Treatment with dextroamphetamine decreases the reacquisition of cocaine self-administration: Consistency across social contexts.

RATIONALE: A return to cocaine use following abstinence frequently occurs in a social context, and the presence of other individuals using cocaine may contribute to the likelihood of use. Previous studies have reported that chronic d-amphetamine treatment decreases cocaine self-administration in laboratory animals and reduces a return to cocaine use following abstinence in humans. OBJECTIVE: The purpose of this study was to examine the effects of chronic d-amphetamine treatment on the reacquisition of cocaine use in rats self-administering cocaine in different social contexts. METHODS: Male and female rats were implanted with intravenous catheters and trained to self-administer cocaine during daily 6-hr sessions. After 14 days, cocaine self-administration was extinguished by substituting saline for the cocaine stimulus. At this time, rats were randomized to receive chronic treatment with either d-amphetamine or saline. After 9 days of extinction, cocaine was again made available during daily 6-hr sessions. At this time, rats were further randomized into three social conditions: (1) rats continued self-administering cocaine in isolation, (2) rats self-administered cocaine in the presence of a same-sex partner that also self-administered cocaine, or (3) rats self-administered cocaine in the presence of a same-sex partner that did not have access to cocaine. Daily treatment with d-amphetamine or saline continued for the duration of reacquisition testing. RESULTS: Chronic treatment with d-amphetamine decreased cocaine intake during reacquisition, but these effects were not influenced by the social context. No sex differences were observed. CONCLUSION: These data support previous studies reporting that d-amphetamine decreases cocaine intake and demonstrate its efficacy across social contexts.

Serine/arginine-rich splicing factor 7 promotes the type I interferon response by activating Irf7 transcription.

Tight regulation of macrophage immune gene expression is required to fight infection without risking harmful inflammation. The contribution of RNA-binding proteins (RBPs) to shaping the macrophage response to pathogens remains poorly understood. Transcriptomic analysis reveals that a member of the serine/arginine-rich (SR) family of mRNA processing factors, SRSF7, is required for optimal expression of a cohort of interferon-stimulated genes in macrophages. Using genetic and biochemical assays, we discover that in addition to its canonical role in regulating alternative splicing, SRSF7 drives transcription of interferon regulatory transcription factor 7 (IRF7) to promote antiviral immunity. At the Irf7 promoter, SRSF7 maximizes STAT1 transcription factor binding and RNA polymerase II elongation via cooperation with the H4K20me1 histone methyltransferase KMT5a (SET8). These studies define a role for an SR protein in activating transcription and reveal an RBP-chromatin network that orchestrates macrophage antiviral gene expression.

Increased iron uptake by splenic hematopoietic stem cells promotes TET2-dependent erythroid regeneration.

Hematopoietic stem cells (HSCs) are capable of regenerating the blood system, but the instructive cues that direct HSCs to regenerate particular lineages lost to the injury remain elusive. Here, we show that iron is increasingly taken up by HSCs during anemia and induces erythroid gene expression and regeneration in a Tet2-dependent manner. Lineage tracing of HSCs reveals that HSCs respond to hemolytic anemia by increasing erythroid output. The number of HSCs in the spleen, but not bone marrow, increases upon anemia and these HSCs exhibit enhanced proliferation, erythroid differentiation, iron uptake, and TET2 protein expression. Increased iron in HSCs promotes DNA demethylation and expression of erythroid genes. Suppressing iron uptake or TET2 expression impairs erythroid genes expression and erythroid differentiation of HSCs; iron supplementation, however, augments these processes. These results establish that the physiological level of iron taken up by HSCs has an instructive role in promoting erythroid-biased differentiation of HSCs.

"Tranq-dope" overdose and mortality: lethality induced by fentanyl and xylazine.

Introduction: The recreational use of fentanyl in combination with xylazine (i.e., "tranq-dope") represents a rapidly emerging public health threat characterized by significant toxicity and mortality. This study quantified the interactions between these drugs on lethality and examined the effectiveness of potential rescue medications to prevent a lethal overdose. Methods: Male and female mice were administered acute doses of fentanyl, xylazine, or their combination via intraperitoneal injection, and lethality was determined 0.5, 1.0, 1.5, 2.0, and 24 h after administration. Both fentanyl and xylazine produced dose-dependent increases in lethality when administered alone. Results: A nonlethal dose of fentanyl (56 mg/kg) produced an approximately 5-fold decrease in the estimated LD50 for xylazine (i.e., the dose estimated to produce lethality in 50% of the population). Notably, a nonlethal dose of xylazine (100 mg/kg) produced an approximately 100-fold decrease in the estimated LD50 for fentanyl. Both drug combinations produced a synergistic interaction as determined via isobolographic analysis. The opioid receptor antagonist, naloxone (3 mg/kg), but not the alpha-2 adrenergic receptor antagonist, yohimbine (3 mg/kg), significantly decreased the lethality of a fentanyl-xylazine combination. Lethality was rapid, with death occurring within 10 min after a high dose combination and generally within 30 min at lower dose combinations. Males were more sensitive to the lethal effects of fentanyl-xylazine combinations under some conditions suggesting biologically relevant sex differences in sensitivity to fentanyl-xylazine lethality. Discussion: These data provide the first quantification of the lethal effects of "tranq-dope" and suggest that rapid administration of naloxone may be effective at preventing death following overdose.

"Tranq-Dope" Overdose and Mortality: Lethality Induced by Fentanyl and Xylazine.

The recreational use of fentanyl in combination with xylazine (i.e., "tranq-dope") represents a rapidly emerging public health threat characterized by significant toxicity and mortality. This study quantified the interactions between these drugs on lethality and examined the effectiveness of potential rescue medications to prevent a lethal overdose. Male and female mice were administered acute doses of fentanyl, xylazine, or their combination via intraperitoneal injection, and lethality was determined 30, 60, 90, 120, and 1440 min (24 hr) after administration. Both fentanyl and xylazine produced dose-dependent increases in lethality when administered alone. A nonlethal dose of fentanyl (56 mg/kg) produced an approximately 5-fold decrease in the estimated LD50 for xylazine (i.e., the dose estimated to produce lethality in 50% of the population). Notably, a nonlethal dose of xylazine (100 mg/kg) produced an approximately 100-fold decrease in the estimated LD50 for fentanyl. The opioid receptor antagonist, naloxone (3 mg/kg), but not the alpha-2 adrenergic receptor antagonist, yohimbine (3 mg/kg), significantly decreased the lethality of a fentanyl-xylazine combination. Lethality was rapid, with death occurring within 10 min after a high dose combination and generally within 30 min at lower dose combinations. Males were more sensitive to the lethal effects of fentanyl-xylazine combinations under some conditions, suggesting biologically relevant sex differences in sensitivity to fentanyl-xylazine lethality. These data provide the first quantification of the lethal effects of "tranq-dope" and suggest that rapid administration of naloxone may be effective at preventing death following overdose.

Intra-operative applications of augmented reality in glioma surgery: a systematic review.

Background: Augmented reality (AR) is increasingly being explored in neurosurgical practice. By visualizing patient-specific, three-dimensional (3D) models in real time, surgeons can improve their spatial understanding of complex anatomy and pathology, thereby optimizing intra-operative navigation, localization, and resection. Here, we aimed to capture applications of AR in glioma surgery, their current status and future potential. Methods: A systematic review of the literature was conducted. This adhered to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guideline. PubMed, Embase, and Scopus electronic databases were queried from inception to October 10, 2022. Leveraging the Population, Intervention, Comparison, Outcomes, and Study design (PICOS) framework, study eligibility was evaluated in the qualitative synthesis. Data regarding AR workflow, surgical application, and associated outcomes were then extracted. The quality of evidence was additionally examined, using hierarchical classes of evidence in neurosurgery. Results: The search returned 77 articles. Forty were subject to title and abstract screening, while 25 proceeded to full text screening. Of these, 22 articles met eligibility criteria and were included in the final review. During abstraction, studies were classified as "development" or "intervention" based on primary aims. Overall, AR was qualitatively advantageous, due to enhanced visualization of gliomas and critical structures, frequently aiding in maximal safe resection. Non-rigid applications were also useful in disclosing and compensating for intra-operative brain shift. Irrespective, there was high variance in registration methods and measurements, which considerably impacted projection accuracy. Most studies were of low-level evidence, yielding heterogeneous results. Conclusions: AR has increasing potential for glioma surgery, with capacity to positively influence the onco-functional balance. However, technical and design limitations are readily apparent. The field must consider the importance of consistency and replicability, as well as the level of evidence, to effectively converge on standard approaches that maximize patient benefit.

Serine arginine-rich splicing factor (SRSF7) cooperates with the histone methyltransferase KMT5a to promote the type I interferon response via transcriptional activation of IRF7.

Tight regulation of macrophage immune gene expression is required to fight infection without risking harmful inflammation. The contribution of RNA binding proteins (RBPs) to shaping the macrophage response to pathogens remains poorly understood. Transcriptomic analysis revealed that a member of the serine/arginine-rich (SR) family of mRNA processing factors, SRSF7, is required for optimal expression of a cohort of interferon stimulated genes (ISGs) in macrophages. Using genetic and biochemical assays, we discovered that in addition to its canonical role in regulating alternative splicing, SRSF7 drives transcription of interferon regulatory transcription factor 7 (IRF7) to promote antiviral immunity. At the Irf7 promoter, SRSF7 maximizes STAT1 transcription factor binding and RNA polymerase II elongation via cooperation with the H4K20me1 histone methyltransferase KMT5a (SET8). These studies define an unorthodox role for an SR protein in activating transcription and reveal an unappreciated RNA binding protein-chromatin network that orchestrates macrophage antiviral gene expression.

Vitamin D insufficiency and serum levels related to the incidence and stage of cutaneous melanoma: a systematic review and meta-analysis.

Cutaneous melanoma (CM) is the deadliest skin cancer, and vitamin D insufficiency has been suggested as a risk factor. We evaluated the relationship between both vitamin D insufficiency and 25-hydroxy vitamin D levels with the incidence and stage of CM. Five databases were searched from inception until 11 July 2022. Inclusion criteria were cohort and case-control studies that reported mean 25-hydroxy vitamin D levels or the presence of vitamin D insufficiency in CM patients and compared with healthy controls; or those that reported vitamin D insufficiency and Breslow tumor depth or the development of metastasis in CM. Fourteen studies were included in the analysis. Statistically significant relationships were found between vitamin D level <20 ng/dl and incidence of CM [pooled RR 1.45, 95% confidence interval (CI) 1.04-2.02]; lower mean vitamin D level and Breslow depth >1 mm (SMD 0.19, 95% CI 0.11-0.28); and vitamin D level >20 ng/dl and Breslow depth <1 mm (pooled RR 0.69, 95% CI 0.58-0.82). Statistical significance was not found in the relationships between vitamin D levels and the presence of metastasis (pooled SMD -0.13, 95% CI, -0.38 to 0.12); or mean vitamin D level and the incidence of CM (pooled SMD -0.39, 95% CI, -0.80 to 0.01). We identified an association of increased incidence of CM and vitamin D insufficiency, as well as less favorable Breslow tumor depth with lower levels of vitamin D and the presence of vitamin D insufficiency.

Interpersonal contrast avoidance as a mechanism for the maintenance of worry.

Despite consistent links between interpersonal problems and worry, mechanisms explaining this relationship remain unknown. The Contrast Avoidance Model (CAM; Newman & Llera, 2011) posits that individuals at risk for chronic worry and generalized anxiety disorder (GAD) fear sudden negative mood shifts, using worry to perpetuate negative moods and avoid these negative emotional contrasts. We propose interpersonal (IP) contrast avoidance (e.g., acting friendly to prevent others from causing mood shifts) as a novel explanation for interpersonal dysfunction in worriers. This study investigated IP contrast avoidance and worry in two samples. A nonclinical sample ranging in GAD symptoms (Study 1; N = 92) reported IP problems at baseline then IP contrast avoidance and worry over eight weeks (637 diaries). As expected, baseline IP problems prospectively predicted worry indirectly through chronic IP contrast avoidance. Affiliative, submissive, cold, and total IP contrast avoidance strategies predicted same-week and lagged next-week worry increases; affiliative, submissive, and total strategies also predicted maintenance of worry over eight weeks in growth models. Lastly, Study 2 showed the relevance of IP contrast avoidance strategies in a treatment-seeking clinical sample (N = 40), correlating with interpersonal problems and worry. Overall, results provide proof-of-concept for extending the CAM to the interpersonal domain.

Epidemiological correlates of overweight and obesity in the Northern Cape Province, South Africa.

Background: In the past several decades, obesity has become a major public health issue worldwide, associated with increased rates of chronic disease and death. Like many developing nations, South Africa is experiencing rapid increases in BMI, and as a result, evidence-based preventive strategies are needed to reduce the increasing burden of overweight and obesity. This study aimed to determine the prevalence and predictors of overweight and obesity among a multi-ethnic cohort from the rural Northern Cape of South Africa. Methods: These data were collected as part of a tuberculosis (TB) case-control study, with 395 healthy control participants included in the final analysis. Overweight and obesity were defined according to WHO classification. Multivariate linear models of BMI were generated using sex, age, education level, smoking, alcohol consumption, and diabetes as predictor variables. We also used multivariable logistic regression analysis to assess the relationship of these factors with overweight and obesity. Results: The average BMI in our study cohort was 25.2. The prevalence of overweight was 18.0% and the prevalence of obesity was 25.0%. We find that female sex, being older, having more years of formal education, having diabetes, and being in a rural area are all positively associated with BMI in our dataset. Women (OR = 5.6, 95% CI [3.3-9.8]), rural individuals (OR = 3.3, 95% CI [1.9-6.0]), older individuals (OR = 1.02, 95% CI [1-1.04]), and those with more years of education (OR = 1.2, 95% CI [1.09-1.32]) were all more likely to be overweight or obese. Alternatively, being a smoker is negatively associated with BMI and decreases one's odds of being overweight or obese (OR = 0.28, 95% CI [0.16-0.46]). Conclusions: We observed a high prevalence of overweight and obesity in this study. The odds of being overweight and obese were higher in women, those living in rural areas, and those with more education, and increases with age. Community-based interventions to control obesity in this region should pay special attention to these groups.

Morphological and Elemental Evaluation of Investigative Mouthwashes to Repair Acid-Eroded Tooth Surface.

Purpose: Erosive tooth wear (ETW) is characterized by subsurface demineralization and tooth substance loss with crater formation. Remineralization of subsurface demineralization has previously been demonstrated; however, repair of the eroded surface is still under investigation. This study investigated the effectiveness of mouthwashes containing hydrolyzed wheat protein (HWP) in repairing ETW through promotion of organized crystal growth. Methods: Enamel Erosion was created on 210 enamel blocks by 10-minute demineralization in 1% Citric Acid (pH 3.5). Then, blocks were randomly assigned to seven groups (30/group); (A) 0.2% HWP, B) 1% HWP, (C) 2% HWP, (D) 1% HWP + 0.05% NaF, (E) Listerine™ mouthwash, (F) 0.02% NaF Crest™ Pro-health mouthwash and (G) artificial saliva (AS) only. Groups were subjected to daily pH-cycling consisting of one 5-minute erosive challenge with citric acid, three 1-minute mouthwash treatment periods, and then storage in AS for the rest of the time for 28 days. Treatment effects were assessed using SEM-EDX. Statistical analysis was by ANOVA and Tukey's multiple comparison. Results: In groups exposed to HWP-containing mouthwashes, there was growth of fiber-like crystals that increased in packing density in a dose-dependent manner (0.2%, 1%, 2%) on the eroded enamel surfaces, with increased calcium and phosphate contents on the treated surfaces. The non-HWP-containing groups had the eroded surfaces covered by structureless deposit layer firmly attached to the surface. Conclusion: Treating eroded enamel surface with HWP-containing mouthwash resulted in repair of the damaged tissue by formation of a protective layer of crystal deposits within and on the eroded enamel tissue.

A test of frequency-dependent selection in the evolution of a generalist phenotype.

A solitary population of consumers frequently evolves to the middle of a resource gradient and an intermediate mean phenotype compared to a sympatric pair of competing species that diverge to either side via character displacement. The forces governing the distribution of phenotypes in these allopatric populations, however, are little investigated. Theory predicts that the intermediate mean phenotype of the generalist should be maintained by negative frequency-dependent selection, whereby alternate extreme phenotypes are favored because they experience reduced competition for resources when rare. However, the theory makes assumptions that are not always met, and alternative explanations for an intermediate phenotype are possible. We provide a test of this prediction in a mesocosm experiment using threespine stickleback that are ecologically and phenotypically intermediate between the more specialized stickleback species that occur in pairs. We manipulated the frequency distribution of phenotypes in two treatments and then measured effects on a focal intermediate population. We found a slight frequency-dependent effect on survival in the predicted direction but not on individual growth rates. This result suggests that frequency-dependent selection might be a relatively weak force across the range of phenotypes within an intermediate population and we suggest several general reasons why this might be so. We propose that allopatric populations might often be maintained at an intermediate phenotype instead by stabilizing or fluctuating directional selection.

A Public Health Framework for Preventing Mental Disorders in the Context of Pandemics.

The COVID-19 pandemic has universally threatened the building blocks of mental health, well-being, and quality of life, namely, expectations of safety, connectedness, hope, and individual and societal efficacy. Consequently, unprecedently large numbers of individuals are significantly stressed and many are at risk for relapse of mental health problems, exacerbations of existing mental and behavioral health problems, and new onset clinical problems. Because of the scope of the problem, a population-based public health perspective is needed, which in the context of disasters has well-established theories and prevention approaches. Public health approaches to disasters and pandemics focus on preventing subclinical problems from becoming clinical disorders, in comparison to clinical care approaches that focus on treating established disorders. Fortunately, specialty care clinicians who typically think about assessing and treating established disorders have the training and clinical competencies to deliver prevention-focused interventions. This paper is designed to help specialty care clinicians who use cognitive-behavioral strategies to understand the biopsychosocial impacts and resource deficits associated with COVID-19-related stressors and the public health perspective to address them. We also provide ways clinicians can help people who are suffering from significant stress and resource deficits bounce back and regain functioning. We describe psychological first aid, stress management, repeated ecological assessment, writing about stressors, problem-solving, and behavioral activation approaches to assist individuals at risk for enduring stress-linked problems.

Development of a Single-Institution Virtual Internal Medicine Subinternship With Near-Peer Teaching in Response to the COVID-19 Pandemic.

PROBLEM: In March 2020, medical students at the University of Washington School of Medicine were removed from clinical settings in response to the COVID-19 pandemic. As subinternships are required for graduation and an important way to prepare for internship, a virtual subinternship was created to include practical elements of in-person learning and to address limited teaching faculty from COVID-19 inpatient surges. APPROACH: A virtual, interactive subinternship was developed with case-based teaching sessions, communication and critical literature evaluation skill building, professional development, and creation of independent learning plans. Near-peer teachers (NPTs) were selected from graduating senior medical students who matched into internal medicine. In addition to teaching topics from the Clerkship Directors of Internal Medicine curriculum, NPTs engaged in course development, recruited teaching faculty, gathered feedback, and facilitated small groups. Participating students completed pre- and postcourse surveys. OUTCOMES: The 10 students (100%) enrolled in the course who completed both surveys indicated significant improvement in mean scores across 4 domains: evaluating medical literature (3.1/5 to 4.5/5; +1.4, P < .001); developing individual learning plans (3.6/5 to 4.7/5; +1.1, P = .001); perceived ability to efficiently evaluate patients with common internal medicine concerns (3.7/5 to 4.6/5; +0.9, P = .004); and formulating initial diagnostic and therapeutic plans (3.6/5 to 4.6/5; +1.0, P < .001). Themes extracted from open-ended responses included initial skepticism of an online format, the course exceeding expectations, and feeling prepared for internship. NEXT STEPS: Although a virtual subinternship lacks direct patient care, students reported improvement in all 4 domains studied. Future courses would benefit from greater use of simulation and role-playing scenarios for practical skills. The experience with NPTs was encouraging, aiding in the success of the subinternship. The role of NPTs should be cultivated to fill gaps in content delivery and enhance the development of students as educators.

A national propensity score-matched analysis of emergency laparoscopic versus open abdominal surgery.

BACKGROUND: Laparoscopy has been widely adopted in elective abdominal surgery but is still sparsely used in emergency settings. The study investigated the effect of laparoscopic emergency surgery using a population database. METHODS: Data for all patients from December 2013 to November 2018 were retrieved from the NELA national database of emergency laparotomy for England and Wales. Laparoscopically attempted cases were matched 2 : 1 with open cases for propensity score derived from a logistic regression model for surgical approach; included co-variates were age, gender, predicted mortality risk, and diagnostic, procedural and surgeon variables. Groups were compared for mortality. Secondary endpoints were blood loss and duration of hospital stay. RESULTS: Of 116 920 patients considered, 17 040 underwent laparoscopic surgery. The most common procedures were colectomy, adhesiolysis, washout and perforated ulcer repair. Of these, 11 753 were matched exactly to 23 506 patients who had open surgery. Laparoscopically attempted surgery was associated with lower mortality (6.0 versus 9.1 per cent, P < 0.001), blood loss (less than 100 ml, 64.4 versus 52.0 per cent, P < 0.001), and duration of hospital stay (median 8 (i.q.r. 5-14) versus 10 (7-18) days, P < 0.001). Similar trends were seen when comparing only successful laparoscopic cases with open surgery, and also when comparing cases converted to open surgery with open surgery. CONCLUSION: In appropriately selected patients, laparoscopy is associated with superior outcomes compared with open emergency surgery.

Minimally invasive (laparoscopic) surgery has been widely adopted in elective surgery but is sparsely used in emergencies. The study used national data to look at outcomes for patients having laparoscopic or open surgery, and used statistical methods to match patients in each group for critical variables such as type of operation, age and how unwell they were at time of surgery. Laparoscopy was found significantly to improve outcomes with reduced duration of stay in hospital, and lower rates of death after surgery. This suggests laparoscopy should be considered for much wider use than is currently employed.

Development and application of high-throughput screens for the discovery of compounds that disrupt ErbB4 signaling: Candidate cancer therapeutics.

Whereas recent clinical studies report metastatic melanoma survival rates high as 30-50%, many tumors remain nonresponsive or become resistant to current therapeutic strategies. Analyses of The Cancer Genome Atlas (TCGA) skin cutaneous melanoma (SKCM) data set suggests that a significant fraction of melanomas potentially harbor gain-of-function mutations in the gene that encodes for the ErbB4 receptor tyrosine kinase. In this work, a drug discovery strategy was developed that is based on the observation that the Q43L mutant of the naturally occurring ErbB4 agonist Neuregulin-2beta (NRG2ß) functions as a partial agonist at ErbB4. NRG2ß/Q43L stimulates tyrosine phosphorylation, fails to stimulate ErbB4-dependent cell proliferation, and inhibits agonist-induced ErbB4-dependent cell proliferation. Compounds that exhibit these characteristics likely function as ErbB4 partial agonists, and as such hold promise as therapies for ErbB4-dependent melanomas. Consequently, three highly sensitive and reproducible (Z' > 0.5) screening assays were developed and deployed for the identification of small-molecule ErbB4 partial agonists. Six compounds were identified that stimulate ErbB4 phosphorylation, fail to stimulate ErbB4-dependent cell proliferation, and appear to selectively inhibit ErbB4-dependent cell proliferation. Whereas further characterization is needed to evaluate the full therapeutic potential of these molecules, this drug discovery platform establishes reliable and scalable approaches for the discovery of ErbB4 inhibitors.