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Multiple myeloma is an aggressive neoplasm of plasma cells. While numerous drugs have gained approval, the absence of established predictive markers for individual drug responses poses a challenge. In this study, we explored the microwell- and fluorescence-based Cellply CC-Array® technology for high-throughput analysis of in vitro drug responses as a potential predictive marker for patient treatment outcomes. Furthermore, we investigated its application for evaluating effector cell effectiveness. Mononuclear cells were isolated from the bone marrow of 22 patients, and in vitro drug response of primary myeloma cells was analyzed. In vitro responses towards melphalan, bortezomib, and dexamethasone in primary patient samples correlated with clinical response of the patients. The approach exhibited limitations in identifying sensitivity towards lenalidomide, daratumumab, and elotuzumab due to limited culturing time caused by poor myeloma viability in vitro. Through the analysis of cell proximity, the platform enabled the assessment of individual anti-tumor activity from NK and T cells. In summary, the CC-Array microwell technology allowed assessment of myeloma cell responses to selected drugs used in multiple myeloma therapy in vitro. To further validate these in vitro results against in vivo outcomes, screening a larger cohort is necessary., Competing Interests: Declaration of Competing Interest A.N. declares consultancy for Celgene, Janssen, Roche, Takeda, Alexion, Sanofi, GSK and BMS and research funding from BMS; Janssen and Celgene. A.B. and L.R. are full-time employees and M.B. is co-founder of Cellply S.r.l. The remaining authors declare no financial interest/relationships to this article., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background: Essential tremor (ET) is a common debilitating condition, yet current treatments often fail to provide satisfactory relief. Transcutaneous spinal cord electrical stimulation (tSCS) has emerged as a potential noninvasive neuromodulation technique capable of disrupting the oscillatory activity underlying tremors., Objective: This study aimed to investigate the potential of tSCS to disrupt tremor in a frequency-dependent manner in a cohort of patients with ET., Methods: Eighteen patients with ET completed the study. The experiment consisted of 60-s postural tremor recording, during tSCS at tremor frequency, at 1 Hz, at 21 Hz, no stimulation, and trapezius stimulation. Tremor frequency and amplitude were analyzed and compared across the conditions., Results: We found tremor amplitude reduction at tremor frequency stimulation significant only during the second half of the stimulation. The same stimulation resulted in the highest number of responders. tSCS at 1 Hz showed a trend toward decreased tremor amplitude in the latter half of stimulation. tSCS at 21 Hz did not produce any significant alterations in tremor, whereas trapezius stimulation exacerbated it. Notably, during tremor frequency stimulation, a subgroup of responders exhibited consistent synchronization between tremor phase and delivered stimulation, indicating tremor entrainment., Conclusions: Cervical tSCS holds promise for alleviating postural tremor in patients with ET when delivered at the subject's tremor frequency. The observed changes in tremor amplitude likely result from the modulation of spinal cord circuits by tSCS, which disrupts the oscillatory drive to muscles by affecting afferent pathways or spinal reflexes. However, the possibility of an interplay between spinal and supraspinal centers cannot be discounted. © 2024 The Author(s). Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society., (© 2024 The Author(s). Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.)

Background: Dystonia presents a growing concern based on evolving prevalence insights. Previous research found that, in cervical dystonia, high-frequency repetitive somatosensory stimulation (RSS; HF-RSS) applied on digital nerves paradoxically diminishes sensorimotor inhibitory mechanisms, whereas low-frequency RSS (LF-RSS) increases them. However, direct testing on affected body parts was not conducted., Objective: This study aims to investigate whether RSS applied directly to forearm muscles involved in focal hand dystonia can modulate cortical inhibitory mechanisms and clinical symptoms., Methods: We applied HF-RSS and LF-RSS, the latter either synchronously or asynchronously, on forearm muscles involved in dystonia. Outcome measures included paired-pulse somatosensory evoked potentials, spatial lateral inhibition measured by double-pulse somatosensory evoked potentials, short intracortical inhibition tested with transcranial magnetic stimulation, electromyographic activity from dystonic muscles, and behavioral measures of hand function., Results: Both synchronous and asynchronous low-frequency somatosensory stimulation improved cortical inhibitory interactions, indicated by increased short intracortical inhibition and lateral spatial inhibition, as well as decreased amplitude of paired-pulse somatosensory evoked potentials. Opposite effects were observed with high-frequency stimulation. Changes in electrophysiological markers were paralleled by behavioral outcomes: although low-frequency stimulations improved hand function tests and reduced activation of dystonic muscles, high-frequency stimulation operated in an opposite direction., Conclusions: Our findings confirm the presence of abnormal homeostatic plasticity in response to RSS in the sensorimotor system of patients with dystonia, specifically in inhibitory circuits. Importantly, this aberrant response can be harnessed for therapeutic purposes through the application of low-frequency electrical stimulation directly over dystonic muscles. © 2024 The Author(s). Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society., (© 2024 The Author(s). Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.)

Objective: Persistent fatigue is a major symptom of the so-called 'long-COVID syndrome', but the pathophysiological processes that cause it remain unclear. We hypothesized that fatigue after COVID-19 would be associated with altered cortical activity in premotor and motor regions., Methods: We used transcranial magnetic stimulation combined with EEG (TMS-EEG) to explore the neural oscillatory activity of the left primary motor area (l-M1) and supplementary motor area (SMA) in a group of sixteen post-COVID patients complaining of lingering fatigue as compared to a sample of age-matched healthy controls. Perceived fatigue was assessed with the Fatigue Severity Scale (FSS) and Fatigue Rating Scale (FRS)., Results: Post-COVID patients showed a remarkable reduction of beta frequency in both areas. Correlation analysis exploring linear relation between neurophysiological and clinical measures revealed a significant inverse correlation between the individual level of beta oscillations evoked by TMS of SMA with the individual scores in the FRS (r(15) = -0.596; p = 0.012)., Conclusions: Post-COVID fatigue is associated with a reduction of TMS-evoked beta oscillatory activity in SMA., Significance: TMS-EEG could be used to identify early alterations of cortical oscillatory activity that could be related to the COVID impact in central fatigue., (Copyright © 2024 International Federation of Clinical Neurophysiology. Published by Elsevier B.V. All rights reserved.)

Chronic pain poses a widespread and distressing challenge; it can be resistant to conventional therapies, often having significant side effects. Non-invasive brain stimulation (NIBS) techniques offer promising avenues for the safe and swift modulation of brain excitability. NIBS approaches for chronic pain management targeting the primary motor area have yielded variable outcomes. Recently, the cerebellum has emerged as a pivotal hub in human pain processing; however, the clinical application of cerebellar NIBS in chronic pain treatment remains limited. This review delineates the cerebellum's role in pain modulation, recent advancements in NIBS for cerebellar activity modulation, and novel biomarkers for assessing cerebellar function in humans. Despite notable progress in NIBS techniques and cerebellar activity assessment, studies targeting cerebellar NIBS for chronic pain treatment are limited in number. Nevertheless, positive outcomes in pain alleviation have been reported with cerebellar anodal transcranial direct current stimulation. Our review underscores the potential for further integration between cerebellar NIBS and non-invasive assessments of cerebellar function to advance chronic pain treatment strategies.

Capitalizing on the widespread adoption of smartphones among farmers and the application of artificial intelligence in computer vision, a variety of mobile applications have recently emerged in the agricultural domain. This paper introduces GranoScan, a freely available mobile app accessible on major online platforms, specifically designed for the real-time detection and identification of over 80 threats affecting wheat in the Mediterranean region. Developed through a co-design methodology involving direct collaboration with Italian farmers, this participatory approach resulted in an app featuring: (i) a graphical interface optimized for diverse in-field lighting conditions, (ii) a user-friendly interface allowing swift selection from a predefined menu, (iii) operability even in low or no connectivity, (iv) a straightforward operational guide, and (v) the ability to specify an area of interest in the photo for targeted threat identification. Underpinning GranoScan is a deep learning architecture named efficient minimal adaptive ensembling that was used to obtain accurate and robust artificial intelligence models. The method is based on an ensembling strategy that uses as core models two instances of the EfficientNet-b0 architecture, selected through the weighted F1-score. In this phase a very good precision is reached with peaks of 100% for pests, as well as in leaf damage and root disease tasks, and in some classes of spike and stem disease tasks. For weeds in the post-germination phase, the precision values range between 80% and 100%, while 100% is reached in all the classes for pre-flowering weeds, except one. Regarding recognition accuracy towards end-users in-field photos, GranoScan achieved good performances, with a mean accuracy of 77% and 95% for leaf diseases and for spike, stem and root diseases, respectively. Pests gained an accuracy of up to 94%, while for weeds the app shows a great ability (100% accuracy) in recognizing whether the target weed is a dicot or monocot and 60% accuracy for distinguishing species in both the post-germination and pre-flowering stage. Our precision and accuracy results conform to or outperform those of other studies deploying artificial intelligence models on mobile devices, confirming that GranoScan is a valuable tool also in challenging outdoor conditions., Competing Interests: SM, EF, MS, SA and PL were employed by Barilla G. e R. Fratelli S.p.A. 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 © 2024 Dainelli, Bruno, Martinelli, Moroni, Rocchi, Morelli, Ferrari, Silvestri, Agostinelli, La Cava and Toscano.)

Background: Approximately 30% of patients presenting with acute ischemic stroke (AIS) due to large vessel occlusion have pre-stroke modified Rankin Scale (mRS) scores ≥2. We aimed to investigate the safety and outcomes of endovascular treatment (EVT) in patients with AIS with moderate pre-stroke disability (mRS score 3) in an extended time frame (ie, 6-24 hours from the last time known well)., Methods: Data were collected from five centers in Europe and the USA from January 2018 to January 2023 and included 180 patients who underwent EVT in an extended time frame. Patients were divided into two groups of 90 each (Group 1: pre-mRS 0-2; Group 2: pre-mRS 3; 71% women, mean age 80.3±11.9 years). Primary outcomes were: (1) 3-month good clinical outcome (Group 1: mRS 0-2, Group 2: mRS 0-3) and ΔmRS; (2) any hemorrhagic transformation (HT); and (3) symptomatic HT. Secondary outcomes were successful and complete recanalization after EVT and 3-month mortality., Results: No between-group differences were found in the 3-month good clinical outcome (26.6% vs 25.5%, P=0.974), any HT (26.6% vs 22%, P=0.733), and symptomatic HT (8.9 vs 4.4%, P=0.232). Unexpectedly, ΔmRS was significantly smaller in Group 2 compared with Group 1 (1.64±1.61 vs 2.97±1.69, P<0.001). No between-group differences were found in secondary outcomes., Conclusion: Patients with pre-stroke mRS 3 are likely to have similar outcomes after EVT in the extended time frame to those with pre-stroke mRS 0-2, with no difference in safety., Competing Interests: Competing interests: T.N. Nguyen discloses advisory board for Brainomix, Aruna Bio; Associate Editor of Stroke. The other authors declare that they have no conflict of interests., (© Author(s) (or their employer(s)) 2024. No commercial re-use. See rights and permissions. Published by BMJ.)

Transcranial magnetic stimulation coupled with electroencephalography (TMS-EEG) is a novel technique to investigate cortical physiology in health and disease. The cerebellum has recently gained attention as a possible new hotspot in the field of TMS-EEG, with several reports published recently. However, EEG responses obtained by cerebellar stimulation vary considerably across the literature, possibly due to different experimental methods. Compared to conventional TMS-EEG, which involves stimulation of the cortex, cerebellar TMS-EEG presents some technical difficulties, including strong muscle twitches in the neck area and a loud TMS click when double-cone coils are used, resulting in contamination of responses by electromyographic activity and sensory potentials. Understanding technical difficulties and limitations is essential for the development of cerebellar TMS-EEG research. In this review, we summarize findings of cerebellar TMS-EEG studies, highlighting limitations in experimental design and potential issues that can result in discrepancies between experimental outcomes. Lastly, we propose a possible direction for academic and clinical research with cerebellar TMS-EEG., Competing Interests: The authors declare no conflicts of interest.

Bone tumors of the upper limb are a common cause of bone pain and pathological fractures in both old and young populations. Surgical reconstruction and limb salvage have become valid options for these patients despite this kind of surgery being challenging due to the need for wide bone resection and the involvement of surrounding soft tissues. Computer-assisted technology helps the surgeon in pre-operative planning and in designing customized implants. The aim of this study was to investigate the surgical outcomes and complications of custom-made prostheses in oncologic reconstruction of the upper limb and if they are reliable options for patients suffering from aggressive tumors. An electronic search on PubMed, Google Scholar, and Web of Knowledge was conducted to identify all available articles on the use of custom-made prostheses in oncological resections of the upper limb. Twenty-one studies were included in the review, comprising a total of 145 patients with a mean age of 33.68 years. The bone involved was the humerus in 93 patients, and the radius was involved in 36 patients. There were only six cases involving proximal ulna, three cases involving the scapula, and seven cases involving the elbow as well as soft tissues around it. The most frequent primary tumor was the giant cell tumor, with 36 cases, followed by osteosarcoma with 25 cases, Ewing Sarcoma with 17 cases, and Chondrosarcoma with 7 total cases. Forty patients were affected by bone metastases (such as renal cell cancer, breast cancer, melanoma, and rectal cancer) or hematologic diseases involving bone (lymphoma, myeloma, or non-Hodgkin disease). Custom-made prostheses are a viable option for patients who suffer from malignant tumors in their upper limbs. They are a reliable aid for surgeons in cases of extensive resections.

Cortical myoclonus is produced by abnormal neuronal discharges within the sensorimotor cortex, as demonstrated by electrophysiology. Our hypothesis is that the loss of cerebellar inhibitory control over the motor cortex, via cerebello-thalamo-cortical connections, could induce the increased sensorimotor cortical excitability that eventually causes cortical myoclonus. To explore this hypothesis, in the present study we applied anodal transcranial direct current stimulation over the cerebellum of patients affected by cortical myoclonus and healthy controls and assessed its effect on sensorimotor cortex excitability. We expected that anodal cerebellar transcranial direct current stimulation would increase the inhibitory cerebellar drive to the motor cortex and therefore reduce the sensorimotor cortex hyperexcitability observed in cortical myoclonus. Ten patients affected by cortical myoclonus of various aetiology and 10 aged-matched healthy control subjects were included in the study. All participants underwent somatosensory evoked potentials, long-latency reflexes and short-interval intracortical inhibition recording at baseline and immediately after 20 min session of cerebellar anodal transcranial direct current stimulation. In patients, myoclonus was recorded by the means of surface EMG before and after the cerebellar stimulation. Anodal cerebellar transcranial direct current stimulation did not change the above variables in healthy controls, while it significantly increased the amplitude of somatosensory evoked potential cortical components, long-latency reflexes and decreased short-interval intracortical inhibition in patients; alongside, a trend towards worsening of the myoclonus after the cerebellar stimulation was observed. Interestingly, when dividing patients in those with and without giant somatosensory evoked potentials, the increment of the somatosensory evoked potential cortical components was observed mainly in those with giant potentials. Our data showed that anodal cerebellar transcranial direct current stimulation facilitates-and does not inhibit-sensorimotor cortex excitability in cortical myoclonus syndromes. This paradoxical response might be due to an abnormal homeostatic plasticity within the sensorimotor cortex, driven by dysfunctional cerebello-thalamo-cortical input to the motor cortex. We suggest that the cerebellum is implicated in the pathophysiology of cortical myoclonus and that these results could open the way to new forms of treatment or treatment targets., (© The Author(s) 2023. Published by Oxford University Press on behalf of the Guarantors of Brain.)

The inhibition of action is a fundamental executive mechanism of human behaviour that involve a complex neural network. In spite of the progresses made so far, many questions regarding the brain dynamics occurring during action inhibition are still unsolved. Here, we used a novel approach optimized to investigate real-time effective brain dynamics, which combines transcranial magnetic stimulation (TMS) with simultaneous electroencephalographic (EEG) recordings. 22 healthy volunteers performed a motor Go/NoGo task during TMS of the hand-hotspot of the primary motor cortex (M1) and whole-scalp EEG recordings. We reconstructed source-based real-time spatiotemporal dynamics of cortical activity and cortico-cortical connectivity throughout the task. Our results showed a task-dependent bi-directional change in theta/gamma supplementary motor cortex (SMA) and M1 connectivity that, when participants were instructed to inhibit their response, resulted in an increase of a specific TMS-evoked EEG potential (N100), likely due to a GABA-mediated inhibition. Interestingly, these changes were linearly related to reaction times, when participants were asked to produce a motor response. In addition, TMS perturbation revealed a task-dependent long-lasting modulation of SMA-M1 natural frequencies, i.e. alpha/beta activity. Some of these results are shared by animal models and shed new light on the physiological mechanisms of motor inhibition in humans., (© 2024. The Author(s).)

Transcranial magnetic stimulation coupled with electroencephalography (TMS-EEG) allows for the study of brain dynamics in health and disease. Cranial muscle activation can decrease the interpretability of TMS-EEG signals by masking genuine EEG responses and increasing the reliance on preprocessing methods but can be at least partly prevented by coil rotation coupled with the online monitoring of signals; however, the extent to which changing coil rotation may affect TMS-EEG signals is not fully understood. Our objective was to compare TMS-EEG data obtained with an optimal coil rotation to induce motor evoked potentials (M1 standard ) while rotating the coil to minimize cranial muscle activation (M1 emg ). TMS-evoked potentials (TEPs), TMS-related spectral perturbation (TRSP), and intertrial phase clustering (ITPC) were calculated in both conditions using two different preprocessing pipelines based on independent component analysis (ICA) or signal-space projection with source-informed reconstruction (SSP-SIR). Comparisons were performed with cluster-based correction. The concordance correlation coefficient was computed to measure the similarity between M1 standard and M1 emg TMS-EEG signals. TEPs, TRSP, and ITPC were significantly larger in M1 standard than in M1 emg conditions; a lower CCC than expected was also found. These results were similar across the preprocessing pipelines. While rotating the coil may be advantageous to reduce cranial muscle activation, it may result in changes in TMS-EEG signals; therefore, this solution should be tailored to the specific experimental context.

Aim The Epibloc elastic-dynamic fixation has been applied for many years at several hand surgery centres in Italy. This technique has been considered safe and reliable in the treatment of distal meta-epiphyseal fractures of the radius with dorsal displacement. The aim of this study was to evaluate an alternative use of this method in the treatment of volar displaced wrist fractures in cases where an internal fixation could not be recommended. Methods The procedure consisted of two flexible pins with a trocar tip and an external plate for locking fixation with compression. The surgical technique was derived from the original procedure, modifying the placement of the pins and performing small surgical accesses to preserve the neuro-vascular structures of the volar aspect of the wrist. To achieve and preserve the reduction of the volar fragment, a third pin was inserted into the fracture with a similar procedure to Kapandji's reduction technique. Results At three-month follow-up, most patients did not experience any pain. In 14 cases, the strength grip was recovered between 75% and 90%, compared to the contralateral hand (Jamar test). In 15 patients, the wrist range of motion was restored with values greater than 100. In 17 cases, forearm pronation-supination was restored to more than 120°. Conclusion In cases of non-comminuted, one or two fragments volar displaced wrist fractures, the elastic-dynamic fixation associated with an intrafocal pinning reduction may be proposed as an alternative to open reduction and internal fixation in elderly patients., (Copyright© by the Medical Assotiation of Zenica-Doboj Canton.)