Telemedicine Beyond Borders: A Mixed-Methods Approach to Understanding Cross-National Usage Intention.

Introduction: Drawing on the Unified Theory of Acceptance and Use of Technology 2 and the Diffusion of Innovation Theory, this article investigates the adoption of telemedicine services from a patient perspective in Germany, Spain, and the United States using a mixed-methods approach. Digital health technologies have the potential to improve access to care and to alleviate the burden on traditional health care systems and are becoming more integrated into everyday medicine. Therefore, understanding the factors that impact patients' intentions to use telemedicine is crucial to ensure successful development. Methods: Based on 1,200 surveys collected in Germany, Spain, and the United States, structural equation modeling (IBM SPSS Amos 24) is employed to test the hypotheses. The article also explores how age and gender moderate the proposed relationships. Results: Seven out of the 10 hypotheses (performance expectancy, hedonic motivation, habit, relative advantage, and perceived security) are found to be positive, direct, and statistically significant. Furthermore, findings suggest stronger effects for telemedicine usage intention for younger female users than their male counterparts. Discussion: With digital health technologies becoming more prevalent, the outcomes of this study can endorse the development of effective strategies to promote the adoption of telemedicine, ultimately improving access to care and contributing to the advancement of and modern health care.

Generation of a heterozygous and a homozygous CSF1R knockout line from iPSC using CRISPR/Cas9.

Mutations in Colony-stimulating factor 1 receptor (CSF1R) lead to CSF1R-related leukoencephalopathy, also known as Adult-onset leukoencephalopathy with axonal spheroids and pigmented glia (ALSP), a rapidly progressing neurodegenerative disease with severe cognitive and motor impairment. In this study, a homozygous and a heterozygous CSF1R knockout induced pluripotent stem cell (iPSC) line were generated by CRISPR/Cas9-based gene editing. These in vitro models will provide a helpful tool for investigating the still largely unknown pathophysiology of CSF1R-related leukoencephalopathy.

High Sensitivity Near-Infrared Imaging of Fluorescent Nanosensors.

Biochemical processes are fast and occur on small-length scales, which makes them difficult to measure. Optical nanosensors based on single-wall carbon nanotubes (SWCNTs) are able to capture such dynamics. They fluoresce in the near-infrared (NIR, 850-1700 nm) tissue transparency window and the emission wavelength depends on their chirality. However, NIR imaging requires specialized indium gallium arsenide (InGaAs) cameras with a typically low resolution because the quantum yield of normal Si-based cameras rapidly decreases in the NIR. Here, an efficient one-step phase separation approach to isolate monochiral (6,4)-SWCNTs (880 nm emission) from mixed SWCNT samples is developed. It enables imaging them in the NIR with high-resolution standard Si-based cameras (>50× more pixels). (6,4)-SWCNTs modified with (GT)10 -ssDNA become highly sensitive to the important neurotransmitter dopamine. These sensors are 1.7× brighter and 7.5× more sensitive and allow fast imaging (<50 ms). They enable high-resolution imaging of dopamine release from cells. Thus, the assembly of biosensors from (6,4)-SWCNTs combines the advantages of nanosensors working in the NIR with the sensitivity of (Si-based) cameras and enables broad usage of these nanomaterials.

Human-Robot Collaboration in Industrial Automation: Sensors and Algorithms.

Technology is changing the manufacturing world [...].

Interdependencies of cellular and humoral immune responses in heterologous and homologous SARS-CoV-2 vaccination.

BACKGROUND: Homologous and heterologous SARS-CoV-2 vaccinations yield different spike protein-directed humoral and cellular immune responses. This study aimed to explore their currently unknown interdependencies. METHODS: COV-ADAPT is a prospective, observational cohort study of 417 healthcare workers who received vaccination with homologous ChAdOx1 nCoV-19, homologous BNT162b2 or with heterologous ChAdOx1 nCoV-19/BNT162b2. We assessed humoral (anti-spike-RBD-IgG, neutralizing antibodies, and avidity) and cellular (spike-induced T-cell interferon-γ release) immune responses in blood samples up to 2 weeks before (T1) and 2-12 weeks following secondary immunization (T2). RESULTS: Initial vaccination with ChAdOx1 nCoV-19 resulted in lower anti-spike-RBD-IgG compared with BNT162b2 (70 ± 114 vs. 226 ± 279 BAU/ml, p < .01) at T1. Booster vaccination with BNT162b2 proved superior to ChAdOx1 nCoV-19 at T2 (anti-spike-RBD-IgG: ChAdOx1 nCoV-19/BNT162b2 2387 ± 1627 and homologous BNT162b2 3202 ± 2184 vs. homologous ChAdOx1 nCoV-19 413 ± 461 BAU/ml, both p < .001; spike-induced T-cell interferon-γ release: ChAdOx1 nCoV-19/BNT162b2 5069 ± 6733 and homologous BNT162b2 4880 ± 7570 vs. homologous ChAdOx1 nCoV-19 1152 ± 2243 mIU/ml, both p < .001). No significant differences were detected between BNT162b2-boostered groups at T2. For ChAdOx1 nCoV-19, no booster effect on T-cell activation could be observed. We found associations between anti-spike-RBD-IgG levels (ChAdOx1 nCoV-19/BNT162b2 and homologous BNT162b2) and T-cell responses (homologous ChAdOx1 nCoV-19 and ChAdOx1 nCoV-19/BNT162b2) from T1 to T2. Additionally, anti-spike-RBD-IgG and T-cell response were linked at both time points (all groups combined). All regimes yielded neutralizing antibodies and increased antibody avidity at T2. CONCLUSIONS: Interdependencies between humoral and cellular immune responses differ between common SARS-CoV-2 vaccination regimes. T-cell activation is unlikely to compensate for poor humoral responses.

Lysosomal acid lipase deficiency in pediatric patients: a scoping review

Abstract Objective: Lysosomal acid lipase deficiency (LAL-D) is an underdiagnosed autosomal recessive disease with onset between the first years of life and adulthood. Early diagnosis is crucial for effective therapy and long-term survival. The objective of this article is to recognize warning signs among the clinical and laboratory characteristics of LAL-D in pediatric patients through a scope review. Sources: Electronic searches in the Embase, PubMed, Livivo, LILACS, Web of Science, Scopus, Google Scholar, Open Gray, and ProQuest Dissertations and Theses databases. The dataset included observational studies with clinical and laboratory characteristics of infants, children and adolescents diagnosed with lysosomal acid lipase deficiency by enzyme activity testing or analysis of mutations in the lysosomal acid lipase gene (LIPA). The reference selection process was performed in two stages. The references were selected by two authors, and the data were extracted in June 2020. Summary of the findings: The initial search returned 1593 studies, and the final selection included 108 studies from 30 countries encompassing 206 patients, including individuals with Wolman disease and cholesteryl ester storage disease (CESD). The most prevalent manifestations in both spectra of the disease were hepatomegaly, splenomegaly, anemia, dyslipidemia, and elevated transaminases. Conclusions: Vomiting, diarrhea, jaundice, and splenomegaly may be correlated, and may serve as a starting point for investigating LAL-D. Familial lymphohistiocytosis should be part of the differential diagnosis with LAL-D, and all patients undergoing upper gastrointestinal endoscopy should be submitted to intestinal biopsy.

Modifying UTAUT2 for a cross-country comparison of telemedicine adoption.

The ongoing COVID19 pandemic has put digital health technologies in the spotlight. To gain a deeper understanding of patients' usage intentions of virtual doctor appointments, the present research adapts the Unified Theory of Acceptance and Use of Technology 2 (UTAUT2) by integrating perceived security and perceived product advantage, two known barriers to successful telemedicine adoption. Applying age-stratified sampling, an online survey was distributed to 800 citizens in Germany and the United States of America. 710 completed and valid questionnaires were subsequently analyzed using SPSS and AMOS (versions 24). Significant, direct, and positive effects of performance expectancy, hedonic motivation, perceived security, and perceived product advantage on the behavioral intention to use virtual doctor appointments were found. The analysis of the moderating variables, age and gender, showed significant differences in user's performance expectancy and effort expectancy, and perceived product advantage, respectively. With virtual health care models on the rise, these results are important for stakeholders such as policymakers, governments, employers, but also physicians, and insurance companies as they offer clear recommendations to design telemedicine adoption strategies to ensure successful patient engagement.

Lysosomal acid lipase deficiency in pediatric patients: a scoping review.

OBJECTIVE: Lysosomal acid lipase deficiency (LAL-D) is an underdiagnosed autosomal recessive disease with onset between the first years of life and adulthood. Early diagnosis is crucial for effective therapy and long-term survival. The objective of this article is to recognize warning signs among the clinical and laboratory characteristics of LAL-D in pediatric patients through a scope review. SOURCES: Electronic searches in the Embase, PubMed, Livivo, LILACS, Web of Science, Scopus, Google Scholar, Open Gray, and ProQuest Dissertations and Theses databases. The dataset included observational studies with clinical and laboratory characteristics of infants, children and adolescents diagnosed with lysosomal acid lipase deficiency by enzyme activity testing or analysis of mutations in the lysosomal acid lipase gene (LIPA). The reference selection process was performed in two stages. The references were selected by two authors, and the data were extracted in June 2020. SUMMARY OF THE FINDINGS: The initial search returned 1593 studies, and the final selection included 108 studies from 30 countries encompassing 206 patients, including individuals with Wolman disease and cholesteryl ester storage disease (CESD). The most prevalent manifestations in both spectra of the disease were hepatomegaly, splenomegaly, anemia, dyslipidemia, and elevated transaminases. CONCLUSIONS: Vomiting, diarrhea, jaundice, and splenomegaly may be correlated, and may serve as a starting point for investigating LAL-D. Familial lymphohistiocytosis should be part of the differential diagnosis with LAL-D, and all patients undergoing upper gastrointestinal endoscopy should be submitted to intestinal biopsy.

NO Synthesis in Immune-Challenged Locust Hemocytes and Potential Signaling to the CNS.

Similar to vertebrates, insects are exposed to a broad variety of pathogens. The innate insect immune system provides several response mechanisms such as phagocytosis, melanization, and the synthesis of antimicrobial or cytotoxic compounds. The cytotoxic nitric oxide (NO), which is also a neurotransmitter, is involved in the response to bacterial infections in various insects but has rarely been shown to be actually produced in hemocytes. We quantified the NO production in hemocytes of Locusta migratoria challenged with diverse immune stimuli by immunolabeling the by-product of NO synthesis, citrulline. Whereas in untreated adult locusts less than 5% of circulating hemocytes were citrulline-positive, the proportion rose to over 40% after 24 hours post injection of heat-inactivated bacteria. Hemocytes surrounded and melanized bacteria in locust nymphs by forming capsules. Such sessile hemocytes also produced NO. As in other insect species, activated hemocytes were found dorsally, close to the heart. In addition, we frequently observed citrulline-positive hemocytes and capsules near the ventral nerve cord. Neurites in the CNS of sterile locust embryos responded with elevation of the second messenger cGMP after contact with purified adult NO-producing hemocytes as revealed by immunofluorescence. We suggest that hemocytes can mediate a response in the CNS of an infected animal via the NO/cGMP signaling pathway.

Developmental Neurotoxicity of Fipronil and Rotenone on a Human Neuronal In Vitro Test System.

Pesticide exposure during in utero and early postnatal development can cause a wide range of neurological defects. However, relatively few insecticides have been recognized as developmental neurotoxicants, so far. Recently, discovery of the insecticide, fipronil, in chicken eggs has raised public concern. The status of fipronil as a potential developmental neurotoxicant is still under debate. Whereas several in vivo and in vitro studies suggest specific toxicity, other in vitro studies could not confirm this concern. Here, we tested fipronil and its main metabolic product, fipronil sulfone both at concentrations between 1.98 and 62.5 µM, alongside with the established developmental neurotoxicant, rotenone (0.004-10 µM) in vitro on the human neuronal precursor cell line NT2. We found that rotenone impaired all three tested DNT endpoints, neurite outgrowth, neuronal differentiation, and precursor cell migration in a dose-dependent manner and clearly separable from general cytotoxicity in the nanomolar range. Fipronil and fipronil sulfone specifically inhibited cell migration and neuronal differentiation, but not neurite outgrowth in the micromolar range. The rho-kinase inhibitor Y-27632 counteracted inhibition of migration for all three compounds (EC50 between 12 and 50 µM). The antioxidant, n-acetyl cysteine, could ameliorate the inhibitory effects of fipronil on all three tested endpoints (EC 50 between 84 and 164 µM), indicating the involvement of oxidative stress. Fipronil sulfone had a stronger effect than fipronil, confirming the importance to test metabolic products alongside original pesticides. We conclude that in vitro fipronil and fipronil sulfone display specific developmental neurotoxicity on developing human model neurons.

Topoisomerase 1 prevents replication stress at R-loop-enriched transcription termination sites.

R-loops have both positive and negative impacts on chromosome functions. To identify toxic R-loops in the human genome, here, we map RNA:DNA hybrids, replication stress markers and DNA double-strand breaks (DSBs) in cells depleted for Topoisomerase I (Top1), an enzyme that relaxes DNA supercoiling and prevents R-loop formation. RNA:DNA hybrids are found at both promoters (TSS) and terminators (TTS) of highly expressed genes. In contrast, the phosphorylation of RPA by ATR is only detected at TTS, which are preferentially replicated in a head-on orientation relative to the direction of transcription. In Top1-depleted cells, DSBs also accumulate at TTS, leading to persistent checkpoint activation, spreading of γ-H2AX on chromatin and global replication fork slowdown. These data indicate that fork pausing at the TTS of highly expressed genes containing R-loops prevents head-on conflicts between replication and transcription and maintains genome integrity in a Top1-dependent manner.

Are Health e-Mavens the New Patient Influencers?

Even though the healthcare industry is usually considered a rather traditional and slowly evolving sector, change is happening. Digitalization is transforming the way of obtaining medical advice and treatment and the Internet has become a key source for the seeking of healthcare information. It has allowed people to turn into more active collaborators in matters of their own health by enabling them to easily search and share information with other patients. Although research points out the growing importance of user-generated content in many sectors and its positive impact on information credibility, trust, engagement, and, ultimately, customer behavior (Malthouse et al., 2016), there is a lack of attention to this topic in healthcare. In this brief review, we address this gap by analyzing the role of health e-mavens, which are a particular type of influencers that possesses both expertise and online social influence. We lastly illustrate possible benefits of their impact on other to the different parties involved and affected by this phenomenon.

Overexpression of Claspin and Timeless protects cancer cells from replication stress in a checkpoint-independent manner.

Oncogene-induced replication stress (RS) promotes cancer development but also impedes tumor growth by activating anti-cancer barriers. To determine how cancer cells adapt to RS, we have monitored the expression of different components of the ATR-CHK1 pathway in primary tumor samples. We show that unlike upstream components of the pathway, the checkpoint mediators Claspin and Timeless are overexpressed in a coordinated manner. Remarkably, reducing the levels of Claspin and Timeless in HCT116 cells to pretumoral levels impeded fork progression without affecting checkpoint signaling. These data indicate that high level of Claspin and Timeless increase RS tolerance by protecting replication forks in cancer cells. Moreover, we report that primary fibroblasts adapt to oncogene-induced RS by spontaneously overexpressing Claspin and Timeless, independently of ATR signaling. Altogether, these data indicate that enhanced levels of Claspin and Timeless represent a gain of function that protects cancer cells from of oncogene-induced RS in a checkpoint-independent manner.

SAMHD1 acts at stalled replication forks to prevent interferon induction.

SAMHD1 was previously characterized as a dNTPase that protects cells from viral infections. Mutations in SAMHD1 are implicated in cancer development and in a severe congenital inflammatory disease known as Aicardi-Goutières syndrome. The mechanism by which SAMHD1 protects against cancer and chronic inflammation is unknown. Here we show that SAMHD1 promotes degradation of nascent DNA at stalled replication forks in human cell lines by stimulating the exonuclease activity of MRE11. This function activates the ATR-CHK1 checkpoint and allows the forks to restart replication. In SAMHD1-depleted cells, single-stranded DNA fragments are released from stalled forks and accumulate in the cytosol, where they activate the cGAS-STING pathway to induce expression of pro-inflammatory type I interferons. SAMHD1 is thus an important player in the replication stress response, which prevents chronic inflammation by limiting the release of single-stranded DNA from stalled replication forks.

Is MGMT promoter methylation to be considered in the decision making for recurrent surgery in glioblastoma patients?

OBJECTIVES: At present, there is no standard therapy approved for recurrent glioblastoma (rGB). In particular, the counselling of patients with an unmethylated O6-methylguanine-DNA methyltransferase (MGMT) promoter GB remains a challenge. Our aim was to compare the overall survival (OS) and progression free survival (PFS) in patients treated surgically and non-surgically at the time of GB recurrence. This was evaluated with particular reference to the impact of recurrent surgery for patients with unmethylated MGMT promoter rGB. PATIENTS AND METHODS: The clinical and radiological data from 127 consecutive cases of rGB was retrospectively identified and evaluated. The PFS and OS from cohorts of surgically and non-surgically treated patients at time of GB recurrence were compared using Kaplan Meier estimations and Log-Rank tests. Multivariate Cox regression analysis included the major influencing variables (surgical resection, MGMT promoter methylation status, Karnofsky performance scale (KPS), age, eloquent tumor location) to analyze the survival benefit. Subgroup analysis of cases depending on the MGMT promoter methylation status was performed. RESULTS: Multiple Cox regression analysis revealed inferior OS (p = 0.029, OR = 1.731, CI 95% 1.059-2.829) of patients treated non-surgically (14 vs. 31 months). MGMT promoter methylation and age were related to longer OS (p < 0.001, OR 2.683, CI 95% 1.631-4.414 and p = 0.009, OR = 1.029, CI95% 1.007-0.052 respectively). Gross total resection (GTR) in comparison to subtotal resection (STR) lead to a median OS of 39 months vs. 22 months and a PFS of seven vs. four months respectively. In the subgroup of cases with unmethylated MGMT promoter rGB, those who underwent GTR survived significantly longer (OS: 31 months) than patients who underwent STR (OS: 15 months, p = 0.024). PFS was six vs. four months after GTR and STR respectively. CONCLUSION: Surgical management for recurrent glioblastoma appears to be a safe procedure which results in longer OS in comparison to non-surgical management. GTR may be of particular benefit to patients with unmethylated MGMT promoter rGB.

Transvascular therapy of Hepatocellular Carcinoma (HCC), status and developments.

Hepatocellular carcinoma (HCC) is the fifth most common cancer worldwide. Only 30-40% of patients diagnosed with HCC are candidates for curative treatment options. The remaining majority of patients undergo local, regional or systemic palliative therapies. Transvascular therapy of HCC takes advantage of the fact that hypervascularized HCCs receive their main perfusion from the hepatic artery. In this context transvascular therapy describes different therapies: bland embolization (transarterial embolization, TAE), cTACE (conventional transarterial chemoembolization), DEB-TACE (TACE with drug-eluting beads, DEB) and SIRT (selective internal radiation therapy, radioembolization). cTACE is the most common type of transvascular treatment and represents a combination of the intra-arterial use of a chemotherapeutic agent and embolization. There is no standardized regimen for cTACE. It remains unclear whether the intra-arterial application of a chemotherapeutic agent is definitely required, because bland embolization alone using very small spherical particles shows tumor necrosis comparable to cTACE. For DEB-TACE microparticles loaded with a chemotherapeutic drug combine the advantages of cTACE and bland embolization.

Development of an Open-Source, Discrete Element Knee Model.

OBJECTIVE: Biomechanical modeling is an important tool in that it can provide estimates of forces that cannot easily be measured (e.g., soft tissue loads). The goal of this study was to develop a discrete element model of the knee that is open source to allow for utilization of modeling by a wider audience of researchers. METHODS: A six degree-of-freedom tibiofemoral and one degree-of-freedom patellofemoral joint were created in OpenSim. Eighteen ligament bundles and tibiofemoral contact were included in the model. RESULTS: During a passive flexion movement, maximum deviation of the model from the literature occurred at the most flexed angle with deviations of 2° adduction, 7° internal rotation, 1-mm posterior translation, 12-mm inferior translation, and 4-mm lateral translation. Similarly, the overall elongation of the ligaments agreed with literature values with strains of less than 13%. CONCLUSION: These results provide validation of the physiological relevance of the model. SIGNIFICANCE: This model is one of the few open source, discrete element knee models to date, and has many potential applications, one being for use in an open-source cosimulation framework.

Comparison of hierarchical and six degrees-of-freedom marker sets in analyzing gait kinematics.

The objective of this study was to determine how marker spacing, noise, and joint translations affect joint angle calculations using both a hierarchical and a six degrees-of-freedom (6DoF) marker set. A simple two-segment model demonstrates that a hierarchical marker set produces biased joint rotation estimates when sagittal joint translations occur whereas a 6DoF marker set mitigates these bias errors with precision improving with increased marker spacing. These effects were evident in gait simulations where the 6DoF marker set was shown to be more accurate at tracking axial rotation angles at the hip, knee, and ankle.

Development of an open-source cosimulation method of the knee.

Rigid body dynamics and soft tissue loads are solved simultaneously in a cosimulation framework to couple musculoskeletal dynamics and tissue mechanics. The goal of this work was to implement a validated, open-source cosimulation framework of the knee to determine how this coupling affects computed cartilage loads. The kinematic knee joint of a generic whole body model in the open-source software OpenSim was replaced by a previously developed discrete element knee model that consisted of a six degree of freedom (dof) tibiofemoral joint and one dof patellofemoral joint. A serial approach was initially used to estimate muscle forces and cartilage contact loads for a simple flexion movement. Then, a cosimulation framework was implemented for a simple knee flexion movement in which neuromusculoskeletal dynamics and knee mechanics were simultaneously solved using a computed muscle control (CMC) algorithm. This work highlights that the choice of computation method and the precise acquisition of all the dofs of the knee are important factors to consider when estimating soft tissue loads.