Spatiotemporally dynamic electric fields for brain cancer treatment: an in vitro investigation

Objective. The treatment of glioblastoma (GBM) using low intensity electric fields (∼1 V cm-1) is being investigated using multiple implanted bioelectrodes, which was termed intratumoral modulation therapy (IMT). Previous IMT studies theoretically optimized treatment parameters to maximize coverage with rotating fields, which required experimental investigation. In this study, we employed computer simulations to generate spatiotemporally dynamic electric fields, designed and purpose-built an IMT device for in vitro experiments, and evaluated the human GBM cellular responses to these fields. Approach. After measuring the electrical conductivity of the in vitro culturing medium, we designed experiments to evaluate the efficacy of various spatiotemporally dynamic fields: (a) different rotating field magnitudes, (b) rotating versus non-rotating fields, (c) 200 kHz versus 10 kHz stimulation, and (d) constructive versus destructive interference. A custom printed circuit board (PCB) was fabricated to enable four-electrode IMT in a 24-well plate. Patient derived GBM cells were treated and analyzed for viability using bioluminescence imaging. Main results. The optimal PCB design had electrodes placed 6.3 mm from the center. Spatiotemporally dynamic IMT fields at magnitudes of 1, 1.5, and 2 V cm-1reduced GBM cell viability to 58%, 37% and 2% of sham controls respectively. Rotating versus non-rotating, and 200 kHz versus 10 kHz fields showed no statistical difference. The rotating configuration yielded a significant reduction (p\u3c 0.01) in cell viability (47 ± 4%) compared to the voltage matched (99 ± 2%) and power matched (66 ± 3%) destructive interference cases. Significance. We found the most important factors in GBM cell susceptibility to IMT are electric field strength and homogeneity. Spatiotemporally dynamic electric fields have been evaluated in this study, where improvements to electric field coverage with lower power consumption and minimal field cancellations has been demonstrated. The impact of this optimized paradigm on cell susceptibility justifies its future use in preclinical and clinical trial investigations

Differential involvement of forearm muscles in ALS does not relate to sonographic structural nerve alterations

We aimed to assess whether differential peripheral nerve involvement parallels dissociated forearm muscle weakness in amyotrophic lateral sclerosis (ALS).The analysis comprised 41 ALS patients and 18 age-, sex-, height- and weight-matched healthy controls. Strength of finger-extension and -flexion was measured using the Medical Research Council (MRC) scale. Radial, median and ulnar nerve sonographic cross-sectional area (CSA) and echogenicity, expressed by the hypoechoic fraction (HF), were determined.In ALS, finger extensors were significantly weaker than finger flexors. Sonographic evaluation revealed peripheral nerve atrophy, affecting various nerve segments in ALS. HF was unaltered.This systematic study confirmed a long-observed physical examination finding in ALS - weakness in finger-extension out of proportion to finger-flexion. This phenomenon was not related to any particular sonographic pattern of upper limb peripheral nerve alteration.In ALS, dissociated forearm muscle weakness could aid in the disease's diagnosis. Nerve ultrasound did not provide additional information on the differential involvement of finger-extension and finger-flexion strength

Preventing type 2 diabetes mellitus in Qatar by reducing obesity, smoking, and physical inactivity: mathematical modeling analyses.

BACKGROUND: The aim of this study was to estimate the impact of reducing the prevalence of obesity, smoking, and physical inactivity, and introducing physical activity as an explicit intervention, on the burden of type 2 diabetes mellitus (T2DM), using Qatar as an example. METHODS: A population-level mathematical model was adapted and expanded. The model was stratified by sex, age group, risk factor status, T2DM status, and intervention status, and parameterized by nationally representative data. Modeled interventions were introduced in 2016, reached targeted level by 2031, and then maintained up to 2050. Diverse intervention scenarios were assessed and compared with a counter-factual no intervention baseline scenario. RESULTS: T2DM prevalence increased from 16.7% in 2016 to 24.0% in 2050 in the baseline scenario. By 2050, through halting the rise or reducing obesity prevalence by 10-50%, T2DM prevalence was reduced by 7.8-33.7%, incidence by 8.4-38.9%, and related deaths by 2.1-13.2%. For smoking, through halting the rise or reducing smoking prevalence by 10-50%, T2DM prevalence was reduced by 0.5-2.8%, incidence by 0.5-3.2%, and related deaths by 0.1-0.7%. For physical inactivity, through halting the rise or reducing physical inactivity prevalence by 10-50%, T2DM prevalence was reduced by 0.5-6.9%, incidence by 0.5-7.9%, and related deaths by 0.2-2.8%. Introduction of physical activity with varying intensity at 25% coverage reduced T2DM prevalence by 3.3-9.2%, incidence by 4.2-11.5%, and related deaths by 1.9-5.2%. CONCLUSIONS: Major reductions in T2DM incidence could be accomplished by reducing obesity, while modest reductions could be accomplished by reducing smoking and physical inactivity, or by introducing physical activity as an intervention

A diabetes risk score for Qatar utilizing a novel mathematical modeling approach to identify individuals at high risk for diabetes

We developed a diabetes risk score using a novel analytical approach and tested its diagnostic performance to detect individuals at high risk of diabetes, by applying it to the Qatari population. A representative random sample of 5,000 Qataris selected at different time points was simulated using a diabetes mathematical model. Logistic regression was used to derive the score using age, sex, obesity, smoking, and physical inactivity as predictive variables. Performance diagnostics, validity, and potential yields of a diabetes testing program were evaluated. In 2020, the area under the curve (AUC) was 0.79 and sensitivity and specificity were 79.0% and 66.8%, respectively. Positive and negative predictive values (PPV and NPV) were 36.1% and 93.0%, with 42.0% of Qataris being at high diabetes risk. In 2030, projected AUC was 0.78 and sensitivity and specificity were 77.5% and 65.8%. PPV and NPV were 36.8% and 92.0%, with 43.0% of Qataris being at high diabetes risk. In 2050, AUC was 0.76 and sensitivity and specificity were 74.4% and 64.5%. PPV and NPV were 40.4% and 88.7%, with 45.0% of Qataris being at high diabetes risk. This model-based score demonstrated comparable performance to a data-derived score. The derived self-complete risk score provides an effective tool for initial diabetes screening, and for targeted lifestyle counselling and prevention programs.Peer reviewe

Epidemiological impact of public health interventions against diabetes in Qatar: mathematical modeling analyses

AimsTo predict the epidemiological impact of specific, and primarily structural public health interventions that address lifestyle, dietary, and commuting behaviors of Qataris as well as subsidies and legislation to reduce type 2 diabetes mellitus (T2DM) burden among Qataris.MethodsA deterministic population-based mathematical model was used to investigate the impact of public health interventions on the epidemiology of T2DM among Qataris aged 20–79 years, which is the age range typically used by the International Diabetes Federation for adults. The study evaluated the impact of interventions up to 2050, a three-decade time horizon, to allow for the long-term effects of different types of interventions to materialize. The impact of each intervention was evaluated by comparing the predicted T2DM incidence and prevalence with the intervention to a counterfactual scenario without intervention. The model was parameterized using representative data and stratified by sex, age, T2DM risk factors, T2DM status, and intervention status.ResultsAll intervention scenarios had an appreciable impact on reducing T2DM incidence and prevalence. A lifestyle management intervention approach, specifically applied to those who are categorized as obese and ≥35 years old, averted 9.5% of new T2DM cases by 2050. An active commuting intervention approach, specifically increasing cycling and walking, averted 8.5% of new T2DM cases by 2050. Enhancing consumption of healthy diets including fruits and vegetables, specifically a workplace intervention involving dietary modifications and an educational intervention, averted 23.2% of new T2DM cases by 2050. A subsidy and legislative intervention approach, implementing subsidies on fruits and vegetables and taxation on sugar-sweetened beverages, averted 7.4% of new T2DM cases by 2050. A least to most optimistic combination of interventions averted 22.8–46.9% of new T2DM cases by 2050, respectively.ConclusionsImplementing a combination of individual-level and structural public health interventions is critical to prevent T2DM onset and to slow the growing T2DM epidemic in Qatar

Type 2 diabetes epidemic and key risk factors in Qatar: A mathematical modeling analysis

Introduction We aimed to characterize and forecast type 2 diabetes mellitus (T2DM) disease burden between 2021 and 2050 in Qatar where 89% of the population comprises expatriates from over 150 countries. Research design and methods An age-structured mathematical model was used to forecast T2DM burden and the impact of key risk factors (obesity, smoking, and physical inactivity). The model was parametrized using data from T2DM natural history studies, Qatar's 2012 STEPwise survey, the Global Health Observatory, and the International Diabetes Federation Diabetes Atlas, among other data sources. Results Between 2021 and 2050, T2DM prevalence increased from 7.0% to 14.0%, the number of people living with T2DM increased from 170 057 to 596 862, and the annual number of new T2DM cases increased from 25 007 to 45 155 among those 20-79 years of age living in Qatar. Obesity prevalence increased from 8.2% to 12.5%, smoking declined from 28.3% to 26.9%, and physical inactivity increased from 23.1% to 26.8%. The proportion of incident T2DM cases attributed to obesity increased from 21.9% to 29.9%, while the contribution of smoking and physical inactivity decreased from 7.1% to 6.0% and from 7.3% to 7.2%, respectively. The results showed substantial variability across various nationality groups residing in Qatar - for example, in Qataris and Egyptians, the T2DM burden was mainly due to obesity, while in other nationality groups, it appeared to be multifactorial. Conclusions T2DM prevalence and incidence in Qatar were forecasted to increase sharply by 2050, highlighting the rapidly growing need of healthcare resources to address the disease burden. T2DM epidemiology varied between nationality groups, stressing the need for prevention and treatment intervention strategies tailored to each nationality

Global monitoring of antimicrobial resistance based on metagenomics analyses of urban sewage

Antimicrobial resistance (AMR) is a serious threat to global public health, but obtaining representative data on AMR for healthy human populations is difficult. Here, we use meta-genomic analysis of untreated sewage to characterize the bacterial resistome from 79 sites in 60 countries. We find systematic differences in abundance and diversity of AMR genes between Europe/North-America/Oceania and Africa/Asia/South-America. Antimicrobial use data and bacterial taxonomy only explains a minor part of the AMR variation that we observe. We find no evidence for cross-selection between antimicrobial classes, or for effect of air travel between sites. However, AMR gene abundance strongly correlates with socio-economic, health and environmental factors, which we use to predict AMR gene abundances in all countries in the world. Our findings suggest that global AMR gene diversity and abundance vary by region, and that improving sanitation and health could potentially limit the global burden of AMR. We propose metagenomic analysis of sewage as an ethically acceptable and economically feasible approach for continuous global surveillance and prediction of AMR.Peer reviewe

Expert consensus document: Clinical and molecular diagnosis, screening and management of Beckwith-Wiedemann syndrome: an international consensus statement.

Beckwith-Wiedemann syndrome (BWS), a human genomic imprinting disorder, is characterized by phenotypic variability that might include overgrowth, macroglossia, abdominal wall defects, neonatal hypoglycaemia, lateralized overgrowth and predisposition to embryonal tumours. Delineation of the molecular defects within the imprinted 11p15.5 region can predict familial recurrence risks and the risk (and type) of embryonal tumour. Despite recent advances in knowledge, there is marked heterogeneity in clinical diagnostic criteria and care. As detailed in this Consensus Statement, an international consensus group agreed upon 72 recommendations for the clinical and molecular diagnosis and management of BWS, including comprehensive protocols for the molecular investigation, care and treatment of patients from the prenatal period to adulthood. The consensus recommendations apply to patients with Beckwith-Wiedemann spectrum (BWSp), covering classical BWS without a molecular diagnosis and BWS-related phenotypes with an 11p15.5 molecular anomaly. Although the consensus group recommends a tumour surveillance programme targeted by molecular subgroups, surveillance might differ according to the local health-care system (for example, in the United States), and the results of targeted and universal surveillance should be evaluated prospectively. International collaboration, including a prospective audit of the results of implementing these consensus recommendations, is required to expand the evidence base for the design of optimum care pathways

Analysis of shared common genetic risk between amyotrophic lateral sclerosis and epilepsy

Because hyper-excitability has been shown to be a shared pathophysiological mechanism, we used the latest and largest genome-wide studies in amyotrophic lateral sclerosis (n = 36,052) and epilepsy (n = 38,349) to determine genetic overlap between these conditions. First, we showed no significant genetic correlation, also when binned on minor allele frequency. Second, we confirmed the absence of polygenic overlap using genomic risk score analysis. Finally, we did not identify pleiotropic variants in meta-analyses of the 2 diseases. Our findings indicate that amyotrophic lateral sclerosis and epilepsy do not share common genetic risk, showing that hyper-excitability in both disorders has distinct origins