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Nucleic acid sensing in the central nervous system: Implications for neural circuit development, function, and degeneration
No full textNucleic acids are a critical trigger for the innate immune response to infection, wherein pathogen-derived RNA and DNA are sensed by nucleic acid sensing receptors. This subsequently drives the production of type I interferon and other inflammatory cytokines to combat infection. While the system is designed such that these receptors should specifically recognize pathogen-derived nucleic acids, it is now clear that self-derived RNA and DNA can also stimulate these receptors to cause aberrant inflammation and autoimmune disease. Intriguingly, similar pathways are now emerging in the central nervous system in neurons and glial cells. As in the periphery, these signaling pathways are active in neurons and glia to present the spread of pathogens in the CNS. They further appear to be active even under steady conditions to regulate neuronal development and function, and they can become activated aberrantly during disease to propagate neuroinflammation and neurodegeneration. Here, we review the emerging new roles for nucleic acid sensing mechanisms in the CNS and raise open questions that we are poised to explore in the future.No embarg
Dog size and patterns of disease history across the canine age spectrum: Results from the Dog Aging Project
Get PDFAge in dogs is associated with the risk of many diseases, and canine size is a major factor in that risk. However, the size patterns are complex. While small size dogs tend to live longer, some diseases are more prevalent among small dogs. In this study we seek to quantify how the pattern of disease history varies across the spectrum of dog size, dog age, and their interaction. Utilizing owner-reported data on disease history from a substantial number of companion dogs enrolled in the Dog Aging Project, we investigate how body size, as measured by weight, associates with the lifetime prevalence of a reported condition and its pattern across age for various disease categories. We found significant positive associations between dog size and the lifetime prevalence of skin, bone/orthopedic, gastrointestinal, ear/nose/throat, cancer/tumor, brain/neurologic, endocrine, and infectious diseases. Similarly, dog size was negatively associated with lifetime prevalence of ocular, cardiac, liver/pancreas, and respiratory disease categories. Kidney/urinary disease prevalence did not vary by size. We also found that the association between age and lifetime disease prevalence varied by dog size for many conditions including ocular, cardiac, orthopedic, ear/nose/throat, and cancer. Controlling for sex, purebred vs. mixed-breed status, and geographic region made little difference in all disease categories we studied. Our results align with the reduced lifespan in larger dogs for most of the disease categories and suggest potential avenues for further examination
Impacts of testing and immunity acquired through vaccination and infection on covid-19 cases in Massachusetts elementary and secondary students
Get PDFBackground: During the 2021-22 academic year, Massachusetts supported several in-school testing programs to facilitate in-person learning. Additionally, COVID-19 vaccines became available to all school-aged children and many were infected with SARS-CoV-2. There are limited studies evaluating the impacts of these testing programs on SARS-CoV-2 cases in elementary and secondary school settings. The aim of this state-wide, retrospective cohort study was to assess the impact of testing programs and immunity on SARS-CoV-2 case rates in elementary and secondary students.
Methods: Community-level vaccination and cumulative incidence rates were combined with data about participation in and results of in-school testing programs (test-to-stay, pooled surveillance testing). School-level impacts of surveillance testing programs on SARS-CoV-2 cases in students were estimated using generalized estimating equations within a target trial emulation approach stratified by school type (elementary/middle/high). Impacts of immunity and vaccination were estimated using random effects linear regression.
Results: Here we show that among N = 652,353 students at 2141 schools participating in in-school testing programs, surveillance testing is associated with a small but measurable decrease in in-school positivity rates. During delta, pooled testing positivity rates are higher in communities with higher cumulative incidence of infection. During omicron, when immunity from prior infection became more prevalent, the effect reversed, such that communities with lower burden of infection during the earlier phases of the pandemic had higher infection rates.
Conclusions: Testing programs are an effective strategy for supporting in-person learning. Fluctuating levels of immunity acquired via natural infection or vaccination are a major determinant of SARS-CoV-2 cases in schools
Intravenous gene therapy improves lifespan and clinical outcomes in feline Sandhoff Disease [preprint]
No full textThis article is a preprint. Preprints are preliminary reports of work that have not been certified by peer review.Sandhoff Disease (SD), a fatal neurodegenerative disorder, is caused by the absence of ß-hexosaminidase (Hex) and subsequent accumulation of GM2 ganglioside in lysosomes. Previous studies have led to adeno-associated virus (AAV) gene therapy for children with GM2 gangliosidosis in both expanded access and Phase I/II clinical trials via intracranial and/or cerebrospinal fluid-based delivery. The current study investigated intravenous (IV) gene therapy of SD cats, treated at one month of age with a bicistronic AAV vector. While untreated SD cats lived to 4.3±0.2 months, cats treated with low and high doses lived to 8.3±1.2 and 12.4±2.7 months, respectively. In-life assessments revealed clear clinical benefit of AAV treatment, with the most dramatic improvement seen in the reduction of overt full-body tremors. Cerebrospinal fluid levels of aspartate aminotransferase (AST) and lactate dehydrogenase (LDH) were decreased, indicating a reduction of cell damage within the central nervous system. Magnetic resonance imaging (MRI) and spectroscopy (MRS) acquired on a 7 Tesla scanner indicated that structural pathology and metabolite abnormalities are partially normalized by AAV treatment. Dose-dependent reduction of GM2 ganglioside storage and increases in Hex activity were most substantial in the caudal regions of the brain and in the spinal cord. Immunohistochemistry revealed reduction in neuroinflammatory cell populations and partial correction of myelin deficits. These results support the dose-dependent efficacy of AAV delivered IV for significant restoration of clinical metrics and Hex function in a feline model of SD.No embarg
Vaping Cessation Support Recommendations from Adolescents Who Vape: A Qualitative Study [preprint]
Get PDFThis article is a preprint. Preprints are preliminary reports of work that have not been certified by peer review.Background: Youth vaping is an epidemic, being more prevalent than any other tobacco use. To inform cessation interventions, we explored what adolescents perceive to be their reasons for quitting and strategies to help in their quit efforts.
Method: Semi-structured interviews were conducted with a convenience sample of 11 adolescents reporting vaping in the past 90 days and recruited from a high school in Massachusetts. Interviews were transcribed, and dual coded. Inductive thematic analysis was employed and thematic summaries were prepared.
Results: Reasons adolescents reported for quitting included: cost; experiencing "nic-sick" from nicotine withdrawal or excess intake; negative impacts on mood, concentration, or health; and experiencing symptoms of nicotine dependence. Nearly all tried to quit multiple times. Barriers to quitting included: exposure to vaping; access to vape products; stress; and "cool" new products or flavors. Quit strategies included: avoiding others vaping; seeking social support to quit; addressing peer pressure to continue vaping; learning successful quit strategies from peers; and using distraction strategies or alternatives to vaping.
Conclusion: Many adolescents who vape want to quit and most have tried multiple times. Interventions need to engage adolescents with varying reasons to quit, barriers, and quit strategy preferences.
Clinical trial registration: This study is registered through ClinicalTrials.gov. The trial registration number is NCT05140915. The trial registration date is 11/18/2021
Sex Differences in Outcomes of Late-Window Endovascular Stroke Therapy
No full textBackground: The association between sex and outcome after endovascular thrombectomy of acute ischemic stroke is unclear. The aim of this study was to compare the clinical and safety outcomes between men and women treated with endovascular thrombectomy in the late 6-to-24-hour window period.
Methods: This multicenter, retrospective observational cohort study included consecutive patients who underwent endovascular thrombectomy of anterior circulation stroke in the late window from 66 clinical sites in 10 countries from January 2014 to May 2022. The primary outcome was the 90-day ordinal modified Rankin Scale score. Secondary outcomes included 90-day functional independence (FI), return of Rankin (RoR) to prestroke baseline, FI or RoR, symptomatic intracranial hemorrhage, and mortality. Multivariable and inverse probability of treatment weighting methods were used. We explored the interaction of sex with baseline characteristics on the outcomes ordinal modified Rankin Scale and FI or RoR.
Results: Of 1932 patients, 1055 were women and 877 were men. Women were older (77 versus 69 years), had higher rates of atrial fibrillation, hypertension, and greater prestroke disability, but there was no difference in baseline National Institutes of Health Stroke Scale score. Inverse probability of treatment weighting analysis showed no difference between women and men in ordinal modified Rankin Scale (odds ratio, 0.98 [95% CI, 0.79-1.21]), FI or RoR (odds ratio, 0.98 [95% CI, 0.78-1.22]), severe disability or mortality (odds ratio, 0.99 [95% CI, 0.80-1.23]). The multivariable analysis of the above end points was concordant. There were no interactions between baseline characteristics and sex on the outcomes of ordinal modified Rankin Scale and FI or RoR.
Conclusions: In late presenting patients with anterior circulation stroke treated with endovascular thrombectomy in the 6 to 24-hour window, there was no difference in clinical or safety outcomes between men and women
Implementation of Health IT for Cancer Screening in US Primary Care: Scoping Review
Get PDFBackground: A substantial percentage of the US population is not up to date on guideline-recommended cancer screenings. Identifying interventions that effectively improve screening rates would enhance the delivery of such screening. Interventions involving health IT (HIT) show promise, but much remains unknown about how HIT is optimized to support cancer screening in primary care.
Objective: This scoping review aims to identify (1) HIT-based interventions that effectively support guideline concordance in breast, cervical, and colorectal cancer screening provision and follow-up in the primary care setting and (2) barriers or facilitators to the implementation of effective HIT in this setting.
Methods: Following scoping review guidelines, we searched MEDLINE, CINAHL Plus, Web of Science, and IEEE Xplore databases for US-based studies from 2015 to 2021 that featured HIT targeting breast, colorectal, and cervical cancer screening in primary care. Studies were dual screened using a review criteria checklist. Data extraction was guided by the following implementation science frameworks: the Reach, Effectiveness, Adoption, Implementation, and Maintenance framework; the Expert Recommendations for Implementing Change taxonomy; and implementation strategy reporting domains. It was also guided by the Integrated Technology Implementation Model that incorporates theories of both implementation science and technology adoption. Reporting was guided by PRISMA-ScR (Preferred Reporting Items for Systematic Reviews and Meta-Analyses extension for Scoping Reviews).
Results: A total of 101 studies met the inclusion criteria. Most studies (85/101, 84.2%) involved electronic health record-based HIT interventions. The most common HIT function was clinical decision support, primarily used for panel management or at the point of care. Most studies related to HIT targeting colorectal cancer screening (83/101, 82.2%), followed by studies related to breast cancer screening (28/101, 27.7%), and cervical cancer screening (19/101, 18.8%). Improvements in cancer screening were associated with HIT-based interventions in most studies (36/54, 67% of colorectal cancer-relevant studies; 9/14, 64% of breast cancer-relevant studies; and 7/10, 70% of cervical cancer-relevant studies). Most studies (79/101, 78.2%) reported on the reach of certain interventions, while 17.8% (18/101) of the included studies reported on the adoption or maintenance. Reported barriers and facilitators to HIT adoption primarily related to inner context factors of primary care settings (eg, staffing and organizational policies that support or hinder HIT adoption). Implementation strategies for HIT adoption were reported in 23.8% (24/101) of the included studies.
Conclusions: There are substantial evidence gaps regarding the effectiveness of HIT-based interventions, especially those targeting guideline-concordant breast and colorectal cancer screening in primary care. Even less is known about how to enhance the adoption of technologies that have been proven effective in supporting breast, colorectal, or cervical cancer screening. Research is needed to ensure that the potential benefits of effective HIT-based interventions equitably reach diverse primary care populations
NexGen Eulogy
Get PDFIntroduction: This week we have a poem again. This time from Dr. Amber Sarkar who is faculty at Family Health Center of Worcester. She is writing here about the transition from one EHR to another EHR. I think most of us have experienced this at least once - I have experienced 8 different EHRs so this really resonates with me. We come to spend more time with our EHR than we do our children! We form a warped bond with it. Like our phones, it gets a grasp on us. We talk about it like it is a living entity. And then sometimes we have to say goodbye. And hope the new one will be better than the old. Amber captures all of this well in her poem
Flow-diverting stents for the treatment of unruptured distal anterior cerebral artery aneurysms: analysis of the CRETA Registry
No full textBackground: Data about the safety and the efficacy of flow diversion for distal anterior cerebral artery (DACA) aneurysms are limited. We present the largest multicenter analysis evaluating the outcomes of flow diversion in unruptured DACA aneurysm treatment.
Methods: Databases from 39 centers were retrospectively reviewed for unruptured DACA aneurysms treated with flow-diverting stents. Demographics, clinical presentation, radiographic characteristics, procedural complications, and outcomes were assessed.
Results: A total of 168 patients with 168 unruptured DACA aneurysms were treated between January 2018 and December 2022. One hundred and twenty-five were women (74.4%) and the median age was 61 (IQR 52-67) years. The most common morphology was saccular (91.7%), with branch involvement in 61.9% of cases. Median parent vessel diameter was 1.9 mm (IQR 1.7-2.2) and stents were successfully deployed in 99.4% of cases. In 96.4% a single stent was implanted, while 3.6% of cases required two stents. Median imaging follow-up was 16.5 (IQR 7-24) months. At last follow-up the rate of occlusion (O'Kelly-Marotta scale C or D) was 82.1%. Symptomatic thromboembolic or hemorrhagic complications occurred in 5.3% of patients and the mortality rate was 0.6%. The rate of retreatment was 1.2%.
Conclusions: Flow-diverting stents are a reasonably safe and effective treatment option for unruptured DACA aneurysms.No embarg
Refining Parent SMART: User Feedback to Optimize a Multi-Modal Intervention
No full textIntroduction: The continuing care period following residential substance use treatment is a time when adolescents are at especially high risk for relapse, yet few families engage in traditional office-based care. Parent SMART (Substance Misuse among Adolescents in Residential Treatment) is a multi-component continuing care intervention for parents that combines three digital health technologies - an "off the shelf" online parenting program, daily phone notifications, and an online parent networking forum - with support from a parent coach. The current study solicited both qualitative and quantitative user feedback about Parent SMART to ensure responsivity to user preferences, refinement, and continuous improvement of the intervention.
Methods: Exit interviews were conducted with 30 parents who received Parent SMART, which includes (1) a parent networking forum; (2) daily text messages reminders of skills, (3) an "off-the-shelf" online parenting program; and (4) in-person or telehealth parent coaching sessions. The study collected qualitative feedback using semi-structured interviews and obtained quantitative feedback via a series of ratings of each Parent SMART component on a 5-point Likert scale administered at each follow-up assessment.
Results: Quantitative feedback suggest that parents rated all four elements of Parent SMART as easy to use. Qualitative feedback revealed that parents valued several aspects of Parent SMART including the brevity and structure of the intervention elements, the reminders to use parenting skills, and the sense of social connectedness fostered by different components. Recommended refinements included a number of strategies to enhance personalization and ease of navigation.
Conclusions: Parent feedback informed enhancements to the Parent SMART intervention prior to implementation in a larger, ongoing pragmatic effectiveness trial. The current study serves as a model for applying a staged person-centered approach and eliciting both quantitative and qualitative feedback to refine digital health technologies.R34 DA039289/DA/NIDA NIH HHS/United States
R37 DA052918/DA/NIDA NIH HHS/United StatesNo embarg