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Abstract Background Repetitive transcranial magnetic stimulation (rTMS) has been used to treat various neurological disorders. However, the molecular mechanism underlying the therapeutic effect of rTMS on Parkinson’s disease (PD) has not been fully elucidated. Neuroinflammation like regulatory T-cells (Tregs) appears to be a key modulator of disease progression in PD. If rTMS affects the peripheral Tregs in PD remains unknown. Methods Here, we conducted a prospective clinical study (Chinese ClinicalTrials. gov: ChiCTR 2100051140) involving 54 PD patients who received 10-day rTMS (10 Hz) stimulation on the primary motor cortex (M1) region or sham treatment. Clinical and function assessment as well as flow cytology study were undertaken in 54 PD patients who were consecutively recruited from the department of neurology at Zhujiang hospital between September 2021 and January 2022. Subsequently, we implemented flow cytometry analysis to examine the Tregs population in spleen of MPTP-induced PD mice that received rTMS or sham treatment, along with quantitative proteomic approach reveal novel molecular targets for Parkinson's disease, and finally, the RNA interference method verifies the role of these new molecular targets in the treatment of PD. Results We demonstrated that a 10-day rTMS treatment on the M1 motor cortex significantly improved motor dysfunction in PD patients. The beneficial effects persisted for up to 40 days, and were associated with an increase in peripheral Tregs. There was a positive correlation between Tregs and motor improvements in PD cases. Similarly, a 10-day rTMS treatment on the brains of MPTP-induced PD mice significantly ameliorated motor symptoms. rTMS reversed the downregulation of circulating Tregs and tyrosine hydroxylase neurons in these mice. It also increased anti-inflammatory mediators, deactivated microglia, and decreased inflammatory cytokines. These effects were blocked by administration of a Treg inhibitor anti-CD25 antibody in MPTP-induced PD mice. Quantitative proteomic analysis identified TLR4, TH, Slc6a3 and especially Syt6 as the hub node proteins related to Tregs and rTMS therapy. Lastly, we validated the role of Treg and rTMS-related protein syt6 in MPTP mice using the virus interference method. Conclusions Our clinical and experimental studies suggest that rTMS improves motor function by modulating the function of Tregs and suppressing toxic neuroinflammation. Hub node proteins (especially Syt6) may be potential therapeutic targets. Trial registration Chinese ClinicalTrials, ChiCTR2100051140. Registered 15 December 2021, https://www.chictr.org.cn/bin/project/edit?pid=133691 Graphical Abstract rTMS is a safe and non-invasive method for Parkinson's disease. In this study, we showed the proportion of CD4+CD25+CD127- regulatory T-cells (Tregs) in the peripheral blood was significantly increased after rTMS treatment. Similar effects of rTMS treatment were verified in MPTP-induced PD mice. Proteomic analysis and RNA interference analyses identified TLR4, TH, Slc6a3 and especially Syt6 as hub node proteins that can be modulated by rTMS therapy in PD.

Abstract The 5-2-1 criteria was developed to facilitate the identification and referral of patients with Parkinson’s Disease (PD) inadequately controlled by oral medications. The criterion was not developed to screen patients with PD for device-aided therapy eligibility. The robust design and validation of the 5-2-1 criteria minimizes over or inappropriate referrals, and supports physicians in the timely identification of patients with PD who may warrant further evaluation for treatment optimization. This response letter clarifies concerns raised by Moes et al.

Abstract The management of Parkinson’s disease (PD) continues to evolve with advancements in non-oral levodopa-based therapies aiming to provide continuous drug delivery (CDD). Such therapies address the challenges posed by the emergence of motor fluctuations, dyskinesias, and non-motor fluctuations (NMF) associated with oral levodopa administration and contributing to define the advanced stage of PD. The key focus of this review is placed on subcutaneous foslevodopa/foscarbidopa (Foslevodopa/foscarbidopa) infusion, showcasing its recent clinical availability and efficacy in providing continuous levodopa delivery. While providing an overview of the other non-oral levodopa-based CDD systems, such as intrajejunal levodopa–carbidopa infusion and levodopa–entacapone–carbidopa infusion, we highlight the current promising evidence for Foslevodopa/foscarbidopa to improve, for example, “on time” without troublesome dyskinesia and reducing “off time” in people with advanced PD. Additionally, Foslevodopa/foscarbidopa demonstrates potential in managing early morning off periods, sleep quality and other motor and non-motor symptoms. Moreover, other non-oral CDD options such as ND0612 and DIZ102/DIZ101 are discussed, with focus on their pharmacokinetics/pharmacodynamics, efficacy, and safety profiles. While these advancements present new therapeutic avenues, long-term observational studies are warranted to elucidate their impact on existing PD therapies. Overall, this review provides insights into the evolving landscape of non-oral CDD therapies and offers a pragmatic approach for their integration into clinical practice.

Abstract The effects of subthalamic nucleus deep brain stimulation (STN-DBS) on anxiety in Parkinson’s disease (PD) are understudied. We identified clinical predictors of STN-DBS effects on anxiety in this study. In this prospective, open-label, multicentre study, we assessed patients with anxiety undergoing STN-DBS for PD preoperatively and at 6-month follow-up postoperatively. We assessed the Hospital Anxiety and Depression Scale (HADS-anxiety and depression subscales), Unified PD Rating Scale-motor examination, Scales for Outcomes in PD-motor (SCOPA-M)-activities of daily living (ADL) and -motor complications, Non-Motor Symptom Scale (NMSS), PDQuestionnaire-8 (PDQ-8), and levodopa-equivalent daily dose. We tested changes at follow-up with Wilcoxon signed-rank test and corrected for multiple comparisons (Bonferroni method). We identified patients with a clinically relevant anxiety improvement of anxiety based on a designated threshold of ½ standard deviation of baseline HADS-anxiety. Moreover, we investigated predictors of HADS-anxiety changes with correlations and linear regressions. We included 50 patients with clinically relevant baseline anxiety (i.e., HADS-anxiety ≥ 8) aged 63.1 years ± 8.3 with 10.4 years ± 4.5 PD duration. HADS-anxiety improved significantly at 6-month follow-up as 80% of our cohort experienced clinically relevant anxiety improvement. In predictor analyses, worse baseline SCOPA-ADL and NMSS-urinary domain were associated with greater HADS-anxiety improvements. HADS-anxiety and PDQ-8 changes correlated moderately. Worse preoperative ADL and urinary symptoms predicted favourable postoperative anxiety outcome, which in turn was directly proportionate to greater QoL improvement. This study highlights the importance of detailed anxiety assessments alongside other non-motor and motor symptoms when advising and monitoring patients undergoing STN-DBS for PD.

Background: The application of the Six Sigma (σ) metric in biochemical laboratories is a powerful tool for reducing the occurrence of errors and prioritizing important improvements in laboratory quality control. The National Accreditation Board for Testing and Calibration Laboratories (NABL) is an accreditation body with an accreditation system established in accordance with ISO/IEC 17011, providing specialty- or scope-based certification based on the conformance of quality indices to medical laboratories. In this context, a study has been designed that considers the quality guidelines set by NABL as well as the sigma metric rule in the assessment of analytical performance. Aims and Objectives: The aims of this study were to identify the gaps and need for strategy modification for quality improvement by assessing the performance of two NABL-accredited medical testing laboratories on a Sigma metric scale. Materials and Methods: A retrospective analytical study was conducted over 6 months (January–June 2021). Internal quality control (IQC) and EQAS data were obtained from third-party QC providers (Bio-Rad, India) and analyzed by calculating sigma (σ) values based on the coefficient of variation, bias, and total error allowable in two NABL-accredited medical testing laboratories. To identify potential problems for analytes with poor sigma values, a quality goal index (QGI) analysis was performed. Results: By analyzing the sigma values obtained by both NABL-accredited laboratories, we can see that laboratory 2 performed better than laboratory 1. After calculating the QGI, there was a problem of inaccuracy and imprecision in laboratory 1, and laboratory 2 had QGI values that indicated only imprecision. Conclusion: Diagnostic laboratories should incorporate Six Sigma metrics to identify gaps in their performance to ensure better quality control and patient safety.

Neonatal sepsis causes substantial morbidity and mortality, the burden of which is carried by low-income countries (LICs). The emergence of multidrug-resistant pathogens in vulnerable neonatal populations poses an urgent threat to infant survival. Acinetobacter spp. are increasingly responsible for severe disease in neonates globally. The cause of this escalation remains unclear, but host, pathogen and environmental factors are all likely to contribute. Acinetobacter spp. strains are frequently resistant to the first line empirical treatment for neonatal sepsis as recommended by the World Health Organization (WHO), ampicillin and gentamicin, rendering these antibiotics ineffectual in many critically ill neonates. The resultant escalation to broader spectrum antibiotic regimens in neonatal intensive care units (NICUs) worldwide has led to the emergence of more resistant strains, including carbapenem-resistant Acinetobacter baumanii (CRAB), resulting in infections that are ever more difficult to treat. While some existing antimicrobial agents are under consideration for treatment of Acinetobacter spp. infections, the majority remain a long way from clinical use in neonates. Further research into the clinical phenotype of these infections, transmission dynamics and preventative measures are urgently needed to reduce neonatal deaths. This review aims to summarise the role of Acinetobacter spp. in neonatal sepsis, including host, pathogen and environmental factors, the global epidemiology and clinical features of the disease, the treatment options, and future research priorities.

With the current trend, the power generation in the future power grids is expected to consist of a large number of converter-interfaced generations (CIGs) with a small percentage of synchronous generators (SGs) producing power from hydro, solar thermal, or even nuclear resources. These notable changes pose significant challenges to the secure operation of the power grid. One such issue is new cascading failure mechanisms introduced by CIGs, especially due to the dc-link voltage collapse in a dc-current limited grid-forming converter (GFC) following a generation outage. Therefore, in the online dynamic security assessment (DSA), the system operators would be interested in knowing the critical outages that may trigger this cascading mechanism in the system. To address this issue, this paper presents a contingency screening and ranking approach (which can be a part of a DSA) for generator outages in a modern grid that consists of SGs and GFCs. Our specific focus is to identify the critical outages that may lead to a cascading failure in the system due to a dc-voltage collapse in the GFCs. To that end, first, a novel contingency screening and ranking index for an (N-1) contingency scenario (i.e., outage of a single generator) is derived based on the traditional generator power tracing algorithm. Then, it is shown that the proposed ranking index can be extended to any (N-k) contingency scenarios. Finally, the effectiveness of the proposed approach following generator outages (up to (N-2) contingencies) is demonstrated using detailed time-domain simulations in two different modified test configurations of a 16-machine 68-bus New York-New England test system with GFCs using the MATLAB/Simulink platform.

Purpose: International guidelines for the management of patients with low back pain (LBP) are available, but there are no India-specific guidelines for the diagnosis and management of LBP in primary care. This article aims to provide clinical insights for the diagnosis and treatment of LBP for primary care practitioners in India. Methods: A 3-step modified Delphi method was used to get insights and opinions from a panel of 9 multidisciplinary specialist (neurology, orthopedics, and pain management). In rounds 1 and 2, 203 and 60 statements, respectively, were circulated to the expert panel and they were asked to respond with an “agree” or “disagree” to each statement and provide comments. At least 80% of the experts had to agree for a statement to reach a concordance. More than 80% concordance was reached for 175 and 32 statements in rounds 1 and 2, respectively. Round 3 was a direct interaction with the experts. Results: There was good agreement among the expert panelist in round 3 for the consensus-derived statements from the earlier two rounds of the survey. The panel agreed that diagnostic triage is important to exclude specific spinal pathology, routine imaging is not recommended unless suspecting serious pathology, specialist referral is needed for serious pathologies/no improvement in pain with treatment, and management is to be individualized depending on etiology and patient factors. Conclusions: Primary care physicians are the first point of contact for patients with back pain. These consensus recommendations will assist primary care physicians in India to choose an appropriate course of action for managing patients with LBP.

Abstract Deep brain stimulation of the subthalamic nucleus (STN-DBS) is an established therapy in advanced Parkinson’s disease (PD). Motor and non-motor outcomes, however, show considerable inter-individual variability. Preoperative morphometry-based metrics have recently received increasing attention to explain treatment effects. As evidence for the prediction of non-motor outcomes is limited, we sought to investigate the association between metrics of voxel-based morphometry and short-term non-motor outcomes following STN-DBS in this prospective open-label study. Forty-nine PD patients underwent structural MRI and a comprehensive clinical assessment at preoperative baseline and 6-month follow-up. Voxel-based morphometry was used to assess associations between cerebral volume and non-motor outcomes corrected for multiple comparisons using a permutation-based approach. We replicated existing results associating volume loss of the superior frontal cortex with subpar motor outcomes. Overall non-motor burden, however, was not significantly associated with morphometric features, limiting its use as a marker to inform patient selection and holistic preoperative counselling.

Introduction: Neonatal sepsis is a global healthcare concern, which is more prevalent in developing countries. However, surprisingly, biomarkers with good sensitivity and specificity to predict mortality and morbidity are lacking. Higher levels of serum lactate are observed in patients exposed to an inflammatory response, but its practical use remains limited. Therefore, the author aimed to investigate the relationship between serum lactate measurements and the severity of neonatal sepsis. Aim: To assess the role of serum lactate clearance as a marker to predict mortality and morbidity in neonatal sepsis. Additionally, the secondary aim was to evaluate the demographic profile of neonatal sepsis and understand the relationship between C-reactive Protein (CRP), Procalcitonin, and lactate clearance in neonatal sepsis. Materials and Methods: A prospective cohort study was conducted in the Sick Newborn Care Unit (SNCU) and Neonatal Intensive Care Unit (NICU) of Chittaranjan Seva Sadan, College of Obstetrics, Gynaecology, and Child Health in Kolkata, India, from June 2020 to May 2021. A total of 93 confirmed cases of neonatal sepsis were included in the study. Serum lactate levels were measured at the time of sepsis diagnosis and 48 hours after the first sample. Lactate clearance was calculated, and the neonates were followed till discharge or death. Various parameters, including complete blood count, CRP, Procalcitonin, culture, and Cerebrospinal Fluid (CSF), were assessed. The data obtained were statistically analysed using paired t-test, one-way Analysis of Variance (ANOVA), and Pearson’s Chi-square test. Results: A total of 93 neonates were included after meeting the inclusion and exclusion criteria. Among them, 10 neonates died, while 83 were successfully discharged. It was found that death was significantly associated (p

Abstract Background Parkinson’s disease is now one of the fastest-growing neurodegenerative disorders in the developed world, with an increasing prevalence and associated socioeconomic costs. Progression of the disease leads to a gradual deterioration in patients’ quality of life, despite optimal treatment, and both medical and societal needs increase, often with the assistance of paid and/or unpaid caregivers. Objective We aimed to quantify the incremental economic burden of Parkinson’s disease by disease severity in a real-world setting across differing geographic regions. Methods Demographics, clinical characteristics, health status, patient quality of life, caregiver burden, and healthcare resource utilization data were drawn from the Adelphi Parkinson’s Disease Specific Program™, conducted in the USA, five European countries, and Japan. Results A total of 563 neurologists provided data for 5299 individuals with Parkinson’s disease; 61% were male, with a mean age of 64 years. Approximately 15% of individuals were deemed to have advanced disease, with significantly more comorbidities, and a poorer quality of life, than those with non-advanced disease. Overall, the mean annual healthcare resource utilization increased significantly with advancing disease, and resulted in a three-fold difference in the USA and Europe. The main drivers behind the high economic burden included hospitalizations, prescription medications, and indirect costs. Conclusions People with Parkinson’s disease, and their caregivers, incur a higher economic burden as their disease progresses. Future interventions that can control symptoms or slow disease progression could reduce the burden on people with Parkinson’s disease and their caregivers, whilst also substantially impacting societal costs.

Abstract Background To date, beneficial effects of multimodal exercise programmes on Parkinson’s disease (PD) have focused on motor symptoms and little attention has been paid to the potential effects of such programmes on the non-motor symptoms of PD, which are now universally known as one of the key drivers of quality of life and a key unmet need. We aim to explore clinical effectiveness of a ballet-based dance programme in addressing non-motor and motor symptoms of Parkinson’s disease across all stages of progression. Methods A randomised, single-blind, controlled trial of 160 people with Parkinson’s across all motor stages (Participants will be stratified into three groups of motor advancement: Hoehn and Yahr (HY) stages I and II being Mild Group, HY Stage III being Moderate Group and HY Stages IV and V being Severe Group) will be randomly allocated to either an intervention or a control group using an independent randomisation body. The primary outcome is an improvement in non-motor symptoms as measured by the Movement Disorders Society Non-Motor Scale (MDS-NMS). The intervention protocol consists of 12 one-weekly dance sessions led by English National Ballet. Each session is followed by a ‘tea and biscuit’ social time. Control group follows standard clinical pathway and joins the ‘tea and biscuit’ to control for any positive effects of social interactions. All participants are assessed at baseline, immediately after completion of the intervention and 3–6 months later to explore any potential longitudinal effects. Discussion To our knowledge, no adequately powered study has explored the effects of a dance-based intervention on non-motor symptoms of Parkinson’s disease, assessing these on both holistic and granular levels. We also aim to stratify participants in accordance with their motor state as assessed by. HY staging to explore specific effects on the symptoms at the initial, moderate and complex stages of the disease. If successful, this trial provides first evidence on clinical effectiveness of a ballet-based dance intervention for symptoms of Parkinson’s disease, assessed in a robust, rigorous manner. Trial registration NCT04719468.

Abstract Polycystic ovary syndrome (PCOS) is indeed one of the most common gynecological endocrine disorders, affecting a significant number of females in their reproductive age. While the exact cause of PCOS is not fully understood, several factors are believed to contribute to its onset. The relationship between polycystic ovary syndrome (PCOS) and low-grade chronic inflammation is complex and not fully understood. While there is evidence to suggest an association between PCOS and inflammation, the exact cause and causal nature of this relationship are still under investigation. Several inflammatory markers, including IL-6 (interleukin-6), TNF-α (tumor necrosis factor-alpha), IL-17 (interleukin-17), CRP (C-reactive protein), NLR (neutrophil-to-lymphocyte ratio), and PLR (platelet-to-lymphocyte ratio), have been studied about PCOS. These markers are substances produced by the immune system in response to inflammation. Increased levels of IL-17, IL-1, and IL-8 were correlated with PCO. CRP to albumin ratio can be employed as a precise bio-marker for PCOS. The neutrophil-to-lymphocyte ratio (NLR) indicates poor cardiovascular health and metabolic syndrome (MS) and can be considered a negative regulator for FSH which indirectly stimulates testosterone production. Platelet/lymphocyte ratio (PLR) and mean platelet volume (MPV) are also recently found to be associated with PCOS. The literature explaining the underlying mechanisms with specific inflammatory markers and how inflammation relates to PCOS will be highlighted in this review article. It will also discuss the roles of inflammation and the association of different inflammatory markers in the pathogenesis of PCOS, which may usher in a new era in the treatment approach for PCOS.

Abstract Advanced Parkinson’s Disease (APD) is complicated by the emergence of motor and non-motor fluctuations, which are initially predictable and eventually become unpredictable, in part due to erratic gastric absorption and short half of oral levodopa. Attempts to manage such fluctuations with oral dopaminergic drugs often lead to disabling dyskinesias. Continuous Subcutaneous Apomorphine Infusion (CSAI), despite being approved for the treatment of APD since 1993, was approved in India only in 2019. We studied the safety, tolerability and efficacy of CSAI in Indian patients with APD in a registry design to raise local awareness of this important treatment. We conducted a prospective registry-based observational audit at 10 centers across different states of India. Patients with APD, not responding to or with significant side effects from oral dopaminergic therapy, were assessed at baseline and at month 6 and 12 following CSAI infusion. Fifty-one patients completed the study, CSAI significantly reduced the functional impact of dyskinesia (p

Abstract DNA replication and repair defects or genotoxic treatments trigger interferon (IFN)-mediated inflammatory responses. However, whether and how IFN signaling in turn impacts the DNA replication process has remained elusive. Here we show that basal levels of the IFN-stimulated gene 15, ISG15, and its conjugation (ISGylation) are essential to protect nascent DNA from degradation. Moreover, IFNβ treatment restores replication fork stability in BRCA1/2-deficient cells, which strictly depends on topoisomerase-1, and rescues lethality of BRCA2-deficient mouse embryonic stem cells. Although IFNβ activates hundreds of genes, these effects are specifically mediated by ISG15 and ISGylation, as their inactivation suppresses the impact of IFNβ on DNA replication. ISG15 depletion significantly reduces cell proliferation rates in human BRCA1-mutated triple-negative, whereas its upregulation results in increased resistance to the chemotherapeutic drug cisplatin in mouse BRCA2-deficient breast cancer cells, respectively. Accordingly, cells carrying BRCA1/2 defects consistently show increased ISG15 levels, which we propose as an in-built mechanism of drug resistance linked to BRCAness.

Abstract Loss of empathy is an early and central symptom of frontotemporal lobar degeneration spectrum diseases. We aimed to investigate the topographical distribution of morphometric brain changes associated with empathy in Progressive Supranuclear Palsy (PSP) and Corticobasal Syndrome (CBS) patients. Twenty-seven participants with CBS and 31 with PSP were evaluated using Interpersonal Reactivity Index scales in correlation with gray matter atrophy using a voxel-based morphometry approach. Lower levels of empathy were associated with an increased atrophy in fronto-temporal cortical structures. At subcortical level, empathy scores were positively correlated with gray matter volume in the amygdala, hippocampus and the cerebellum. These findings allow to extend the traditional cortico-centric view of cognitive empathy to the cerebellar regions in patients with neurodegenerative disorders and suggest that the cerebellum may play a more prominent role in social cognition than previously appreciated.

Abstract Introduction Foslevodopa/foscarbidopa, a soluble formulation of levodopa/carbidopa (LD/CD) prodrugs for the treatment of Parkinson’s disease (PD), is administered as a 24-hour/day continuous subcutaneous infusion (CSCI) with a single infusion site. The efficacy and safety of foslevodopa/foscarbidopa versus oral immediate-release LD/CD was previously demonstrated in patients with PD in a 12-week, randomized, double-blind, phase 3 trial (NCT04380142). We report the results of a separate 52-week, open-label, phase 3 registrational trial (NCT03781167) that evaluated the safety/tolerability and efficacy of 24-hour/day foslevodopa/foscarbidopa CSCI in patients with advanced PD. Methods Male and female patients with levodopa-responsive PD and ≥ 2.5 hours of “Off” time/day received 24-hour/day foslevodopa/foscarbidopa CSCI at individually optimized therapeutic doses (approximately 700–4250 mg of LD per 24 hours) for 52 weeks. The primary endpoint was safety/tolerability. Secondary endpoints included changes from baseline in normalized “Off” and “On” time, percentage of patients reporting morning akinesia, Movement Disorder Society Unified Parkinson’s Disease Rating Scale (MDS-UPDRS), Parkinson’s Disease Sleep Scale–2 (PDSS-2), 39-item Parkinson’s Disease Questionnaire (PDQ-39), and EuroQol 5-dimension questionnaire (EQ-5D-5L). Results Of 244 enrolled patients, 107 discontinued, and 137 completed treatment. Infusion site events were the most common adverse events (AEs). AEs were mostly nonserious (25.8% of patients reported serious AEs) and mild/moderate in severity. At week 52, “On” time without troublesome dyskinesia and “Off” time were improved from baseline (mean [standard deviation (SD)] change in normalized “On” time without troublesome dyskinesia, 3.8 [3.3] hours; normalized “Off” time, −3.5 [3.1] hours). The percentage of patients experiencing morning akinesia dropped from 77.7% at baseline to 27.8% at week 52. Sleep quality (PDSS-2) and quality of life (PDQ-39 and EQ-5D-5L) also improved. Conclusion Foslevodopa/foscarbidopa has the potential to provide a safe and efficacious, individualized, 24-hour/day, nonsurgical alternative for patients with PD. Trial Registration Number ClinicalTrials.gov identifier NCT03781167.

Early-morning off periods, causing early-morning akinesia, can lead to significant motor and nonmotor morbidity in levodopa-treated fluctuating Parkinson’s disease (PD) cases. Despite validated bedside scales in clinical practice, such early-morning off periods may remain undetected unless specific wearable technologies, such as the Parkinson’s KinetiGraph™ (PKG) watch, are used. We report five PD cases for whom the PKG detected early-morning off periods that were initially clinically undetected and as such, untreated. These five cases serve as exemplars of this clinical gap in care. Post-PKG assessment, clinicians were alerted and targeted therapies helped abolish the early-morning off periods.