Radiosensitization of Allogenic Subcutaneous C6 Glioma Model with Focused Ultrasound-Induced Mild Hyperthermia.

The radiosensitization potential of focused ultrasound (FUS)-induced mild hyperthermia was assessed in an allogenic subcutaneous C6 glioma tumor model in rats. Mild hyperthermia at 42 °C was induced in tumors using a single-element 350 kHz FUS transducer. Radiation was delivered with a small animal radiation research platform using a single-beam irradiation technique. The combined treatment involved 20 min of FUS hyperthermia immediately before radiation. Tumor growth changes were observed one week post-treatment. A radiation dose of 2 Gy alone showed limited tumor control (30% reduction). However, when combined with FUS hyperthermia, there was a significant reduction in tumor growth compared to other treatments (tumor volumes: control-1174 ± 554 mm3, FUS-HT-1483 ± 702 mm3, 2 Gy-609 ± 300 mm3, FUS-HT + 2 Gy-259 ± 186 mm3; ANOVA p < 0.00001). Immunohistological analysis suggested increased DNA damage as a short-term mechanism for tumor control in the combined treatment. In conclusion, FUS-induced mild hyperthermia can enhance the effectiveness of radiation in a glioma tumor model, potentially improving the outcome of standard radiation treatments for better tumor control.

Trypanosoma brucei Invariant Surface Glycoprotein 75 Is an Immunoglobulin Fc Receptor Inhibiting Complement Activation and Antibody-Mediated Cellular Phagocytosis.

Various subspecies of the unicellular parasite Trypanosoma brucei cause sleeping sickness, a neglected tropical disease affecting millions of individuals and domestic animals. Immune evasion mechanisms play a pivotal role in parasite survival within the host and enable the parasite to establish a chronic infection. In particular, the rapid switching of variant surface glycoproteins covering a large proportion of the parasite's surface enables the parasite to avoid clearance by the adaptive immune system of the host. In this article, we present the crystal structure and discover an immune-evasive function of the extracellular region of the T. brucei invariant surface gp75 (ISG75). Structural analysis determined that the ISG75 ectodomain is organized as a globular head domain and a long slender coiled-coil domain. Subsequent ligand screening and binding analysis determined that the head domain of ISG75 confers interaction with the Fc region of all subclasses of human IgG. Importantly, the ISG75-IgG interaction strongly inhibits both activation of the classical complement pathway and Ab-dependent cellular phagocytosis by competing with C1q and host cell FcγR CD32. Our data reveal a novel immune evasion mechanism of T. brucei, with ISG75 able to inactivate the activities of Abs recognizing the parasite surface proteins.

A simulation study on the sensitivity of transcranial ray-tracing ultrasound modeling to skull properties.

In transcranial focused ultrasound therapies, such as treating essential tremor via thermal ablation in the thalamus, acoustic energy is focused through the skull using a phased-array transducer. Ray tracing is a computationally efficient method that can correct skull-induced phase aberrations via per-element phase delay calculations using patient-specific computed tomography (CT) data. However, recent studies show that variations in CT-derived Hounsfield unit may account for only 50% of the speed of sound variability in human skull specimens, potentially limiting clinical transcranial ultrasound applications. Therefore, understanding the sensitivity of treatment planning methods to material parameter variations is essential. The present work uses a ray-tracing simulation model to explore how imprecision in model inputs, arising from clinically significant uncertainties in skull properties or considerations of acoustic phenomena, affects acoustic focusing quality through the skull. We propose and validate new methods to optimize ray-tracing skull simulations for clinical treatment planning, relevant for predicting intracranial target's thermal rise, using experimental data from ex-vivo human skulls.

Past-Year Blunt Smoking among Youth: Differences by LGBT and Non-LGBT Identity.

Blunt use (co-use of tobacco and marijuana) is a growing phenomenon among youth and disproportionately affects minority populations. LGBT+ populations are significantly more likely to use marijuana and tobacco, but this relationship has yet to be examined among LGBT+ adolescents. This analysis aimed to investigate past-year blunt use among a national sample of youth and delineate the differences between non-LGBT and LGBT+ youth. We used Wave 2 of the Population and Tobacco Health (PATH) study. We analyzed data from 7518 youth, comparing past-year blunt use between LGBT+ and non-LGBT youth, controlling for biological sex, race, and age using weighted logistic regression models. Greater than 1 in 10 youth (10.6%) reported using blunts in the past year. More than one in five (21.6%) LGBT+ youth reported using blunts in the past year. There were no significant differences between boys and girls. Older youth (17 years old) were more likely to use blunts in the past year (aPR: 3.04, 95% CI 2.48, 3.79) than younger youth. Compared with non-LGBT youth, LGBT+ youth were 2.17 times (95% CI 1.86, 2.54) more likely to report using blunts in the past year. Blunt use and its respective impact on health outcomes among developing youth are of concern to public health. These findings demonstrate that certain subgroups of youth are more at risk for use and emphasize the need for tailored interventions to mitigate initiation and current use, given that one of the goals of the Healthy People 2030 initiative is to "Improve the health, safety, and well-being of lesbian, gay, bisexual, and transgender (LGBT) individuals".

How Do Colorado Public Libraries Respond to Patron Queries about Opioid Use Disorder? A Secret Shopper Study.

Background: Colorado's age-adjusted fatal opioid overdose rate increased over 400% from 2000 to 2020. Public libraries are increasingly valuable community resources for accessing health-related information. We sought to evaluate the availability and types of opioid use disorder (OUD)-related resources offered through Colorado Public Library branches using secret shoppers to collect data. Methods: This was a cross sectional study of 197 Colorado Public Libraries in 2021. Anonymous auditors posed as library patrons asking a brief standardized script about availability of OUD-related resources over the phone. We conducted descriptive analyses of the libraries contacted, the response types of OUD resources provided, and information about naloxone availability. Outcomes were compared between urban/rural and libraries within/outside the Denver Public Library (DPL) system via means comparison tests. Results: Approximately 50% of libraries were classified as urban. Most (81%) of the libraries offered a valid OUD-resource, and over half (51%) provided a referral to a treatment center offering at least one medication for OUD. Over a third (36%) of librarians referenced the statewide naloxone standing order allowing patients to obtain naloxone from a pharmacy without prescription. One in ten libraries provided at least one invalid referral resource. Libraries within the DPL system referenced Colorado's naloxone standing order at higher rates than non-DPL libraries. Conclusions: Public libraries may benefit from the development of a standard for OUD-related resource training/education that can be distributed across the state to create a space for community members to obtain resources related to substance use.

Small airway function measured using forced expiratory flow between 25% and 75% of vital capacity and its relationship to airflow limitation in symptomatic ever-smokers: a cross-sectional study.

BACKGROUND: Chronic obstructive pulmonary disease (COPD) is diagnosed and its severity graded by traditional spirometric parameters (forced expiratory volume in 1 s (FEV1)/forced vital capacity (FVC) and FEV1, respectively) but these parameters are considered insensitive for identifying early pathology. Measures of small airway function, including forced expiratory flow between 25% and 75% of vital capacity (FEF25-75), may be more valuable in the earliest phases of COPD. This study aimed to determine the prevalence of low FEF25-75 in ever-smokers with and without airflow limitation (AL) and to determine whether FEF25-75 relates to AL severity. METHOD: A retrospective analysis of lung function data of 1458 ever-smokers suspected clinically of having COPD. Low FEF25-75 was defined by z-score<-0.8345 and AL was defined by FEV1/FVC z-scores<-1.645. The severity of AL was evaluated using FEV1 z-scores. Participants were placed into three groups: normal FEF25-75/ no AL (normal FEF25-75/AL-); low FEF25-75/ no AL (low FEF25-75/AL-) and low FEF25-75/ AL (low FEF25-75/AL+). RESULTS: Low FEF25-75 was present in 99.9% of patients with AL, and 50% of those without AL. Patients in the low FEF25-75/AL- group had lower spirometric measures (including FEV1 FEF25-75/FVC and FEV3/FVC) than those in the normal FEF25-75/AL- group. FEF25-75 decreased with AL severity. A logistic regression model demonstrated that in the absence of AL, the presence of low FEF25-75 was associated with lower FEV1 and FEV1/FVC even when smoking history was accounted for. CONCLUSIONS: Low FEF25-75 is a physiological trait in patients with conventional spirometric AL and likely reflects early evidence of impairment in the small airways when spirometry is within the 'normal range'. FEF25-75 likely identifies a group of patients with early evidence of pathological lung damage who warrant careful monitoring and reinforced early intervention to abrogate further lung injury.

Models of gene-culture evolution are incomplete without incorporating epigenetic effects.

Epigenetics impacts gene-culture coevolution by amplifying phenotypic variation, including clustering, and bridging the difference in timescales between genetic and cultural evolution. The dual inheritance model described by Uchiyama et al. could be modified to provide greater explanatory power by incorporating epigenetic effects.

Modulation of DNA methylation and protein expression in the prefrontal cortex by repeated administration of D-lysergic acid diethylamide (LSD): Impact on neurotropic, neurotrophic, and neuroplasticity signaling.

AIM: Psychedelic compounds elicit relief from mental disorders. However, the underpinnings of therapeutic improvement remain poorly understood. Here, we investigated the effects of repeated lysergic acid diethylamide (LSD) on whole-genome DNA methylation and protein expression in the mouse prefrontal cortex (PFC). METHODS: Whole genome bisulphite sequencing (WGBS) and proteomics profiling of the mouse prefrontal cortex (PFC) were performed to assess DNA methylation and protein expression changes following 7 days of repeated LSD administration (30 µg/kg/day); a treatment we previously found to potentiate excitatory neurotransmission and to increase dendritic spine density in the PFC in mice. qRT-PCR was employed to validate candidate genes detected in both analyses. RESULTS: LSD significantly modulated DNA methylation in 635 CpG sites of the mouse PFC, and in an independent cohort the expression level of 178 proteins. Gene signaling pathways affected are involved in nervous system development, axon guidance, synaptic plasticity, quantity and cell viability of neurons and protein translation. Four genes and their protein product were detected as differentially methylated and expressed, and their transcription was increased. Specifically, Coronin 7 (Coro7), an axon guidance cue; Penta-EF-Hand Domain Containing 1 (Pef1), an mTORC1 and cell cycle modulator; Ribosomal Protein S24 (Rps24), required for pre-rRNA maturation and biogenesis of proteins involved with cell proliferation and migration, and Abhydrolase Domain Containing 6, Acylglycerol Lipase (Abhd6), a post-synaptic lipase. CONCLUSIONS: LSD affects DNA methylation, altering gene expression and protein expression related to neurotropic-, neurotrophic- and neuroplasticity signaling. This could represent a core mechanism mediating the effects of psychedelics.

Locoregional therapies and their effects on the tumoral microenvironment of pancreatic ductal adenocarcinoma.

Pancreatic ductal adenocarcinoma (PDAC) is expected to become the second leading cause of death from cancer by 2030. Despite intensive research in the field of therapeutics, the 5-year overall survival is approximately 8%, with only 20% of patients eligible for surgery at the time of diagnosis. The tumoral microenvironment (TME) of the PDAC is one of the main causes for resistance to antitumoral treatments due to the presence of tumor vasculature, stroma, and a modified immune response. The TME of PDAC is characterized by high stiffness due to fibrosis, with hypo microvascular perfusion, along with an immunosuppressive environment that constitutes a barrier to effective antitumoral treatment. While systemic therapies often produce severe side effects that can alter patients' quality of life, locoregional therapies have gained attention since their action is localized to the pancreas and can thus alleviate some of the barriers to effective antitumoral treatment due to their physical effects. Local hyperthermia using radiofrequency ablation and radiation therapy - most commonly using a local high single dose - are the two main modalities holding promise for clinical efficacy. Recently, irreversible electroporation and focused ultrasound-derived cavitation have gained increasing attention. To date, most of the data are limited to preclinical studies, but ongoing clinical trials may help better define the role of these locoregional therapies in the management of PDAC patients.

Pancreatic Ductal Adenocarcinoma: Current and Emerging Therapeutic Uses of Focused Ultrasound.

Pancreatic ductal adenocarcinoma (PDAC) diagnosis accompanies a somber prognosis for the patient, with dismal survival odds: 5% at 5 years. Despite extensive research, PDAC is expected to become the second leading cause of mortality by cancer by 2030. Ultrasound (US) has been used successfully in treating other types of cancer and evidence is flourishing that it could benefit PDAC patients. High-intensity focused US (HIFU) is currently used for pain management in palliative care. In addition, clinical work is being performed to use US to downstage borderline resectable tumors and increase the proportion of patients eligible for surgical ablation. Focused US (FUS) can also induce mechanical effects, which may elicit an anti-tumor response through disruption of the stroma and can be used for targeted drug delivery. More recently, sonodynamic therapy (akin to photodynamic therapy) and immunomodulation have brought new perspectives in treating PDAC. The aim of this review is to summarize the current state of those techniques and share our opinion on their future and challenges.

Systematic reviews do not (yet) represent the 'gold standard' of evidence: A position paper.

The low quality of included trials, insufficient rigour in review methodology, ignorance of key pain issues, small size, and over-optimistic judgements about the direction and magnitude of treatment effects all devalue systematic reviews, supposedly the 'gold standard' of evidence. Available evidence indicates that almost all systematic reviews in the published literature contain fatal flaws likely to make their conclusions incorrect and misleading. Only 3 in every 100 systematic reviews are deemed to have adequate methods and be clinically useful. Examples of research waste and questionable ethical standards abound: most trials have little hope of providing useful results, and systematic review of hopeless trials inspires no confidence. We argue that results of most systematic reviews should be dismissed. Forensically critical systematic reviews are essential tools to improve the quality of trials and should be encouraged and protected.

Community Versus Hospital Opioid-Related Overdose Deaths in Illinois.

OBJECTIVE: To better understand approaches to reducing mortality from the opioid epidemic, we analyzed in-hospital versus community opioid-related overdose deaths in Illinois. METHODS: We used data from the Statewide Unintentional Drug Overdose Reporting System (July 2017 through December 2018) to identify deaths that occurred in hospitals and communities (ie, homes or public spaces). We used census tract-level data for 34 Illinois counties to create bivariate mapping by overdose death rates. We used logistic regression to analyze the association of demographic and overdose characteristics with the likelihood of death in a hospital versus a community. RESULTS: During the study period, 2833 opioid-related overdose deaths occurred in 24 Illinois counties, 655 (23.1%) of which occurred in the hospital; of 2178 community deaths, 1888 (86.7%) occurred in the same census tract as the decedent's recorded residence and 1285 (59.0%) occurred in the decedent's home. Non-Hispanic Black people were 1.63 (95% CI, 1.27-2.10) times more likely than non-Hispanic White people to die in a hospital. Decedents from suburban Cook County and other Chicago suburban counties were significantly more likely to die in the hospital than decedents from Chicago or other Illinois counties. Documentation of a previous overdose, history of opioid use, and having bystanders present were significantly associated with hospital deaths. Evidence of a rapid overdose, fentanyl present, or prescription opioids were significantly associated with deaths in a community. CONCLUSIONS: The high number of opioid-related overdose deaths in the community illustrates the need to decriminalize illicit drug use and facilitate treatment seeking. Establishing supervised safe consumption sites may have the biggest effect in reducing the number of opioid-related overdose deaths.

Additively manufactured high-performance polymeric materials and their potential use in the oil and gas industry.

The oil and gas industry has been tagged as among the largest revenue-generating sectors in the world. High-performance polymers (HPPs), on the other hand, are among the most useful industrial materials, while the utility of 3D printing technologies has evolved and transitioned from rapid prototyping of composite materials to manufacturing of functional parts. In this prospective, we highlight the potential uses and industrial applications of 3D-printed HPP materials in the oil and gas sector, including the challenges and opportunities present.

Microglia do not restrict SARS-CoV-2 replication following infection of the central nervous system of K18-hACE2 transgenic mice

Unlike SARS-CoV-1 and MERS-CoV, infection with SARS-CoV-2, the viral pathogen responsible for COVID-19, is often associated with neurologic symptoms that range from mild to severe, yet increasing evidence argues the virus does not exhibit extensive neuroinvasive properties. We demonstrate SARS-CoV-2 can infect and replicate in human iPSC-derived neurons and that infection shows limited anti-viral and inflammatory responses but increased activation of EIF2 signaling following infection as determined by RNA sequencing. Intranasal infection of K18 human ACE2 transgenic mice (K18-hACE2) with SARS-CoV-2 resulted in lung pathology associated with viral replication and immune cell infiltration. In addition, [~]50% of infected mice exhibited CNS infection characterized by wide-spread viral replication in neurons accompanied by increased expression of chemokine (Cxcl9, Cxcl10, Ccl2, Ccl5 and Ccl19) and cytokine (Ifn-{lambda} and Tnf-) transcripts associated with microgliosis and a neuroinflammatory response consisting primarily of monocytes/macrophages. Microglia depletion via administration of colony-stimulating factor 1 receptor inhibitor, PLX5622, in SARS-CoV-2 infected mice did not affect survival or viral replication but did result in dampened expression of proinflammatory cytokine/chemokine transcripts and a reduction in monocyte/macrophage infiltration. These results argue that microglia are dispensable in terms of controlling SARS-CoV-2 replication in in the K18-hACE2 model but do contribute to an inflammatory response through expression of pro-inflammatory genes. Collectively, these findings contribute to previous work demonstrating the ability of SARS-CoV-2 to infect neurons as well as emphasizing the potential use of the K18-hACE2 model to study immunological and neuropathological aspects related to SARS-CoV-2-induced neurologic disease. ImportanceUnderstanding the immunological mechanisms contributing to both host defense and disease following viral infection of the CNS is of critical importance given the increasing number of viruses that are capable of infecting and replicating within the nervous system. With this in mind, the present study was undertaken to evaluate the role of microglia in aiding in host defense following experimental infection of the central nervous system (CNS) of K18-hACE2 with SARS-CoV-2, the causative agent of COVID-19. Neurologic symptoms that range in severity are common in COVID-19 patients and understanding immune responses that contribute to restricting neurologic disease can provide important insight into better understanding consequences associated with SARS-CoV-2 infection of the CNS.

On the progress of 3D-printed hydrogels for tissue engineering.

ABSTRACT: Additive manufacturing or more commonly known as 3D printing, is currently driving innovations and applications in diverse fields such as prototyping, manufacturing, aerospace, education, and medicine. Recent technological and materials research breakthroughs have enabled 3D bioprinting, where biomaterials and cells are used to create scaffolds and functional living tissues (e.g. skin, cartilage, etc.). This prospective focuses on the classification and applications of hydrogels, and design considerations in their production (i.e. physical and biological parameters). The materials for 3D printing of hydrogels, such as biopolymers, synthetic polymers, and nanocomposites, are mainly discussed. More importantly, future perspectives on 3D printing hydrogels including new materials, 4D printing, emerging printing technologies, etc. and their importance in biomedical and bioengineering applications are discussed.

Correction to: Pathologic Clavicle Fracture Secondary to Cutibacterium acnes Abscess: Case Report and Review of Literature.

[This corrects the article DOI: 10.1007/s43465-020-00042-5.].

Seven-month kinetics of SARS-CoV-2 antibodies and protective role of pre-existing antibodies to seasonal human coronaviruses on COVID-19

Unraveling the long-term kinetics of antibodies to SARS-CoV-2 and its determinants, including the impact of pre-existing antibodies to human coronaviruses causing common cold (HCoVs), is essential to understand protective immunity to COVID-19 and devise effective surveillance strategies. IgM, IgA and IgG levels against six SARS-CoV-2 and four HCoV antigens were quantified by Luminex, and antibody neutralization capacity was assessed by flow cytometry, in a cohort of health care workers followed-up for 6 months. Seroprevalence increased over time from 13.5% (month 0) and 15.6% (month 1) to 16.4% (month 6). Levels of antibodies, including those with neutralizing capacity, were stable over time, except IgG to nucleocapsid antigen and IgM levels that waned. After the peak response, anti-spike antibody levels increased from [~]150 days post-symptom onset in all individuals (73% for IgG), in the absence of any evidence of re-exposure. Pre-existing antibodies to alpha-HCoV were lower in individuals who subsequently seroconverted for SARS-CoV-2. IgG and IgA to HCoV were significantly higher in asymptomatic than symptomatic seropositive individuals. Thus, pre-existing cross-reactive HCoVs antibodies could have a protective effect against SARS-CoV-2 infection and COVID-19 disease.