Over 300 billion of cells die every day in the human body, producing a large number of endogenous apoptotic extracellular vesicles (apoEVs). Also, allogenic stem cell transplantation, a commonly used therapeutic approach in current clinical practice, generates exogenous apoEVs. It is well known that phagocytic cells engulf and digest apoEVs to maintain the body's homeostasis. In this study, we show that a fraction of exogenous apoEVs is metabolized in the integumentary skin and hair follicles. Mechanistically, apoEVs activate the Wnt/β-catenin pathway to facilitate their metabolism in a wave-like pattern. The migration of apoEVs is enhanced by treadmill exercise and inhibited by tail suspension, which is associated with the mechanical force-regulated expression of DKK1 in circulation. Furthermore, we show that exogenous apoEVs promote wound healing and hair growth via activation of Wnt/β-catenin pathway in skin and hair follicle mesenchymal stem cells. This study reveals a previously unrecognized metabolic pathway of apoEVs and opens a new avenue for exploring apoEV-based therapy for skin and hair disorders.
Frontotemporal lobar degeneration (FTLD) is a diverse group of neurodegenerative diseases associated with variable clinical phenotypes. Most FTLD cases are characterized by the accumulation of abnormal protein inclusions comprised of either TDP-43 or tau and in concert with neuron loss and gliosis of frontal and temporal regions. We describe here the neuropathologic subtypes of FTLD and their corresponding clinical phenotypes. We also highlight the structures and functions of key FTLD-related proteins including C9orf72, TDP-43, progranulin, and tau. Finally, we provide an overview of preclinical studies and clinical trials for the treatment of FTLD and related disorders based on advances in our understanding of the pathophysiology of TDP-43 and tau proteinopathies. Thus, this review highlights the neuropathologic, clinical, and molecular heterogeneity of the FTLD spectrum of diseases that forms the basis for therapeutic development.
Leukemias, lymphomas, plasma cell disorders, and related neoplasms are hematologic malignancies characterized by various recurrent acquired genetic and genomic abnormalities. Identification of these anomalies can assist in diagnosis, therapeutic choice, risk assessment, prognosis, and disease monitoring. Conventional cytogenetics (karyotyping), fluorescence in situ hybridization, single-nucleotide polymorphism, chromosomal microarray, single-gene mutational assays, and next-generation sequencing/massively parallel sequencing (NGS/MPS) are techniques used to detect disease-related genomic aberrations, including genomic imbalances, gene mutations, fusion genes, and other chromosomal rearrangements. Each of these techniques has advantages and limitations, thus choosing the appropriate testing is dependent on the disease state, tissue source, suspected type of abnormality, and turnaround time to assure results in a clinically useful timeframe. Additionally, germline variants associated with predisposition to hematological malignancies have been identified in the pediatric and adult populations, with significant differences in age of presentation compared with cancers arising from mutations in traditional cancer predisposition genes. The identification of the Philadelphia chromosome in chronic myeloid leukemia (CML) demonstrated the first direct evidence that cancer is a genetic disease (Nowell and Hungerford, 1960) and serves as a model for rational, molecularly targeted therapy. The Philadelphia chromosome was later shown to be a translocation involving chromosomes 9 and 22 (Rowley, 1973), demonstrating that nonrandom chromosomal rearrangements were associated with malignancy. The discovery that the t(9;22) leads to a novel fusion gene, BCR::ABL1, with a dysregulated a tyrosine kinase opened the door for development of a highly specific ABL1 inhibitor, imatinib. More recent studies have shown that some CML patients in a deep molecular response can be cured of their cancer through use of targeted therapy (reviewed in (Braun et al., 2020)). Many more genetic and genomic alterations have been identified in hematological malignancies that affect a variety of pathways using conventional cytogenetics and broad genomic sequencing, leading to more targeted and personalized therapies available. This chapter will focus on the cytogenetic and molecular alterations known to be associated with various hematologic malignancies and how detection of different disease associated mutations can be used for diagnosis, prognosis, risk assessment, and treatment.
Plasma gasification is considered an emerging technology within the so-called waste-to-energy technologies. The pure equilibrium models have been failing to estimate the amounts of the syngas components, especially the methane quantity. In this investigation, a restricted or quasi-equilibrium model was developed in Aspen Plus® to evaluate the performance of the plasma co-gasification process of biomass and coal. The developed model was validated against literature data. A comprehensive parametric study was performed considering the variation of the equivalence ratio, biomass ratio, temperature, and steam to feedstock ratio on the quality of syngas and hydrogen production. Three gasifying agents (air, steam, and oxygen) were used. The syngas lower heating value and the cold gas efficiency are taken as a measure of the syngas quality and process efficiency. The developed restricted model shows to estimate the amount of methane much closer to the experimental data than pure equilibrium models. The highest amount of hydrogen was obtained for steam followed by pure oxygen and lastly for the air as gasifying agents. The use of coal in the feedstock mixture allows obtaining higher LHV of the syngas and CGE of the process. The results of this parametric study represent a humble contribution to the increase of plasma gasification technology market penetration.
While dealloying is widely used to create nanoporous materials, it has rarely been employed to isolate difficult-to-synthesize intermediate phases. Here we show how air-free, electrolytic dealloying at room temperature can be used to isolate the ternary intermetallic Mg11Cu6Al12 phase. We create a ternary Mg-Cu-Al parent alloy containing the Mg11Cu6Al12 compound and other phases, then subsequently remove these other phases via electrolytic dealloying to isolate the Mg11Cu6Al12 phase. Isolated Mg11Cu6Al12 phase exhibits ≈1 μm diameter rod-shaped microstructure. Phase and chemical analysis conducted using various techniques, including inductively coupled plasma and lab and synchrotron-based X-ray diffraction, show minimal impurities. This new approach to isolate the Mg11Cu6Al12 phase can unlock its use in fundamental research and can be applied to other difficult-to-synthesize intermetallic compounds.
Febrile seizures are among the most common types of convulsions in children. Why young children are susceptible to these events is rooted in fundamental steps of brain development. Neural circuit formation in the developing brain involves activity-dependent processes which drive the formation of neural connections. Thus, excitatory mechanisms are robust, and inhibitory drive is underdeveloped. The likely cellular and molecular underpinnings of this enhanced excitation include the relatively late development of interneurons and expression patterns of receptors, channels, and transporters favoring excitatory transmission and intrinsic excitability. This chapter will provide an overview of some of the important features of the immature brain which likely tip the excitatory/inhibitory balance toward excitation. A more complete understanding of these factors may reveal novel targets for new therapeutics for the treatment of epilepsy and neurodevelopmental disorders.
Dravet syndrome (DS) is a severe neurodevelopmental disorder largely due to heterozygous pathogenic variants in SCN1A encoding the voltage-gated sodium channel α-subunit NaV1.1. DS is clinically defined by normal early childhood development followed by infantile onset of recurrent and prolonged seizures with prominent temperature sensitivity, as well as developmental delay, autism spectrum disorder, behavioral dysfunction, ataxia, and increased mortality. As the most temperature-sensitive form of epilepsy, the study of DS may enlighten our understanding of the mechanisms of febrile seizures more generally. The majority of DS-associated variants in SCN1A exert a loss of function effect on NaV1.1-containing sodium channels, which are critical for the generation and propagation of action potentials. NaV1.1 is preferentially expressed in GABAergic inhibitory interneurons throughout the brain, and specific subsets of interneurons are dysfunctional in DS, which may lead to a net impairment of synaptic inhibition as the pathomechanism underlying epilepsy in this syndrome. Extensive research on basic mechanisms of DS over the last 20 years has provided important insights informing basic mechanisms underlying febrile seizures in general.
Cognitive behavioral therapy for insomnia (CBT-I) is an effective treatment in adults. However, access to care is limited. One potential solution is telemedicine. Though synchronous video-based telemedicine CBT-I has been shown to be non-inferior to in-person treatment, there is no study to date that evaluates patient and provider experiences with video-based treatment. Our study team evaluated patient and provider perceptions of CBT-I delivered via telemedicine versus an in-person format. As part of a larger randomized control trial, we interviewed patients and providers in both arms of the study (in-person and via telemedicine). 20 minute interviews were conducted over the phone and were transcribed and coded to identify themes. While patients shared initial concerns about telemedicine CBT-I, including privacy and technological issues, they were satisfied with the approach and had similar experiences as the patients receiving in-person treatment. Providers shared concerns about challenges establishing a strong therapeutic alliance, patient engagement, and accountability in CBT-I, but felt these did not interfere with their overall ability to deliver care. Patients and providers were satisfied with CBT-I treatment delivered via telemedicine when compared to those being treated in-person. Patients in both arms noted that virtual care could increase access and provide convenience. © 2022 The Author(s). This open access article is distributed under a Creative Commons Attribution (CC-BY) 4.0 license.
Interventional oncologists provide several effective treatment options for patients with metastatic colorectal cancer (mCRC), including embolization and ablation-based techniques. Molecular imaging methods such as positron emission tomography (PET) can play an important role in managing mCRC patients. In this review, we aim to highlight the role of molecular imaging in mCRC management by interventional oncologists including: initial staging and pretreatment planning; predicting molecular subtypes, prognosis, and treatment outcomes; intraprocedural guidance; and assessing treatment response and post-procedural monitoring.
Complications of short bowel syndrome (SBS) include malabsorption and bacterial overgrowth, requiring prolonged dependence on parenteral nutrition (PN). We hypothesized that the intolerance of whole food in some SBS patients might be due to the effect of dietary fiber on the gut microbiome. Shotgun metagenomic sequencing and targeted metabolomics were performed using biospecimens collected from 55 children with SBS and a murine dietary fiber model. Bioinformatic analyses were performed on these datasets as well as from a healthy human dietary intervention study. Compared to healthy controls, the gut microbiota in SBS had lower diversity and increased Proteobacteria, a pattern most pronounced in children on PN and inversely correlated with whole food consumption. Whole food intake correlated with increased glycoside hydrolases (GH) and bile salt hydrolases (BSH) with reduced fecal conjugated bile acids suggesting that dietary fiber regulates BSH activity via GHs. Mechanistic evidence supporting this notion was generated via fecal and plasma bile acid profiling in a healthy human fiber-free dietary intervention study as well as in a dietary fiber mouse experiment. Gaussian mixture modeling of fecal bile acids was used to identify three clinically relevant SBS phenotypes. Dietary fiber is associated with bile acid deconjugation likely via an interaction between gut microbiota BSHs and GHs in the small intestine, which may lead to whole food intolerance in patients with SBS. This mechanism not only has potential utility in clinical phenotyping and targeted therapeutics in SBS based on bile acid metabolism but may have relevance to other intestinal disease states.
Background Little is known about voluntary divestment of firearms among US firearm owners. Here, we aim to estimate the proportion of handgun owners who divest their handguns in the years following their initial acquisition; examine the timing, duration, and dynamics of those divestments; and describe characteristics of those who divest. Methods We use data from the Longitudinal Study of Handgun Ownership and Transfer, a cohort of registered voters in California with detailed information on 626,756 adults who became handgun owners during the 12-year study period, 2004–2016. For the current study, persons were followed from the time of their initial handgun acquisition until divestment, loss to follow-up, death, or the end of the study period. We describe the cumulative proportion who divest overall and by personal and area-level characteristics. We also estimate the proportion who reacquired handguns among persons who divested. Results Overall, 4.5% (95% CI 4.5–4.6) of handgun owners divested within 5 years of their first acquisition, with divestment relatively more common among women and among younger adults. Among those who divested, 36.6% (95% CI 35.8–37.5) reacquired a handgun within 5 years. Conclusions Handgun divestment is rare, with the vast majority of new handgun owners retaining them for years.
Background Destination left ventricular assist device placement is increasing as a result of donor shortages and changing patient attitudes. As organ shortages become critical, LVAD programs become fundamental even in more remote regions of the world including island states. Here, we provide a look into the current state and availability of LVAD programs in island states. Main body A narrative review was performed using the World Health Organization Global Index Medicus and PubMed/MEDLINE databases to identify articles describing the island states having reported LVAD placements and programs. Additionally, INTERMACS reports were used. Data were retrieved and a review is presented describing the current state of LVADs in island states. The Caribbean region as a whole has a heart failure (HF) prevalence of 814 per 100,000 and Oceania 667 per 100,000 people. We estimate that over 3000 people in these islands need either a heart transplant or an LVAD. Short conclusion For HF patients living in island regions, special attention should be paid to the inability of having access to specialized mainland medical care. The continuous quest for a solution to HF in island regions should include the establishing of high-quality LVAD programs in a transfer-network centralized/regionalized system to care for those patients not candidates for long-distance air-bridging.
Background This implementation feasibility study was conducted to determine whether an evidence-based parent-implemented distance-learning intervention model for young children at high likelihood of having ASD could be implemented at fidelity by Part C community providers and by parents in low-resource communities. Methods The study used a community-academic partnership model to adapt an evidence-based intervention tested in the current pilot trial involving randomization by agency in four states and enrollment of 35 coaches and 34 parent-family dyads. After baseline data were gathered, providers in the experimental group received 12–15 h of training while control providers received six webinars on early development. Providers delivered 6 months of intervention with children-families, concluding with data collection. Regression analyses were used to model outcomes of the coach behaviors, the parent fidelity ratings, and child outcomes. Results A block design model-building approach was used to test the null model followed by the inclusion of group as a predictor, and finally the inclusion of the planned covariates. Model fit was examined using changes in R ² and F -statistic. As hypothesized, results demonstrated significant gains in (1) experimental provider fidelity of coaching implementation compared to the control group; and (2) experimental parent fidelity of implementation compared to the control group. There were no significant differences between groups on child developmental scores. Conclusions Even though the experimental parent group averaged less than 30 min of intervention weekly with providers in the 6 months, both providers and parents demonstrated statistically significant gains on the fidelity of implementation scores with moderate effect sizes compared to control groups. Since child changes in parent-mediated models are dependent upon the parents’ ability to deliver the intervention, and since parent delivery is dependent upon providers who are coaching the parents, these results demonstrated that two of these three links of the chain were positively affected by the experimental implementation model. However, a lack of significant differences in child group gains suggests that further work is needed on this model. Factors to consider include the amount of contact with the provider, the amount of practice children experience, the amount of contact both providers and parents spend on training materials, and motivational strategies for parents, among others. Trial registration Registry of Efficacy and Effectiveness Studies: #4360, registered 1xx, October, 2020 – Retrospectively registered, https://sreereg.icpsr.umich.edu/sreereg/
Complete or improving civil registration systems in sub-national areas in low- and middle-income countries provide several opportunities to better understand population health and its determinants. In this article, we provide an assessment of vital statistics in Kerala, India. Kerala is home to more than 33 million people and is a comparatively low-mortality context. We use individual-level vital registration data on more than 2.8 million deaths between 2006 and 2017 from the Kerala MARANAM (Mortality and Registration Assessment and Monitoring) Study. Comparing age-specific mortality rates from the Civil Registration System (CRS) to those from the Sample Registration System (SRS), we do not find evidence that the CRS underestimates mortality. Instead, CRS rates are smoother across ages and less variable across periods. In particular, the CRS records higher death rates than the SRS for ages, where mortality is usually low and for women. Using these data, we provide the first set of annual sex-specific life tables for any state in India. We find that life expectancy at birth was 77.9 years for women in 2017 and 71.4 years for men. Although Kerala is unique in many ways, our findings strengthen the case for more careful attention to mortality records within low- and middle-income countries, and for their better dissemination by government agencies. Supplementary information: The online version contains supplementary material available at 10.1186/s41118-021-00149-z.
While COVID-19 diagnosis and prognosis artificial intelligence models exist, very few can be implemented for practical use given their high risk of bias. We aimed to develop a diagnosis model that addresses notable shortcomings of prior studies, integrating it into a fully automated triage pipeline that examines chest radiographs for the presence, severity, and progression of COVID-19 pneumonia. Scans were collected using the DICOM Image Analysis and Archive, a system that communicates with a hospital’s image repository. The authors collected over 6,500 non-public chest X-rays comprising diverse COVID-19 severities, along with radiology reports and RT-PCR data. The authors provisioned one internally held-out and two external test sets to assess model generalizability and compare performance to traditional radiologist interpretation. The pipeline was evaluated on a prospective cohort of 80 radiographs, reporting a 95% diagnostic accuracy. The study mitigates bias in AI model development and demonstrates the value of an end-to-end COVID-19 triage platform.
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