disorders (ALSmd), and 45 healthy controls (HC) were included. Serum neurofilament light chain (NfL), ubiquitin carboxyl-terminal hydrolase isozyme L1 (UCHL1), glial fibrillary acidic protein (GFAP), and total tau protein levels were measured using ultrasensitive single molecule array., Results: NfL correlated with disease progression rate (p < 0.001) and with the measures of upper motor neuron burden (p < 0.001). NfL was higher in the ALS patients with classic and pyramidal phenotype. GFAP was raised in ALS with cognitive-behavioral impairment compared with ALS with normal cognition. NfL displayed the best diagnostic performance in discriminating ALS from HC (area under the curve [AUC] = 0.990), DEG (AUC = 0.946), and ALSmd (AUC = 0.850). UCHL1 performed well in distinguishing ALS from HC (AUC = 0.761), whereas it was not helpful in differentiating ALS from DEG and ALSmd. In multivariate analysis, NfL (p < 0.001) and UCHL1 (p = 0.038) were independent prognostic factors. Survival analysis combining NfL and UCHL1 effectively stratified patients with lower NfL levels (p < 0.001)., Conclusions: NfL is a useful biomarker for the diagnosis of ALS and the strongest predictor of survival. UCHL1 is an independent prognostic factor helpful in stratifying survival in patients with low NfL levels, likely to have slowly progressive disease. GFAP reflects extramotor involvement, namely cognitive impairment or frontotemporal dementia., (© 2022 The Authors. European Journal of Neurology published by John Wiley & Sons Ltd on behalf of European Academy of Neurology.)

In recent years, multiple technological and methodological advances have increased our ability to estimate phylogenies, leading to more accurate dating of the primate tree of life. Here we provide an overview of the limitations and potentials of some of these advancements and discuss how dated phylogenies provide the crucial temporal scale required to understand primate evolution. First, we review new methods, such as the total-evidence dating approach, that promise a better integration between the fossil record and molecular data. We then explore how the ever-increasing availability of genomic-level data for more primate species can impact our ability to accurately estimate timetrees. Finally, we discuss more recent applications of mutation rates to date divergence times. We highlight example studies that have applied these approaches to estimate divergence dates within primates. Our goal is to provide a critical overview of these new developments and explore the promises and challenges of their application in evolutionary anthropology., (© 2022 Wiley Periodicals LLC.)

Introduction: In the last few years, different studies highlighted a significant enrichment of NEK1 loss of function (LoF) variants in amyotrophic lateral sclerosis (ALS), and an additional role for the p.Arg261His missense variant in the disease susceptibility. Several other missense variants have been described so far, whose pathogenic relevance remains however unclear since many of them have been reported in both patients and controls. This study aimed to investigate the presence of NEK1 variants and their correlation with phenotype in a cohort of Italian patients with ALS., Methods: We sequenced a cohort of 350 unrelated Italian patients with ALS by next-generation sequencing (NGS) and then we analyzed the clinical features of NEK1 carriers., Results: We detected 20 different NEK1 rare variants (four LoF and 16 missense) in 33 unrelated patients with sporadic ALS (sALS). The four LoF variants (two frameshift and two splice-site variants) were all novel. The p.Arg261His missense variant was enriched in the patients' cohort ( p < 0.001). Excluding this variant from counting, the difference in the frequency of NEK1 rare missense variants between patients and controls was not statistically significant. NEK1 carriers had a higher frequency of flail arm (FA) phenotype compared with the other patients of the cohort (29.2% vs. 6.4%). Nine NEK1 carriers (37.5%) also harbored variants in other ALS-related genes., Conclusion: This study confirms that NEK1 LoF and p.Arg261. His missense variants are associated with ALS in an Italian ALS cohort and suggests a correlation between the presence of NEK1 variants and FA phenotype., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Riva, Pozzi, Russo, Pipitone, Schito, Domi, Agosta, Quattrini, Carrera and Filippi.)

Service robotics is a fast-developing sector, requiring embedded intelligence into robotic platforms to interact with the humans and the surrounding environment. One of the main challenges in the field is robust and versatile manipulation in everyday life activities. An appealing opportunity is to exploit compliant end-effectors to address the manipulation of deformable objects. However, the intrinsic compliance of such grippers results in increased difficulties in grasping control. Within the described context, this work addresses the problem of optimizing the grasping of deformable objects making use of a compliant, under-actuated, sensorless robotic hand. The main aim of the paper is, therefore, finding the best position and joint configuration for the mentioned robotic hand to grasp an unforeseen deformable object based on collected RGB image and partial point cloud. Due to the complex grasping dynamics, learning-from-simulations approaches (e.g., Reinforcement Learning) are not effective in the faced context. Thus, trial-and-error-based methodologies have to be exploited. In order to save resources, a samples-efficient approach has to be employed. Indeed, a Bayesian approach to address the optimization of the grasping strategy is proposed, enhancing it with transfer learning capabilities to exploit the acquired knowledge to grasp (partially) new objects. A PAL Robotics TIAGo (a mobile manipulator with a 7-degrees-of-freedom arm and an anthropomorphic underactuated compliant hand) has been used as a test platform, executing a pouring task while manipulating plastic (i.e., deformable) bottles. The sampling efficiency of the data-driven learning is shown, compared to an evenly spaced grid sampling of the input space. In addition, the generalization capability of the optimized model is tested (exploiting transfer learning) on a set of plastic bottles and other liquid containers, achieving a success rate of the 88%., (© 2022. The Author(s).)

Motor neuron disease includes a heterogeneous group of relentless progressive neurological disorders defined and characterized by the degeneration of motor neurons. Amyotrophic lateral sclerosis is the most common and aggressive form of motor neuron disease with no effective treatment so far. Unfortunately, diagnostic and prognostic biomarkers are lacking in clinical practice. Neurofilaments are fundamental structural components of the axons and neurofilament light chain and phosphorylated neurofilament heavy chain can be measured in both cerebrospinal fluid and serum. Neurofilament light chain and phosphorylated neurofilament heavy chain levels are elevated in amyotrophic lateral sclerosis, reflecting the extensive damage of motor neurons and axons. Hence, neurofilaments are now increasingly recognized as the most promising candidate biomarker in amyotrophic lateral sclerosis. The potential usefulness of neurofilaments regards various aspects, including diagnosis, prognosis, patient stratification in clinical trials and evaluation of treatment response. In this review paper, we review the body of literature about neurofilaments measurement in amyotrophic lateral sclerosis. We also discuss the open issues concerning the use of neurofilaments clinical practice, as no overall guideline exists to date; finally, we address the most recent evidence and future perspectives., Competing Interests: None

Human Cytomegalovirus (HCMV) and Epstein-Barr virus (EBV) are endowed with the ability of establishing lifelong latency in human hosts and reactivating in immunocompromised subjects, including patients suffering from ulcerative colitis (UC). We, therefore, aimed to investigate virus-specific immunity in UC patients. A cohort of 24 UC patients (14 responders and 10 refractory to therapy) and 26 control subjects was prospectively enrolled to undergo virus-specific serology (by ELISA assay) and assessment of both CD4 + and CD8 + virus-specific T-cell response (by interferon-γ enzyme-linked immunospotanalysis). In parallel, mucosal viral load was determined by quantitative real-time PCR and the values were correlated with both clinical and endoscopic indexes of activity. For statistics, the t-test, Mann-Withney test, Fisher's exact test and Spearman rank correlation test were applied; p < 0.05 was considered significant. EBV-specific CD4 + and CD8 + T-cell responses were significantly lower in UC patients compared to controls (p < 0.0001 and p = 0.0006, respectively), whereas no difference was found for HCMV-specific T-cell response. When dividing the UC group according to response to therapy, both responders and refractory UC patients showed a deficient EBV-specific CD4 + T-cell response with respect to controls (p < 0.04 and p = 0.0003, respectively). Moreover, both EBV and HCMV mucosal loads were significantly higher in refractory UC than in responders and controls (p = 0.007 and 0.003; and p = 0.02 and 0.001, respectively), and correlated with activity indexes. Steroid therapy seemed the main risk factor for triggering EBV colitis. Finally, no cases of IgM positivity were found in the study population. An impaired EBV-specific immunity was clearly evident in UC patients, mostly in those refractory to therapy. The ELISPOT assay may serve as new tool for quantifying and monitoring virus-specific T-cell immunity in UC.

Background: COVID-19 patients have an increased susceptibility to develop thrombotic complications, thus thromboprophylaxis is warranted which may increase risk of upper gastrointestinal bleeding (UGIB). Our aim was to evaluate incidence of UGIB and use of upper GI endoscopy in COVID-19 inpatients., Methods: The medical and endoscopic management of UGIB in non-ICU COVID-19 patients has been retrospectively evaluated. Glasgow Blatchford score was calculated at onset of signs of GI bleeding. Timing between onset of signs of GI bleeding and execution, if performed, of upper GI endoscopy was evaluated. Endoscopic characteristics and outcome of patients were evaluated overall or according to the execution or not of an upper GI endoscopy before and after 24h., Results: Out of 4871 COVID-19 positive patients, 23 presented signs of UGIB and were included in the study (incidence 0.47%). The majority (78%) were on anticoagulant therapy or thromboprophylaxis. In 11 patients (48%) upper GI endoscopy was performed within 24h, whereas it was not performed in 5. Peptic ulcer was the most common finding (8/18). Mortality rate was 21.7% for worsening of COVID-19 infection. Mortality and rebleeding were not different between patients having upper GI endoscopy before or after 24h/not performed. Glasgow Blatchford score was similar between the two groups (13;12-16 vs 12;9-15)., Conclusion: Upper GI bleeding complicated hospital stay in almost 0.5% of COVID-19 patients and peptic ulcer disease is the most common finding. Conservative management could be an option in patients that are at high risk of respiratory complications., (Copyright © 2020 Elsevier Masson SAS. All rights reserved.)

Background: Colorectal cancer (CRC) diagnosed before the age of 50, known as early-onset CRC (eoCRC), is considered uncommon. We aimed at analysing the incidence of preneoplastic and neoplastic lesions of the colon and rectum in patients under 50 years old and to identify possible predictors Methods: We retrospectively collected data from 1778 patients under 50 years old (mean age 39.9±7.8) referred for colonoscopy between 2015-2018. Cumulative incidence of adenomas and eoCRC was assessed. Multivariable regression models were fitted Results: The cumulative incidence for adenomas was 11.0% (95% CI 9-12), while it was 1.5% (95% CI 1-2) for eoCRC (metastatic disease in 13/27 patients). Age as a continuous variable was associated with the presence of adenomas (incidence rate ratio 1.06; 95% CI 1.03-1.09; p<0.001). EoCRC arose in most cases in the rectum (13/27, 48.1%). Age ≥40 was the main risk factor (OR 2.25; 95% CI 1.35-3.73; p=0.002) for both adenomas (160/196 patients, 81.6%) and eoCRC (20/27 patients, 74.1%), while smoking seemed to have no role (p=0.772). The presence of alarm symptoms was statistically significant at bivariable analysis for eoCRC only (OR 3.70; 95% CI 1.49-9.22; p=0.005), as well as having multiple gastrointestinal symptoms (OR 19.85; 95% CI 2.64-149.42; p=0.004). Only 3/27 (11.1%) patients with eoCRC had a family history for CRC Conclusions: A high cumulative incidence rate of both adenomas and eoCRC was found, this latter occurring more common in patients aged 40-49, without apparent risk factors. The presence of alarm symptoms or multiple gastrointestinal symptoms led to a late diagnosis., (Copyright © 2021. Published by Elsevier B.V.)

Iliopsoas impingement (IPI) causes persistent groin pain and functional impairment after total hip arthroplasty (THA). It is caused most often by an overhang of the cup. Psoas tenotomy may successfully treat IPI in overhangs <8 mm. Cup revision usually is recommended for larger overhangs. Muscle sparing reconstruction of the anterior acetabular wall may be an alternative when malposition of the cup at THA caused a bony defect that would persist after simple cup revision. The surgical technique and results from one patient are presented. The patient rapidly became asymptomatic and remained pain free at 2-year follow-up. Any bone substance defect of the acetabulum should be considered when evaluating treatment options for IPI after THA., (© 2020 The Authors.)

Introduction: Although percutaneous endoscopic gastrostomy with jejunal extension (PEG-J) is currently indicated in a variety of conditions, limited data are available regarding its safety and the best timing for its replacement. We herein describe a single-centre cohort of patients who underwent PEG-J placement or replacement to assess the short- and long-term safety of the procedure., Methods: Demographic and procedure-related data regarding all patients undergoing a PEG-J procedure between March 2010 and 2020, either first placement or any replacement, at the Endoscopy Unit of a University Hospital in Northern Italy (IRCCS Policlinico San Matteo, Pavia, Italy), were retrospectively collected. Data were collected until last available follow-up., Results: We included 73 patients (mean age 70 ± 9.7, 60.3% female) who underwent a PEG-J procedure. Data on a total of 215 procedures were gathered with a median follow up time of 21 months (IQR 9.3-39.5). No immediate adverse events (AEs) were reported. Short-term (within 30 days) AEs, including jejunal extension dislocations, accidental removal, obstruction and kinking occurred in 12 patients (5.6% of the total procedures), whilst long-term AEs (obstruction, tube malfunctions, inner tube dislocation, pyloric ulcer, hypergranulation tissue, wear, buried bumper syndrome and accidental removal) were reported in 40 patients. The risk of developing an AE was not reduced if tube replacement was performed electively. The median duration of the PEG-J before replacement was 12 months (IQR 6-16 months)., Conclusion: PEG-J placement and replacement are safe procedures. Although PEG-J durability is variable an elective procedure might be indicated to reduce urgent replacements.

The recently described genus Paragalago is a complex of several nocturnal and morphologically cryptic species distributed in the forests of eastern Africa. Species diversity within this genus has been mainly described using species-specific differences in their loud calls. However, molecular data are still lacking for this group and species boundaries remain unclear. In this study, we explore species diversity within the zanzibaricus-complex using a combination of mitochondrial and nuclear data and comparing multiple species delimitation methods. Our results consistently support the existence of three independent lineages, P. cocos, P. zanzibaricus, and P. granti, confirming previous hypotheses based on vocal data. We conclude that these three lineages represent valid cryptic species and we hypothesize that speciation within this complex was characterized by cycles of forest expansion and contraction in the Plio-Pleistocene., (Copyright © 2020 Elsevier Inc. All rights reserved.)

To investigate the prognostic role and the major determinants of serum phosphorylated neurofilament heavy -chain (pNfH) concentration across a large cohort of motor neuron disease (MND) phenotypes. Enzyme-linked immunosorbent assay (ELISA) was used to measure serum pNfH concentration in 219 MND patients consecutively enrolled in our tertiary MND clinic. A multifactorial analysis was carried out to investigate the major clinical determinants of serum pNfH. Kaplan-Meier survival curves and Cox regression analysis were performed to explore the prognostic value of serum pNfH. Serum pNfH levels were not homogenous among MND phenotypes; higher concentrations in pyramidal, bulbar, and classic phenotypes were observed. C9orf72-MND exhibited higher pNfH concentrations compared to non-C9orf72 MND. Multiple linear regression analysis revealed mean MEP/cMAP and disease progression rate as the two major predictors of serum pNfH levels (R 2  = 0.188; p ≤ 0.001). Kaplan-Meier curves showed a significant difference of survival among MND subgroups when divided into quartiles based on pNfH concentrations, log-rank X 2  = 53.0, p ≤ 0.0001. Our study evidenced that higher serum pNfH concentration is a negative independent prognostic factor for survival. In Cox multivariate model, pNfH concentration showed the highest hazard ratio compared to the other factors influencing survival included in the analysis. pNfH differs among the MND phenotypes and is an independent prognostic factor for survival. This study provides supporting evidence of the role of pNfH as useful prognostic biomarker for MND patients. Neurofilament measurements should be considered in the future prognostic models and in clinical trials for biomarker-based stratification, and to evaluate treatment response.

The province of Cadiz, Spain, is a highly industrialized area with numerous registered industrial plants, which has led to major concern regarding the possible influence of these facilities on the high rate of cancer-related mortality observed. Our objective was to evaluate the association between digestive cancer mortality and proximity to industrial installations in the province of Cadiz over the period 1992-2014 and to analyse this risk according to different categories of carcinogenic substances. An ecological study at the census tract level was carried out. Mortality due to digestive cancer (involving the oral cavity, pharynx, oesophagus, stomach, liver, pancreas, gallbladder, colon and rectum) was analysed. Using the spatial Besag, York and Mollié (BYM) approach, we assessed the relative risk of dying from these cancers for people living between 500 m and 5 km from industrial installations. The models were adjusted to account for socioeconomic deprivation. We detected a significant, excess risk of dying due to cancer in the following organs (expressed as relative risk with 95% confidence intervals): colon/rectum (1.13; 1.04-1.22 at 4 km), stomach (1.13; 1.00-1.29 at 2 km), liver (1.28; 1.02-1.61 at 1 km), pancreas (1.19; 1.03-1.39 at 2 km), oral and pharyngeal (1.40; 1.08-1.82 at 1 km), oesophagus (2.05; 1.18-3.56 at 500 m) and gallbladder (2.80; 1.14-6.89 at 500 m) for men; and from colorectal (1.21; 1.00-1.46 at 1 km), stomach (1.15; 1.01-1.31 at 4 km) and liver (1.58; 1.20- 2.07 at 1 km) cancers for women. The results support the hypothesis of an association between several digestive cancers and proximity to polluting industrial plants.

Introduction: Geographical variations in cancer mortality can be explained, in part, by their association with social inequalities. The objective of our study was to analyse the spatial pattern of mortality in relation to the most common causes of cancer in the Spanish autonomous community of Andalusia and its possible association with social inequalities., Materials and Methods: A small area cross-sectional study in Andalusia, with census tracts as units of spatial analysis, for the period 2002-2013. Cases and person-years, sex and age group came from the Longitudinal Population Database of Andalusia. Standardized mortality rates and smoothed risk ratios were calculated using the Besag, York and Mollié model for lung, colorectal, breast, prostate, bladder and stomach cancer. In order to evaluate the association with social inequalities we included the deprivation index of the census tract as a covariate., Results: The results show an East-West mortality pattern with higher risk in the west for lung and bladder cancer among men, and breast cancer among women. For all of Andalusia, the association between deprivation index of the census tract and mortality relative risks is positive and significant for lung, stomach and bladder cancers in men, while in women we observed a negative association for lung cancer and a positive for stomach cancer., Conclusions: Knowledge regarding the spatial distribution of cancer mortality and the socioeconomic inequalities related should contribute to the design of specific health and social policies-aimed at tackling cancer mortality and social inequalities in areas of high mortality and/or levels of deprivation., Competing Interests: The authors have declared that no competing interests exist.

Although the genetic architecture of amyotrophic lateral sclerosis (ALS) is incompletely understood, recent findings suggest a complex model of inheritance in ALS, which is consistent with a multistep pathogenetic process. Therefore, the aim of our work is to further explore the architecture of ALS using targeted next generation sequencing (NGS) analysis, enriched in motor neuron diseases (MND)-associated genes which are also implicated in axonal hereditary motor neuropathy (HMN), in order to investigate if disease expression, including the progression rate, could be influenced by the combination of multiple rare gene variants. We analyzed 29 genes in an Italian cohort of 83 patients with both familial and sporadic ALS. Overall, we detected 43 rare variants in 17 different genes and found that 43.4% of the ALS patients harbored a variant in at least one of the investigated genes. Of note, 27.9% of the variants were identified in other MND- and HMN-associated genes. Moreover, multiple gene variants were identified in 17% of the patients. The burden of rare variants is associated with reduced survival and with the time to reach King stage 4, i.e., the time to reach the need for percutaneous endoscopic gastrostomy (PEG) positioning or non-invasive mechanical ventilation (NIMV) initiation, independently of known negative prognostic factors. Our data contribute to a better understanding of the molecular basis of ALS supporting the hypothesis that rare variant burden could play a role in the multistep model of disease and could exert a negative prognostic effect. Moreover, we further extend the genetic landscape of ALS to other MND-associated genes traditionally implicated in degenerative diseases of peripheral axons, such as HMN and CMT2., Competing Interests: The authors declare no conflict of interest. The funders had no role in the design of the study; in the collection, analyses, or interpretation of data; in the writing of the manuscript, or in the decision to publish the results.

We characterized the biologic background of prothrombotic platelet function in the setting of durable left ventricular assist devices (LVADs) evaluating the role of different antithrombotic regimens. Platelet-mediated thrombin generation was quantified using the Platelet Activity State (PAS) Assay and the Thrombin Generation Test (TGT) in 78 patients implanted with the HeartMate II (n = 10, 13%), the HeartMate 3 (HM3) (n = 30, 38%), or the HVAD (n = 38, 49%) and managed with oral anticoagulation plus aspirin (n = 46, 59%) or anticoagulation alone (n = 32, 41%). Coagulation parameters (platelet count, International Normalized Ratio (INR), activated Partial Thromboplastin Time, Fibrinogen and D-Dimer levels) and hemolysis (lactate dehydrogenase levels [LDH]) were also recorded to comprehensively characterize the hemostatic profile in the two groups. In patients without aspirin, the PAS assay revealed low-intensity increase in platelet prothrombinase activity (1.11-fold, p = 0.03). Similarly the TGT revealed moderate higher platelet reactivity when compared with patients receiving aspirin, consistent with reduction in lag time (0.87-fold, p < 0.001), increase in peak of thrombin generation (1.5-fold, p = 0.002) and thrombin generation rate (2-fold, p = 0.02), but comparable endogenous thrombin potential (p = 0.50). Coagulation parameters and LDH were comparable in the two groups (p > 0.05). Moreover, no differences were noted in platelet prothrombinase activity of patients implanted with the HM3 or HVAD. Our results suggest that, in the setting of durable LVADs, aspirin minimally modulates the biochemical pathway of platelet-mediated thrombin generation. Accordingly, re-evaluation of current antithrombotic management criteria in patients stratified according to bleeding/thromboembolic risk might be safe and beneficial to prevent adverse events.

Residential proximity to industrial facilities that release pollutants is a source of exposure to a high number of toxics, many of them known or suspected carcinogens. The objective of the study was to analyze the association between lung, larynx, bladder, and kidney cancer mortality and deprivation in areas proximate to polluting industrial facilities in Cadiz, a highly industrialized province in Spain. An ecological study at census tract level was carried out to estimate the mortality rates associated with deprivation and proximity to polluting industrial facilities (1-5 km) using the Besag-York-Mollié model. The results show a negative social gradient for lung and larynx cancers in males and greater risk of lung cancer was observed in the least deprived areas in females. These associations were found regardless the distance to industrial facilities. Increasing excess risk (relative risk; 95% credibility interval) of lung cancer for males (1.09; 1.02-1.16 at 5 km vs 1.24; 1.08-1.41 at 1 km) and bladder cancer for males (1.11; 1.01-1.22 at 5 km vs 1.32; 1.08-1.60 at 1 km) and females (1.32; 1.04-1.69 at 4 km vs 1.91; 1.28-2.86 at 1 km) was found as proximity to polluting industrial facilities increased. For kidney cancer, high risks were observed near such facilities for both sexes. Knowing the possible influence of industrial pollution and social inequalities over cancer risk allows the definition of policies aimed at reducing the risk.

Nonhuman primate societies vary tremendously in size and composition, but how and why evolutionary transitions among different states occurred remains highly controversial. In particular, how many times pair living evolved and the social states of the ancestors of pair- and group-living species remains contentious. We examined evolutionary transitions in primate social evolution by using new, independent categorizations of sociality and different phylogenetic hypotheses with a vastly expanded dataset. Using Bayesian phylogenetic comparative methods, we consistently found the strongest support for a model that invokes frequent transitions between solitary ancestors and pair-living descendants, with the latter giving rise to group-living species. This result was robust to systematic variation in social classification, sample size, and phylogeny. Our analyses therefore indicate that pair living was a stepping stone in the evolution of structurally more complex primate societies, a result that bolsters the role of kin selection in social evolution., (Copyright © 2019 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works. Distributed under a Creative Commons Attribution License 4.0 (CC BY).)

Variants in tank-binding kinase 1 (TBK1) are responsible for a significant proportion of amyotrophic lateral sclerosis (ALS) cases. In the present study, we analyzed variants in TBK1 extracted by targeted sequencing of 32 genes in a group of 406 Italian patients with ALS. We identified 7 different TBK1 variants in 7 sporadic cases, resulting in a frequency of 1.7%. Three patients had missense variants (p.R357Q, p.R358H, and p.R724C), one patient had a small deletion (p.E618del), and 3 had truncating variants (p.Y482*, p.R229*, and p.N681*). Notably, we found that 4 patients had an additional variant in ALS-related genes: 2 in OPTN and 2 in the 3'UTR region of FUS. By studying an independent group of 7 TBK1-mutated patients previously reported, we found another variant in the 3'UTR region of FUS in one patient. The presence of a second variant in TBK1 variant carriers is an interesting finding that needs to be investigated in larger cohorts of patients. These findings suggest that TBK1 belongs to the category of genes conferring a significantly increased risk but not sufficient to cause disease., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Background: Thrombocytopenia is a serious issue for all patients with classical Wiskott-Aldrich syndrome (WAS) and X-linked thrombocytopenia (XLT) because it causes severe and life-threatening bleeding. Lentiviral gene therapy (GT) for WAS has shown promising results in terms of immune reconstitution. However, despite the reduced severity and frequency of bleeding events, platelet counts remain low in GT-treated patients., Objective: We carefully investigated platelet defects in terms of phenotype and function in untreated patients with WAS and assessed the effect of GT treatment on platelet dysfunction., Methods: We analyzed a cohort of 20 patients with WAS/XLT, 15 of them receiving GT. Platelet phenotype and function were analyzed by using electron microscopy, flow cytometry, and an aggregation assay. Platelet protein composition was assessed before and after GT by means of proteomic profile analysis., Results: We show that platelets from untreated patients with WAS have reduced size, abnormal ultrastructure, and a hyperactivated phenotype at steady state, whereas activation and aggregation responses to agonists are decreased. GT restores platelet size and function early after treatment and reduces the hyperactivated phenotype proportionally to WAS protein expression and length of follow-up., Conclusions: Our study highlights the coexistence of morphologic and multiple functional defects in platelets lacking WAS protein and demonstrates that GT normalizes the platelet proteomic profile with consequent restoration of platelet ultrastructure and phenotype, which might explain the observed reduction of bleeding episodes after GT. These results are instrumental also from the perspective of a future clinical trial in patients with XLT only presenting with microthrombocytopenia., (Copyright © 2019 The Authors. Published by Elsevier Inc. All rights reserved.)

We describe a patient, previously known for NMOSD, who presented a rapidly progressive worsening of muscle strength, respiratory, and bulbar functions. ALS associated with cognitive impairment was diagnosed, while genetic analysis revealed a hexanucleotide repeat expansion in the C9orf72 gene. To the best of our knowledge, this is the first reported C9orf72-ALS patient with concurrent NMOSD. In consideration of the low prevalence of these two diseases, a by-chance co-occurrence is unlikely. Although the discovery of a disease-specific serum AQP4-IgG antibody has led to a broadening of the NMOSD, a progressive neurological deterioration, as shown by our patient, should be considered as a "red flag", leading to alternative diagnostic hypotheses. Our report supports the hypothesis that in C9orf72-ALS neuroinflammation may contribute to disease penetrance or to determine an aggressive clinical phenotype. Further investigations are needed in order to establish possible shared neuroinflammatory patterns between ALS, NMOSD, and other neuroinflammatory disorders.

Monogamy is a rare strategy among mammals but relatively common among primates. The study of the evolution of monogamy in mammals and primates is lacking empirical studies that assess the relationship between a pair-living social organization and genetic monogamy. Sexual or genetic monogamy can only be assessed by performing molecular analyses and investigating rates of extra-pair paternity (EPP). Studying the occurrence of EPP can provide valuable insights into reproductive strategies and their adaptive value. The indri is a pair-living primate that lives in stable groups. Their social units are composed of the reproductive pair and up to four more individuals, but extra-pair copulation (EPC) can occur. This raises the question of whether this event may or may not lead to EPP. Here, we investigated whether a pair-living social organization corresponds to genetic monogamy in indris (Indri indri). We analyzed the paternity of 12 offspring from seven pairs using a set of six microsatellite loci on fecal samples (mean number of alleles 11.7 ± 1.8 (mean ± standard deviation). We found that in 92% of cases the genetic profile of the offspring matched the paired male of the group for all the loci considered. In the only case of paternity mismatch, the paternity assignment remained inconclusive. Our results show that I. indri genetic monogamy is the norm and supports the hypothesis that pair-living social organization is associated with low EPP rate. Also, our results are in contrast with the hypothesis of infertility as a reason to engage in EPC for this species., (© 2019 Wiley Periodicals, Inc.)

Describing primate biodiversity is one of the main goals in primatology. Species are the fundamental unit of study in phylogeny, behaviour, ecology and conservation. Identifying species boundaries is particularly challenging for nocturnal taxa where only subtle morphological variation is present. Traditionally, vocal signals have been used to identify species within nocturnal primates: species-specific signals often play a critical role in mate recognition, and they can restrict gene flow with other species. However, little research has been conducted to test whether different "acoustic forms" also represent genetically distinct species. Here, we investigate species boundaries between two putative highly cryptic species of Eastern dwarf galagos (Paragalago cocosand P. zanzibaricus). We combined vocal and genetic data: molecular data included the complete mitochondrial cytochrome b gene (1,140 bp) for 50 samples across 11 localities in Kenya and Tanzania, while vocal data comprised 221 vocalisations recorded across 8 localities. Acoustic analyses showed a high level of correct assignation to the putative species (approx. 90%), while genetic analyses identified two separate clades at the mitochondrial level. We conclude that P. cocos and P. zanzibaricus represent two valid cryptic species that probably underwent speciation in the Late Pliocene while fragmented in isolated populations in the eastern forests., (© 2019 S. Karger AG, Basel.)

Aims: To correlate the dynamics of platelet activation with the development of thromboembolic events in patients with continuous-flow left ventricular assist device (cf-LVAD)., Methods and Results: The platelet activity state (PAS) assay was utilized to evaluate platelet activation in 68 cf-LVAD patients implanted with the HeartMate II (n = 15, 22%), HeartMate 3 (n = 15, 22%), or HeartWare HVAD (n = 38, 56%). PAS was measured preoperatively, early post-implant, and at long-term follow-up (1, 3, 6, 12, 18, and 24 months post-implant). PAS was also measured at the occurrence of adverse events in patients who developed thrombotic complications. Data on patient demographics, medical history, antithrombotic therapy, and coagulation parameters were also analysed. Over a median follow-up of 602 (234-942) days, PAS values did not increase over time in the overall population (P = 0.15). However, PAS measured at event was 15-fold higher in the six patients (9%) who suffered pump thrombosis (n = 2) or ischaemic stroke (n = 4) vs. the rest of the population [6.67% (5.59%-11.98%) vs. 0.45% (0.33%-0.75%); P = 0.012], despite comparable coagulation profile. Pre-implant PAS values were 4.5-fold higher in these patients [1.90% (1.24%-3.17%) vs. 0.42% (0.32%-0.72%); P = 0.006]. Neither preoperative variables nor the type of the pump or the antiplatelet strategy were associated with a higher risk of complications., Conclusions: Thrombotic events are associated with altered PAS values. Moreover, baseline elevated PAS values in patients who developed thrombotic events suggest patient-specific tendency to post-implant thromboembolic complications. Prospectively, systematic monitoring of PAS might guide the development of refined patient-tailored antithrombotic strategies and the technological improvement of LVAD design., (© 2017 The Authors. European Journal of Heart Failure © 2017 European Society of Cardiology.)

In patients with left ventricular assist device support and aspirin allergy, the choice of effective antiplatelet strategy remains a challenge. We compared the antithrombotic effect of clopidogrel vs ticagrelor in an LVAD patient with aspirin allergy by using a modified protocol of the thrombin generation test, accounting selectively for the platelet contribution on thrombin generation. Our results demonstrate enhanced antithrombotic efficacy offered by ticagrelor. Consistent with experimental results, the patient has passed more than 300 days without thromboembolic complications. This study provides additional mechanistic rationale supporting clinical evidence and opens the perspective to identify individual poor responsiveness to drugs by specifically evaluating drug-mediated platelet function., (Copyright © 2018 The Society of Thoracic Surgeons. Published by Elsevier Inc. All rights reserved.)

Background: TANK-binding kinase 1 ( TBK1 ) gene has been recently identified as a causative gene of amyotrophic lateral sclerosis (ALS)., Methods: We sequenced the TBK1 gene in a cohort of 154 Italian patients with ALS with unclear genetic aetiology. We subsequently assessed the pathogenic potential of novel identified TBK1 variants using functional in vitro studies: expression, targeting and activity were evaluated in patient-derived fibroblasts and in cells transfected with mutated- TBK1 plasmids., Results: We identified novel genomic TBK1 variants including two loss-of-function (LoF) (p.Leu59Phefs*16 and c.358+5G>A), two missense (p.Asp118Asn and p.Ile397Thr) and one intronic variant (c.1644-5&#95;1644-2delAATA), in addition to two previously reported pathogenetic missense variants (p.Lys291Glu and p.Arg357Gln). Functional studies in patient-derived fibroblasts revealed that the c.358+5G>A causes aberrant pre-mRNA processing leading TBK1 haploinsufficiency. Biochemical studies in cellular models showed that the truncating variant p.Leu59Phefs*16 abolishes TBK1 protein expression, whereas the p.Asp118Asn variant severely impairs TBK1 phosphorylation activity. Conversely, the p.Ile397Thr variant displayed enhanced phosphorylation activity, whose biological relevance is not clear., Conclusion: The observed frequency of TBK1 LoF variants was 1.3% (2/154), increasing up to 3.2% (5/154) by taking into account also the functional missense variants that we were able to classify as potentially pathogenic, supporting the relevance of TBK1 in the Italian population with ALS., Competing Interests: Competing interests: None declared., (© Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2017. All rights reserved. No commercial use is permitted unless otherwise expressly granted.)