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Item Functional Electrical Stimulation of the Lateral Knee Muscles Can Reduce Peak Knee Adduction Moment during Stepping: A Pilot Study(MDPI, 2024-08-30) Baghi, Raziyeh; Alon, Gad; Oppizzi, Giovanni; Badhyal, Subham; Bowman, Peter; Zhang, Li-QunKnee osteoarthritis (KOA) is an age-dependent disease dominantly affected by mechanical loading. Balancing the forces acting on the medial knee compartment has been the focus of KOA interventions. This pilot study investigated the effects of functional electrical stimulation (FES) of the biceps femoris and lateral gastrocnemius on reducing peak knee adduction moment (pKAM) in healthy adults and individuals with medial KOA while stepping on an instrumented elliptical system. Sixteen healthy individuals and five individuals with medial KOA stepped on the robotic stepping system, which measured footplate-reaction forces/torques and ankle kinematics and calcu- lated 3-D knee moments in real time using inverse dynamics. Participants performed four different tasks: regular stepping without FES as the baseline condition, stepping with continuous FES of the lateral gastrocnemius (FESLG), biceps femoris (FESBF), and simultaneous FES of both lateral gastrocnemius and biceps femoris (FESLGBF), throughout the elliptical cycle. The 3-D knee moments, tibia kinematics, and footplate-reaction forces were compared between the baseline and the three FES stepping conditions. Healthy participants demonstrated lower pKAM during each of the three FES conditions compared to baseline (FESLG (p = 0.041), FESBF (p = 0.049), FESLGBF (p = 0.048)). Partici- pants with KOA showed a trend of lower pKAM during FES, which was not statistically significant given the small sample available. Incorporating elliptical + FES as a training strategy is feasible and may help to enhance selective force generation of the targeted muscles and reduce the medial knee compartment loading.Item Assessment of psychosocial parameters in adolescents seeking orthodontic treatment(Springer Nature, 2024-10-26) Doughan, Maria; Khandakji, Mohannad; Khoury, Brigitte; Ghafari, Joseph G.Aim The aim of this study was to investigate the psychosocial impact of malocclusion and the motivation for seeking orthodontic treatment among adolescents. Methods A cross-sectional study included 102 adolescents (ages 11–18) whose malocclusion was rated using 3 occlusal indices: IOTN, DAI, and PAR. The participants answered three structured questionnaires selected to measure Oral Health Related Quality of Life (OHRQoL) through the short form of the Child Oral Health Impact Profile (COHIP), the patient’s perceived impact related to orthodontics through the Psychosocial Impact of Dental Aesthetics Ques- tionnaire (PIDAQ), and self-esteem through the Rosenberg Self-Esteem Scale (RSES). Independent two-tailed t-tests, one-way mixed analysis of variance (ANOVA), and Spearman’s correlations were used to test various associations. Results Patients with higher malocclusion scores displayed increased psychosocial impact with weak to moderate correlations (0.2 < r < 0.3; p < 0.05), but 98% wished their teeth looked better, and 70% were unhappy about their smile esthetics. The IOTN esthetic component AC was better associated with psychosocial implications of malocclusion (p < 0.01). Self-motivated patients (over 80%) had higher impactful psychosocial scores than patients whose parents were motivated for treatment. Sex did not influence the findings. Older adolescents and bullied individuals were more affected by the psychological burden of malocclusion. Conclusion The results indicate the prevalence of psychosocial and esthetic impacts of malocclusion over oral and functional problems. PIDAQ discriminated better than COHIP between varying degrees of dental aesthetics. The results suggest that the orthodontist should explore patients’ expectations of treatment outcomes, not only the chief complaint.Item SpeciateIT and vSpeciateDB: novel, fast, and accurate per sequence 16S rRNA gene taxonomic classification of vaginal microbiota(Springer Nature, 2024-09-27) Holm, Johanna B.; Gajer, Pawel; Ravel, JacquesBackground: Clustering of sequences into operational taxonomic units (OTUs) and denoising methods are a mainstream stopgap to taxonomically classifying large numbers of 16S rRNA gene sequences. Environment-specific reference databases gen- erally yield optimal taxonomic assignment. Results: We developed SpeciateIT, a novel taxonomic classification tool which rapidly and accurately classifies individual amplicon sequences (https:// github. com/ Ravel- Labor atory/ speci ateIT). We also present vSpeciateDB, a custom reference database for the taxonomic classification of 16S rRNA gene amplicon sequences from vaginal microbiota. We show that SpeciateIT requires minimal computational resources relative to other algorithms and, when combined with vSpeciateDB, affords accurate species level classification in an environment-specific manner. Conclusions: Herein, two resources with new and practical importance are described. The novel classification algorithm, SpeciateIT, is based on 7th order Markov chain models and allows for fast and accurate per-sequence taxonomic assignments (as little as 10 min for 107 sequences). vSpeciateDB, a meticulously tailored reference database, stands as a vital and pragmatic contribution. Its significance lies in the superiority of this environment-specific database to provide more species-resolution over its universal counterparts..Item Contributions of Medical Greenhouse Gases to Climate Change and Their Possible Alternatives(MDPI, 2024-11-22) Wang, Joyce; DasSarma, ShiladityaConsiderable attention has recently been given to the contribution of the greenhouse gas (GHG) emissions of the healthcare sector to climate change. GHGs used in medical practice are regularly released into the atmosphere and contribute to elevations in global temperatures that produce detrimental effects on the environment and human health. Consequently, a comprehensive assessment of their global warming potential over 100 years (GWP) characteristics, and clinical uses, many of which have evaded scrutiny from policy makers due to their medical necessity, is needed. Of major interest are volatile anesthetics, analgesics, and inhalers, as well as fluorinated gases used as tamponades in retinal detachment surgery. In this review, we conducted a literature search from July to September 2024 on medical greenhouse gases and calculated estimates of these gases’ GHG emissions in metric tons CO2 equivalent (MTCO2e) and their relative GWP. Notably, the anesthetics desflurane and nitrous oxide contribute the most emissions out of the major medical GHGs, equivalent to driving 12 million gasoline-powered cars annually in the US. Retinal tamponade gases have markedly high GWP up to 23,500 times compared to CO2 and long atmospheric lifetimes up to 10,000 years, thus bearing the potential to contribute to climate change in the long term. This review provides the basis for discussions on examining the environmental impacts of medical gases with high GWP, determining whether alternatives may be available, and reducing emissions while maintaining or even improving patient care.Item Standardized Preoperative Tooth Documentation to Reduce Risk of Peri-Anesthetic Dental Injury(2024-05) Gruendling, Lacey; Watson, Melissa D.N.P., C.R.N.A.Problem & Purpose: Literature confirms that peri-anesthetic dental injury (PDI) is one of the most common negative anesthesia-related events and a frequent topic in anesthesia-related litigation. There are over 30 reported PDIs per year at an academic level II trauma center In the mid-Atlantic United States. This quality improvement project aims to improve dental assessment and documentation to mitigate the risk of PDI at the project site. The population is adult inpatients receiving anesthesia, excluding obstetrics. Methods: The project lead (PL) and the site’s Chief Anesthesiologist selected a standardized numeric dental diagram. It was inserted into the physical examination section of the existing electronic pre-anesthesia evaluation (PAE). PAEs are completed preoperatively by anesthesia providers for all inpatients receiving anesthesia. Tooth numbers in the diagram are a reference for providers to accurately document dental damage. About 45 anesthesia providers were educated on access and use of the diagram. Real-time one-on-one demonstrations were provided. Step-by-step visual and written instructions were placed in anesthesia offices. The PL reviewed charts weekly to monitor compliance with numeric documentation of pre-existing dental damage. Results: The PL reviewed 659 charts. There were 461 charts excluded due to teeth within normal limits, presence of an endotracheal tube before surgery, edentulousness, lack of electronic PAE, lack of dental documentation in the PAE, inability to assess the mouth, and surgery on a weekend or holiday. The remaining 198 charts were included. Average compliance with using tooth numbers to document pre-existing dental damage was 47% during the 14-week implementation period. There have been at least two reported PDIs during those 14 weeks. Both PAEs revealed incomplete dental documentation. Conclusion: Evidence suggests a standardized numeric diagram can improve compliance with dental documentation. Literature states that thorough preoperative dental assessment and documentation can result in the anesthetist modifying airway instrumentation techniques to reduce PDI risk and lead to PDI-related litigation results in favor of the anesthesia department.Item Quality Improvement Project to Increase Meaning and Joy at Work and Reduce Nursing Turnover(2024-05) Frost, Christine; Yarbrough, Karen L.Problem and Purpose: Nationwide, nursing turnover is 23%. Chronic fatigue, low meaning and joy at work are high contributors. On a 30 bed Medical Surgical (MSU) the turnover rate was 30%. The purpose of this quality improvement (QI) project was to assist nurses to identify and eliminate barriers to achieving meaning and joy at work with a goal of reducing turnover. Methods: Project launched with the Meaning and Joy at Work Questionnaire (MJWQ) presurvey (two supplemental questions about Intent to Leave), followed by focus groups, action plans and a post intervention MJWQ. Turnover was measured monthly. Results: Of the 45 eligible nurses on MSU, 38% completed the pre-survey. The highest percentage of nurses completing the survey indicated no intent to leave their position, 47.1% or the profession in the next year, 94.1%. Many of the MJW questions scored positively, with most staff reporting they agree or strongly agree. Resulting interventions included staff recognition, coordination with departments to ensure supply delivery, and launching a Disruptive Behavior Policy. Post-Survey: Of the 45 eligible nurses, 17.8% completed the post-survey. Scores decreased in areas of feeling respected and meaning for the work, all other questions improved. The Intent to Leave data showed a 28% increase in staff indicating they did not intend to leave, a total of 75.1%. A slight increase in staff reporting they would leave the profession within the next year, from 5.9% pre to 12.5% post intervention. Turnover decreased over several months to 26.94%, and then 23.35%. Conclusions: Reasons nurses find meaning and joy at work are a sense of purpose and being present for patients. Teamwork, support and adequate staffing drive a sense of purpose. Facilitated focus groups provide nurses with an opportunity to explore perceptions of meaning, joy at work and to identify barriers. Barriers include staffing, resources, communication recognition, and disruptive behavior by patients and families. Staff and leadership interventions that address barriers are an effective tool to improve meaning, joy and reduce turnover.Item Extracellular vesicles in sepsis plasma mediate neuronal inflammation in the brain through miRNAs and innate immune signaling(Springer Nature, 2024-10-07) Park, Chanhee; Lei, Zhoufan; Li, Yun; Ren, Boyang; He, Junyun; Huang, Huang; Chen, Fengqian; Li, Hui; Brunner, Kavitha; Zhu, Jing; Jay, Steven M.; Williams, Brittney; Chao, Wei; Wu, Junfang; Zou, LinBackground Neuroinflammation reportedly plays a critical role in the pathogenesis of sepsis-associated encephalopathy (SAE). We previously reported that circulating plasma extracellular vesicles (EVs) from septic mice are proinflammatory. In the current study, we tested the role of sepsis plasma EVs in neuroinflammation. Methods To track EVs in cells and tissues, HEK293T cell-derived EVs were labeled with the fluorescent dye PKH26. Cecal ligation and puncture (CLP) was conducted to model polymicrobial sepsis in mice. Plasma EVs were isolated by ultracentrifugation and their role in promoting neuronal inflammation was tested following intracerebroventricular (ICV) injection. miRNA inhibitors (anti-miR-146a, -122, -34a, and -145a) were applied to determine the effects of EV cargo miRNAs in the brain. A cytokine array was performed to profile microglia-released protein mediators. TLR7- or MyD88-knockout (KO) mice were utilized to determine the underlying mechanism of EVs-mediated neuroinflammation. Results We observed the uptake of fluorescent PKH26-EVs inside the cell bodies of both microglia and neurons. Sepsis plasma EVs led to a dose-dependent cytokine release in cultured microglia, which was partially attenuated by miRNA inhibitors against the target miRNAs and in TLR7-KO cells. When administered via the ICV, sepsis plasma EVs resulted in a marked increase in the accumulation of innate immune cells, including monocyte and neutrophil and cytokine gene expression, in the brain. Although sepsis plasma EVs had no direct effect on cytokine production or neuronal injury in vitro, the conditioned media (CM) of microglia treated with sepsis plasma EVs induced neuronal cell death as evidenced by increased caspase-3 cleavage and Annexin-V staining. Cytokine arrays and bioinformatics analysis of the microglial CM revealed multiple cytokines/chemokines and other factors functionally linked to leukocyte chemotaxis and migration, TLR signaling, and neuronal death. Moreover, sepsis plasma EV-induced brain inflammation in vivo was significantly dependent on MyD88. Conclusions Circulating plasma EVs in septic mice cause a microglial proinflammatory response in vitro and a brain innate immune response in vivo, some of which are in part mediated by TLR7 in vitro and MyD88 signaling in vivo. These findings highlight the importance of circulating EVs in brain inflammation during sepsis.Item Implementation of Isopropyl Caps to Increase Intravenous Catheter Disinfection by Anesthesia Providers(2024-05) Friedman, Beth G.; Amos, Veronica Y.Problem: Blood stream infections are a significant cause of morbidity and mortality in post procedural patients. Intravenous catheters can become portals of entry for microbials without proper disinfection. A single infection can cost institutions up to 75000 dollars. In an endoscopy unit at an inner city academic medical center less than 10% of anesthesia providers reported disinfection of intravenous catheters between medication injections. The biggest barrier to disinfection was lack of time due to the dynamic working environment. Purpose: The purpose of this quality improvement project was to implement isopropyl caps by anesthesia providers in an endoscopy unit at an academic medical center and change intravenous tubing assembly practices by endoscopy nursing staff with utilization of closed lumen claves on open lumen stopcocks. Methods: This project was implemented over a 15-week period following education to endoscopy nurses (N=9), providers (N=14), and anesthesia technicians (N=2). Three endoscopy nursing champions were appointed to facilitate intravenous tubing assembly practices and encourage providers to utilize caps. Visual reminders were placed in the preprocedural areas and operating suites to remind providers and nurses about process changes. To track adherence a quality response code linked to a survey was laminated at each anesthesia workspace for providers to scan and complete each shift. Results: Following implementation strategies, at the end of week one 50% of providers were utilizing caps between medication injections and 37.5% of intravenous tubing sets were reported to have closed lumen claves. The median compliance by week 15 was 54% and 56% respectively. Conclusions: Implementation of caps decreases intravenous catheter disinfection time making it more feasible for anesthesia providers to utilize. Unit champions and visual reminders helped to change intravenous tubing assembly practices allowing caps to fit onto injection ports. Agreement of champions to continue the practice and interest of underclassmen students in project can help to achieve sustainability and further dissemination of this intervention.Item Implementing Chlorhexidine Skin Preparation to Improve Antimicrobial Skin Preparation for Neuraxial Anesthetics(2024-05) Filkoski, Jennifer L.; Conley, Richard P.Problem: In a small community hospital, Povidone-Iodine (PVP-I) is the primary skin preparation for regional anesthetics despite evidence that chlorhexidine gluconate in alcohol (CHG-alcohol) is more effective at decreasing bacterial colonization on the skin and catheter tips. 35 knee and hip arthroplasty procedures with neuraxial anesthesia occur weekly. with 89% receiving PVP-I skin preparation due to CHG-alcohol unavailability. Purpose: This quality improvement initiative aimed to improve antimicrobial skin preparation by increasing the availability of CHG-alcohol for skin preparation in adults receiving neuraxial anesthesia for hip or knee surgeries. Methods: The project lead worked with site leaders to ensure adequate supply of CHG-alcohol for the anesthesia department and in the operating rooms. Staff were educated, and attendance and stocking data were collected via direct observation on week one. CHGalcohol use compliance was monitored weekly via chart review and EPIC-generated reports— staff received weekly updates. Adults receiving neuraxial anesthesia for total knee or total hip arthroplasty procedures were included; exclusions were a chlorhexidine allergy. Strategies included early adopters, change champions, collaboration, communication, and increased accountability and buy-in. Team members included the project lead, site sponsor, clinical site representative, anesthesia technicians, and anesthesia providers. Results: All 41 anesthesia providers received written education, and 38 attendees attended the in-person education sessions. CHG-alcohol supply was 100% available. 545 patients were included and three were excluded. After improving availability, CHG-alcohol use increased to a median compliance of 77% and averaged 77% compared to 11% pre-implementation. Conclusions: Findings suggest increased availability of CHG-alcohol improved compliance with CHG-alcohol skin preparation.Item Transitioning to Cue-Based Feeding by Implementing an Evidence-Based Protocol(2024-05) Fetalvo, Tina Marie; Wilson, JaniceProblem: In an urban 70-bed level IV Neonatal Intensive Care Unit, cue-based feeding scores were previously implemented into the electronic medical record without sufficient education, leading to a lack of documentation by nursing staff. In a random chart audit, only 4% (n=1) of eligible patients had feeding scores documented. As a result, premature infants were not provided developmentally appropriate care that could improve their feeding outcomes. Purpose: The purpose of this quality improvement initiative was to improve the documentation of feeding scores by implementing and evaluating an electronic medical record alert and cue-based feeding rounds to notify providers of cue-based feeding eligibility. Methods: An EMR alert was developed to identify patient eligibility, and cue-based feeding rounds were utilized to notify providers of patients who qualified for cue-based feeding. Eligibility criteria included patients who were 34 weeks corrected gestational age or older, on 4 liters Vapotherm or less, and with a diet order to oral feed. The intent of the alert was to trigger the provider to order feeding score documentation as well as to remind nurses of cue-based feeding assessment and documentation. Results: Forty six percent of staff completed cue-based feeding education (n=105), 100% of eligible patients were identified (N=137), and 27% (n=37) of orders were documented in the EMR. Sixty one percent of eligible patients (n=83) had feeding scores documented. Conclusions: Two hundred forty-two interdisciplinary providers participated in the project. One hundred thirty-seven patients were included in the project. Findings suggest that cue-based feeding rounds can be useful in identifying patients who are eligible for cue-based feeding and reminding staff to document feeding scores. Weekly staff reminders are helpful in identification of eligible infants and in documentation.Item Role of cellular effectors in the induction and maintenance of IgA responses leading to protective immunity against enteric bacterial pathogens(Frontiers, 2024-09-11) Carreto-Binaghi, Laura E.; Sztein, Marcelo B.; Booth, Jayaum S.The mucosal immune system is a critical first line of defense to infectious diseases, as many pathogens enter the body through mucosal surfaces, disrupting the balanced interactions between mucosal cells, secretory molecules, and microbiota in this challenging microenvironment. The mucosal immune system comprises of a complex and integrated network that includes the gut-associated lymphoid tissues (GALT). One of its primary responses to microbes is the secretion of IgA, whose role in the mucosa is vital for preventing pathogen colonization, invasion and spread. The mechanisms involved in these key responses include neutralization of pathogens, immune exclusion, immune modulation, and cross-protection. The generation and maintenance of high affinity IgA responses require a delicate balance of multiple components, including B and T cell interactions, innate cells, the cytokine milieu (e.g., IL-21, IL-10, TGF-b), and other factors essential for intestinal homeostasis, including the gut microbiota. In this review, we will discuss the main cellular components (e.g., T cells, innate lymphoid cells, dendritic cells) in the gut microenvironment as mediators of important effector responses and as critical players in supporting B cells in eliciting and maintaining IgA production, particularly in the context of enteric infections and vaccination in humans. Understanding the mechanisms of humoral and cellular components in protection could guide and accelerate the development of more effective mucosal vaccines and therapeutic interventions to efficiently combat mucosal infections.Item Role of circulating T follicular helper subsets following Ty21a immunization and oral challenge with wild type S. Typhi in humans(Frontiers, 2024-09-12) Booth, Jayaum S.; Rapaka, Rekha R; McArthur, Monica A.; Fresnay, Stephanie; Darton, Thomas C.; Blohmke, Christoph J; Jones, Claire; Waddington, Claire S.; Levine, Myron M. (Myron Max), 1944-; Pollard, Andrew J.; Sztein, Marcelo B.Despite decades of intense research, our understanding of the correlates of protection against Salmonella Typhi (S. Typhi) infection and disease remains incomplete. T follicular helper cells (TFH), an important link between cellular and humoral immunity, play an important role in the development and production of high affinity antibodies. While traditional TFH cells reside in germinal centers, circulating TFH (cTFH) (a memory subset of TFH) are present in blood. We used specimens from a typhoid controlled human infection model whereby participants were immunized with Ty21a live attenuated S. Typhi vaccine and then challenged with virulent S. Typhi. Some participants developed typhoid disease (TD) and some did not (NoTD), which allowed us to assess the association of cTFH subsets in the development and prevention of typhoid disease. Of note, the frequencies of cTFH were higher in NoTD than in TD participants, particularly 7 days after challenge. Furthermore, the frequencies of cTFH2 and cTFH17, but not cTFH1 subsets were higher in NoTD than TD participants. However, we observed that ex-vivo expression of activation and homing markers were higher in TD than in NoTD participants, particularly after challenge. Moreover, cTFH subsets produced higher levels of S. Typhi-specific responses (cytokines/chemokines) in both the immunization and challenge phases. Interestingly, unsupervised analysis revealed unique clusters with distinct signatures for each cTFH subset that may play a role in either the development or prevention of typhoid disease. Importantly, we observed associations between frequencies of defined cTFH subsets and anti-S. Typhi antibodies. Taken together, our results suggest that circulating TFH2 and TFH17 subsets might play an important role in the development or prevention of typhoid disease. The contribution of these clusters was found to be distinct in the immunization and/or challenge phases. These results have important implications for vaccines aimed at inducing longlived protective T cell and antibody responses.Item Changes in monocyte subsets in volunteers who received an oral wild-type Salmonella Typhi challenge and reached typhoid diagnosis criteria(Frontiers, 2024-08-27) Toapanta, Franklin R.; Hu, Jingping; Shirey, Kari Ann; Bernal, Paula J.; Darton, Thomas C.; Waddington, Claire S.; Pollard, Andrew J.; Sztein, Marcelo B.; Levine, Myron M. (Myron Max), 1944-An oral Controlled Human Infection Model (CHIM) with wild-type S. Typhi was re-established allowing us to explore the development of immunity. In this model, ~55% of volunteers who received the challenge reached typhoid diagnosis criteria (TD), while ~45% did not (NoTD). Intestinal macrophages are one of the first lines of defense against enteric pathogens. Most organs have selfrenewing macrophages derived from tissue-resident progenitor cells seeded during the embryonic stage; however, the gut lacks these progenitors, and all intestinal macrophages are derived from circulating monocytes. After infecting gut-associated lymphoid tissues underlying microfold (M) cells, S. Typhi causes a primary bacteremia seeding organs of the reticuloendothelial system. Following days of incubation, a second bacteremia and clinical disease ensue. S. Typhi likely interacts with circulating monocytes or their progenitors in the bone marrow. We assessed changes in circulating monocytes after CHIM. The timepoints studied included 0 hours (pre-challenge) and days 1, 2, 4, 7, 9, 14, 21 and 28 after challenge. TD participants provided extra samples at the time of typhoid diagnosis, and 48-96 hours later (referred as ToD). We report changes in Classical Monocytes -CM-, Intermediate Monocytes -IM- and Non-classical Monocytes -NCM-. Changes in monocyte activation markers were identified only in TD participants and during ToD. CM and IM upregulated molecules related to interaction with bacterial antigens (TLR4, TLR5, CD36 and CD206). Of importance, CM and IM showed enhanced binding of S. Typhi. Upregulation of inflammatory molecules like TNF-a were detected, but mechanisms involved in limiting inflammation were also activated (CD163 and CD354 downregulation). CM upregulated molecules to interact/modulate cells of the adaptive immunity, including T cells (HLA-DR, CD274 and CD86) and B cells (CD257). Both CM and IM showed potential to migrate to the gut as integrin a4b7 was upregulated. Unsupervised analysis revealed 7 dynamic cell clusters. Five of these belonged to CM showing that this is the main population activated during ToD. Overall, we provide new insights into the changes that diverse circulating monocyte subsets undergo after typhoid diagnosis, which might be important to control this disease since these cells will ultimately become intestinal macrophages once they reach the gut.Item Mobilization of endocannabinoids by midbrain dopamine neurons is required for the encoding of reward prediction(2023-11-01) Luján, Miguel A.; Covey, Dan P.; Young-Morrison, Reana; Zhang, Lan-Yuan; Kim, Andrew; Morgado, Fiorella; Patel, Sachin; Bass, Caroline; Paladini, Carlos; Cheer, JosephBrain levels of the endocannabinoid 2-arachidonoylglycerol (2-AG) shape motivated behavior and nucleus accumbens (NAc) dopamine release. However, it is not clear whether mobilization of 2-AG specifically from midbrain dopamine neurons is necessary for dopaminergic responses to external stimuli predicting forthcoming reward. Here, we use a viral-genetic strategy to prevent the expression of the 2-AG-synthesizing enzyme diacylglycerol lipase α (DGLα) from ventral tegmental area (VTA) dopamine cells in adult mice. We find that DGLα deletion fromVTA dopamine neurons prevents depolarizationinduced suppression of excitation (DSE), a form of 2-AG-mediated synaptic plasticity, in dopamine neurons. DGLα deletion also decreases effortful, cuedriven reward-seeking but has no effect on non-cued or low-effort operant tasks and other behaviors. Moreover, dopamine recording in the NAc reveals that deletion of DGLα impairs the transfer of accumbal dopamine signaling from a reward to its earliest predictors. These results demonstrate that 2-AG mobilization from VTA dopamine neurons is a necessary step for the generation of dopamine-based predictive associations that are required to direct and energize reward-oriented behavior.Item Antidepressant treatment initiation among children and adolescents with acute versus long COVID: a large retrospective cohort study(bmc, 2024-08-01) Tran, Phuong; Amill-Rosario, Alejandro; dosReis, SusanBackground Child and adolescent antidepressant use increased post-pandemic, but it is unknown if this disproportionally affected those who develop post-acute sequelae of coronavirus disease 2019 (COVID) or long COVID. This study compared the risk of antidepressant initiation among children and adolescents with long COVID with those who had COVID but did not have evidence of long COVID. Methods Our retrospective cohort study of children and adolescents aged 3–17 years at the first evidence of COVID or long COVID from October 1, 2021 through April 4, 2022 was conducted within Komodo’s Healthcare Map™ database. The index date was the earliest date of a medical claim associated with a COVID (COVID comparators) or long COVID diagnosis (long COVID cases). The baseline period was six months before the index date. The outcome was antidepressant initiation within twelve months after the index date. Due to the large number of COVID relative to long COVID cases, COVID comparators were randomly selected with a ratio of 2 COVID to 1 long COVID. We used propensity score matching to control for confounding due to imbalances in the baseline covariates. Log-binomial models estimated the relative risk (RR) of antidepressant initiation in the propensity score matched sample. We conducted several sensitivity analyses to test the robustness of our findings to several assumptions. Results Our child and adolescent sample included 18 274 with COVID and 9137 with long COVID. Compared with those with COVID, a larger proportion of long COVID children and adolescents had psychiatric disorders, psychotropic use, medical comorbidities, were previously hospitalized, or visited the emergency department. In the propensity score-adjusted analysis, the long COVID group had a statistically significant higher risk of antidepressant initiation relative to the COVID comparator (adjusted-RR: 1.40, 95% CI = 1.20, 1.62). Our findings were robust across sensitivity analyses. Conclusions The increased risk of antidepressant initiation following long COVID warrants further study to better understand the underlying reasons for this higher risk. Emerging evidence of long COVID’s impact on child mental health has important implications for prevention and early interventions.Item Impact of the US Food and Drug Administration warning regarding increased risk of aortic aneurysms or aortic dissections on fluoroquinolone prescribing trends(BMJ Group, 2024-07-06) Rizk, John; Slejko, Julia F.; Heil, Emily; Seo, Dominique; Qato, DanyaBackground The US Food and Drug Administration (FDA) issued a warning in December 2018 regarding an increased risk of aortic aneurysms and aortic dissections associated with fluoroquinolone (FQ) use. This warning specifically targeted older adults and patients with conditions such as hypertension, Marfan syndrome, Ehlers-Danlos syndrome, atherosclerosis, peripheral vascular disease and history of aneurysms. Objective To evaluate the impact of the safety warning on prescribing trends of FQs in the targeted population. Methods This cross-sectional study with an interrupted time series (ITS) analysis (January 2018–December 2019) used a 25% random sample of IQVIA PharMetrics® Plus for Academics health plan claims database. The impact of the warning on FQ utilisation was quantified among the targeted population and a non-targeted population. Results From 2018 to 2019, both study populations saw a decrease in the year-over- year percent change of FQ prescriptions per 100 000 beneficiaries (−11%, from 14 227 to 12 662, targeted; −15%, from 5227 to 4446, non-targeted) and proportion of FQ use versus other antibiotics (from 15.6% to 13.8%, targeted; from 9.4% to 8%, non-targeted). In the targeted population, the ITS analysis did not show a significant trend change, a change in level or postwarning trend in the monthly rate of FQ prescriptions per 1000 beneficiaries. A positive trend change was observed in the non-targeted population (0.07, <0.01–0.13), but there were no significant changes in level or post-warning trend. Conclusion We did not find a change in FQ prescription rates after the warning. The utility of safety advisories as a primary tool for mitigating FQ use in high-risk populations should be revisited.Item County-level factors associated with a mismatch between opioid overdose mortality and availability of opioid treatment facilities(2024-04-05) Rizk, John; Saini, Jannat; Kim, Kyungha; Pathan, Uzma; Qato, DanyaOpioid overdose deaths in the United States remain a major public health crisis. Little is known about counties with high rates of opioid overdose mortality but low availability of opioid use disorder (OUD) treatment facilities. We sought to identify characteristics of United States (US) counties with high rates of opioid overdose mortality and low rates of opioid treatment facilities. Rates of overdose mortality from 3,130 US counties were compared with availability of opioid treatment facilities that prescribed or allowed medications for OUD (MOUD), from 2018- 2019. The outcome variable, “risk-availability mismatch” county, was a binary indicator of a high rate (above national average) of opioid overdose mortality with a low (below national average) rate of opioid treatment facilities. Covariates of interest included county-level sociodemographics and rates of insurance, unemployment, educational attainment, poverty, urbanicity, opioid prescribing, depression, heart disease, Gini index, and Theil index. Multilevel logistic regression, accounting for the clustering of counties within states, was used to determine associations with being a “risk-availability mismatch” county. Of 3,130 counties, 1,203 (38.4%) had high rates of opioid overdose mortality. A total of 1,098 counties (35.1%) lacked a publicly-available opioid treatment facility in 2019. In the adjusted model, counties with an additional 1% of: white residents (odds ratio, OR, 1.02; 95% CI, 1.01-1.03), unemployment (OR, 1.11; 95% CI, 1.05-1.19), and residents without insurance (OR, 1.04; 95% CI, 1.01-1.08) had increased odds of being a mismatch county. Counties that were metropolitan (versus non-metropolitan) had an increased odds of being a mismatch county (OR, 1.85; 95% CI, 1.45-2.38). Assessing mismatch between treatment availability and need provides useful information to characterize counties that require greater public health investment. Interventions to reduce overdose mortality are unlikely to be effective if they do not take into account diverse upstream factors, including sociodemographics, disease burden, and geographic context of communities.Item DeepFreeze 3D-biofabrication for Bioengineering and Storage of Stem Cells in Thick and Large-Scale Human Tissue Analogs(2023-10-18) Brown, Robert A.; Benyamien Roufaeil, Daniel; Gupta, Aditi; Lipford, Erika L.; Muthusamy, Divya; Zalzman, Amihai; Lowe, Tao; Kumar, Alok; Hertzano, Ronna; Stains, Joseph; Zalzman, MichalItem Shigella virulence protein VirG is a broadly protective antigen and vaccine candidate(2024-01-02) Desalegn, Girmay; Tamilselvi, Chitradevi S.; Lemme-Dumit, Jose M.; Heine, Shannon J.; Dunn, Dylan; Ndungo, Esther; Kapoor, Neeraj; Oaks, Edwin V.; Fairman, Jeff; Pasetti, Marcela F.Item Opioid use disorder in pregnancy: leveraging provider perceptions to inform comprehensive treatment(2021-03-10) Titus-Glover, Doris; Shaya, Fadia T.; Welsh, Christopher, M.D.; Qato, Danya; Shah, Savyasachi; Gresssler, Laura E.; Vivrette, RebeccaBackground: Medications for opioid use disorder (MOUD) are recommended with adjuvant behavioral therapies, counseling, and other services for comprehensive treatment of maternal opioid use disorder. Inadequate access to treatment, lack of prescribing providers and complex delivery models are among known barriers to care. Multidisciplinary provider input can be leveraged to comprehend factors that facilitate or inhibit treatment. The objective of this study is to explore provider perceptions of MOUD and factors critical to comprehensive treatment delivery to improve the care of pregnant women with opioid use disorder. Methods: A qualitative research approach was used to gather data from individual provider and group semistructured interviews. Providers (n = 12) responded to questions in several domains related to perceptions of MOUD, treatment delivery, access to resources, and challenges/barriers. Data were collected, transcribed, coded (by consensus) and emerging themes were analyzed using grounded theory methodology. Results: Emerging themes revealed persistent gaps in treatment and challenges in provider, health systems and patient factors. Providers perceived MOUD to be a “lifeline” to women. Conclusions: Inconsistencies in treatment provision, access and uptake can be improved by leveraging provider perceptions, direct experiences and recommendations for an integrated team-based, patient-centered approach to guide the care of pregnant women with opioid use disorder.