Targeting thalamic circuits rescues motor and mood deficits in PD mice.

Although bradykinesia, tremor and rigidity are the hallmark motor defects in patients with Parkinson's disease (PD), patients also experience motor learning impairments and non-motor symptoms such as depression1. The neural circuit basis for these different symptoms of PD are not well understood. Although current treatments are effective for locomotion deficits in PD2,3, therapeutic strategies targeting motor learning deficits and non-motor symptoms are lacking4-6. Here we found that distinct parafascicular (PF) thalamic subpopulations project to caudate putamen (CPu), subthalamic nucleus (STN) and nucleus accumbens (NAc). Whereas PF→CPu and PF→STN circuits are critical for locomotion and motor learning, respectively, inhibition of the PF→NAc circuit induced a depression-like state. Whereas chemogenetically manipulating CPu-projecting PF neurons led to a long-term restoration of locomotion, optogenetic long-term potentiation (LTP) at PF→STN synapses restored motor learning behaviour in an acute mouse model of PD. Furthermore, activation of NAc-projecting PF neurons rescued depression-like phenotypes. Further, we identified nicotinic acetylcholine receptors capable of modulating PF circuits to rescue different PD phenotypes. Thus, targeting PF thalamic circuits may be an effective strategy for treating motor and non-motor deficits in PD.

Neurotensin orchestrates valence assignment in the amygdala.

The ability to associate temporally segregated information and assign positive or negative valence to environmental cues is paramount for survival. Studies have shown that different projections from the basolateral amygdala (BLA) are potentiated following reward or punishment learning1-7. However, we do not yet understand how valence-specific information is routed to the BLA neurons with the appropriate downstream projections, nor do we understand how to reconcile the sub-second timescales of synaptic plasticity8-11 with the longer timescales separating the predictive cues from their outcomes. Here we demonstrate that neurotensin (NT)-expressing neurons in the paraventricular nucleus of the thalamus (PVT) projecting to the BLA (PVT-BLA:NT) mediate valence assignment by exerting NT concentration-dependent modulation in BLA during associative learning. We found that optogenetic activation of the PVT-BLA:NT projection promotes reward learning, whereas PVT-BLA projection-specific knockout of the NT gene (Nts) augments punishment learning. Using genetically encoded calcium and NT sensors, we further revealed that both calcium dynamics within the PVT-BLA:NT projection and NT concentrations in the BLA are enhanced after reward learning and reduced after punishment learning. Finally, we showed that CRISPR-mediated knockout of the Nts gene in the PVT-BLA pathway blunts BLA neural dynamics and attenuates the preference for active behavioural strategies to reward and punishment predictive cues. In sum, we have identified NT as a neuropeptide that signals valence in the BLA, and showed that NT is a critical neuromodulator that orchestrates positive and negative valence assignment in amygdala neurons by extending valence-specific plasticity to behaviourally relevant timescales.

The Medical Costs of Firearm Injuries in the United States: A Systematic Review.

BACKGROUND: Firearm injury poses a significant public health burden in the United States. OBJECTIVES: The purpose of this systematic review was to provide a comprehensive accounting of the medical costs of firearm injuries in the United States. METHODS: A systematic literature review was conducted to identify studies published between January 1, 2000 and July 13, 2022 that reported medical costs of firearm injuries. A search of Embase, PubMed, and the Cochrane Library databases was performed by a medical librarian. The National Institutes of Health Quality Assessment Tool for Observational Cohort and Cross-Sectional Studies was used to evaluate for risk of bias. Health care-related charges and costs per firearm injury were presented and trends were identified. RESULTS: Sixty-four studies were included in the analysis. Study sample sizes ranged from 18 to 868,483 patients. Reported costs per injury ranged from $261 to $529,609. The median cost reported was $27,820 (interquartile range [IQR] $15,133-$40,124) and median charge reported was $53,832 (IQR $38,890-$98,632). Studies that divided initial hospitalization costs and follow-up medical costs identified that initial hospitalization accounts for about 60% of total costs. CONCLUSIONS: We found a significant volume of literature about the medical costs of firearm injury, which identified a highly heterogeneous cost burden. A significant amount of cost burden occurs after the index hospitalization, which is the only cost reported in most studies. Limitations of this study include reporting bias that favors hospitalized patients as well as a large focus on hospital charges as measurements of cost identified in the literature.

Illicit Fentanyl Exposure Among Victims of Violence Treated at a Trauma Center.

INTRODUCTION: Opioid overdoses and violent injury are leading causes of death in the United States, yet testing for novel opioids like fentanyl remains uncommon. The purpose of this investigation is to characterize a population of victims of violence who test positive for illicit fentanyl. METHODS: Retrospective cohort study of patients treated at a level-one trauma center between January 31, 2019 and February 21, 2020. Data were extracted from the electronic medical record. Subjects were included if they had an encounter diagnosis for a violent or intentional injury, using the International Classification of Diseases, v10 (X92-Y09). We excluded patients who received licit fentanyl as a part of their care before testing. Those who tested positive for fentanyl exposure on our standard hospital urine drug screen were considered to have been exposed to illicit fentanyl. Those testing negative for fentanyl were considered controls. RESULTS: Of the 1132 patients treated for intentional injuries during the study period, 366 were included in the study (32.3%). Of these, 133 (36.3%) subjects were exposed to illicit fentanyl prehospital. There were no demographic differences between cases and controls. Cases had a lower GCS voice score on arrival (median = 4, interquartile range [IQR] = 4-5 versus median = 5, IQR = 4-5, P = 0.02), higher rates of ventilator usage (32.3% versus 21.5%, P = 0.02), and more intensive care unit admissions (27.1% versus 12.0%, P = 0.005). More than half of cases tested negative for opiates (78/133, 58.6%). Cases had more trauma center encounters (26.3% had ≥2 visits versus 15.5%). CONCLUSIONS: Exposure to illicit fentanyl was common among victims of violence in this single-center study. These patients are at increased risk of being admitted to intensive care units and repeated trauma center visits, suggesting fentanyl testing may help identify those who could benefit from violence prevention and substance abuse treatment.

Sources of off-target expression from recombinase-dependent AAV vectors and mitigation with cross-over insensitive ATG-out vectors.

In combination with transgenic mouse lines expressing Cre or Flp recombinases in defined cell types, recombinase-dependent adeno-associated viruses (AAVs) have become the tool of choice for localized cell-type-targeted gene expression. Unfortunately, applications of this technique when expressing highly sensitive transgenes are impeded by off-target, or "leak" expression, from recombinase-dependent AAVs. We investigated this phenomenon and find that leak expression is mediated by both infrequent transcription from the inverted transgene in recombinant-dependent AAV designs and recombination events during bacterial AAV plasmid production. Recombination in bacteria is mediated by homology across the antiparallel recombinase-specific recognition sites present in recombinase-dependent designs. To address both of these issues we designed an AAV vector that uses mutant "cross-over insensitive" recognition sites combined with an "ATG-out" design. We show that these CIAO (cross-over insensitive ATG-out) vectors virtually eliminate leak expression. CIAO vectors provide reliable and targeted transgene expression and are extremely useful for recombinase-dependent expression of highly sensitive transgenes.

Striatal transcriptome changes linked to drug-induced repetitive behaviors.

Disruptive or excessive repetitive motor patterns (stereotypies) are cardinal symptoms in numerous neuropsychiatric disorders. Stereotypies are also evoked by psychomotor stimulants such as amphetamine. The acquisition of motor sequences is paralleled by changes in activity patterns in the striatum, and stereotypies have been linked to abnormal plasticity in these reinforcement-related circuits. Here, we designed experiments in mice to identify transcriptomic changes that underlie striatal plasticity occurring alongside the development of drug-induced stereotypic behavior. We identified three schedules of amphetamine treatment inducing different degrees of stereotypy and used bulk RNAseq to compare striatal gene expression changes among groups of mice treated with the different drug-dose schedules and vehicle-treated, cage-mate controls. Mice were identified as naïve, sensitized, or tolerant to drug-induced stereotypy. All drug-treated groups exhibited expression changes in genes that encode members of the extracellular signal-regulated kinase (ERK) cascades known to regulate psychomotor stimulant responses. In the sensitized group with the most prolonged stereotypy, we found dysregulation of 20 genes that were not changed in other groups. Gene set enrichment analysis indicated highly significant overlap with genes regulated by neuregulin 1 (Nrg1). Nrg1 is known to be a schizophrenia and autism susceptibility gene that encodes a ligand for Erb-B receptors, which are involved in neuronal migration, myelination, and cell survival, including that of dopamine-containing neurons. Stimulant abuse is a risk factor for schizophrenia onset, and these two disorders share behavioral stereotypy phenotypes. Our results raise the possibility that drug-induced sensitization of the Nrg1 signaling pathway might underlie these links.

Vedolizumab Dose Escalation Improves Therapeutic Response in a Subset of Patients with Ulcerative Colitis.

BACKGROUND: The Gemini trial failed to detect a significant difference in response rate for patients with ulcerative colitis (UC) randomized to standard (every 8 week) vedolizumab dosing vs escalated (every 4 week) dosing. Subsequent real-world data imply the Gemini trial design may have obscured a benefit of escalated dosing. AIMS: We investigated outcomes after vedolizumab dose escalation for patients with UC. We also explored potential clinical predictors of dose escalation requirement. METHODS: In this retrospective study, we included patients with UC who received vedolizumab between 1/2017-1/2019. We compared rates of clinical response (decrease in partial Mayo score by ≥ 2) and remission (partial Mayo < 2) for standard vs escalated dosing. RESULTS: Among the 90 patients reviewed, 52 achieved and maintained remission on standard dosing. The average time to remission with standard dosing was 33.3 ± 6.6 weeks. After an average of 56.3 ± 7.4 weeks standard dosing, 24 patients (22 "partial responders" and 2 "non-responders") were dose-escalated. Of the 22 "partial responders" dose-escalated, 10 (45%) achieved remission, 10 (45%) achieved further improvement. Neither "non-responder" demonstrated further clinical benefit. Prior anti-tumor necrosis factor (anti-TNF) biologic exposure predicted dose escalation requirement (p = 0.008). Patients requiring dose escalation had more severe disease at baseline as measured by both full Mayo (p = 0.009) and partial Mayo scores (p = 0.01). CONCLUSIONS: We show dose escalation benefited patients with UC who exhibit a "partial response" to standard dosing. Early vedolizumab dose escalation should be considered in both patients with severe disease and those with prior anti-TNF experience.

Trauma-Informed Care for Violently Injured Patients in the Emergency Department.

Violent traumatic injury remains a common condition treated by emergency physicians. The medical management of these patients is well described and remains an area of focus for providers. However, violently injured patients disproportionately carry a history of physical and psychological trauma that frequently affects clinical care in the emergency department. The alteration of our clinical approach, taking into consideration how a patient's previous experiences influence how he or she may perceive and react to medical care, is a concept referred to as trauma-informed care. This approach is based on 4 pillars: knowledge of the effect of trauma, recognition of the signs and symptoms of trauma, avoidance of retraumatization, and the development of appropriate policies and procedures. Using this framework, we provide practical considerations for emergency physicians in the delivery of trauma-informed care for violently injured patients.

A Content Analysis of Hospitals' Community Health Needs Assessments in the Most Violent U.S. Cities.

The emergence of evidence-supported interventions allows hospitals the opportunity to reduce future reinjury among patients who are violently injured. However, hospital knowledge of these interventions and their perceived role in violence prevention is unknown. The Patient Protection and Affordable Care Act created new legal requirements for non-profit hospitals to conduct community health needs assessments (CHNA) every three years to maintain not-for-profit status. In turn, this allows an empiric evaluation of hospital recognition and response to community violence. To do so, this study performed a content analysis of hospital CHNAs from the 20 U.S. cities with the highest violent crime rates. A total of 77 CHNAs were examined for specific violence-related keywords as well as whether violence prevention was listed as a priority community need. Overall, 74% of CHNAs mentioned violence-related terms and only 32% designated violence prevention as a priority need. When discussed, 88% of CHNAs referenced community violence, 42% intimate partner or sexual violence, and 22% child abuse. This study suggests that hospitals may lack awareness of violence as an actionable, preventable public health issue. Further, evidence-based program models are available to hospitals that can reduce the recurrence of assaultive injuries.

Public Health Interventions in the Emergency Department: A Framework for Evaluation.

Emergency departments (ED) in the United States serve a dual role in public health: a portal of entry to the health system and a safety net for the community at large. Public health officials often target the ED for public health interventions due to the perception that it is uniquely able to reach underserved populations. However, under time and resource constraints, emergency physicians and public health officials must make calculated decisions in choosing which interventions in their local context could provide maximal impact to achieve public health benefit. We identify how decisions regarding public health interventions are affected by considerations of cost, time, and available personnel, and further consider the role of local community needs, health department goals, and political environment. We describe a sample of ED-based public health interventions and demonstrate how to use a proposed framework to assess interventions. We posit a series of questions and variables to consider: local disease prevalence; ability of the ED to perform the intervention; relative efficacy of the ED vs community partnerships as the primary intervention location; and expected outcomes. In using this framework, clinicians should be empowered to improve the public health in their communities.

Monosynaptic restriction of the anterograde herpes simplex virus strain H129 for neural circuit tracing.

Identification of synaptic partners is a fundamental task for systems neuroscience. To date, few reliable techniques exist for whole brain labeling of downstream synaptic partners in a cell-type-dependent and monosynaptic manner. Herein, we describe a novel monosynaptic anterograde tracing system based on the deletion of the gene UL6 from the genome of a cre-dependent version of the anterograde Herpes Simplex Virus 1 strain H129. Given that this knockout blocks viral genome packaging and thus viral spread, we reasoned that co-infection of a HSV H129 ΔUL6 virus with a recombinant adeno-associated virus expressing UL6 in a cre-dependent manner would result in monosynaptic spread from target cre-expressing neuronal populations. Application of this system to five nonreciprocal neural circuits resulted in labeling of neurons in expected projection areas. While some caveats may preclude certain applications, this system provides a reliable method to label postsynaptic partners in a brain-wide fashion.

States should use Medicaid to support violence intervention efforts.

ABSTRACT: In recent years, calls to address gun violence through public health approaches have increased. However, securing funding for health-based community violence intervention models has remained a challenge. New actions suggest that this may be shifting. Upon taking office, the Biden administration announced a series of funding opportunities for these programs, which ranged from competitive grant programs to a proposed 8-year, $5 billion plan. Less publicized, but just as important, is the administration's announcement that Medicaid can be used to reimburse this work, specifically noting the eligibility of hospital-based violence intervention and prevention programs. For these programs, this creates a predictable and reliable funding source that has not existed to date. This integration of violence prevention programming in the traditional health care and financing systems represents a critical inflection point in the United States' shifting response to community violence. However, the decision to use this optional benefit lies with each state. States should strongly consider harnessing Medicaid as a wise investment to address the United States' gun violence epidemic. LEVEL OF EVIDENCE: Economic and value-based evaluation, level IV.

Once- Versus Twice-Daily Angiotensin-Converting Enzyme Inhibitors for Blood Pressure Control in Adult Patients With Hypertension.

This review aimed to assess the efficacy and safety of once- versus twice-daily administration of angiotensin-converting enzyme (ACE) inhibitors for the management of hypertension. A literature search on PubMed and Google Scholar was performed (January 1980 to June 2020) using the following search terms: ACE inhibitors, lisinopril, enalapril, fosinopril, trandolapril, ramipril, perindopril, captopril, benazepril, ambulatory blood pressure, hypertension, twice-daily dosing, once-daily dosing. Reference lists from retrieved articles were examined for additional reports. Relevant English-language studies or those conducted in humans were considered. Overall, six studies were included that compared the efficacy of once-daily to twice-daily dosing of ACE inhibitors. Similar blood pressure-lowering effects, and, in some studies, greater blood pressure lowering has been noted in the twice-daily administration arm than once-daily administration of ACE inhibitors. ACE inhibitors' pharmacokinetic and pharmacodynamic properties play an integral role in determining the expected blood pressure-lowering outcome. It is noteworthy that adherence issues may arise when transitioning from a once-daily regimen to a twice-daily regimen. There appear to be no added safety concerns between twice-daily and once-daily administration of ACE inhibitors regarding safety outcomes. After reviewing the available literature, twice-daily dosing of ACE inhibitors may promote added blood pressure-lowering effects, with the advantages of reducing cost, reducing the risk of drug-drug interactions, reducing polypharmacy, and reducing patient confusion about their medications. Recommendations for twice-daily administration of ACE -inhibitors should be made via shared decision-making with the patient, and clinician judgment, to drive treatment selection.

Balancing Efficiency and Access: Discouraging Emergency Department Boarding in a Global Budget System.

Reducing cost without sacrificing quality of patient care is an important yet challenging goal for healthcare professionals and policymakers alike. This challenge is at the forefront in the United States, where per capita healthcare costs are much higher than in similar countries around the world. The state of Maryland is unique in the hospital financing landscape due to its "capitation" payment system (also known as "global budget"), in which revenue for hospital-based services is set at the beginning of the year. Although Maryland's system has yielded many benefits, including reduced Medicare spending, it also has had unintentional adverse consequences. These consequences, such as increased emergency department boarding and ambulance diversion, constrain Maryland hospitals' ability to fulfill their role as emergency care providers and act as a safety net for vulnerable patient populations. In this article, we suggest policy remedies to mitigate the unintended consequences of Maryland's model that should also prove instructive for a variety of emerging alternative payment mechanisms.

Reversing Bleeding Associated With Antiplatelet Use: The Role of Tranexamic Acid.

Dual antiplatelet therapy (DAPT) is the mainstay of therapy in patients that have been diagnosed with coronary artery disease. DAPT has known risk factors such as an increased risk of bleeding, and, currently, no specific medication is indicated to reverse bleeding associated with antiplatelet use. One medication that may help reduce blood loss is tranexamic acid (TXA). A retrospective review of the literature regarding TXA in the setting of antiplatelet associated bleeding through a systematic search strategy was conducted. This review of the literature followed the PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analysis) guidelines and included seven studies. Multiple studies demonstrated the impact on platelet function resulting from administering TXA through lower volumes of blood loss, lower transfusion requirements, and lower incidence of reoperations. TXA is not widely recommended to reverse antiplatelet medications; however, it is widely available, has a positive track record for use in various types of bleeding, and is relatively inexpensive and safe. Large-scale randomized trials are warranted to make a strong recommendation for TXA in reversing bleeding associated with antiplatelet therapy.

Role of Tranexamic Acid in the Clinical Setting.

Tranexamic acid (TXA) is labeled as an antifibrinolytic agent that decreases mortality, reduces blood loss after trauma or surgery, and lowers transfusion requirements in trauma patients with bleeding. This review of the literature is related to TXA use in a variety of settings, with a specific focus on trauma patients, to assess therapeutic efficacy and safety. As seen in large, randomized, placebo-controlled trials, TXA has been shown to decrease mortality over placebo in trauma patients, It is also noted to have good safety parameters upon administration and should be recommended for use in trauma patients with bleeding. Further studies are warranted for the use of TXA in gastrointestinal bleeding and pediatric trauma.

Prevention Professional for Violence Intervention: A Newly Recognized Health Care Provider for Population Health Programs.

The National Uniform Claim Committee recognized a new type of health care provider for violence intervention: prevention professional. This creates a pathway for population health interventions to obtain reimbursement through traditional medical financing systems. In addition to violence, prevention professionals may specialize in other conditions of public health importance.