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Increased adoption of personalized medicine has brought comprehensive genomic profiling (CGP) to the forefront. However, differences in assay, bioinformatics, and reporting systems and lack of understanding of their complex interplay are a challenge for implementation and achieving uniformity in CGP testing. Two commercially available, tissue-based, in-house CGP assays were compared, in combination with a tertiary analysis solution in a research use only (RUO) context: the AVENIO Tumor Tissue CGP RUO Kit paired with navify Mutation Profiler (RUO) software and the TruSight Oncology 500 RUO assay paired with PierianDx Clinical Genomics Workspace software. Agreements and differences between the assays were assessed for short variants, copy number alterations, rearrangements, tumor mutational burden, and microsatellite instability, including variant categorization and clinical trial-matching (CTM) recommendations. Results showed good overall agreement for short variant, known gene fusion, and microsatellite instability detection. Important differences were obtained in tumor mutational burden scoring, copy number alteration detection, and CTM. Differences in variant and biomarker detection could be explained by bioinformatic approaches to variant calling, filtering, tiering, and normalization; differences in CTM, by underlying reported variants and conceptual differences in system parameters. Thus, distinctions between different approaches may lead to inconsistent results. Complexities in calling, filtering, and interpreting variants illustrate key considerations for implementation of any high-quality CGP in the laboratory and bringing uniformity to genomic insight results., Competing Interests: Disclosure Statement H.-P.A., F.F., and U.S. are employees of Signature Diagnostics GmbH (H.-P.A. at the time of the analysis, but now retired). M.C.H., J.O., and J.M.A. are employees of Foundation Medicine, Inc. (J.O. at the time of the analysis, but is no longer an employee), and M.C., S.O., and T.W. are employees of Foundation Medicine GmbH; all hold stock in F. Hoffmann-La Roche Ltd. K.H. is an employee of Helios MVZ Pathologie Erfurt GmbH. M.T. is an employee of F. Hoffmann-La Roche AG and holds stock in F. Hoffmann-La Roche Ltd. D.G. holds stock in Univ8 Genomics Ltd.; has received honoraria (institution) from Roche, Illumina, Novartis, AstraZeneca, Eli Lilly, Amgen, and Janssen; has participated in a consulting or advisory role (institution) for AstraZeneca and Novartis; has participated in a speakers' bureau (institution) for AstraZeneca; and has received travel, accommodations, and expenses (institution) from Roche, AstraZeneca, and Illumina. E.P. received compensation for speaking engagements and advisory roles, with payments made directly to his affiliated university, from Roche, AstraZeneca, Novartis, and MSD. H.S. and M.D.V. are employees of Roche Diagnostics Solutions, Inc., and M.D.V. holds stock in F. Hoffmann-La Roche Ltd. E.S. reports lectures for Bio-Rad, Seracare, Novartis, Roche, Biocartis, Illumina, Eli Lilly, Janssen-Cilag, Pfizer, AstraZeneca, and Agena Bioscience; he is consultant in advisory boards for MSD/Merck, GSK, AstraZeneca, Astellas Pharma, Sysmex, Roche, Pfizer, Novartis, Bayer, Bristol Myers Squibb, Eli Lilly, Amgen, Biocartis, Illumina, Agena Bioscience, Janssen-Cilag (Johnson & Johnson), Sinnovisionlab, Diaceutics, and CC Diagnostics; and received research grants from Pfizer, Biocartis, Invitae-ArcherDX, AstraZeneca, Agena Bio-science, Bristol Myers Squibb, Bio-Rad, Roche, Boehringer Ingelheim, CC Diagnostics, and Abbott (all paid to University Medical Center Groningen account); and travel reimbursements from Bio-Rad, Abbott, Illumina, Agena Bioscience, and Roche. All authors received support in the form of third-party writing assistance for this manuscript, furnished by Nucleus Global, an Inizio company, and provided by F. Hoffmann-La Roche Ltd./Roche Diagnostics Solutions, Inc., (Copyright © 2024 Association for Molecular Pathology and American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved.)

Objectives: Moderate daily mocha pot coffee intake has been associated with better mood and cognition in patients with mild vascular cognitive impairment (VCI). Similarly, moderate red wine consumption has shown protective effects on cognitive disorders, including Alzheimer's disease and vascular dementia. The aim of this study was to explore the synergistic relation between red wine and coffee intake on mood and cognitive status in mild VCI patients at risk for dementia., Methods: A total of 300 non-demented older patients with mild VCI were asked for coffee and red wine consumption and administered with the 17-items Hamilton Depression Rating Scale (HDRS), the Mini Mental State Examination (MMSE), and the Stroop Color-Word Interference Test (Stroop T), as well as the Activities of Daily Living (ADL) and the Instrumental ADL to measure their mood status, cognitive performance, and functional independence. Linear regression models were used to test the association between variables., Results: Moderate wine drinkers tended to show the best Stroop T score at any level of coffee consumption; conversely, heavy wine consumers performed worse at the Stroop T, especially in patients reporting high coffee intake. Moderate drinkers of both coffee and wine showed the lowest HDRS scores. Finally, a progressive increase in MMSE score was evident with increasing coffee consumption, which peaks when combined with a moderate wine consumption., Conclusions: Daily mocha pot coffee and red wine intake seem to be synergistically associated with global cognition, executive functioning, and mood status in patients with mild VCI; the association was not linear, resulting in a protective direction for moderate intake and detrimental for heavy consumption. Future studies are needed to further corroborate the present findings and the potential long-term protective effects of these dietary compounds over time., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

Dementia and the other neurodegenerative disorders represent a complex pathophysiological process [...].

Restless Legs Syndrome (RLS) is a common sleep disorder characterized by an urge to move the legs that is responsive to movement (particularly during rest), periodic leg movements during sleep, and hyperarousal. Recent evidence suggests that the involvement of the adenosine system may establish a connection between dopamine and glutamate dysfunction in RLS. Transcranial magnetic stimulation (TMS) is a non-invasive electrophysiological technique widely applied to explore brain electrophysiology and neurochemistry under different experimental conditions. In this pilot study protocol, we aim to investigate the effects of dipyridamole (a well-known enhancer of adenosinergic transmission) and caffeine (an adenosine receptor antagonist) on measures of cortical excitation and inhibition in response to TMS in patients with primary RLS. Initially, we will assess cortical excitability using both single- and paired-pulse TMS in patients with RLS. Then, based on the measures obtained, we will explore the effects of dipyridamole and caffeine, in comparison to placebo, on various TMS parameters related to cortical excitation and inhibition. Finally, we will evaluate the psycho-cognitive performance of RLS patients to screen them for cognitive impairment and/or mood-behavioral dysfunction, thus aiming to correlate psycho-cognitive findings with TMS data. Overall, this study protocol will be the first to shed lights on the neurophysiological mechanisms of RLS involving the modulation of the adenosine system, thus potentially providing a foundation for innovative "pharmaco-TMS"-based treatments. The distinctive TMS profile observed in RLS holds indeed the potential utility for both diagnosis and treatment, as well as for patient monitoring. As such, it can be considered a target for both novel pharmacological (i.e., drug) and non-pharmacological (e.g., neuromodulatory), "TMS-guided", interventions., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2024 Lanza et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Difference of Gaussians (DoG) convolutional filters are one of the earliest image processing methods employed for detecting microcalcifications on mammogram images before machine and deep learning methods became widespread. DoG is a blob enhancement filter that consists in subtracting one Gaussian-smoothed version of an image from another less Gaussian-smoothed version of the same image. Smoothing with a Gaussian kernel suppresses high-frequency spatial information, thus DoG can be regarded as a band-pass filter. However, due to their small size and overimposed breast tissue, microcalcifications vary greatly in contrast-to-noise ratio and sharpness. This makes it difficult to find a single DoG configuration that enhances all microcalcifications. In this work, we propose a convolutional network, named DoG-MCNet, where the first layer automatically learns a bank of DoG filters parameterized by their associated standard deviations. We experimentally show that when employed for microcalcification detection, our DoG layer acts as a learnable bank of band-pass preprocessing filters and improves detection performance by 4.86% AUFROC over baseline MCNet and 1.53% AUFROC over state-of-the-art multicontext ensemble of CNNs., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Background: Differentiating between physiologic and altered motor evoked potentials (MEPs) to transcranial magnetic stimulation (TMS) is crucial in clinical practice. Some physical characteristics, such as height and age, introduce sources of variability unrelated to neural dysfunction. We provided new age- and height-adjusted normal values for cortical latency, central motor conduction time (CMCT), and peripheral motor conduction time (PMCT) from a large cohort of healthy subjects., Methods: Previously reported data from 587 participants were re-analyzed. Nervous system disorders were ruled out by clinical examination and magnetic resonance imaging. MEP latency was determined as stimulus-to-response latency through stimulation with a circular coil over the "hot spot" of the First Dorsal Interosseous and Tibialis Anterior muscles, during mild tonic contraction. CMCT was estimated as the difference between MEP cortical latency and PMCT by radicular magnetic stimulation. Additionally, right-to-left differences were calculated. For each parameter, multiple linear regression models of increasing complexity were fitted using height, age, and sex as regressors., Results: Motor evoked potential cortical latency, PMCT, and CMCT were shown to be age- and height-dependent, although age had only a small effect on CMCT. Relying on Bayesian information criterion for model selection, MEP cortical latency and PMCT were explained best by linear models indicating a positive correlation with both height and age. Also, CMCT to lower limbs positively correlated with height and age. CMCT to upper limbs positively correlated to height, but slightly inversely correlated to age, as supported by non-parametric bootstrap analysis. Males had longer cortical latencies and CMCT to lower limbs, as well as longer PMCT and cortical latencies to upper limbs, even when accounting for differences in body height. Right-to-left-differences were independent of height, age, and sex. Based on the selected regression models, sex-specific reference values were obtained for all TMS-related latencies and inter-side differences, with adjustments for height and age, where warranted., Conclusion: A significant relationship was observed between height and age and all MEP latency values, in both upper and lower limbs. These set of reference values facilitate the evaluation of MEPs in clinical studies and research settings. Unlike previous reports, we also highlighted the contribution of sex., 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 © 2023 Cantone, Lanza, Fisicaro, Bella, Ferri, Pennisi, Waterstraat and Pennisi.)

Background: The POLG gene encodes the catalytic subunit of DNA polymerase γ, which is crucial for mitochondrial DNA (mtDNA) repair and replication. Gene mutation alters the stability of mtDNA and is associated with several clinical presentations, such as dysarthria and ophthalmoplegia (SANDO), progressive external ophthalmoplegia (PEO), spinocerebellar ataxia and epilepsy (SCAE), Alpers syndrome, and sensory ataxic neuropathy. Recent evidence has also indicated that POLG mutations may be involved in some neurodegenerative disorders, although systematic screening is currently lacking., Methods: To investigate the frequency of POLG gene mutations in neurodegenerative disorders, we screened a group of 33 patients affected by neurodegenerative diseases, including Parkinson's disease, some atypical parkinsonisms, and dementia of different types., Results: Mutational analysis revealed the presence of the heterozygous Y831C mutation in two patients, one with frontotemporal dementia and one with Lewy body dementia. The allele frequency of this mutation reported by the 1000 Genomes Project in the healthy population is 0.22%, while in our group of patients, it was 3.03%, thus showing a statistically significant difference between the two groups., Conclusions: Our results may expand the genotype-phenotype spectrum associated with mutations in the POLG gene and strengthen the hypothesis of a pathogenic role of the Y831C mutation in neurodegeneration.

Background: Although the antidepressant potential of repetitive transcranial magnetic stimulation (rTMS), the pleiotropic effects in geriatric depression (GD) are poorly investigated. We tested rTMS on depression, cognitive performance, growth/neurotrophic factors, cerebral blood flow (CBF) to transcranial Doppler sonography (TCD), and motor-evoked potentials (MEPs) to TMS in GD., Methods: In this case series study, six drug-resistant subjects (median age 68.0 years) underwent MEPs at baseline and after 3 weeks of 10 Hz rTMS on the left dorsolateral prefrontal cortex. The percentage change of serum nerve growth factor, vascular endothelial growth factor, brain-derived growth factor, insulin-like growth factor-1, and angiogenin was obtained. Assessments were performed at baseline, and at the end of rTMS; psychocognitive tests were also repeated after 1, 3, and 6 months., Results: Chronic cerebrovascular disease was evident in five patients. No adverse/undesirable effect was reported. An improvement in mood was observed after rTMS but not at follow-up. Electrophysiological data to TMS remained unchanged, except for an increase in the right median MEP amplitude. TCD and neurotrophic/growth factors did not change., Conclusions: We were unable to detect a relevant impact of high-frequency rTMS on mood, cognition, cortical microcircuits, neurotrophic/growth factors, and CBF. Cerebrovascular disease and exposure to multiple pharmacological treatments might have contributed.

Background: Sex differences in vascular cognitive impairment (VCI) at risk for future dementia are still debatable. Transcranial magnetic stimulation (TMS) is used to evaluate cortical excitability and the underlying transmission pathways, although a direct comparison between males and females with mild VCI is lacking., Methods: Sixty patients (33 females) underwent clinical, psychopathological, functional, and TMS assessment. Measures of interest consisted of: resting motor threshold, latency of motor evoked potentials (MEPs), contralateral silent period, amplitude ratio, central motor conduction time (CMCT), including the F wave technique (CMCT-F), short-interval intracortical inhibition (SICI), intracortical facilitation, and short-latency afferent inhibition, at different interstimulus intervals (ISIs)., Results: Males and females were comparable for age, education, vascular burden, and neuropsychiatric symptoms. Males scored worse at global cognitive tests, executive functioning, and independence scales. MEP latency was significantly longer in males, from both sides, as well CMCT and CMCT-F from the left hemisphere; a lower SICI at ISI of 3 ms from the right hemisphere was also found. After correction for demographic and anthropometric features, the effect of sex remained statistically significant for MEP latency, bilaterally, and for CMCT-F and SICI. The presence of diabetes, MEP latency bilaterally, and both CMCT and CMCT-F from the right hemisphere inversely correlated with executive functioning, whereas TMS did not correlate with vascular burden., Conclusions: We confirm the worse cognitive profile and functional status of males with mild VCI compared to females and first highlight sex-specific changes in intracortical and cortico-spinal excitability to multimodal TMS in this population. This points to some TMS measures as potential markers of cognitive impairment, as well as targets for new drugs and neuromodulation therapies., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2023 Cantone et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Background: Bradykinesia, tremor, rigidity and postural instability are the hallmark of Parkinson's disease (PD). Non-motor symptoms including cognitive, behavioral, and neuropsychiatric changes, sensory and sleep disturbances that may precede the motor symptoms by years. The peculiar pathological features of PD are decreased dopaminergic neurons and dopamine levels in the substantia nigra pars compacta and pontine locus coeruleus. Humanin is produced by a small gene peptide, which is located in the mitochondria genome. Inflammation, oxidative stress, mitochondrial dysfunction and altered transcription have been recognized as causative factors of PD. This evidence has prompted many researchers to focus on studying the functions of DNA and mitochondria. The purpose of the present study was to evaluate Humanin mRNA levels in peripheral blood mononuclear cells (PBMCs) of PD subjects, compared with those in PBMCs of normal control (NC) subjects., Methods and Results: A total of 220 participants, including 154 PD patients (57 females and 97 males; mean age 71.54 years, SD 7.8) and 66 CN (28 females and 38 males; mean age 70.54 years, SD 9.45) were enrolled for the qRT-PCR analysis. Increased Humanin mRNA levels were found in PD samples, compared to controls., Conclusion: In conclusion, the present data confirm the tendency of mitochondria to overexpress mRNA in PD, which could be a cellular attempt to reduce apoptotic damage in PD subjects. Humanin might be useful as a marker for a better diagnosis of PD, and we cannot exclude that in the future it might also play a role on prognosis and in the possible therapies for PD., (© 2022. The Author(s), under exclusive licence to Springer Nature B.V.)

Repetitive transcranial magnetic stimulation (rTMS) is a widely used non-invasive neuromodulatory technique. When applied in sleep medicine, the main hypothesis explaining its effects concerns the modulation of synaptic plasticity and the strength of connections between the brain areas involved in sleep disorders. Recently, there has been a significant increase in the publication of rTMS studies in primary sleep disorders. A multi-database-based search converges on the evidence that rTMS is safe and feasible in chronic insomnia, obstructive sleep apnea syndrome (OSAS), restless legs syndrome (RLS), and sleep deprivation-related cognitive deficits, whereas limited or no data are available for narcolepsy, sleep bruxism, and REM sleep behavior disorder. Regarding efficacy, the stimulation of the dorsolateral prefrontal cortex bilaterally, right parietal cortex, and dominant primary motor cortex (M1) in insomnia, as well as the stimulation of M1 leg area bilaterally, left primary somatosensory cortex, and left M1 in RLS reduced subjective symptoms and severity scale scores, with effects lasting for up to weeks; conversely, no relevant effect was observed in OSAS and narcolepsy. Nevertheless, several limitations especially regarding the stimulation protocols need to be considered. This review should be viewed as a step towards the further contribution of individually tailored neuromodulatory techniques for sleep disorders., Competing Interests: Declaration of competing interest The authors have no conflict of interest to disclose., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Convolutional Neural Networks (CNN) have received a large share of research in mammography image analysis due to their capability of extracting hierarchical features directly from raw data. Recently, Vision Transformers are emerging as viable alternative to CNNs in medical imaging, in some cases performing on par or better than their convolutional counterparts. In this work, we conduct an extensive experimental study to compare the most recent CNN and Vision Transformer architectures for whole mammograms classification. We selected, trained and tested 33 different models, 19 convolutional- and 14 transformer-based, on the largest publicly available mammography image database OMI-DB. We also performed an analysis of the performance at eight different image resolutions and considering all the individual lesion categories in isolation (masses, calcifications, focal asymmetries, architectural distortions). Our findings confirm the potential of visual transformers, which performed on par with traditional CNNs like ResNet, but at the same time show a superiority of modern convolutional networks like EfficientNet.

Although primary degenerative diseases are the main cause of dementia, a non-negligible proportion of patients is affected by a secondary and potentially treatable cognitive disorder. Therefore, diagnostic tools able to early identify and monitor them and to predict the response to treatment are needed. Transcranial magnetic stimulation (TMS) is a non-invasive neurophysiological technique capable of evaluating in vivo and in "real time" the motor areas, the cortico-spinal tract, and the neurotransmission pathways in several neurological and neuropsychiatric disorders, including cognitive impairment and dementia. While consistent evidence has been accumulated for Alzheimer's disease, other degenerative cognitive disorders, and vascular dementia, to date a comprehensive review of TMS studies available in other secondary dementias is lacking. These conditions include, among others, normal-pressure hydrocephalus, multiple sclerosis, celiac disease and other immunologically mediated diseases, as well as a number of inflammatory, infective, metabolic, toxic, nutritional, endocrine, sleep-related, and rare genetic disorders. Overall, we observed that, while in degenerative dementia neurophysiological alterations might mirror specific, and possibly primary, neuropathological changes (and hence be used as early biomarkers), this pathogenic link appears to be weaker for most secondary forms of dementia, in which neurotransmitter dysfunction is more likely related to a systemic or diffuse neural damage. In these cases, therefore, an effort toward the understanding of pathological mechanisms of cognitive impairment should be made, also by investigating the relationship between functional alterations of brain circuits and the specific mechanisms of neuronal damage triggered by the causative disease. Neurophysiologically, although no distinctive TMS pattern can be identified that might be used to predict the occurrence or progression of cognitive decline in a specific condition, some TMS-associated measures of cortical function and plasticity (such as the short-latency afferent inhibition, the short-interval intracortical inhibition, and the cortical silent period) might add useful information in most of secondary dementia, especially in combination with suggestive clinical features and other diagnostic tests. The possibility to detect dysfunctional cortical circuits, to monitor the disease course, to probe the response to treatment, and to design novel neuromodulatory interventions in secondary dementia still represents a gap in the literature that needs to be explored., 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 Lanza, Fisicaro, Dubbioso, Ranieri, Chistyakov, Cantone, Pennisi, Grasso, Bella and Di Lazzaro.)

Background: Sonographic mesenteric pattern in celiac disease (CD) suggests a hyperdynamic circulation. Despite the well-known CD-related neurological involvement, no study has systematically explored the cerebral hemodynamics to transcranial Doppler sonography., Materials and Methods: Montreal Cognitive Assessment (MoCA) and 17-item Hamilton Depression Rating Scale (HDRS) were assessed in 15 newly diagnosed subjects with CD and 15 age-, sex-, and education-matched healthy controls. Cerebral blood flow (CBF) velocities and indices of resistivity (RI) and pulsatility (PI) from the middle cerebral artery (MCA), bilaterally, and the basilar artery (BA) were recorded. We also assessed cerebral vasomotor reactivity (CVR) through the breath-holding test (BHT)., Results: Worse scores of MoCA and HDRS were found in patients compared to controls. Although patients showed higher values of CBF velocity from MCA bilaterally compared to controls, both at rest and after BHT, no comparison reached a statistical significance, whereas after BHT both RI and PI from BA were significantly higher in patients. A significant negative correlation between both indices from BA and MoCA score were also noted., Conclusion: These treatment-naïve CD patients may show some subtle CVR changes in posterior circulation, thus possibly expanding the spectrum of pathomechanisms underlying neuroceliac disease and in particular gluten ataxia. Subclinical identification of cerebrovascular pathology in CD may help adequate prevention and early management of neurological involvement., 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 Fisicaro, Lanza, D’Agate, Pennisi, Cantone, Pennisi, Hadjivassiliou and Bella.)

Coffee intake has been recently associated with better cognition and mood in mild vascular cognitive impairment (mVCI). As tobacco can reduce the caffeine half-life, we excluded smokers from the original sample. Hamilton Depression Rating Scale (HDRS), mini-mental state examination (MMSE), Stroop Colour-Word Interference Test (Stroop), activities of daily living (ADL0) and instrumental ADL were the outcome measures. Significant differences were observed in higher consumption groups (moderate intake for HDRS; high intake for MMSE and Stroop) compared to the other groups, as well as in age and education. With age, education and coffee used as independent predictors, and HDRS, Stroop and MMSE as dependent variables, a correlation was found between age and both MMSE and Stroop, as well as between education and MMSE and between HDRS and Stroop; coffee intake negatively correlated with HDRS and Stroop. Higher coffee consumption was associated with better psycho-cognitive status among non-smokers with mVCI.