Influence of autozygosity on common disease risk across the phenotypic spectrum.

Autozygosity is associated with rare Mendelian disorders and clinically relevant quantitative traits. We investigated associations between the fraction of the genome in runs of homozygosity (FROH) and common diseases in Genes & Health (n = 23,978 British South Asians), UK Biobank (n = 397,184), and 23andMe. We show that restricting analysis to offspring of first cousins is an effective way of reducing confounding due to social/environmental correlates of FROH. Within this group in G&H+UK Biobank, we found experiment-wide significant associations between FROH and twelve common diseases. We replicated associations with type 2 diabetes (T2D) and post-traumatic stress disorder via within-sibling analysis in 23andMe (median n = 480,282). We estimated that autozygosity due to consanguinity accounts for 5%-18% of T2D cases among British Pakistanis. Our work highlights the possibility of widespread non-additive genetic effects on common diseases and has important implications for global populations with high rates of consanguinity.

Medial Prefrontal Cortex Stimulation Reduces Retrieval-Induced Forgetting via Fronto-parietal Beta Desynchronization.

The act of recalling memories can paradoxically lead to the forgetting of other associated memories, a phenomenon known as retrieval-induced forgetting (RIF). Inhibitory control mechanisms, primarily mediated by the prefrontal cortex, are thought to contribute to RIF. In this study, we examined whether stimulating the medial prefrontal cortex (mPFC) with transcranial direct current stimulation modulates RIF and investigated the associated electrophysiological correlates. In a randomized study, 50 participants (27 males and 23 females) received either real or sham stimulation before performing retrieval practice on target memories. After retrieval practice, a final memory test to assess RIF was administered. We found that stimulation selectively increased the retrieval accuracy of competing memories, thereby decreasing RIF, while the retrieval accuracy of target memories remained unchanged. The reduction in RIF was associated with a more pronounced beta desynchronization within the left dorsolateral prefrontal cortex (left-DLPFC), in an early time window (<500 ms) after cue onset during retrieval practice. This led to a stronger beta desynchronization within the parietal cortex in a later time window, an established marker for successful memory retrieval. Together, our results establish the causal involvement of the mPFC in actively suppressing competing memories and demonstrate that while forgetting arises as a consequence of retrieving specific memories, these two processes are functionally independent. Our findings suggest that stimulation potentially disrupted inhibitory control processes, as evidenced by reduced RIF and stronger beta desynchronization in fronto-parietal brain regions during memory retrieval, although further research is needed to elucidate the specific mechanisms underlying this effect.

Effects of high-definition tDCS targeting individual motor hotspot with EMG-driven robotic hand training on upper extremity motor function: a pilot randomized controlled trial.

BACKGROUND: Delivering HD-tDCS on individual motor hotspot with optimal electric fields could overcome challenges of stroke heterogeneity, potentially facilitating neural activation and improving motor function for stroke survivors. However, the intervention effect of this personalized HD-tDCS has not been explored on post-stroke motor recovery. In this study, we aim to evaluate whether targeting individual motor hotspot with HD-tDCS followed by EMG-driven robotic hand training could further facilitate the upper extremity motor function for chronic stroke survivors. METHODS: In this pilot randomized controlled trial, eighteen chronic stroke survivors were randomly allocated into two groups. The HDtDCS-group (n = 8) received personalized HD-tDCS using task-based fMRI to guide the stimulation on individual motor hotspot. The Sham-group (n = 10) received only sham stimulation. Both groups underwent 20 sessions of training, each session began with 20 min of HD-tDCS and was then followed by 60 min of robotic hand training. Clinical scales (Fugl-meyer Upper Extremity scale, FMAUE; Modified Ashworth Scale, MAS), and neuroimaging modalities (fMRI and EEG-EMG) were conducted before, after intervention, and at 6-month follow-up. Two-way repeated measures analysis of variance was used to compare the training effect between HDtDCS- and Sham-group. RESULTS: HDtDCS-group demonstrated significantly better motor improvement than the Sham-group in terms of greater changes of FMAUE scores (F = 6.5, P = 0.004) and MASf (F = 3.6, P = 0.038) immediately and 6 months after the 20-session intervention. The task-based fMRI activation significantly shifted to the ipsilesional motor area in the HDtDCS-group, and this activation pattern increasingly concentrated on the motor hotspot being stimulated 6 months after training within the HDtDCS-group, whereas the increased activation is not sustainable in the Sham-group. The neuroimaging results indicate that neural plastic changes of the HDtDCS-group were guided specifically and sustained as an add-on effect of the stimulation. CONCLUSIONS: Stimulating the individual motor hotspot before robotic hand training could further enhance brain activation in motor-related regions that promote better motor recovery for chronic stroke. TRIAL REGISTRATION: This study was retrospectively registered in ClinicalTrials.gov (ID NCT05638464).

Role of Proton Beam Therapy in Spinal Chordomas: A Narrative Review of The Literature.

Chordomas are rare malignant neoplasms arising from vestigial remnants of the embryonic notochord. Approximately 55-70% of chordomas develop within the vertebral column. Their affinity to develop within the bones of the axial skeleton and propensity to locally invade and recur makes them challenging candidates for complete surgical excision. Adjuvant therapies are hence necessary to improve outcomes; for which chemotherapy has been observed to be largely ineffective, owing to the tumour being resistant to it. Radiotherapy is the current adjuvant therapy of choice for chordoma management. Over the years, proton beam therapy (PBT) has been the subject of medical attention, given the dosimetric benefits it confers over traditional radiotherapy, allowing more concentrated radiation to be given to the target of interest and reducing damage to surrounding normal tissue. A review of the current literature reveals PBT offers significantly better outcomes when used as an adjuvant to maximal surgical resection rather than as a definitive therapy.

Developing a non-cadaveric brain tumour surgery lab in resource-constrained settings.

OBJECTIVE: To develop the country's first brain tumour surgery lab in resource-constrained settings, for training young neurosurgeons and residents. METHODS: A workshop was developed using mixed-fidelity models for assessing and training a participant's psychomotor skills, hand-eye coordination, and teaching the principles of brain tumour surgery. Affordable noncadaveric models were used to compare and contrast the benefit of each teaching model. Within the existing space for wet labs at our institution, 8 different dissection stations were set up with adequate space for 2 people to work at a time. Each station was equipped with an operating room-Caliber microscope, a lighting system and a camera linked to a screen and high-powered electric drills and basic surgical equipment. RESULTS: Our team was able to develop and use 3D-printed skull models and animal brain models for training in complex approaches and craniotomy. CONCLUSIONS: Surgical simulation training, in a cost-effective manner, provides the benefit of training residents and students in neurosurgical techniques in a safe, controlled environment leading to improvement in skills and technique.

Consensus guidelines for the management of vestibular schwannoma for lowand middle-income countries.

Vestibular Schwannoma (VS), previously known as acoustic neuroma, constitutes the majority of tumours found in the cerebellopontine angle (CPA). Most guidelines for managing CPA tumours have been developed by high-income countries (HICs). However, these guidelines often fall short in addressing the unique challenges encountered in low- and middle-income countries (LMICs), such as Pakistan. In LMICs, issues related to a limited healthcare workforce, inadequate infrastructure, and constrained financial resources hinder the effective implementation of these HIC-derived guidelines. Additionally, it has been observed that VS tends to present at a larger size in LMICs compared to HICs. Given that VS is the predominant type of CPA tumour and other types are covered under separate guidelines, this article aims to provide practical, contextspecific recommendations for the screening, diagnosis, and management of Vestibular Schwannoma in LMIC settings. Our focus is to bridge the gap in care strategies and adapt them to the resource constraints and clinical realities of LMICs.

Developing neuro-oncology clinical trials in low- and middle-income countries: a scoping review of the current literature.

Low- and middle-income countries (LMICs) have historically been under-represented in clinical trials, leading to a disparity in evidence-based recommendations for the management of neurooncological conditions. To address this knowledge gap, we conducted a scoping review to assess the current literature on clinical trials in neuro-oncology from LMICs. The eligibility criteria for inclusion in this review included clinical trials registered and conducted with human subjects, with available English language text or translation, and focussed on neuro-oncological cases. The literature search strategy captured 408 articles, of which 61 met these criteria, with a significant number of randomised controlled trials from specific LMICs. The review found that LMIC clinical trials have contributed significantly to understanding surgical, chemotherapeutic, and radiation therapy interventions for brain tumours, paediatric cancers, and the repurposing of drugs as new targets in neuro-oncology. These findings highlight the potential for expanding clinical trials research in neuro-oncology in LMICs, which may significantly impact global understanding and management of these conditions, particularly from diverse populations from the global south.

Consensus guidelines for the management of intracranial metastases for low- and middle-income countries.

Metastatic tumours are among the most common types of brain tumours. However, in low- and middle-income countries (LMICs), the numbers are considerably lower. This does not necessarily indicate a decreased incidence but rather points to decreased survival rates or limited access to healthcare. The challenge of achieving better outcomes, along with associated costs and resource constraints, often hinders the effective management of brain metastasis. Even in cases where localised disease can potentially be managed to improve survival, these challenges persist. The purpose of these guidelines is to address these challenges and outline a management strategy within the context of LMICs.

Consensus guidelines for the management of intracranial ependymoma for low- and middle-income countries.

This paper presents comprehensive consensus guidelines for the management of intracranial ependymoma, neoplasms arising from ependymal cells in the central nervous system's ventricular system, in low- and middleincome countries (LMICs). Acknowledging the distinct epidemiological patterns of ependymomas, notably their higher incidence in paediatric patients, and variable survival rates, these guidelines emphasize tailored management approaches for different age groups. An expert panel, comprising specialists in neuro-oncology, convened to address gaps in diagnosis and management within LMICs, considering the varying clinical presentation based on tumour size and location. Emphasizing surgical intervention as the cornerstone of treatment, the guidelines also address challenges such as intraoperative bleeding and tumour location impacting complete resection. The role of molecular subgrouping in stratifying treatment and predicting prognosis is highlighted, alongside a careful consideration of radiotherapy timing, dose, and volume based on risk factors. Chemotherapy's role, especially in paediatric cases, is explored. The paper synthesizes current research and expert opinions, including the need for standardisation, genetic testing, and exploration of less invasive treatment modalities, to address the unique healthcare infrastructure challenges in LMICs. The guidelines also emphasize multidisciplinary teams, aiming to bridge the care gap between high-income countries and LMICs, and improve survival rates and quality of life for patients with intracranial ependymoma. This article serves as a valuable resource for clinicians, researchers, and policymakers in Pakistan and beyond, facilitating the development of evidence-based strategies in diverse healthcare settings.

Consensus guidelines for the management of craniopharyngioma in low- and middle-income countries.

Craniopharyngiomas are benign, extra-axial epithelial tumours originating from the pituitary stalk, impacting areas such as the hypothalamus, optic chiasm, and various cranial nerves. These tumours present unique surgical challenges due to their proximity to critical neurovascular structures. Management typically involves maximal safe resection as the primary approach. However, in low- and middle-income countries (LMICs), factors like late presentation, higher risks of endocrine and visual complications, frequent recurrence, and potential for incomplete resection complicate treatment. These challenges are exacerbated by limited access to specialised expertise and surgical equipment, increasing the risk of damage during surgery compared to High- Income Countries. This manuscript outlines management guidelines tailored for LMICs, emphasizing that a combination of surgical resection and chemoradiation therapy, as advised by a neuro-oncology tumour board, often yields the best outcomes.

Consensus guidelines for the management of adult low-grade gliomas for low and middle-income countries.

Low-grade gliomas (LGG) are brain tumors of glial cells origin. They are grade 1 and grade 2 tumors according to the WHO classification. Diagnosis of LGG is made through imaging, histopathological analysis, and use of molecular markers. Imaging alone does not establish the grade of the tumor and thus a histopathological examination of tissue is crucial in establishing the definite histopathological diagnosis. Clinical presentation varies according to the location and size of the tumor. Surgical resection is strongly recommended in LGG over observation to improve overall survival as surgery leads to greater benefit due to progression-free survival. Radiation has shown benefits in LGG patients in randomized controlled trials and chemotherapy with temozolomide has also shown good results. This paper covers the principles of low-grade gliomas management and summarizes the recommendations for the LMICs.

Judicious and evidence-based use of radiosurgery - recommendations for low-middle income countries.

Surgical removal remains the primary treatment for most brain tumours. However, radiosurgery presents an effective, less invasive alternative or additional treatment for certain types. Our goal was to explore radiosurgery's roles in treating various brain tumours, focussing on its application in low- and middle-income countries (LMICs). We reviewed all relevant systematic reviews, metaanalyses, and guidelines to determine the most effective radiosurgical approaches. Additionally, we consulted a panel of experts with over ten years of experience in LMICs, such as Pakistan. For brain tumours, stereotactic radiosurgery should generally follow a confirmed histopathological diagnosis. Exceptions include tumours identified through Magnetic Resonance Imaging (MRI), like Vestibular Schwannoma (VS), pre-diagnosed Neurofibromatosis type 2 (NF2), multiple typical meningiomas, and metastases with a known histology from another site. While radiosurgery is gaining traction as a primary and adjunct treatment in some LMICs, the lack of regional guidelines, trained personnel, and collaboration among specialists hinders its wider adoption. Addressing these gaps is crucial for expanding radiosurgical care in these regions.

The need for economic evaluations for neuro-oncology in low- and middleincome: the Pakistan perspective.

The incidence and prevalence of brain tumours have steadily increased within low- and middle-income countries, similar to patterns seen in high-income countries. In addition to the epidemiological landscape of brain tumours in Pakistan, it is important to consider the economics of brain tumour diagnosis and management to inform policy on neuro-oncological healthcare service delivery. The challenges associated with conducting economic evaluations in LMICs include the ability to receive funding for country-specific estimates, dearth of existing data and methodological development, and the need for investment in economic evaluations of health. Economic evaluations are most useful when funding support is given to country-specific initiatives to allocate resources. Cost and cost components must also be meticulously collected to enable accurate calculations of economic evidence for the decision-making process. To put neuro-oncological care at the forefront of the national health agenda, it is crucial for vigorous epidemiological and economic evidence to be available for policymakers.

Role of neurosurgeons In strengthening paediatric neuro-oncology In low- and middle-income countries: a narrative review with case examples.

Paediatric neuro-oncology in low- and middle-income countries (LMICs) accounts for a significant proportion of cancer-related mortalities in this age group. The current dearth of structured paediatric neurosurgery training programmes in LMICs requires multidisciplinary coordination; neurosurgeons play certain key roles, as discussed in this article, in ensuring safe and effective care for paediatric neuro-oncology patients. This document intends to elaborate through illustrative cases of the technical and structural nuances required by neurosurgeons in LMICs to provide appropriate surgical care.

Consensus guidelines for the management of primary supra-tentorial intraventricular tumour for low- and middle-income countries.

Almost any primary or metastatic brain tumour can manifest in intraventricular (IV) locations. These tumours may either originate within the ventricular system or extend into the IV space through growth. Such neoplasms represent a broad spectrum, with supratentorial IV tumours forming a heterogeneous group. This group includes primary ependymal tumours, central neurocytomas, choroid plexus tumours, and notably, meningiomas, as well as a variety of non-neoplastic, benign, glial, and metastatic lesions that can secondarily invade the IV compartment. Often presenting with nonspecific symptoms, these tumours can lead to delayed medical attention. The diversity in potential diagnoses, combined with their deep and complex locations, poses significant management challenges. This paper aims to delineate optimal management strategies, underscoring the importance of multidisciplinary care, especially in settings with limited resources, to effectively navigate the complexities associated with treating intraventricular brain tumours.

Consensus guidelines for the management of pediatric medulloblastoma in low and middle-income countries.

The management of medulloblastoma, a pediatric brain tumor, has evolved significantly with the advent of genomic subgrouping, yet morbidity and mortality remain high in LMICs like Pakistan due to inadequate multidisciplinary care infrastructure. This paper aims to establish evidence-based guidelines tailored to the constraints of such countries. An expert panel comprising neuro-oncologists, neurosurgeons, radiologists, radiation oncologists, neuropathologists, and pediatricians collaborated to develop these guidelines, considering the specific challenges of pediatric brain tumor care in Pakistan. The recommendations cover various aspects of medulloblastoma treatment, including pre-surgical workup, neurosurgery, neuropathology, chemotherapy, radiation therapy, and supportive care. They offer both minimum required and additional optional protocols for more advanced centers, ensuring comprehensive patient management with attention to complications and complexities encountered in Pakistan. The paper's consensus guidelines strive for uniformity in healthcare delivery and address significant gaps in diagnosis, treatment, and follow-up of pediatric medulloblastoma patients.

Plastic Surgery Teaching to United Kingdom Undergraduate Medical Students: A Systematic Review.

Background There are varying reports about United Kingdom medical students' exposure and teaching methods regarding plastic and reconstructive surgery. To date, no systematic review has been done looking at this topic. Methods Three databases (PubMed, Embase, and Medline) were searched from January 1, 2011 to July 20, 2023 for studies that assessed United Kingdom medical students' exposure to plastic surgery and suggested recommendations to improve teaching. Three authors performed data extraction and screening, as per the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. Results Fifteen studies were included. Medical students' average current exposure to plastic surgery was 29.44%, but this was highly variable across the studies. The most common method of currently teaching plastic surgery was through lectures (34% of studies), and the most common suggested method of teaching was through courses (40% of studies). Many of the studies (12/15) were deemed as being at high risk of bias. Conclusion More recent studies need to be performed to assess current levels of teaching of plastic surgery in the United Kingdom medical school curriculum. Greater exposure to plastic surgery through lectures and integrated clinical placements is needed to ensure equitable access for all medical students to plastic surgery as a profession.

A Privacy and Energy-Aware Federated Framework for Human Activity Recognition.

Human activity recognition (HAR) using wearable sensors enables continuous monitoring for healthcare applications. However, the conventional centralised training of deep learning models on sensor data poses challenges related to privacy, communication costs, and on-device efficiency. This paper proposes a federated learning framework integrating spiking neural networks (SNNs) with long short-term memory (LSTM) networks for energy-efficient and privacy-preserving HAR. The hybrid spiking-LSTM (S-LSTM) model synergistically combines the event-driven efficiency of SNNs and the sequence modelling capability of LSTMs. The model is trained using surrogate gradient learning and backpropagation through time, enabling fully supervised end-to-end learning. Extensive evaluations of two public datasets demonstrate that the proposed approach outperforms LSTM, CNN, and S-CNN models in accuracy and energy efficiency. For instance, the proposed S-LSTM achieved an accuracy of 97.36% and 89.69% for indoor and outdoor scenarios, respectively. Furthermore, the results also showed a significant improvement in energy efficiency of 32.30%, compared to simple LSTM. Additionally, we highlight the significance of personalisation in HAR, where fine-tuning with local data enhances model accuracy by up to 9% for individual users.

A Two-Stage Multi-Agent EV Charging Coordination Scheme for Maximizing Grid Performance and Customer Satisfaction.

Advancements in technology and awareness of energy conservation and environmental protection have increased the adoption rate of electric vehicles (EVs). The rapidly increasing adoption of EVs may affect grid operation adversely. However, the increased integration of EVs, if managed appropriately, can positively impact the performance of the electrical network in terms of power losses, voltage deviations and transformer overloads. This paper presents a two-stage multi-agent-based scheme for the coordinated charging scheduling of EVs. The first stage uses particle swarm optimization (PSO) at the distribution network operator (DNO) level to determine the optimal power allocation among the participating EV aggregator agents to minimize power losses and voltage deviations, whereas the second stage at the EV aggregator agents level employs a genetic algorithm (GA) to align the charging activities to achieve customers' charging satisfaction in terms of minimum charging cost and waiting time. The proposed method is implemented on the IEEE-33 bus network connected with low-voltage nodes. The coordinated charging plan is executed with the time of use (ToU) and real-time pricing (RTP) schemes, considering EVs' random arrival and departure with two penetration levels. The simulations show promising results in terms of network performance and overall customer charging satisfaction.

FedBranched: Leveraging Federated Learning for Anomaly-Aware Load Forecasting in Energy Networks.

Increased demand for fast edge computation and privacy concerns have shifted researchers' focus towards a type of distributed learning known as federated learning (FL). Recently, much research has been carried out on FL; however, a major challenge is the need to tackle the high diversity in different clients. Our research shows that using highly diverse data sets in FL can lead to low accuracy of some local models, which can be categorised as anomalous behaviour. In this paper, we present FedBranched, a clustering-based framework that uses probabilistic methods to create branches of clients and assigns their respective global models. Branching is performed using hidden Markov model clustering (HMM), and a round of branching depends on the diversity of the data. Clustering is performed on Euclidean distances of mean absolute percentage errors (MAPE) obtained from each client at the end of pre-defined communication rounds. The proposed framework was implemented on substation-level energy data with nine clients for short-term load forecasting using an artificial neural network (ANN). FedBranched took two clustering rounds and resulted in two different branches having individual global models. The results show a substantial increase in the average MAPE of all clients; the biggest improvement of 11.36% was observed in one client.