Cellular and behavioral effects of nicotine vapor exposure on mouse mesolimbic reward circuitry

Nicotine is a highly addictive compound in tobacco products such as combustible cigarettes and electronic cigarettes. Although the trends for smoking combustible cigarettes in the United States have decreased over the last couple decades, the emergence of electronic nicotine delivery systems (ENDS) products have grown in popularity and use in adults and adolescents. These products are often marketed as a safer alternative to combustible cigarettes, however the effects of electronically delivered nicotine vapor exposure on the brain remain unclear. In the first set of experiments, we validated and utilized a preclinical electronic nicotine vapor exposure paradigm to examine the behavioral and cellular effects of vaporized nicotine. We found that a single session versus repeated sessions of intermittent nicotine vapor exposure differentially altered body temperature, locomotion, and neuronal activity in a stress-relevant nucleus, the central amygdala (CeA). In the second set of experiments, we examined the effects of different nicotine concentrations and formulations (freebase versus salt) delivered via vapor exposure. We found sex differences by concentration and formulation in serum nicotine levels, neuronal activity in the CeA and ventral tegmental area (VTA), and anxiety-like and motivated behavior. In the last set of experiments, we investigated the neuronal activity and inhibitory control of corticotropin-releasing factor receptor 1 (CRF1) neurons in the VTA following acute and chronic nicotine vapor exposure. VTA CRF1 neurons, which are mainly dopaminergic and project to the nucleus accumbens, showed sex-specific basal differences in phasic inhibition. Following acute nicotine vapor exposure, tonic inhibition was enhanced in females but reduced in males, and overall neuronal activity was increased in both sexes. These effects were no longer observed following chronic nicotine vapor exposure suggestive of neuroadaptations that occur with repeated nicotine vapor exposure. Overall, these findings demonstrated that exposure to electronic nicotine vapor induces sex-, exposure timing-, nicotine dose-, and formulation-specific changes on reward and stress related neural populations and circuits, which may have significant implications for understanding how ENDS use impacts human populations.Doctor of Philosoph

Long Noncoding RNA Can Be a Probable Mechanism and a Novel Target for Diagnosis and Therapy in Fragile X Syndrome

Fragile X syndrome (FXS) is the most common congenital hereditary disease of low intelligence after Down syndrome. Its main pathogenic gene is fragile X mental retardation 1 (FMR1) gene associated with intellectual disability, autism, and fragile X-related primary ovarian insufficiency (FXPOI) and fragile X-associated tremor/ataxia syndrome (FXTAS). FMR1 gene transcription leads to the absence of fragile X mental retardation protein (FMRP). How to relieve or cure disorders associated with FXS has also become a clinically disturbing problem. Previous studies have recently shown that long noncoding RNAs (lncRNAs) contribute to the pathogenesis. And it has been identified that several lncRNAs including FMR4, FMR5, and FMR6 contribute to developing FXPOI/FXTAS, originating from the FMR1 gene locus. FMR4 is a product of RNA polymerase II and can regulate the expression of relevant genes during differentiation of human neural precursor cells. FMR5 is a sense-oriented transcript while FMR6 is an antisense lncRNA produced by the 3′ UTR of FMR1. FMR6 is likely to contribute to developing FXPOI, and it overlaps exons 15–17 of FMR1 as well as two microRNA binding sites. Additionally, BC1 can bind FMRP to form an inhibitory complex and lncRNA TUG1 also can control axonal development by directly interacting with FMRP through modulating SnoN–Ccd1 pathway. Therefore, these lncRNAs provide pharmaceutical targets and novel biomarkers. This review will: (1) describe the clinical manifestations and traditional pathogenesis of FXS and FXTAS/FXPOI; (2) summarize what is known about the role of lncRNAs in the pathogenesis of FXS and FXTAS/FXPOI; and (3) provide an outlook of potential effects and future directions of lncRNAs in FXS and FXTAS/FXPOI researches

Identification of Causal Relationship between Amyloid-beta Accumulation and Alzheimer's Disease Progression via Counterfactual Inference

Alzheimer's disease (AD) is a neurodegenerative disorder that is beginning with amyloidosis, followed by neuronal loss and deterioration in structure, function, and cognition. The accumulation of amyloid-beta in the brain, measured through 18F-florbetapir (AV45) positron emission tomography (PET) imaging, has been widely used for early diagnosis of AD. However, the relationship between amyloid-beta accumulation and AD pathophysiology remains unclear, and causal inference approaches are needed to uncover how amyloid-beta levels can impact AD development. In this paper, we propose a graph varying coefficient neural network (GVCNet) for estimating the individual treatment effect with continuous treatment levels using a graph convolutional neural network. We highlight the potential of causal inference approaches, including GVCNet, for measuring the regional causal connections between amyloid-beta accumulation and AD pathophysiology, which may serve as a robust tool for early diagnosis and tailored care

Association of inpatient use of angiotensin converting enzyme inhibitors and angiotensin II receptor blockers with mortality among patients with hypertension hospitalized with COVID-19

Rationale: Use of angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin II receptor blockers (ARBs) is a major concern for clinicians treating coronavirus disease 2019 (COVID-19) in patients with hypertension. Objective: To determine the association between in-hospital use of ACEI/ARB and all-cause mortality in COVID-19 patients with hypertension. Methods and Results: This retrospective, multi-center study included 1128 adult patients with hypertension diagnosed with COVID-19, including 188 taking ACEI/ARB (ACEI/ARB group; median age 64 [IQR 55-68] years; 53.2% men) and 940 without using ACEI/ARB (non-ACEI/ARB group; median age 64 [IQR 57-69]; 53.5% men), who were admitted to nine hospitals in Hubei Province, China from December 31, 2019 to February 20, 2020. Unadjusted mortality rate was lower in the ACEI/ARB group versus the non-ACEI/ARB group (3.7% vs. 9.8%; P = 0.01). In mixed-effect Cox model treating site as a random effect, after adjusting for age, gender, comorbidities, and in-hospital medications, the detected risk for all-cause mortality was lower in the ACEI/ARB group versus the non-ACEI/ARB group (adjusted HR, 0.42; 95% CI, 0.19-0.92; P =0.03). In a propensity score-matched analysis followed by adjusting imbalanced variables in mixed-effect Cox model, the results consistently demonstrated lower risk of COVID-19 mortality in patients who received ACEI/ARB versus those who did not receive ACEI/ARB (adjusted HR, 0.37; 95% CI, 0.15-0.89; P = 0.03). Further subgroup propensity score-matched analysis indicated that, compared to use of other antihypertensive drugs, ACEI/ARB was also associated with decreased mortality (adjusted HR, 0.30; 95%CI, 0.12-0.70; P = 0.01) in COVID-19 patients with hypertension. Conclusions: Among hospitalized COVID-19 patients with hypertension, inpatient use of ACEI/ARB was associated with lower risk of all-cause mortality compared with ACEI/ARB non-users. While study interpretation needs to consider the potential for residual confounders, it is unlikely that in-hospital use of ACEI/ARB was associated with an increased mortality risk

Redefining cardiac biomarkers in predicting mortality and adverse outcomes of inpatients with COVID-19

The prognostic power of circulating cardiac biomarkers, their utility and pattern of release in coronavirus disease 2019 (COVID-19) patients have not been clearly defined. In this multi-centered retrospective study, we enrolled 3,219 patients with diagnosed COVID-19 admitted to 9 hospitals from December 31, 2019 to March 4, 2020, to estimate the associations and prognostic power of circulating cardiac injury markers with the poor outcomes of COVID-19. In the mixed-effect Cox model, after adjusting for age, gender and comorbidities, the adjusted hazard ratios of 28-day mortality for high-sensitivity cardiac troponin I (hs-cTnI) was 7.12 (95%CI, 4.60-11.03; P<0.001), NT-proB-type natriuretic peptide (NT-proBNP) was 5.11 (95%CI, 3.50-7.47; P<0.001), CK-MB was 4.86 (95%CI, 3.33-7.09; P<0.001), myoglobin was 4.50 (95%CI, 3.18-6.36; P < 0.001), and CK was 3.56 (95%CI, 2.53-5.02; P < 0.001). The cutoffs of those cardiac biomarkers for effective prognosis of 28-day mortality of COVID-19 were found to be much lower than for regular heart disease at about 49% of the currently recommended thresholds. Patients with elevated cardiac injury markers above the newly established cutoffs were associated with significantly increased risk of COVID-19 death. In conclusion, cardiac biomarker elevations are significantly associated with 28-day death in patients with COVID-19. The prognostic cutoffs for of these values might be much lower than the current reference standards. These findings can assist better management of COVID-19 patients to improve outcomes. Importantly, the newly established cutoff levels of COVID-19 associated cardiac biomarkers may serve as useful criteria for the future prospective studies and clinical trials

Redefining Cardiac Biomarkers in Predicting Mortality of Inpatients With COVID-19

The prognostic power of circulating cardiac biomarkers, their utility, and pattern of release in coronavirus disease 2019 (COVID-19) patients have not been clearly defined. In this multicentered retrospective study, we enrolled 3219 patients with diagnosed COVID-19 admitted to 9 hospitals from December 31, 2019 to March 4, 2020, to estimate the associations and prognostic power of circulating cardiac injury markers with the poor outcomes of COVID-19. In the mixed-effects Cox model, after adjusting for age, sex, and comorbidities, the adjusted hazard ratio of 28-day mortality for hs-cTnI (high-sensitivity cardiac troponin I) was 7.12 ([95% CI, 4.60-11.03] P\u3c0.001), (NT-pro)BNP (N-terminal pro-B-type natriuretic peptide or brain natriuretic peptide) was 5.11 ([95% CI, 3.50-7.47] P\u3c0.001), CK (creatine phosphokinase)-MB was 4.86 ([95% CI, 3.33-7.09] P\u3c0.001), MYO (myoglobin) was 4.50 ([95% CI, 3.18-6.36] P\u3c0.001), and CK was 3.56 ([95% CI, 2.53-5.02] P\u3c0.001). The cutoffs of those cardiac biomarkers for effective prognosis of 28-day mortality of COVID-19 were found to be much lower than for regular heart disease at about 19%-50% of the currently recommended thresholds. Patients with elevated cardiac injury markers above the newly established cutoffs were associated with significantly increased risk of COVID-19 death. In conclusion, cardiac biomarker elevations are significantly associated with 28-day death in patients with COVID-19. The prognostic cutoff values of these biomarkers might be much lower than the current reference standards. These findings can assist in better management of COVID-19 patients to improve outcomes. Importantly, the newly established cutoff levels of COVID-19-associated cardiac biomarkers may serve as useful criteria for the future prospective studies and clinical trials

The impact of nurse-led nonpharmacological multidisciplinary holistic nursing care on fatigue patients receiving hemodialysis: a randomized, parallel-group, controlled trial

Abstract Background Fatigue is a symptom characterized by an elevated prevalence in patients undergoing hemodialysis, which may cause extreme mental and muscular debilitation, significantly influencing social interaction, life quality and well-being. However, the significance of fatigue to patients undergoing hemodialysis has not been recognized yet, and prevention and management of fatigue in this population have not been thoroughly investigated. Additionally, previous studies mainly focused on muscular fatigue, while mental fatigue has been seldom discussed. This study aims to investigate the interaction between nurses and multidisciplinary of nonpharmacological integrated care interventions (NICIs) and assess the impact of fatigue on patients undergoing hemodialysis. Methods The integrative nonpharmacological care interventions in this study included walking, motivational interviewing (MI) and health education regarding behavioral self-management. A single-center randomized controlled trial was conducted in the dialysis center of the nephrological department in a tertiary affiliated hospital of medical university from January to June 2019. A total of 118 patients were selected and randomly divided into the intervention group (IG) and the control group (CG). Four patients dropped out during the study, and 114 patients were enrolled for the eventual analysis. The 60 patients in the IG received routine nursing combined with integrated care interventions, while the 54 patients in the CG received routine nursing only. This study lasted for six months. Results The experimental group exhibited significant reductions of overall fatigue (2.26 vs. 0.48), mental fatigue (1.41 vs. 0.54), muscular fatigue (2.13 vs. 0.75), and some biochemical indicators (e.g., serum urea) (P<0.05), compared with the CG. Conclusions Nurses and multidisciplinary teams have been demonstrated to play a key role and interplay function in chronic disease management. Hence, the nurse-led multidisciplinary NICIs significantly alleviated total fatigue (muscular fatigue and mental fatigue) and improved other parameters. Trial registration ChiCTR-IOR-16008621 (March 18, 2016

Feasibility of electroacupuncture at Baihui (GV20) and Zusanli (ST36) on survival with a favorable neurological outcome in patients with postcardiac arrest syndrome after in-hospital cardiac arrest: study protocol for a pilot randomized controlled trial

Abstract Background At present, even the first-line medication epinephrine still shows no evidence of a favourable neurological outcome in patients with sudden cardiac arrest (SCA). The high mortality of patients with postcardiac arrest syndrome (PCAS) can be attributed to brain injury, myocardial dysfunction, systemic ischaemia/reperfusion response, and persistent precipitating pathology. Targeted temperature management, the only clinically proven method in the treatment of PCAS, is still associated with a series of problems that have not been completely resolved. Acupuncture is a crucial therapy in traditional Chinese medicine. On the basis of the results of previous studies, we hypothesize that electroacupuncture (EA) might provide therapeutic benefits in the treatment of PCAS. This study will explore the feasibility of EA on SCA patients. Methods This is a prospective pilot, randomized controlled clinical trial. Eligible patients with PCAS after in-hospital cardiac arrest (IHCA) admitted to our department will be randomly allocated to the control group or the EA group. Both groups will receive standard therapy according to American Heart Association guidelines for cardiopulmonary resuscitation. However, the EA group will also receive acupuncture at the Baihui acupoint (GV20) and Zusanli acupoint (ST36) with EA stimulation for 30 min using a dense-dispersed wave at frequencies of 20 and 100 Hz, a current intensity of less than 10 mA, and a pulse width of 0.5 ms. EA treatment will be administered for up to 14 days (until either discharge or death). The primary endpoint is survival with a favourable neurological outcome. The secondary endpoints are neurological scores, cardiac function parameters, and other clinical parameters, including Sequential Organ Failure Assessment (SOFA) scores and Acute Physiology and Chronic Health Evaluation (APACHE) II scores, on days 0 to 28. Discussion This study will provide crucial clinical evidence on the efficacy of EA in PCAS when used as an adjunctive treatment with AHA standard therapy. Trial registration chictr.org.cn : ChiCTR2000040040. Registered on 19 November 2020. Retrospectively registered. http://www.chictr.org.cn/

Electronic Vaporization of Nicotine Salt or Freebase produces differential effects on metabolism, neuronal activity and behavior in male and female C57BL/6J mice

The use of Electronic Nicotine Delivery Systems (ENDS) is increasing in prevalence and popularity. ENDS are a rapidly evolving technology as devices and e-liquid formulations adapt to policy restrictions and market demand. To identify the impacts of nicotine formulation and concentration, we exposed female and male C57BL/6J mice to passive electronic vaporization of different nicotine formulations (freebase or salt) and concentrations (1% or 3%) and measured serum nicotine metabolite levels, brain activity by cFos expression, and anxiety-like and motivated behavior using the novelty suppressed feeding test. We found that the 3% freebase nicotine vapor group displayed significantly higher serum nicotine levels than either 1% or 3% nicotine salt formulations, and female mice displayed higher serum nicotine and cotinine levels compared to males. Central amygdala (CeA) activity was significantly elevated in male mice following nicotine vapor exposure, but the increase was not significantly different between nicotine vapor groups. CeA activity in female mice was unaffected. In contrast, increased activity in the ventral tegmental area (VTA) was only observed in female mice exposed to 3% nicotine freebase and specifically in the dopaminergic population. Anxiety-like behavior in female mice was relatively unaffected by nicotine vapor exposure, however male mice displayed increased anxiety-like behavior and reduced motivation to feed after vapor exposure, specifically in the 3% freebase group. These results identify important sex differences in the impact of nicotine formulation and concentration on nicotine metabolism, brain region-specific activity and anxiety-like behavior, which may have significant relevance for different consequences of vaping in men and women