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EBioMedicine Jun 2024Pancreatic ductal adenocarcinoma (PDAC) is a tumour entity with unmet medical need. To assess the therapeutic potential of oncolytic virotherapy (OVT) against PDAC,...
BACKGROUND
Pancreatic ductal adenocarcinoma (PDAC) is a tumour entity with unmet medical need. To assess the therapeutic potential of oncolytic virotherapy (OVT) against PDAC, different oncolytic viruses (OVs) are currently investigated in clinical trials. However, systematic comparisons of these different OVs in terms of efficacy against PDAC and biomarkers predicting therapeutic response are lacking.
METHODS
We screened fourteen patient-derived PDAC cultures which reflect the intra- and intertumoural heterogeneity of PDAC for their sensitivity to five clinically relevant OVs, namely serotype 5 adenovirus Ad5-hTERT, herpes virus T-VEC, measles vaccine strain MV-NIS, reovirus jin-3, and protoparvovirus H-1PV. Live cell analysis, quantification of viral genome/gene expression, cell viability as well as cytotoxicity assays and titration of viral progeny were conducted. Transcriptome profiling was employed to identify potential predictive biomarkers for response to OV treatment.
FINDINGS
Patient-derived PDAC cultures showed individual response patterns to OV treatment. Twelve of fourteen cultures were responsive to at least one OV, with no single OV proving superior or inferior across all cultures. Known host factors for distinct viruses were retrieved as potential biomarkers. Compared to the classical molecular subtype, the quasi-mesenchymal or basal-like subtype of PDAC was found to be more sensitive to H-1PV, jin-3, and T-VEC. Generally, expression of viral entry receptors did not correlate with sensitivity to OV treatment, with one exception: Expression of Galectin-1 (LGALS1), a factor involved in H-1PV entry, positively correlated with H-1PV induced cell killing. Rather, cellular pathways controlling immunological, metabolic and proliferative signaling appeared to determine outcome. For instance, high baseline expression of interferon-stimulated genes (ISGs) correlated with relative resistance to oncolytic measles virus, whereas low cyclic GMP-AMP synthase (cGAS) expression was associated with exceptional response. Combination treatment of MV-NIS with a cGAS inhibitor improved tumour cell killing in several PDAC cultures and cells overexpressing cGAS were found to be less sensitive to MV oncolysis.
INTERPRETATION
Considering the heterogeneity of PDAC and the complexity of biological therapies such as OVs, no single biomarker can explain the spectrum of response patterns. For selection of a particular OV, PDAC molecular subtype, ISG expression as well as activation of distinct signaling and metabolic pathways should be considered. Combination therapies can overcome resistance in specific constellations. Overall, oncolytic virotherapy is a viable treatment option for PDAC, which warrants further development. This study highlights the need for personalised treatment in OVT. By providing all primary data, this study provides a rich source and guidance for ongoing developments.
FUNDING
German National Science Foundation (Deutsche Forschungsgemeinschaft, DFG), German Cancer Aid (Deutsche Krebshilfe), German National Academic Scholarship Foundation (Studienstiftung des deutschen Volkes), Survival with Pancreatic Cancer Foundation.
PubMed: 38941955
DOI: 10.1016/j.ebiom.2024.105219 -
Poultry Science Jun 2024Newcastle disease virus, a member of the Paramyxoviridae family, causes significant economic losses in poultry worldwide. To identify novel antiviral agents against NDV,...
Newcastle disease virus, a member of the Paramyxoviridae family, causes significant economic losses in poultry worldwide. To identify novel antiviral agents against NDV, 36 canthin-6-one analogs were evaluated in this study. Our data showed that 8 compounds exhibited excellent inhibitory effects on NDV replication with IC values in the range of 5.26 to 11.76 μM. Besides, these analogs inhibited multiple NDV strains with IC values within 12 μM and exerted antiviral activity against peste des petits ruminants virus (PPRV) and canine distemper virus (CDV). Among these analogs, 16 presented the strongest anti-NDV activity (IC = 5.26 μM) and minimum cytotoxicity (CC > 200 μM) in DF-1 cells. Furthermore, 16 displayed antiviral activity in different cell lines. Our results showed that 16 did not affect the viral adsorption while it can inhibit the entry of NDV by suppressing the Akt pathway. Further study found that 16-treatment inhibited the NDV-activated ERK pathway, thereby promoting the expression of interferon-related genes. Our findings reveal an antiviral mechanism of canthin-6-one analogs through inhibition of the Akt and ERK signaling pathways. These results point to the potential value of canthin-6-one analogs to serve as candidate antiviral agents for NDV.
PubMed: 38941786
DOI: 10.1016/j.psj.2024.103944 -
Ultrasonics Sonochemistry Jun 2024The Doppler ultrasound twinkling artifact, a rapid color shift, appears on pathological mineralizations and is theorized to arise from scattering off micron-sized...
The Doppler ultrasound twinkling artifact, a rapid color shift, appears on pathological mineralizations and is theorized to arise from scattering off micron-sized crevice microbubbles. However, the influence of crevice number and size as well as the bubble dynamics on twinkling is not well-understood. Cylinders with diameters of 0.8-1.2 µm and depths of 1 µm were etched into a silicon wafer and crevice bubbles were driven at 0.75, 2.5, and 5.0 MHz while monitoring with high-speed photography. Experimental results were compared to a derived crevice bubble model. On three separate wafers, cylindrical crevices (10 or 100) with diameters of 1, 10, or 100 µm and depths of 10 µm were etched and imaged with a research ultrasound system in Doppler mode at 5, 7.8, and 18.5 MHz. Within the pressure ranges studied here (∼1MPa), no bubble oscillation was observed for the 0.8-1.2 µm crevice bubbles which matched computational results. Crevices with 1 and 10 µm diameters produced more twinkling than 100 µm crevices at 5 and 7.8 MHz. In contrast, 100 µm crevices produced more twinkling than 1 or 10 µm crevices at 18.5 MHz (p < 0.001 in all cases). These results provide better insight into how crevice bubbles cause twinkling on pathological mineralizations.
PubMed: 38941704
DOI: 10.1016/j.ultsonch.2024.106971 -
Ultrasonics Sonochemistry Jun 2024Sonoporation is a non-invasive method that uses ultrasound for drug and gene delivery for therapeutic purposes. Here, both Finite Element Method (FEM) and Lattice...
Sonoporation is a non-invasive method that uses ultrasound for drug and gene delivery for therapeutic purposes. Here, both Finite Element Method (FEM) and Lattice Boltzmann Method (LBM) are applied to study the interaction physics of microbubble oscillation and collapse near flexible tissue. After validating the Finite Element Method with the nonlinear excited lipid-coated microbubble as well as the Lattice Boltzmann Method with experimental results, we have studied the behavior of a three-dimensional compressible microbubble in the vicinity of tissue. In the FEM phase, the oscillation microbubble with a lipid shell interacts with the boundary. The range of pressure and ultrasound frequency have been considered in the field of therapeutic applications of sonoporation. The viscoelastic and interfacial tension as the coating properties of the microbubble shell have been investigated. The presence of an elastic boundary increases the resonance frequency of the microbubble compared to that of a free microbubble. The increase in pressure leads to an expansion in the range of the microbubble's motion, the velocity induced in the fluid, and the shear stress on the boundary walls of tissue. An enhancement in the surface tension of the microbubble can influence fluid flow and reduce the shear stress on the boundary. The multi-pseudo-potential interaction LBM is used to reduce thermodynamic inconsistency and high-density ratio in a two-phase system for modeling the cavitation process. The three-dimensional shape of the microbubble during the collapse stages and the counter of pressure are displayed. There is a time difference between the occurrence of maximum velocity and pressure. All results in detail are presented in the article bodies.
PubMed: 38941703
DOI: 10.1016/j.ultsonch.2024.106972 -
Journal of Medical Internet Research Jun 2024Previous mobile health (mHealth) studies have revealed significant links between depression and circadian rhythm features measured via wearables. However, the...
BACKGROUND
Previous mobile health (mHealth) studies have revealed significant links between depression and circadian rhythm features measured via wearables. However, the comprehensive impact of seasonal variations was not fully considered in these studies, potentially biasing interpretations in real-world settings.
OBJECTIVE
This study aims to explore the associations between depression severity and wearable-measured circadian rhythms while accounting for seasonal impacts.
METHODS
Data were sourced from a large longitudinal mHealth study, wherein participants' depression severity was assessed biweekly using the 8-item Patient Health Questionnaire (PHQ-8), and participants' behaviors, including sleep, step count, and heart rate (HR), were tracked via Fitbit devices for up to 2 years. We extracted 12 circadian rhythm features from the 14-day Fitbit data preceding each PHQ-8 assessment, including cosinor variables, such as HR peak timing (HR acrophase), and nonparametric features, such as the onset of the most active continuous 10-hour period (M10 onset). To investigate the association between depression severity and circadian rhythms while also assessing the seasonal impacts, we used three nested linear mixed-effects models for each circadian rhythm feature: (1) incorporating the PHQ-8 score as an independent variable, (2) adding seasonality, and (3) adding an interaction term between season and the PHQ-8 score.
RESULTS
Analyzing 10,018 PHQ-8 records alongside Fitbit data from 543 participants (n=414, 76.2% female; median age 48, IQR 32-58 years), we found that after adjusting for seasonal effects, higher PHQ-8 scores were associated with reduced daily steps (β=-93.61, P<.001), increased sleep variability (β=0.96, P<.001), and delayed circadian rhythms (ie, sleep onset: β=0.55, P=.001; sleep offset: β=1.12, P<.001; M10 onset: β=0.73, P=.003; HR acrophase: β=0.71, P=.001). Notably, the negative association with daily steps was more pronounced in spring (β of PHQ-8 × spring = -31.51, P=.002) and summer (β of PHQ-8 × summer = -42.61, P<.001) compared with winter. Additionally, the significant correlation with delayed M10 onset was observed solely in summer (β of PHQ-8 × summer = 1.06, P=.008). Moreover, compared with winter, participants experienced a shorter sleep duration by 16.6 minutes, an increase in daily steps by 394.5, a delay in M10 onset by 20.5 minutes, and a delay in HR peak time by 67.9 minutes during summer.
CONCLUSIONS
Our findings highlight significant seasonal influences on human circadian rhythms and their associations with depression, underscoring the importance of considering seasonal variations in mHealth research for real-world applications. This study also indicates the potential of wearable-measured circadian rhythms as digital biomarkers for depression.
Topics: Humans; Seasons; Female; Circadian Rhythm; Male; Wearable Electronic Devices; Adult; Longitudinal Studies; Depression; Middle Aged; Retrospective Studies; Telemedicine
PubMed: 38941600
DOI: 10.2196/55302 -
JMIR Research Protocols Jun 2024Osteoarthritis (OA) is a disabling condition that affects more than one-third of people older than 65 years. Currently, 80% of these patients report movement...
Assessment of the Feasibility of Objective Parameters as Primary End Points for Patients Affected by Knee Osteoarthritis: Protocol for a Pilot, Open Noncontrolled Trial (:SMILE:).
BACKGROUND
Osteoarthritis (OA) is a disabling condition that affects more than one-third of people older than 65 years. Currently, 80% of these patients report movement limitations, 20% are unable to perform major activities of daily living, and approximately 11% require personal care. In 2014, the European Society for Clinical and Economic Aspects of Osteoporosis and Osteoarthritis (ESCEO) recommended, as the first step in the pharmacological treatment of knee osteoarthritis, a background therapy with chronic symptomatic slow-acting osteoarthritic drugs such as glucosamine sulfate, chondroitin sulfate, and hyaluronic acid. The latter has been extensively evaluated in clinical trials as intra-articular and oral administration. Recent reviews have shown that studies on oral hyaluronic acid generally measure symptoms using only subjective parameters, such as visual analog scales or quality of life questionnaires. As a result, objective measures are lacking, and data validity is generally impaired.
OBJECTIVE
The main goal of this pilot study with oral hyaluronic acid is to evaluate the feasibility of using objective tools as outcomes to evaluate improvements in knee mobility. We propose ultrasound and range of motion measurements with a goniometer that could objectively correlate changes in joint mobility with pain reduction, as assessed by the visual analog scale. The secondary objective is to collect data to estimate the time and budget for the main double-blind study randomized trial. These data may be quantitative (such as enrollment rate per month, number of screening failures, and new potential outcomes) and qualitative (such as site logistical issues, patient reluctance to enroll, and interpersonal difficulties for investigators).
METHODS
This open-label pilot and feasibility study is conducted in an orthopedic clinic (Timisoara, Romania). The study includes male and female participants, aged 50-70 years, who have been diagnosed with symptomatic knee OA and have experienced mild joint discomfort for at least 6 months. Eight patients must be enrolled and treated with Syalox 300 Plus (River Pharma) for 8 weeks. It is a dietary supplement containing high-molecular-weight hyaluronic acid, which has already been marketed in several European countries. Assessments are made at the baseline and final visits.
RESULTS
Recruitment and treatment of the 8 patients began on February 15, 2018, and was completed on May 25, 2018. Data analysis was planned to be completed by the end of 2018. The study was funded in February 2019. We expect the results to be published in a peer-reviewed clinical journal in the last quarter of 2024.
CONCLUSIONS
The data from this pilot study will be used to assess the feasibility of a future randomized clinical trial in OA. In particular, the planned outcomes (eg, ultrasound and range of motion), safety, and quantitative and qualitative data must be evaluated to estimate in advance the time and budget required for the future main study. Finally, the pilot study should provide preliminary information on the efficacy of the investigational product.
TRIAL REGISTRATION
ClinicalTrials.gov NCT03421054; https://clinicaltrials.gov/study/NCT03421054.
INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID)
RR1-10.2196/13642.
Topics: Humans; Osteoarthritis, Knee; Pilot Projects; Feasibility Studies; Hyaluronic Acid; Male; Female; Aged; Middle Aged; Quality of Life; Endpoint Determination
PubMed: 38941599
DOI: 10.2196/13642 -
JMIR Formative Research Jun 2024Higher availability of alcohol is associated with higher levels of alcohol consumption and harm. Alcohol is increasingly accessible online, with rapid delivery often...
BACKGROUND
Higher availability of alcohol is associated with higher levels of alcohol consumption and harm. Alcohol is increasingly accessible online, with rapid delivery often offered by a third-party driver. Remote delivery and online availability are important from a public health perspective, but to date, relatively little research has explored the availability of alcohol offered by online platforms.
OBJECTIVE
This cross-sectional exploratory study describes the availability of alcohol on the third-party platform Deliveroo within London, England.
METHODS
We extracted the number of outlets offering alcohol on Deliveroo for each London borough and converted these into crude rates per 1000 population (18-64 years). Outlets were grouped as outlets exclusively selling alcohol, off-licenses, and premium. We calculated Pearson correlation coefficients to explore the association between borough's crude rate of outlets per 1000 population and average Indices of Multiple Deprivation (IMD) 2019 scores. We extracted the number of outlets also selling tobacco or e-cigarettes and used non-Deliveroo drivers. We searched addresses of the top 20 outlets delivering to the most boroughs by outlet type (60 total) to determine their associated premise.
RESULTS
We identified 4277 total Deliveroo-based outlets offering alcohol across London, including outlets delivering in multiple boroughs. The crude rate of outlets per 1000 population aged 18-64 years was 0.73 and ranged from 0.22 to 2.29 per borough. Most outlets exclusively sold alcohol (3086/4277, 72.2%), followed by off-licenses (770/4277, 18.0%) and premium (421/4277, 9.8%). The majority of outlets exclusively selling alcohol sold tobacco or e-cigarettes (2951/3086, 95.6%) as did off-licenses to a lesser extent (588/770, 76.4%). Most outlets exclusively offering alcohol used drivers not employed by Deliveroo (2887/3086, 93.6%), and the inverse was true for premium outlets (50/421, 11.9%) and off-licenses (73/770, 9.5%). There were 1049 unique outlets, of which 396 (37.8%) were exclusively offering alcohol-these outlets tended to deliver across multiple boroughs unlike off-licenses and premium outlets. Of outlets with confirmed addresses, self-storage units were listed as the associated premise for 85% (17/20) of outlets exclusively offering alcohol, 11% (2/19) of off-licenses, and 12% (2/17) of premium outlets. We found no significant relationship between borough IMD scores and crude rate of outlets per 1000 population overall (P=.87) or by any outlet type: exclusively alcohol (P=.41), off-license (P=.58), and premium (P=.18).
CONCLUSIONS
London-based Deliveroo outlets offering alcohol are common and are sometimes operating from self-storage units that have policies prohibiting alcohol storage. This and the potential for increased alcohol accessibility online have implications for public health given the relationship between alcohol's availability and consumption or harm. There is a need to ensure that regulations for delivery are adequate for protecting children and vulnerable adults. The Licensing Act 2003 may require modernization in the digital age. Future research must explore a relationship between online alcohol availability and deprivation.
PubMed: 38941596
DOI: 10.2196/54587 -
JMIR Formative Research Jun 2024Conduct disorder increases risks of educational dropout, future mental illness, and incarceration if untreated. First-line treatment of conduct disorder involves...
BACKGROUND
Conduct disorder increases risks of educational dropout, future mental illness, and incarceration if untreated. First-line treatment of conduct disorder involves evidence-based parenting skills programs. Time-outs, a frequent tool in these programs, can be effective at improving behavior, and recent apps have been developed to aid this process. However, these apps promote the use of time-outs in inconsistent or developmentally inappropriate ways, potentially worsening behavior problems. Digital microinterventions like these apps could guide parents through high-quality time-outs in the moment, but current time-out apps lack features promoting adherence to the evidence-based best practice. Agile scrum is a respected approach in the software development industry.
OBJECTIVE
We aimed to explore the feasibility of using the agile scrum approach to build a digital microintervention to help parents deliver an evidence-based time-out.
METHODS
The agile scrum methodology was used. Four sprints were conducted. Figma software was used for app design and wireframing. Insights from 42 expert stakeholders were used during 3 sprint reviews. We consulted experts who were identified from councils around the Midlands region of the United Kingdom and charities through personal contacts and a snowballing approach.
RESULTS
Over 4 development sprints from August 2022 to March 2023, the app was iteratively designed and refined based on consultation with a diverse group of 42 experts who shared their knowledge about the content of common parenting programs and the challenges parents commonly face. Modifications made throughout the process resulted in significant app enhancements, including tailored timer algorithms and enhanced readability, as well as an onboarding zone, mindfulness module, and pictorial information to increase inclusivity. By the end of the fourth sprint, the app was deemed ready for home use by stakeholders, demonstrating the effectiveness of our agile scrum development approach.
CONCLUSIONS
We developed an app to support parents to use the evidence-based time-out technique. We recommend the agile scrum approach to create mobile health apps. Our experience highlights the valuable role that frontline health and social care professionals, particularly those working with vulnerable families, can play as experts in scrum reviews. There is a need for research to both evaluate the impact of digital microinterventions on child behavioral change and also create digital microinterventions that cater to non-English speakers and individuals who participate in parenting programs in settings outside the United Kingdom.
PubMed: 38941594
DOI: 10.2196/54892 -
Neurology(R) Neuroimmunology &... Sep 2024To systematically describe the clinical picture of double-antibody seronegative neuromyelitis optica spectrum disorders (DN-NMOSD) with specific emphasis on retinal...
BACKGROUND AND OBJECTIVES
To systematically describe the clinical picture of double-antibody seronegative neuromyelitis optica spectrum disorders (DN-NMOSD) with specific emphasis on retinal involvement.
METHODS
Cross-sectional data of 25 people with DN-NMOSD (48 eyes) with and without a history of optic neuritis (ON) were included in this study along with data from 25 people with aquaporin-4 antibody seropositive neuromyelitis optica spectrum disorder (AQP4-NMOSD, 46 eyes) and from 25 healthy controls (HCs, 49 eyes) for comparison. All groups were matched for age and sex and included from the collaborative retrospective study of retinal optical coherence tomography (OCT) in neuromyelitis optica (CROCTINO). Participants underwent OCT with central postprocessing and local neurologic examination and antibody testing. Retinal neurodegeneration was quantified as peripapillary retinal nerve fiber layer thickness (pRNFL) and combined ganglion cell and inner plexiform layer thickness (GCIPL).
RESULTS
This DN-NMOSD cohort had a history of [median (inter-quartile range)] 6 (5; 9) attacks within their 5 ± 4 years since onset. Myelitis and ON were the most common attack types. In DN-NMOSD eyes after ON, pRNFL ( < 0.001) and GCIPL ( = 0.023) were thinner compared with eyes of HCs. Even after only one ON episode, DN-NMOSD eyes already had considerable neuroaxonal loss compared with HCs. In DN-NMOSD eyes without a history of ON, pRNFL ( = 0.027) and GCIPL ( = 0.022) were also reduced compared with eyes of HCs. However, there was no difference in pRNFL and GCIPL between DN-NMOSD and AQP4-NMOSD for the whole group and for subsets with a history of ON and without a history of ON-as well as between variances of retinal layer thicknesses.
DISCUSSION
DN-NMOSD is characterized by severe retinal damage after ON and attack-independent retinal neurodegeneration. Most of the damage occurs during the first ON episode, which highlights the need for better diagnostic markers in DN-NMOSD to facilitate an earlier diagnosis as well as for effective and early treatments. In this study, people with DN-NMOSD presented with homogeneous clinical and imaging findings potentially suggesting a common retinal pathology in these patients.
Topics: Humans; Neuromyelitis Optica; Female; Male; Adult; Cross-Sectional Studies; Middle Aged; Tomography, Optical Coherence; Aquaporin 4; Retrospective Studies; Autoantibodies; Retina
PubMed: 38941573
DOI: 10.1212/NXI.0000000000200273 -
JMIR Formative Research Jun 2024Loneliness, depression, and anxiety are highly prevalent among US adults, especially among socio-demographically vulnerable populations. Virtual peer support is a...
Loneliness, depression, and anxiety are highly prevalent among US adults, especially among socio-demographically vulnerable populations. Virtual peer support is a potentially cost-effective, scalable intervention. This study prospectively evaluated the effects of digitally-enabled peer support on mental health outcomes and estimated medical cost reductions among 243 vulnerable adults with symptomatic depression, anxiety, and significant loneliness. We found that participants from diverse race/ethnicities, genders and socio-economic groups engaged with peer support and experienced statistically and clinically significant improvements in their mental health and an estimated annual medical costs reduction of $1,025 per participant. We believe this work will inform ongoing discussions related to the use of digitally-enabled peer support to address the mental health crisis in the US.
PubMed: 38941568
DOI: 10.2196/58263