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  • Catheter-directed computed tomography angiography: A pictorial essay.

    Ghosh, Abheek; Moxley, Ellen; Waghmarae, Suneet; Stoner, James; Anand, Sheena; Akhter, Nabeel M (2022-08-18)
    Catheter-directed computed tomography angiography (CDCTA) is an imaging technique where CT images are acquired after selective catheterization of a vessel. Images obtained in this fashion provide several advantages over conventional imaging techniques such as fluoroscopic angiography, digital subtraction angiography, cone-beam CT, and conventional CT angiography. At this point, there is still limited literature on the subject, with prior studies examining a small number of potential uses. The goal of this pictorial essay is to illustrate our single tertiary care center experience using CDCTA.
  • Transradial versus transfemoral arterial access in DEB-TACE for hepatocellular carcinoma.

    Ghosh, Abheek; Gupta, Vikash; Al Khalifah, Abdullah; Akhter, Nabeel Mohsin (2022-07-15)
    Objectives: Transradial access has become increasingly popular in body interventional procedures but has not been ubiquitously adapted. This retrospective study compares the efficacy of this approach versus transfemoral access in hepatocellular carcinoma (HCC) patients who underwent drug-eluting bead transarterial chemoembolization (DEB-TACE). Materials and methods: A total of 130 HCC patients underwent 146 DEB-TACE procedures within our institution from June 2015 to May 2020. About 90 and 56 procedures were logged for the transradial and transfemoral cohorts, respectively. Peak skin dose, fluoroscopy time, administered contrast volume, total procedure time, and equipment cost data for each procedure were reviewed to evaluate for statistical differences between the two groups. Results: All 146 cases were technically successful without major complications or access failures in either group. No statistical differences were present between the two access groups in regards to peak skin dose or fluoroscopy time. Transradial access recorded a significantly higher contrast volume (P < 0.05), and a significantly longer procedural time than transfemoral access (P < 0.01). However, transradial access also displayed a significantly lower procedural equipment cost (P < 0.01) between the two groups. Conclusion: Transradial DEB-TACE has similar trends to transfemoral DEB-TACE in several pertinent radiation parameters and is also significantly more cost-efficacious. The results of this investigation suggest the consideration of transradial access whenever viable as an alternative to transfemoral access in the DEB-TACE treatment of HCC patients.
  • A Tale of 2 Wheels: When Too Much "Spinning" Can Get You in Trouble.

    Restrepo, Alejandro Jimenez (2022-09-07)
    Cycling is a worldwide passionately practiced and followed by millions of people across the globe. While many of us see it as an enjoyable leisure activity or a healthy way to commute to and from work, for some recreational cyclists it can become an obsession. Avid recreational cyclists oftentimes put their body through such rigorous and demanding training blocks in order to achieve peak levels of performance that they can reach workloads comparable to those endured by professional cyclists. Whether it is watching cycling pros battling fierce uphill inclines every summer at the Tour de France or trying to overtake a fellow cyclist on a local hill during a weekend Café ride, cycling enthusiasts live their sport with passion and an almost religious-like devotion.
  • Inactivation of the basolateral amygdala to insular cortex pathway makes sign-tracking sensitive to outcome devaluation.

    Keefer, Sara E; Kochli, Daniel E; Calu, Donna J (2022-09-20)
    Goal-tracking rats are sensitive to Pavlovian outcome devaluation while sign-tracking rats are devaluation insensitive. During outcome devaluation, goal-tracking (GT) rats flexibly modify responding to cues based on the current value of the associated outcome. However, sign-tracking (ST) rats rigidly respond to cues regardless of the current outcome value. Prior work demonstrated disconnection of the basolateral amygdala (BLA) and anterior insular cortex (aIC) decreased both goal- and sign-tracking behaviors. Given the role of these regions in appetitive motivation and behavioral flexibility we predicted that disrupting BLA to aIC pathway during outcome devaluation would reduce flexibility in GT rats and reduce rigid appetitive motivation in ST rats. We inhibited the BLA to aIC pathway by infusing inhibitory DREADDs (hM4Di-mcherry) or control (mCherry) virus into the BLA and implanted cannulae into the aIC to inhibit BLA terminals using intracranial injections of clozapine N-oxide (CNO). After training, we used a within-subject satiety-induced outcome devaluation procedure in which we sated rats on training pellets (devalued condition) or homecage chow (valued condition). All rats received bilateral CNO infusions into the aIC prior to brief non-reinforced test sessions. Contrary to our hypothesis, BLA-IC inhibition did not interfere with devaluation sensitivity in GT rats but did make ST behaviors sensitive to devaluation. Intermediate rats showed the opposite effect, showing rigid responding to cues with BLA-aIC pathway inactivation. Together, these results demonstrate BLA-IC projections mediate tracking-specific Pavlovian devaluation sensitivity and highlights the importance of considering individual differences in Pavlovian approach when evaluating circuitry contributions to behavioral flexibility.
  • Decreased PRESET-Score corresponds with improved survival in COVID-19 veno-venous extracorporeal membrane oxygenation.

    Powell, Elizabeth K; Lankford, Allison S; Ghneim, Mira; Rabin, Joseph; Haase, Daniel J; Dahi, Siamak; Deatrick, Kristopher B; Krause, Eric; Bittle, Gregory; Galvagno, Samuel M; et al. (2022-09-16)
    Introduction: The PREdiction of Survival on ECMO Therapy Score (PRESET-Score) predicts mortality while on veno-venous extracorporeal membrane oxygenation (VV ECMO) for acute respiratory distress syndrome. The aim of our study was to assess the association between PRESET-Score and survival in a large COVID-19 VV ECMO cohort. Methods: This was a single-center retrospective study of COVID-19 VV ECMO patients from 15 March 2020, to 30 November 2021. Univariable and Multivariable analyses were performed to assess patient survival and score differences. Results: A total of 105 patients were included in our analysis with a mean PRESET-Score of 6.74. Overall survival was 65.71%. The mean PRESET-Score was significantly lower in the survivor group (6.03 vs 8.11, p < 0.001). Patients with a PRESET-Score less than or equal to six had improved survival compared to those with a PRESET-Score greater than or equal to 8 (97.7% vs. 32.5%, p < 0.001). In a multivariable logistic regression, a lower PRESET-Score was also predictive of survival (OR 2.84, 95% CI 1.75, 4.63, p < 0.001). Conclusion: We demonstrate that lower PRESET scores are associated with improved survival. The utilization of this validated, quantifiable, and objective scoring system to help identify COVID-19 patients with the greatest potential to benefit from VV-ECMO appears feasible. The incorporation of the PRESET-Score into institutional ECMO candidacy guidelines can help insure and improve access of this limited healthcare resource to all critically ill patients.
  • Intravenous versus oral iron for iron deficiency anaemia in pregnant Nigerian women (IVON): study protocol for a randomised hybrid effectiveness-implementation trial

    Afolabi, Bosede B.; Babah, Ochuwa A.; Akinajo, Opeyemi R.; Adaramoye, Victoria O.; Adeyemo, Titilope A.; Balogun, Mobolanle; Banke-Thomas, Aduragbemi; Quao, Rachel A.; Olorunfemi, Gbenga; Abioye, Ajibola I.; et al. (2022-09-08)
    BACKGROUND: Anaemia in pregnancy is highly prevalent in African countries. High-dose oral iron is the current recommended treatment for pregnancy-related iron deficiency anaemia (IDA) in Nigeria and other African countries. This oral regimen is often poorly tolerated and has several side effects. Parenteral iron preparations are now available for the treatment of IDA in pregnancy but not widely used in Africa. The IVON trial is investigating the comparative effectiveness and safety of intravenous ferric carboxymaltose versus oral ferrous sulphate standard-of-care for pregnancy-related IDA in Nigeria. We will also measure the implementation outcomes of acceptability, feasibility, fidelity, and cost-effectiveness for intravenous ferric carboxymaltose. METHODS: This is an open-label randomised controlled trial with a hybrid type 1 effectiveness-implementation design, conducted at 10 health facilities in Kano (Northern) and Lagos (Southern) states in Nigeria. A total of 1056 pregnant women at 20-32 weeks' gestational age with moderate or severe anaemia (Hb < 10g/dl) will be randomised 1:1 into two groups. The interventional treatment is one 1000-mg dose of intravenous ferric carboxymaltose at enrolment; the control treatment is thrice daily oral ferrous sulphate (195 mg elemental iron daily), from enrolment till 6 weeks postpartum. Primary outcome measures are (1) the prevalence of maternal anaemia at 36 weeks and (2) infant preterm birth (<37 weeks' gestation) and will be analysed by intention-to-treat. Maternal full blood count and iron panel will be assayed at 4 weeks post-enrolment, 36 weeks' gestation, delivery, and 6 weeks postpartum. Implementation outcomes of acceptability, feasibility, fidelity, and cost will be assessed with structured questionnaires, key informant interviews, and focus group discussions. DISCUSSION: The IVON trial could provide both effectiveness and implementation evidence to guide policy for integration and uptake of intravenous iron for treating anaemia in pregnancy in Nigeria and similar resource-limited, high-burden settings. If found effective, further studies exploring different intravenous iron doses are planned.
  • Blunt splenic injury: Assessment of follow-up CT utility using quantitative volumetry.

    Dreizin, David; Yu, Theresa; Motley, Kaitlynn; Li, Guang; Morrison, Jonathan J; Liang, Yuanyuan (2022-07-22)
    Purpose: Trials of non-operative management (NOM) have become the standard of care for blunt splenic injury (BSI) in hemodynamically stable patients. However, there is a lack of consensus regarding the utility of follow-up CT exams and relevant CT features. The purpose of this study is to determine imaging predictors of splenectomy on follow-up CT using quantitative volumetric measurements. Methods: Adult patients who underwent a trial of non-operative management (NOM) with follow-up CT performed for BSI between 2017 and 2019 were included (n = 51). Six patients (12% of cohort) underwent splenectomy; 45 underwent successful splenic salvage. Voxelwise measurements of splenic laceration, hemoperitoneum, and subcapsular hematoma were derived from portal venous phase images of admission and follow-up scans using 3D slicer. Presence/absence of pseudoaneurysm on admission and follow-up CT was assessed using arterial phase images. Multivariable logistic regression was used to determine independent predictors of decision to perform splenectomy. Results: Factors significantly associated with splenectomy in bivariate analysis incorporated in multivariate logistic regression included final hemoperitoneum volume (p = 0.003), final subcapsular hematoma volume (p = 0.001), change in subcapsular hematoma volume between scans (p = 0.09) and new/persistent pseudoaneurysm (p = 0.003). Independent predictors of splenectomy in the logistic regression were final hemoperitoneum volume (unit OR = 1.43 for each 100 mL change; 95% CI: 0.99-2.06) and new/persistent pseudoaneurysm (OR = 160.3; 95% CI: 0.91-28315.3). The AUC of the model incorporating both variables was significantly higher than AAST grading (0.91 vs. 0.59, p = 0.025). Mean combined effective dose for admission and follow up CT scans was 37.4 mSv. Conclusion: Follow-up CT provides clinically valuable information regarding the decision to perform splenectomy in BSI patients managed non-operatively. Hemoperitoneum volume and new or persistent pseudoaneurysm at follow-up are independent predictors of splenectomy.
  • Dynamics of the Gut Microbiome in Shigella-Infected Children during the First Two Years of Life.

    Ndungo, Esther; Holm, Johanna B; Gama, Syze; Buchwald, Andrea G; Tennant, Sharon M; Laufer, Miriam K; Pasetti, Marcela F; Rasko, David A (2022-09-19)
    Shigella continues to be a major contributor to diarrheal illness and dysentery in children younger than 5 years of age in low- and middle-income countries. Strategies for the prevention of shigellosis have focused on enhancing adaptive immunity. The interaction between Shigella and intrinsic host factors, such as the microbiome, remains unknown. We hypothesized that Shigella infection would impact the developing microbial community in infancy and, conversely, that changes in the gastrointestinal microbiome may predispose infections. To test this hypothesis, we characterized the gastrointestinal microbiota in a longitudinal birth cohort from Malawi that was monitored for Shigella infection using 16S rRNA amplicon sequencing. Children with at least one Shigella quantitative polymerase chain reaction (qPCR) positive sample during the first 2 years of life (cases) were compared to uninfected controls that were matched for sex and age. Overall, the microbial species diversity, as measured by the Shannon diversity index, increased over time, regardless of case status. At early time points, the microbial community was dominated by Bifidobacterium longum and Escherichia/Shigella. A greater abundance of Prevotella 9 and Bifidobacterium kashiwanohense was observed at 2 years of age. While no single species was associated with susceptibility to Shigella infection, significant increases in Lachnospiraceae NK4A136 and Fusicatenibacter saccharivorans were observed following Shigella infection. Both taxa are in the family Lachnospiraceae, which are known short-chain fatty acid producers that may improve gut health. Our findings identified temporal changes in the gastrointestinal microbiota associated with Shigella infection in Malawian children and highlight the need to further elucidate the microbial communities associated with disease susceptibility and resolution. IMPORTANCE Shigella causes more than 180 million cases of diarrhea globally, mostly in children living in poor regions. Infection can lead to severe health impairments that reduce quality of life. There is increasing evidence that disruptions in the gut microbiome early in life can influence susceptibility to illnesses. A delayed or impaired reconstitution of the microbiota following infection can further impact overall health. Aiming to improve our understanding of the interaction between Shigella and the developing infant microbiome, we investigated changes in the gut microbiome of Shigella-infected and uninfected children over the course of their first 2 years of life. We identified species that may be involved in recovery from Shigella infection and in driving the microbiota back to homeostasis. These findings support future studies into the elucidation of the interaction between the microbiota and enteric pathogens in young children and into the identification of potential targets for prevention or treatment.
  • Concomitant and productive genital infections by HSV-2 and HPV in two young women: A case report.

    Uysal, Ilkay Başak; Boué, Vanina; Murall, Carmen Lia; Graf, Christelle; Selinger, Christian; Hirtz, Christophe; Bernat, Claire; Ravel, Jacques; Reynes, Jacques; Bonneau, Marine; et al. (2022-08-19)
    Human papillomaviruses (HPVs), the most oncogenic virus known to humans, are often associated with Herpes Simplex Virus-2 (HSV-2) infections. The involvement of the latter in cervical cancer is controversial but its long-term infections might modulate the mucosal microenvironment in a way that favors carcinogenesis. We know little about coinfections between HSV-2 and HPVs, and studying the immunological and microbiological dynamics in the early stages of these infections may help identify or rule out potential interactions. We report two cases of concomitant productive, although asymptomatic, HSV-2 and HPV infections in young women (aged 20 and 25). The women were followed up for approximately a year, with clinical visits every two months and weekly self-samples. We performed quantitative analyses of their HSV-2 and HPV viral loads, immunological responses (IgG and IgM antibodies and local cytokines expression profiles), vaginal microbiota composition, as well as demographic and behavior data. We detect interactions between virus loads, immune response, and the vaginal microbiota, which improve our understanding of HSV-2 and HPVs' coinfections and calls for further investigation with larger cohorts.
  • Preferences for Treatments for Major Depressive Disorder: Formative Qualitative Research Using the Patient Experience.

    dosReis, Susan; Bozzi, Laura M; Butler, Beverly; Xie, Richard Z; Chapman, Richard H; Bright, Jennifer; Malik, Erica; Slejko, Julia F (2022-09-19)
    Objectives: The goals of this formative research are to elicit attributes of treatment and desired outcomes that are important to individuals with major depressive disorder (MDD), to develop a stated preference instrument, and to pre-test the instrument. Methods: A three-phase survey study design elicited the patient's journey with MDD to design and pre-test the discrete choice experiment (DCE) instrument. Participants were 20 adults aged ≥ 18 with MDD who did not also have bipolar disorder or post-partum depression. We engaged patient advocates and a multi-disciplinary stakeholder advisory group to select and refine attributes for inclusion in a DCE instrument. The DCE was incorporated into a survey that also collected depression treatment and management and sociodemographic characteristics. The DCE was pre-tested with ten adults with MDD. Results: Six attributes were included in the DCE: mode of treatment (medicine only, psychotherapy only, all modalities including brain stimulation), time to treatment effect (6, 9, 12 weeks), days of hopefulness (2, 4, 6 days/week), effect on productivity (40%, 60%, 90% increase), relations with others (strained, improved, no impact), and out-of-pocket costs ($30, $60, $90/month). The DCE test led to the refinement of mode of treatment (medicine, medicine and psychotherapy, and all modalities); time to treatment effect (4, 6, 9 weeks); monthly out-of-pocket costs ($30, $90, $270). Conclusions: MDD treatment preferences revealed trade-offs among mode of treatment, time to treatment effect, functional outcomes, and cost. The findings demonstrate the potential for meaningfully incorporating the patient experience in preference measures.
  • Vaccine-induced seroconversion in participants in the North Carolina COVID-19 community Research Partnership.

    Friedman-Klabanoff, DeAnna J; Tjaden, Ashley H; Santacatterina, Michele; Munawar, Iqra; Sanders, John W; Herrington, David M; Wierzba, Thomas F; Berry, Andrea A (2022-09-12)
    Well-regulated clinical trials have shown FDA-approved COVID-19 vaccines to be immunogenic and highly efficacious. We evaluated seroconversion rates in adults reporting ≥ 1 dose of an mRNA COVID-19 vaccine in a cohort study of nearly 8000 adults residing in North Carolina to validate immunogenicity using a novel approach: at-home, participant administered point-of-care testing. Overall, 91.4% had documented seroconversion within 75 days of first vaccination (median: 31 days). Participants who were older and male participants were less likely to seroconvert (adults aged 41-65: adjusted hazard ratio [aHR] 0.69 [95% confidence interval (CI): 0.64, 0.73], adults aged 66-95: aHR 0.55 [95% CI: 0.50, 0.60], compared to those 18-40; males: aHR 0.92 [95% CI: 0.87, 0.98], compared to females). Participants with evidence of prior infection were more likely to seroconvert than those without (aHR 1.50 [95% CI: 1.19, 1.88]) and those receiving BNT162b2 were less likely to seroconvert compared to those receiving mRNA-1273 (aHR 0.84 [95% CI: 0.79, 0.90]). Reporting at least one new symptom after first vaccination did not affect time to seroconversion, but participants reporting at least one new symptom after second vaccination were more likely to seroconvert (aHR 1.11 [95% CI: 1.05, 1.17]). This data demonstrates the high community-level immunogenicity of COVID-19 vaccines, albeit with notable differences in older adults, and feasibility of using at-home, participant administered point-of-care testing for community cohort monitoring.
  • An assessment of physician assistant student diversity in the United States: a snapshot for the healthcare workforce.

    Bradley-Guidry, Carolyn; Burwell, Nicole; Dorough, Ramona; Bester, Vanessa; Kayingo, Gerald; Suzuki, Sumihiro (2022-09-15)
    Background: The Physician Assistant (PA) workforce falls short of mirroring national demographics mainly due to a lack of diversity in student enrollment. Few studies have systematically examined diversity across PA programs at the national level, and little is known about best practices for consistently graduating a diverse group of students. We descriptively characterized the extent to which PA programs are graduating a diverse group of students and identified top performing PA programs. Methods: Data from the Integrated Postsecondary Education Data System (IPEDS) were used to calculate the number and proportion of racial or ethnically diverse graduates. The study sample included 139 accredited PA programs that had graduated a minimum of five cohorts from 2014-2018. Within each of the United States Census Divisions, programs were ranked according to the number and proportion of graduates who were underrepresented minority (URM) race, Hispanic ethnicity, and of non-white (URM race, Hispanic, and Asian). Results: Amongst PA programs in the United States, a large disparity in the number and proportion of racial and ethnic graduates was observed. Of 34,625 PA graduates, only 2,207 (6.4%) were Hispanic ethnicity and 1,220 (3.5%) were URM race. Furthermore, a large number of diverse graduates came from a small number of top performing programs. Conclusion: Despite the abundance of evidence for the need to diversify the healthcare workforce, PA programs have had difficulty recruiting and graduating a diverse group of students. This study provides empirical evidence that PA programs have not been able to attain the level of diversity necessary to shift the lack of diversity in the PA workforce. Based upon this study's findings, the top performing PA programs can be used as role models to establish benchmarks for other programs. The results of this descriptive study are currently being used to guide a qualitative study to identify the top performers' strategies for success.
  • Estimating deaths averted and cost per life saved by scaling up mRNA COVID-19 vaccination in low-income and lower-middle-income countries in the COVID-19 Omicron variant era: a modelling study.

    Savinkina, Alexandra; Bilinski, Alyssa; Fitzpatrick, Meagan; Paltiel, A David; Rizvi, Zain; Salomon, Joshua; Thornhill, Thomas; Gonsalves, Gregg (2022-09-13)
    Objectives: While almost 60% of the world has received at least one dose of COVID-19 vaccine, the global distribution of vaccination has not been equitable. Only 4% of the population of low-income countries (LICs) has received a full primary vaccine series, compared with over 70% of the population of high-income nations. Design: We used economic and epidemiological models, parameterised with public data on global vaccination and COVID-19 deaths, to estimate the potential benefits of scaling up vaccination programmes in LICs and lower-middle-income countries (LMICs) in 2022 in the context of global spread of the Omicron variant of SARS-CoV2. Setting: Low-income and lower-middle-income nations. Main outcome measures: Outcomes were expressed as number of avertable deaths through vaccination, costs of scale-up and cost per death averted. We conducted sensitivity analyses over a wide range of parameter estimates to account for uncertainty around key inputs. Findings: Globally, universal vaccination in LIC/LMIC with three doses of an mRNA vaccine would result in an estimated 1.5 million COVID-19 deaths averted with a total estimated cost of US$61 billion and an estimated cost-per-COVID-19 death averted of US$40 800 (sensitivity analysis range: US$7400-US$81 500). Lower estimated infection fatality ratios, higher cost-per-dose and lower vaccine effectiveness or uptake lead to higher cost-per-death averted estimates in the analysis. Conclusions: Scaling up COVID-19 global vaccination would avert millions of COVID-19 deaths and represents a reasonable investment in the context of the value of a statistical life. Given the magnitude of expected mortality facing LIC/LMIC without vaccination, this effort should be an urgent priority.
  • Durability of protection and immunogenicity of AZD1222 (ChAdOx1 nCoV-19) COVID-19 vaccine over 6 months.

    Sobieszczyk, Magdalena E; Maaske, Jill; Falsey, Ann R; Sproule, Stephanie; Robb, Merlin L; Frenck, Robert W; Tieu, Hong-Van; Mayer, Kenneth H; Corey, Lawrence; Neuzil, Kathleen M; et al. (2022-09-15)
    Background. We report updated safety, efficacy, and immunogenicity of AZD1222 (ChAdOx1 nCoV-19) from an ongoing phase 3 trial. Methods. Adults at increased risk of SARS-CoV-2 infection were randomized (2:1), stratified by age, to receive 2 doses of AZD1222 or placebo. The primary efficacy end point was confirmed SARS-CoV-2 reverse-transcriptase PCR–positive (RT-PCR–positive) symptomatic COVID-19 at 15 or more days after a second dose in baseline SARS-CoV-2–seronegative participants. The 21,634 and 10,816 participants were randomized to AZD1222 and placebo, respectively. Findings. Data cutoff for this analysis was July 30, 2021; median follow-up from second dose was 78 and 71 days for the double-blind period (censoring at unblinding or nonstudy COVID-19 vaccination) and 201 and 82 days for the period to nonstudy COVID-19 vaccination (regardless of unblinding) in the AZD1222 and placebo groups, respectively. For the primary efficacy end point in the double-blind period (141 and 184 events; incidence rates: 39.2 and 118.8 per 1,000 person years), vaccine efficacy was 67.0% (P < 0.001). In the period to nonstudy COVID-19 vaccination, incidence of events remained consistently low and stable through 6 months in the AZD1222 group; for the primary efficacy end point (328 and 219 events; incidence rates: 36.4, 108.4) and severe/critical disease (5 and 13 events; incidence rates: 0.6, 6.4), respective vaccine efficacy estimates were 65.1% and 92.1%. AZD1222 elicited humoral immune responses over time, with waning at day 180. No emergent safety issues were seen. Conclusion. AZD1222 is safe and well tolerated, demonstrating durable protection and immunogenicity with median follow-up (AZD1222 group) of 6 months.
  • Invited Perspective: The Relevance of Animal Models of Domoic Acid Neurotoxicity to Human Health.

    Grattan, Lynn M (2022-09-14)
    On 18 August 1961, the Santa Cruz Sentinel reported1 that thousands of “crazed seabirds” were diving into lamp posts, buildings, cars, and streets to their death on the shores of North Monterey Bay, California. The birds appeared to be confused and disoriented, exhibited seizure activity, and flew at terrified residents. Eight people were bitten, but none suffered a related illness. Alfred Hitchcock contacted the newspaper for details. As the story is told, the Hollywood movie producer used the incident as research material for the classic 1963 thriller The Birds. About 30 years later it was established that the culprit of this extreme event was an algal bloom of Pseudo-nitzchia, select species of which produce domoic acid (DA).2 DA is a potent neurotoxin that bioaccumulates in filter-feeding shellfish and subsequently enters the food web. DA has been responsible for multiple mass illness and mortality events of shore birds3 and marine4–6 and coastal-dwelling mammals,7 particularly on the U.S. Pacific Coast. These events provided opportunities to capture the naturally occurring physical, physiological, neurologic, cardiac, and behavioral impacts of DA exposure, as well as advance understanding of delayed effects, reexposures, and rehabilitation possibilities.8,9 Laboratory studies of zebrafish, shellfish, marine mammals, and mice further expanded the capacity for hypothesis testing relevant to protecting public health.10–12 Nonhuman primate studies, such as that presented by Petroff et al.8 in this issue of Environmental Health Perspectives, represent a unique opportunity to improve understanding of an important contemporary issue: the neural mechanisms underlying chronic exposure to presumably safe levels of DA.
  • Current Applications of Dynamic Navigation System in Endodontics: A Scoping Review

    Martinho, Frederico Canato; Griffin, Ina Laurie; Corazza, Bruna Jordão Motta (2022-01-01)
    This scoping review (SCR) was conducted to map the existing literature on dynamic navigation system (DNS), to examine the extent, range, and nature of research activity. Additionally, this SCR disseminates research findings, determines the value of conducting a full systematic review with meta-analysis, and identifies gaps in the existing literature and future directions. This SCR followed Arksey and O'Malley's five stages framework. The electronic search was performed in PubMed (Medline), Scopus (Elsevier), and Web of Science (Clarivate Analytics) databases using a search strategy. Five themes emerged during the descriptive analysis that captured the DNS application in endodontics. The DNS has been explored for creating access cavities (8/18, 44.44%), locating calcified canals (4/18, 22.2%), microsurgery (3/18, 16.6%), post removal (2/18, 11.1%), and intraosseous anesthesia (1/18, 5.5%). Out of the 18 studies included, 12 are in vitro (66.6%), five are in vivo (case report) (27.7%), and one is ex vivo (5.5%). The DNS demonstrated accuracy and efficiency in performing minimally invasive access cavities, locating calcified canals, and performing endodontic microsurgery, and it helped target the site for intraosseous anesthesia.
  • In Vivo Detection of Cyclic-di-AMP in Staphylococcus aureus

    Mukkayyan, Nagaraja; Poon, Raymond; Sander, Philipp N.; Lai, Li Yin; Zubair-Nizami, Zahra; Hammond, Ming C.; Chatterjee, Som S. (2022-01-01)
    Cyclic-di-AMP (CDA) is a signaling molecule that controls various cellular functions including antibiotic tolerance and osmoregulation in Staphylococcus aureus (S. aureus). In this study, we developed a novel biosensor (bsuO P6-4) for in vivo detection of CDA in S. aureus. The fluorescent biosensor is based on a natural CDA riboswitch from Bacillus subtilis connected at its P6 stem to the dye-binding aptamer Spinach. Our study showed that bsuO P6-4 could detect a wide concentration range of CDA in both laboratory and clinical strains, making it suitable for use in both basic and clinical research applications.
  • Comorbidity of Novel CRHR2 Gene Variants in Type 2 Diabetes and Depression

    Amin, Mutaz; Ott, Jurg; Gordon, Derek; Wu, Rongling; Postolache, Teodor T.; Vergare, Michael; Gragnoli, Claudia (2022-08-29)
    The corticotropin-releasing hormone receptor 2 (CRHR2) gene encodes CRHR2, contributing to the hypothalamic–pituitary–adrenal stress response and to hyperglycemia and insulin resistance. CRHR2−/− mice are hypersensitive to stress, and the CRHR2 locus has been linked to type 2 diabetes and depression. While CRHR2 variants confer risk for mood disorders, MDD, and type 2 diabetes, they have not been investigated in familial T2D and MDD. In 212 Italian families with type 2 diabetes and depression, we tested 17 CRHR2 single nucleotide polymorphisms (SNPs), using two-point parametric-linkage and linkage-disequilibrium (i.e., association) analysis (models: dominant-complete-penetrance-D1, dominant-incomplete-penetrance-D2, recessive-complete-penetrance-R1, recessive-incomplete-penetrance-R2). We detected novel linkage/linkage-disequilibrium/association to/with depression (3 SNPs/D1, 2 SNPs/D2, 3 SNPs/R1, 3 SNPs/R2) and type 2 diabetes (3 SNPs/D1, 2 SNPs/D2, 2 SNPs/R1, 1 SNP/R2). All detected risk variants are novel. Two depression-risk variants within one linkage-disequilibrium block replicate each other. Two independent novel SNPs were comorbid while the most significant conferred either depression- or type 2 diabetes-risk. Although the families were primarily ascertained for type 2 diabetes, depression-risk variants showed higher significance than type 2 diabetes-risk variants, implying CRHR2 has a stronger role in depression-risk than type 2 diabetes-risk. In silico analysis predicted variants’ dysfunction. CRHR2 is for the first time linked to/in linkage-disequilibrium/association with depression-type 2 diabetes comorbidity and may underlie the shared genetic pathogenesis via pleiotropy.
  • The Relationship between Gastrointestinal Health, Micronutrient Concentrations, and Autoimmunity: A Focus on the Thyroid

    Ruscio, Michael; Guard, Gavin; Piedrahita, Gabriela; D'Adamo, Christopher R. (2022-08-30)
    Currently, there is a lack of understanding of why many patients with thyroid dysfunction remain symptomatic despite being biochemically euthyroid. Gastrointestinal (GI) health is imperative for absorption of thyroid-specific nutrients as well as thyroid function directly. This comprehensive narrative review describes the impact of what the authors have conceptualized as the "nutrient-GI-thyroid axis". Compelling evidence reveals how gastrointestinal health could be seen as the epicenter of thyroid-related care given that: (1) GI conditions can lower thyroid-specific nutrients; (2) GI care can improve status of thyroid-specific nutrients; (3) GI conditions are at least 45 times more common than hypothyroidism; (4) GI care can resolve symptoms thought to be from thyroid dysfunction; and (5) GI health can affect thyroid autoimmunity. A new appreciation for GI health could be the missing link to better nutrient status, thyroid status, and clinical care for those with thyroid dysfunction.
  • Long-term treatment of an ischemic jejunal stricture: Is stenting a viable option?

    Canakis, Andrew; Irani, Shayan S. (2022-09-01)
    Small-bowel strictures can present with variable patterns of obstructive symptoms. Determining the etiology can guide the appropriate management. Anastomotic or postsurgical causes from open abdominal surgeries can increase the risk of occurrence. In the setting of long, complex strictures, surgery is the mainstay of treatment.1 In addition to surgically related adverse events, more than 70% of patients can develop recurrent strictures significantly increasing the risk of malnutrition and short bowel syndrome.2,3 Endoscopic management with balloon dilation has been used in uncomplicated short length (<5 cm) strictures, although there is a risk of perforation.1,3 The fibrostenotic changes around a stricture may be amenable to stenting. Although no fully covered self-expanding metal stents (FCSEMSs) are available for enteral stenting in the United States, biliary and esophageal stents could be repurposed.4, 5, 6, 7 However, their migration rates can be very high; securing them to a percutaneous endoscopic gastrostomy (PEG) tube with a suture can reduce their inward migration.8 We present a case in which we managed a long, ulcerated, ischemic jejunal stricture with an FCSEMS (Video 1, available online at

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