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1.
Front Public Health ; 12: 1413258, 2024.
Article in English | MEDLINE | ID: mdl-38989114

ABSTRACT

As a result of the United States withdrawal from Afghanistan in fall 2021, 1,260 Afghan evacuees arrived in Minnesota between October 2021 and February 2022. Several contextual factors including an overtaxed health system under duress from COVID-19 and uncertain benefit eligibility prompted a coordinated public health response to appropriately address the acute and pressing medical concerns of our new neighbors. This community case study describes the State of Minnesota's cross-sectoral response that created a welcoming environment, identified public health concerns, and addressed acute medical needs. Medical volunteers provided an initial health and safety check for Afghan families upon arrival. Volunteers also offered onsite culturally and linguistically appropriate mental health assessments, group therapy, women's clinics, vaccine clinics, medication refills, and ongoing walk-in primary care. Care coordinators facilitated primary care and specialty care referrals. The majority (96%) of eligible arrivals were screened as part of this response and the median time between arrival to Minnesota and initial health screening was 2 days. Half of all arrivals screened reported at least one health concern and 56% were referred to a specialty for further evaluation. Almost one in four adults (24%) reported mental health concerns. Existing partnerships across local sectors can be leveraged to provide comprehensive physical and mental health services to newcomers in an emergency response.


Subject(s)
COVID-19 , Humans , Minnesota , Afghanistan , COVID-19/epidemiology , Female , Refugees , Adult , Male , Primary Health Care
2.
bioRxiv ; 2024 Jun 12.
Article in English | MEDLINE | ID: mdl-38915638

ABSTRACT

In schizophrenia, layer 3 pyramidal neurons (L3PNs) in the dorsolateral prefrontal cortex (DLPFC) are thought to receive fewer excitatory synaptic inputs and to have lower expression levels of activity-dependent genes and of genes involved in mitochondrial energy production. In concert, these findings from previous studies suggest that DLPFC L3PNs are hypoactive in schizophrenia, disrupting the patterns of activity that are crucial for working memory, which is impaired in the illness. However, whether lower PN activity produces alterations in inhibitory and/or excitatory synaptic strength has not been tested in the primate DLPFC. Here, we decreased PN excitability in rhesus monkey DLPFC in vivo using adeno-associated viral vectors (AAVs) to produce Cre recombinase-mediated overexpression of Kir2.1 channels, a genetic silencing tool that efficiently decreases neuronal excitability. In acute slices prepared from DLPFC 7-12 weeks post-AAV microinjections, Kir2.1-overexpressing PNs had a significantly reduced excitability largely attributable to highly specific effects of the AAV-encoded Kir2.1 channels. Moreover, recordings of synaptic currents showed that Kir2.1-overexpressing DLPFC PNs had reduced strength of excitatory synapses whereas inhibitory synaptic inputs were not affected. The decrease in excitatory synaptic strength was not associated with changes in dendritic spine number, suggesting that excitatory synapse quantity was unaltered in Kir2.1-overexpressing DLPFC PNs. These findings suggest that, in schizophrenia, the excitatory synapses on hypoactive L3PNs are weaker and thus might represent a substrate for novel therapeutic interventions. Significance Statement: In schizophrenia, dorsolateral prefrontal cortex (DLPFC) pyramidal neurons (PNs) have both transcriptional and structural alterations that suggest they are hypoactive. PN hypoactivity is thought to produce synaptic alterations in schizophrenia, however the effects of lower neuronal activity on synaptic function in primate DLPFC have not been examined. Here, we used, for the first time in primate neocortex, adeno-associated viral vectors (AAVs) to reduce PN excitability with Kir2.1 channel overexpression and tested if this manipulation altered the strength of synaptic inputs onto the Kir2.1-overexpressing PNs. Recordings in DLPFC slices showed that Kir2.1 overexpression depressed excitatory (but not inhibitory), synaptic currents, suggesting that, in schizophrenia, the hypoactivity of PNs might be exacerbated by reduced strength of the excitatory synapses they receive.

3.
J Neurosci Methods ; 407: 110133, 2024 Jul.
Article in English | MEDLINE | ID: mdl-38588922

ABSTRACT

BACKGROUND: High-precision neurosurgical targeting in nonhuman primates (NHPs) often requires presurgical anatomical mapping with noninvasive neuroimaging techniques (MRI, CT, PET), allowing for translation of individual anatomical coordinates to surgical stereotaxic apparatus. Given the varied tissue contrasts that these imaging techniques produce, precise alignment of imaging-based coordinates to surgical apparatus can be cumbersome. MRI-compatible stereotaxis with radiopaque fiducial markers offer a straight-forward and reliable solution, but existing commercial options do not fit in conformal head coils that maximize imaging quality. NEW METHOD: We developed a compact MRI-compatible stereotaxis suitable for a variety of NHP species (Macaca mulatta, Macaca fascicularis, and Cebus apella) that allows multimodal alignment through technique-specific fiducial markers. COMPARISON WITH EXISTING METHODS: With the express purpose of compatibility with clinically available MRI, CT, and PET systems, the frame is no larger than a human head, while allowing for imaging NHPs in the supinated position. This design requires no marker implantation, special software, or additional knowledge other than the operation of a common large animal stereotaxis. RESULTS: We demonstrated the applicability of this 3D-printable apparatus across a diverse set of experiments requiring presurgical planning: 1) We demonstrate the accuracy of the fiducial system through a within-MRI cannula insertion and subcortical injection of a viral vector. 2) We also demonstrated accuracy of multimodal (MRI and CT) alignment and coordinate transfer to guide a surgical robot electrode implantation for deep-brain electrophysiology. CONCLUSIONS: The computer-aided design files and engineering drawings are publicly available, with the modular design allowing for low cost and manageable manufacturing.


Subject(s)
Brain Mapping , Cebus , Magnetic Resonance Imaging , Animals , Magnetic Resonance Imaging/methods , Magnetic Resonance Imaging/instrumentation , Brain Mapping/methods , Brain Mapping/instrumentation , Stereotaxic Techniques/instrumentation , Brain/diagnostic imaging , Brain/surgery , Brain/anatomy & histology , Fiducial Markers , Multimodal Imaging/methods , Multimodal Imaging/instrumentation , Macaca mulatta , Male
4.
Nat Neurosci ; 27(3): 391-392, 2024 Mar.
Article in English | MEDLINE | ID: mdl-38351324

Subject(s)
Gyrus Cinguli , Learning , Reward
5.
Travel Med Infect Dis ; 56: 102653, 2023.
Article in English | MEDLINE | ID: mdl-37852594

ABSTRACT

BACKGROUND: The continued increase in global migration compels clinicians to be aware of specific health problems faced by refugees, immigrants, and migrants (RIM). This analysis aimed to characterize RIM evaluated at GeoSentinel sites, their migration history, and infectious diseases detected through screening and diagnostic workups. METHODS: A case report form was used to collect data on demographics, migration route, infectious diseases screened, test results, and primary infectious disease diagnosis for RIM patients seen at GeoSentinel sites. Descriptive statistics were performed. RESULTS: Between October 2016 and November 2018, 5,319 RIM patients were evaluated at GeoSentinel sites in 19 countries. Africa was the region of birth for 2,436 patients (46 %), followed by the Americas (1,644, 31 %), and Asia (1,098, 21 %). Tuberculosis (TB) was the most common infection screened and reported as positive (853/2,273, 38 % positive by any method). TB, strongyloidiasis, and hepatitis B surface antigen positivity were observed across all migration administrative categories and regions of birth. Chagas disease was reported only among RIM patients from the Americas (393/394, 100 %) and schistosomiasis predominantly in those from Africa (480/510, 94 %). TB infection (694/5,319, 13 %) and Chagas disease (524/5,319, 10 %) were the leading primary infectious disease diagnoses. CONCLUSIONS: Several infections of long latency (e.g. TB, hepatitis B, and strongyloidiasis) with potential for long-term sequelae were seen among RIM patients across all migration administrative categories and regions of origin. Obtaining detailed epidemiologic information from RIM patients is critical to optimize detection of diseases of individual and public health importance, particularly those with long latency periods.


Subject(s)
Chagas Disease , Emigrants and Immigrants , Hepatitis B , Refugees , Strongyloidiasis , Transients and Migrants , Tuberculosis , Humans
6.
Am J Prev Med ; 65(6): 993-1002, 2023 12.
Article in English | MEDLINE | ID: mdl-37406745

ABSTRACT

INTRODUCTION: Understanding of COVID-19-related disparities in the U.S. is largely informed by traditional race/ethnicity categories that mask important social group differences. This analysis utilizes granular information on patients' country of birth and preferred language from a large health system to provide more nuanced insights into health disparities. METHODS: Data from patients seeking care from a large Midwestern health system between January 1, 2019 and July 31, 2021 and COVID-19-related events occurring from March 18, 2020 to July 31, 2021 were used to describe COVID-19 disparities. Statistics were performed between January 1, 2022 and March 15, 2023. Age-adjusted generalized linear models estimated RR across race/ethnicity, country of birth grouping, preferred language, and multiple stratified groups. RESULTS: The majority of the 1,114,895 patients were born in western advanced economies (58.6%). Those who were Hispanic/Latino, were born in Latin America and the Caribbean, and preferred Spanish language had highest RRs of infection and hospitalization. Black-identifying patients born in sub-Saharan African countries had a higher risk of infection than their western advanced economies counterparts. Subanalyses revealed elevated hospitalization and death risk for White-identifying patients from Eastern Europe and Central Asia and Asian-identifying patients from Southeast Asia and the Pacific. All non-English languages had a higher risk of all COVID-19 outcomes, most notably Hmong and languages from Burma/Myanmar. CONCLUSIONS: Stratifications by country of birth grouping and preferred language identified culturally distinct groups whose vulnerability to COVID-19 would have otherwise been masked by traditional racial/ethnic labels. Routine collection of these data is critical for identifying social groups at high risk and for informing linguistically and culturally relevant interventions.


Subject(s)
COVID-19 , Health Status Disparities , Humans , Asian People , Black People , COVID-19/epidemiology , Language , Hispanic or Latino , Health Disparate Minority and Vulnerable Populations
7.
J Immigr Minor Health ; 25(5): 1211-1219, 2023 Oct.
Article in English | MEDLINE | ID: mdl-37284967

ABSTRACT

Effective COVID-19 case investigation and contact tracing (CICT) among refugee, immigrant, and migrant (RIM) communities requires innovative approaches to address linguistic, cultural and community specific preferences. The National Resource Center for Refugees, Immigrants, and Migrants (NRC-RIM) is a CDC-funded initiative to support state and local health departments with COVID-19 response among RIM communities, including CICT. This note from the field will describe NRC-RIM and initial outcomes and lessons learned, including the use of human-centered design to develop health messaging around COVID-19 CICT; training developed for case investigators, contact tracers, and other public health professionals working with RIM community members; and promising practices and other resources related to COVID-19 CICT among RIM communities that have been implemented by health departments, health systems, or community-based organizations.


Subject(s)
COVID-19 , Emigrants and Immigrants , Refugees , Transients and Migrants , Humans , Contact Tracing
9.
JAMA Netw Open ; 6(4): e237877, 2023 04 03.
Article in English | MEDLINE | ID: mdl-37043199

ABSTRACT

Importance: Beyond traditional race and ethnicity demographic characteristics, additional discrete data variables are needed for informed health interventions in the US. Objective: To examine whether COVID-19 vaccine uptake patterns and associated disease outcomes differ among language preference groups. Design, Setting, and Participants: A cohort study of 851 410 individuals aged 18 years or older in a large multispecialty health system in Minnesota and western Wisconsin was conducted between December 15, 2020, and March 31, 2022. Exposure: Self-identified language preference and limited English proficiency (LEP) as measured by interpreter need were used to create subgroups using US census categories and attention to capture languages known to represent refugee groups. Main Outcomes and Measures: The primary outcome was COVID-19 vaccination uptake rates and time to first vaccine. Secondary outcomes were rates of COVID-19-associated hospitalization and death. Results: Most of the 851 410 participants (women, 493 910 [58.0%]; median age, 29 [IQR, 35-64] years) were US-born English speakers; 7.5% were born in other countries, 4.0% had a language preference other than English (LPOE), and 3.0% indicated LEP as measured by interpreter need. Marked temporal clusters were observed for COVID-19 vaccination uptake, hospitalizations, and deaths associated with primary series vaccine eligibility, booster availability, and COVID-19 variants. Delayed first-dose vaccine was observed with LPOE (hazard ratio [HR], 0.83; 95% CI, 0.82-0.84) and interpreter need (HR, 0.81; 95% CI, 0.80-0.82) compared with those with English language preference and proficiency. Patients with LPOE were approximately twice as likely to be hospitalized (rate ratio [RR], 1.85; 95% CI, 1.63-2.08) or die (RR, 2.13; 95% CI, 1.65-2.69). Patients with LEP experienced even higher rates of hospitalization (RR, 1.98; 95% CI, 1.73-2.25) and COVID-19-associated death (RR, 2.32; 95% CI, 1.79-2.95). Outcomes varied for individual language preference groups. Conclusions and Relevance: In this study, delayed time to first-dose vaccine was associated with increased COVID-19 hospitalization and death rates for specific LPOE and LEP groups. The findings suggest that data collection of language preference and interpreter need provides actionable health intervention information. Standardized system-level data collection, including at a national level, may improve efficient identification of social groups with disproportionate health disparities and provide key information on improving health equity in the US.


Subject(s)
COVID-19 Vaccines , COVID-19 , Humans , Female , Adult , Cohort Studies , Communication Barriers , COVID-19/epidemiology , COVID-19/prevention & control , SARS-CoV-2 , Language
10.
Nat Neurosci ; 26(5): 850-857, 2023 05.
Article in English | MEDLINE | ID: mdl-37095398

ABSTRACT

Economic deliberations are slow, effortful and intentional searches for solutions to difficult economic problems. Although such deliberations are critical for making sound decisions, the underlying reasoning strategies and neurobiological substrates remain poorly understood. Here two nonhuman primates performed a combinatorial optimization task to identify valuable subsets and satisfy predefined constraints. Their behavior revealed evidence of combinatorial reasoning-when low-complexity algorithms that consider items one at a time provided optimal solutions, the animals adopted low-complexity reasoning strategies. When greater computational resources were required, the animals approximated high-complexity algorithms that search for optimal combinations. The deliberation times reflected the demands created by computational complexity-high-complexity algorithms require more operations and, concomitantly, the animals deliberated for longer durations. Recurrent neural networks that mimicked low- and high-complexity algorithms also reflected the behavioral deliberation times and were used to reveal algorithm-specific computations that support economic deliberation. These findings reveal evidence for algorithm-based reasoning and establish a paradigm for studying the neurophysiological basis for sustained deliberation.


Subject(s)
Algorithms , Neural Networks, Computer , Animals , Decision Making
11.
J Travel Med ; 2023 Apr 19.
Article in English | MEDLINE | ID: mdl-37074145

ABSTRACT

BACKGROUND: The risk of developing strongyloidiasis hyperinfection syndrome appears to be elevated among individuals who initiate corticosteroid treatment. Presumptive treatment or treatment after screening for populations from Strongyloides stercoralis-endemic areas has been suggested before initiating corticosteroids. However, potential clinical and economic impacts of preventative strategies have not been evaluated. METHODS: Using a decision tree model for a hypothetical cohort of 1000 individuals from S. stercoralis-endemic areas globally initiating corticosteroid treatment, we evaluated clinical and economic impacts of two interventions, 'Screen and Treat' (i.e. screening and ivermectin treatment after a positive test), and 'Presumptively Treat,' compared to current practice (i.e. 'No Intervention'). We evaluated the cost-effectiveness (net cost per death averted) of each strategy using broad ranges of pre-intervention prevalence and hospitalization rates for chronic strongyloidiasis patients initiating corticosteroid treatment. RESULTS: For the baseline parameter estimates, 'Presumptively Treat' was cost-effective (i.e. clinically superior with cost per death averted less than a threshold of $10.6 million per life) compared to 'No Intervention' ($532 000 per death averted) or 'Screen and Treat' ($39 000 per death averted). The two parameters contributing the most uncertainty to the analysis were the hospitalization rate for individuals with chronic strongyloidiasis who initiate corticosteroids (baseline 0.166%) and prevalence of chronic strongyloidiasis (baseline 17.3%) according to a series of one-way sensitivity analyses. For hospitalization rates greater than 0.022%, 'Presumptively Treat' would remain cost-effective. Similarly, 'Presumptively Treat' remained preferred at prevalence rates of 4% or above; 'Screen and Treat' was preferred for prevalence between 2% and 4%, and 'No Intervention' was preferred for prevalence less than 2%. CONCLUSIONS: The findings support decision-making for interventions for populations from S. stercoralis endemic areas before initiating corticosteroid treatment. Although some input parameters are highly uncertain and prevalence varies across endemic countries, 'Presumptively Treat' would likely be preferred across a range for many populations given plausible parameters.

12.
Transpl Infect Dis ; 25(2): e14039, 2023 Apr.
Article in English | MEDLINE | ID: mdl-36856346

ABSTRACT

BACKGROUND: Foreign-born kidney transplant recipients (FBKTRs) are at increased risk for reactivation of latent infections that may impact outcomes. We aimed to compare the etiology of infections and outcomes between FBKTR and United States KTRs (USKTR). METHODS: We performed a retrospective study of patients who underwent kidney transplantation between January 1, 2014 and December 31, 2018 at two transplant centers in Minnesota. Frequency and etiology of infections as well as outcomes (graft function, rejection, and patient survival) at 1-year post-transplant between FBKTR and USKTR were compared. RESULTS: Of the 573 transplant recipients, 124 (21.6%) were foreign-born and 449 (78.4%) US-born. At least one infection occurred in 411 (71.7%) patients (38.2% bacterial, 55% viral, 9.4% fungal). Viral infections were more frequent in FBKTR, particularly BK viremia (38.7% vs. 21.2%, p < .001). No statistical differences were found for bacterial or fungal infections; no parasitic infections were identified in either group. No geographically-restricted infections were noted aside from a single case of Madura foot in a FBKTR. Rejection episodes were more common in USKTR (p = .037), but stable/improving graft function (p = .976) and mortality (p = .451) at 1-year posttransplantation were similar in both groups. After adjusting for covariates, previous transplantation was associated with a higher number of infections (IRR 1.35, 95% confidence intervals 1.05-1.73, p = .020). CONCLUSION: Although viral infections were more frequent in FBKTR, overall frequency and etiology of most infections and outcomes were similar between FBKTR and USKTR suggesting that comprehensive transplant care is providing timely prevention, diagnosis, and treatment of latent infections in FBKTR.


Subject(s)
Kidney Transplantation , Latent Infection , Humans , Emigration and Immigration , Graft Rejection/epidemiology , Graft Rejection/prevention & control , Kidney Transplantation/adverse effects , Minnesota/epidemiology , Retrospective Studies , Transplant Recipients
13.
J Travel Med ; 30(3)2023 05 18.
Article in English | MEDLINE | ID: mdl-36718673

ABSTRACT

We estimated inpatient and outpatient payments for malaria treatment in the USA. The mean cost per hospitalized patient was significantly higher than for non-hospitalized patients (e.g. $27 642 vs $1177 among patients with private insurance). Patients with severe malaria payed two to four times more than those hospitalized with uncomplicated malaria.


Subject(s)
Malaria , Humans , United States/epidemiology , Malaria/drug therapy , Malaria/epidemiology , Hospitalization , Health Care Costs
14.
Am J Trop Med Hyg ; 108(1): 12-14, 2023 01 11.
Article in English | MEDLINE | ID: mdl-36450230

ABSTRACT

Ultrasound (US) is an invaluable clinical tool. New point-of-care US technology holds great promise for hard-to-reach and mobile populations such as refugees. The implementation of US in unique and challenging settings has been hindered by cost, fragility of equipment, need for uninterrupted electricity, training, and difficulty in sharing data/image files impeding quality assurance. The recent development of more flexible, durable, high-quality, low-cost, handheld US technology has offered increased potential to address many of these barriers. We describe a pilot program using a new point-of-care US technology to identify and monitor splenomegaly in United States-bound Congolese refugees. This experience and model may hold lessons for planning and development of similar approaches in other hard-to-reach mobile populations.


Subject(s)
Refugees , Humans , United States , Splenomegaly/diagnostic imaging , Point-of-Care Systems
15.
Clin Infect Dis ; 76(3): e864-e866, 2023 02 08.
Article in English | MEDLINE | ID: mdl-36056897

ABSTRACT

Intravenous artesunate has been the global standard of care for severe malaria for over 2 decades. Yet, until recently, artesunate has only been available to patients through an expanded-access protocol from the Centers for Disease Control and Prevention. In May 2020, the Food and Drug Administration approved artesunate, allowing US hospitals to stock the drug and ensuring prompt treatment for this life-threatening infection. However, because of artesunate's high cost and the infrequency of severe malaria in the United States, hospitals may be reluctant to stock the drug. As US health systems weigh the decision to stock artesunate, we propose a hospital tier framework to inform this decision and support clinicians caring for patients who present with severe malaria.


Subject(s)
Antimalarials , Artemisinins , Malaria , Humans , United States , Artesunate/therapeutic use , Antimalarials/therapeutic use , United States Food and Drug Administration , Artemisinins/therapeutic use , Malaria/drug therapy
16.
Am J Trop Med Hyg ; 107(4): 780-784, 2022 10 12.
Article in English | MEDLINE | ID: mdl-35995133

ABSTRACT

To assess appropriate drug treatment of parasitic diseases in the United States, we examined the treatment rates of 11 selected parasitic infections with standard-of-care prescription drugs and compared them to the treatment rates of two more common bacterial infections (Clostridioides difficile and streptococcal pharyngitis). We used the 2013 to 2019 IBM® MarketScan® Commercial Claims and Encounters and MarketScan® Multi-State Medicaid databases, which included up to 7 years of data for approximately 88 million and 17 million individuals, respectively, to estimate treatment rates of each infection. The number of patients diagnosed with each parasitic infection varied from 57 to 5,266, and from 12 to 2,018, respectively, across the two databases. Treatment rates of 10 of 11 selected parasitic infections (range, 0-56%) were significantly less than those for streptococcal pharyngitis and Clostridioides difficile (range, 65-85%); giardiasis treatment (64%) was comparable to Clostridioides difficile (65%) in patients using Medicaid. Treatment rates for patients with opisthorchiasis, clonorchiasis, and taeniasis were less than 10%. Although we could not verify that patients had active infections because of limitations inherent to claims data, including coding errors and the inability to review patients' charts, these data suggest a need for improved treatment of parasitic infections. Further research is needed to verify the results and identify potential clinical and public health consequences.


Subject(s)
Parasitic Diseases , Pharyngitis , Prescription Drugs , Databases, Factual , Humans , Prescriptions , United States/epidemiology
17.
Am J Trop Med Hyg ; 107(4): 841-844, 2022 10 12.
Article in English | MEDLINE | ID: mdl-35995136

ABSTRACT

Drug utilization and payment estimates for standard-of-care treatment of schistosomiasis have not been reported previously in the United States. This study estimates the utilization of praziquantel (standard-of-care drug) among patients with schistosomiasis and outpatient payments among those who were treated with praziquantel, and investigates the factors associated with praziquantel use from 2013-19 using IBM's MarketScan® Commercial Claims and Encounters database. Claims data showed that only 21% of patients with schistosomiasis diagnoses were treated with praziquantel. The mean total drug payments per patient treated with praziquantel increased from $110 in 2013-14 to $612 in 2015-18 (P < 0.01), and use decreased. These factors, including residing in a rural area, having a documented Schistosoma haematobium infection, or having a first schistosomiasis diagnosis in 2015-16, were associated with a decreased likelihood of patients receiving standard-of-care treatment. Policy solutions to exorbitant drug pricing, and better awareness and education among healthcare providers about schistosomiasis-especially those practicing in rural areas with high immigrant populations-are needed.


Subject(s)
Anthelmintics , Anti-Infective Agents , Schistosomiasis haematobia , Animals , Anthelmintics/therapeutic use , Anti-Infective Agents/therapeutic use , Antiparasitic Agents/therapeutic use , Humans , Outpatients , Praziquantel/therapeutic use , Schistosoma haematobium , Schistosomiasis haematobia/drug therapy , United States/epidemiology
18.
Elife ; 112022 05 16.
Article in English | MEDLINE | ID: mdl-35576146

ABSTRACT

Recent discoveries of extreme cellular diversity in the brain warrant rapid development of technologies to access specific cell populations within heterogeneous tissue. Available approaches for engineering-targeted technologies for new neuron subtypes are low yield, involving intensive transgenic strain or virus screening. Here, we present Specific Nuclear-Anchored Independent Labeling (SNAIL), an improved virus-based strategy for cell labeling and nuclear isolation from heterogeneous tissue. SNAIL works by leveraging machine learning and other computational approaches to identify DNA sequence features that confer cell type-specific gene activation and then make a probe that drives an affinity purification-compatible reporter gene. As a proof of concept, we designed and validated two novel SNAIL probes that target parvalbumin-expressing (PV+) neurons. Nuclear isolation using SNAIL in wild-type mice is sufficient to capture characteristic open chromatin features of PV+ neurons in the cortex, striatum, and external globus pallidus. The SNAIL framework also has high utility for multispecies cell probe engineering; expression from a mouse PV+ SNAIL enhancer sequence was enriched in PV+ neurons of the macaque cortex. Expansion of this technology has broad applications in cell type-specific observation, manipulation, and therapeutics across species and disease models.


Subject(s)
Enhancer Elements, Genetic , Machine Learning , Neurons , Sequence Analysis, DNA , Animals , Cerebral Cortex/metabolism , Computational Biology/methods , Enhancer Elements, Genetic/genetics , Globus Pallidus , Mice , Neurons/metabolism , Parvalbumins/metabolism , Sequence Analysis, DNA/methods
19.
Mol Ther Methods Clin Dev ; 25: 476-489, 2022 Jun 09.
Article in English | MEDLINE | ID: mdl-35615708

ABSTRACT

Gene therapy is a rapidly developing field, and adeno-associated viruses (AAVs) are a leading viral-vector candidate for therapeutic gene delivery. Newly engineered AAVs with improved abilities are now entering the clinic. It has proven challenging, however, to predict the translational potential of gene therapies developed in animal models due to cross-species differences. Human retinal explants are the only available model of fully developed human retinal tissue and are thus important for the validation of candidate AAV vectors. In this study, we evaluated 18 wild-type and engineered AAV capsids in human retinal explants using a recently developed single-cell RNA sequencing (RNA-seq) AAV engineering pipeline (scAAVengr). Human retinal explants retained the same major cell types as fresh retina, with similar expression of cell-specific markers except for a photoreceptor population with altered expression of photoreceptor-specific genes. The efficiency and tropism of AAVs in human explants were quantified with single-cell resolution. The top-performing serotypes, K91, K912, and 7m8, were further validated in non-human primate and human retinal explants. Together, this study provides detailed information about the transcriptome profiles of retinal explants and quantifies the infectivity of leading AAV serotypes in human retina, accelerating the translation of retinal gene therapies to the clinic.

20.
Am J Trop Med Hyg ; 2022 Mar 07.
Article in English | MEDLINE | ID: mdl-35483390

ABSTRACT

The most common causes of eosinophilia globally are helminth parasites. Refugees from high endemic areas are at increased risk of infection compared with the general U.S. population. It is widely accepted that eosinophilia is a good marker for helminth infection in this population, yet its absence has little predictive value for excluding infection. During an enhanced premigration health program, the CDC offered voluntary testing and management of intestinal parasites, among other conditions, to U.S.-bound refugees in Thailand. Stool specimens were tested for Ascaris lumbricoides, Strongyloides stercoralis, Trichuris trichiura, hookworms, Giardia lamblia, Cryptosporidium spp., and Entamoeba histolytica using quantitative polymerase chain reaction. Complete blood counts were performed to identify eosinophilia. Predictive values of eosinophilia for parasitic infections were calculated within nematode groups. Between July 9, 2012 and November 29, 2013, 2,004 participants were enrolled. About 73% were infected with at least one parasite. The overall median eosinophil count was 483 cells/µL (interquartile range [IQR] = 235-876 cells/µL). Compared with participants who did not test positive for any infection, higher eosinophil counts were observed in those infected with A. lumbricoides (RR = 1.3, 95% CI = 1.1-1.4), S. stercoralis (RR = 1.8, 95% CI = 1.4-2.4), Necator americanus (RR = 1.2, 95% CI = 1.1-1.4), and Ancylostoma ceylanicum (RR = 1.8, 95% CI = 1.5-2.2). Eosinophil counts were higher in younger participants (2-4 years versus 65+ years: RR = 4.2, 95% CI = 2.5-6.9), and lower in female participants (RR = 0.9, 95% CI = 0.8-0.9). Sensitivities ranged from 51% to 73%, specificities from 48% to 65%, and predictive values from 4% to 98%. The predictive value of eosinophilia is poor for the most common parasitic infections, and it should not be used alone for screening refugees.

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