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Besides, for both measures, the intraclass correlations were good to excellent on all ROMs of the forearm, wrist, and fingers except for MCP of the middle and ring fingers (0.68-0.88). The present study results indicated that the LMC-based Fizyosoft® HandROM System could sensitively track changes in the active motion of the thumb, wrist, and forearm. It is a viable alternative for assessing ROMs of the forearm, wrist, and thumb in patient follow-up.

Hypokinetic dysarthria is a common but difficult-to-treat symptom of Parkinson's disease (PD).

We evaluated the long-term effects of multiple-session repetitive transcranial magnetic stimulation on hypokinetic dysarthria in PD. Neural mechanisms of stimulation were assessed by functional MRI.

A randomized parallel-group sham stimulation-controlled design was used. Patients were randomly assigned to ten sessions (2 weeks) of real (1Hz) or sham stimulation over the right superior temporal gyrus. Stimulation effects were evaluated at weeks 2, 6, and 10 after the baseline assessment. Articulation, prosody, and speech intelligibility were quantified by speech therapist using a validated tool (Phonetics score of the Dysarthric Profile). Activations of the speech network regions and intrinsic connectivity were assessed using 3T MRI. Linear mixed models and post-hoc tests were utilized for data analyses.

Altogether 33 PD patients completed the study (20 in the real stimulation group and 13 in the sham stimulation group). Linear mixed models revealed significant effects of time (F(3, 88.1)=22.7, p<0.001) and time-by-group interactions F(3, 88.0)=2.8, p=0.040) for the Phonetics score. Real as compared to sham stimulation led to activation increases in the orofacial sensorimotor cortex and caudate nucleus and to increased intrinsic connectivity of these regions with the stimulated area.

This is the first study to show the long-term treatment effects of non-invasive brain stimulation for hypokinetic dysarthria in PD. Neural mechanisms of the changes are discussed.

This is the first study to show the long-term treatment effects of non-invasive brain stimulation for hypokinetic dysarthria in PD. Neural mechanisms of the changes are discussed.

Neural oscillations in the cerebral cortex are associated with a range of cognitive processes and neuropsychiatric disorders. However, non-invasively modulating oscillatory activity remains technically challenging, due to limited strength, duration, or non-synchronization of stimulation waveforms with endogenous rhythms.

We hypothesized that applying controllable phase-synchronized repetitive transcranial magnetic stimulation pulses (rTMS) with alternating currents (tACS) may induce and stabilize neuro-oscillatory resting-state activity at targeted frequencies.

Using a novel circuit to precisely synchronize rTMS pulses with phase of tACS, we empirically tested whether combined, 10-Hz prefrontal bilateral stimulation could induce and stabilize 10-Hz oscillations in the bilateral prefrontal cortex (PFC). 25 healthy participants took part in a repeated-measures design. Whole-brain resting-state EEG in eyes-open (EO) and eyes-closed (EC) was recorded before (baseline), immediately (1-min), and 15- and 30-mi oscillatory tone is attenuated, such as disorders of consciousness or major depression.Virulence factor, sortase A (SrtA), has crucial roles in the pathogenesis of Gram-positive superbugs. SrtA is a bacterial cell membrane enzyme that anchors crucial virulence factors to the cell wall surface of Gram-positive bacteria. SrtA is not necessary for bacterial growth and viability and is conveniently accessible in the cell membrane; therefore, it is an ideal target for antivirulence drug development. In this review, we focus on antimicrobial resistance (AMR)-expressing bacteria and SrtA as a potential target for overcoming AMR. TP0427736 The mechanism of action of SrtA and its inhibition by various types of inhibitors, such as synthetic small molecules, peptides, and natural products, are provided. Future SrtA research perspectives for alternative drug development to antibiotics are also proposed.Three decades of promise have culminated in the development of gene therapies that can be applied to a broad range of human diseases. After a brief history, we provide an overview of gene therapy types and delivery methods, gene editing technologies, regulatory affairs, clinical trials, approved products, ongoing challenges, and future goals. Information on clinical trials of candidates and on approved products for gene therapy developed between 1988 and 2020 is systematically collated. To obtain this global information, we scanned and reviewed more than 46,000 records of clinical trials from 17 clinical trial database providers. The medical benefits of transformative gene therapies are gradually being accepted by payors, and a significant increase in the number of gene therapy clinical trials and approved gene therapy products has resulted.Granulocyte colony-stimulating factor (G-CSF) is a cytokine used in pharmaceutical preparations for the treatment of chemotherapy-induced neutropenia. Evidence from experimental studies indicates that G-CSF exerts relevant activities in the central nervous system (CNS) in particular after lesions. In acute, subacute, and chronic CNS lesions, G-CSF appears to have strong anti-inflammatory, antiapoptotic, antioxidative, myelin-protective, and axon-regenerative activities. Additional effects result in the stimulation of angiogenesis and neurogenesis as well as in bone marrow stem cell mobilization to the CNS. There are emerging preclinical and clinical data indicating that G-CSF is a safe and effective drug for the treatment of acute and chronic traumatic spinal cord injury (tSCI), which we summarize in this review.Many patients with acute myeloid leukemia (AML) experience poor outcomes following traditional high-dose chemotherapies and complete remission rates remain suboptimal. Chemoresistance is an obstacle to effective chemotherapy and the precise mechanisms involved remain to be determined. Recently, long noncoding RNAs (lncRNAs) have been identified as relevant factors in the development of drug resistance in patients with AML. Furthermore, accumulating data support the importance of lncRNAs as potentially useful novel therapeutic targets in many cancers. Here, we review the role of lncRNAs in the development and induction of the chemoresistance in AML, and suggest lncRNAs as novel molecular markers for diagnosis, prediction of patient response to chemotherapy, and novel therapeutic targets for AML.Development of curative treatments for glioblastoma (GBM) has been stagnant in recent decades largely because of significant financial risks. A portfolio-based strategy for the parallel discovery of breakthrough therapies can effectively reduce the financial risks of potentially transformative clinical trials for GBM. Using estimates from domain experts at the National Brain Tumor Society (NBTS), we analyze the performance of a portfolio of 20 assets being developed for GBM, diversified across different development phases and therapeutic mechanisms. We find that the portfolio generates a 14.9% expected annualized rate of return. By incorporating the adaptive trial platform GBM AGILE in our simulations, we show that at least one drug candidate in the portfolio will receive US Food and Drug Administration (FDA) approval with a probability of 79.0% in the next decade.'Diabesity' refers to a rising epidemic indicated by the intricate relationship between obesity and diabetes. The global prevalence of these coexisting, insidious diseases increases social and economic health burdens at a rapid pace. Numerous reports delineate the involvement of the underlying endocannabinoid (EC) signaling system through the cannabinoid-1 (CB1) receptor in the regulation of metabolism and adiposity. Conversely, EC inverse agonists can result in severe depression and suicidal thoughts through interactions with CB1/2 receptors in the brain. This review attempts to elucidate a possible mechanism for the amelioration of diabesity. Moreover, we also highlight the available targets of the CB1 receptor, which could pave the way for safe and effective therapy.Neuromyelitis optica spectrum disorder (NMOSD) is a rare disease of the central nervous system (CNS) that is associated with poor outcomes for patients. Until recently, when complement inhibitors were approved, there was no approved therapy. Most recently, clinical trials of interleukin-6 (IL-6) blockade showed a therapeutic benefit for NMOSD. In this review, we introduce the immunological basis of IL-6 blockade in NMOSD and summarize current knowledge about the clinical use of the IL-6 receptor inhibitors tocilizumab and satralizumab. The aim of extending the half-life of monoclonal antibodies (mAbs) has been actualized by successful clinical translation for Satralizumab, achieved via the neonatal Fc receptor (FcRn) pathway. The basic principles of FcRn are highlighted in this review together with the potential therapeutic benefits of this emerging technology.The enzyme cholesteryl ester transfer protein (CETP), involved in cholesterol metabolism and transportation, is one of the main causes of cardiovascular (CV) disease (CVD). When the CETP concentration is decreased by CETP inhibitors (e.g., anacetrapib, torcetrapib, obicetrapib, etc.), high-density lipoprotein (HDL) particles are formed and low-density lipoprotein (LDL) is decreased along with cholesterol transportation alteration, which reduces the development of atherosclerosis. Here, we discuss the role of CETP inhibitors in reducing well-known 'bad' cholesterols and the current status of trials of different CETP inhibitors, their adverse effects, and limitations, as well as the pathophysiology of CETP.Disruption of circadian oscillations has a wide-ranging impact on health, with the potential to induce the development of clock-related diseases. Small-molecule modulators of the circadian clock (SMMCC) target core or noncore clock proteins, modulating physiological effects as a consequence of agonist, inverse agonist, or antagonist interference. These pharmacological modulators are usually identified using chemical screening of large libraries of active compounds. However, target-based screens, chemical optimization, and circadian crystallography have recently assisted in the identification of these compounds. In this review, we focus on established and novel SMMCCs targeting both core and noncore clock proteins, identifying their circadian targets, detailed circadian effects, and specific physiological effects. In addition, we discuss their therapeutic potential for the treatment of diverse clock-related disorders (such as metabolic-associated disorders, autoimmune diseases, mood disorders, and cancer) and as chronotherapeutics. Future perspectives are also considered, such as clinical trials, and potential safety hazards, including those in the absence of clinical trials.With the emergence of the new variants of concern (VOC) of the SARS-CoV-2, the efficacy of certain vaccines against them requires further research and considerations for future scenarios of COVID-19 vaccination. The vaccines' lack of efficacy against VOC will pose at risk to the vaccinated population and is a public health threat. In this commentary, we discuss Nepal's recent experiences and expectations regarding the confirmation of VOC B.1.1.7 from the United Kingdom in the country.