Long-term benefits of hematopoietic stem cell-based macrophage/microglia delivery of GDNF to the CNS in a mouse model of Parkinson's disease.

Glial cell line-derived neurotrophic factor (GDNF) protects dopaminergic neurons in various models of Parkinson's disease (PD). Cell-based GDNF gene delivery mitigates neurodegeneration and improves both motor and non-motor functions in PD mice. As PD is a chronic condition, this study aims to investigate the long-lasting benefits of hematopoietic stem cell (HSC)-based macrophage/microglia-mediated CNS GDNF (MMC-GDNF) delivery in an MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine) mouse model. The results indicate that GDNF treatment effectively ameliorated MPTP-induced motor deficits for up to 12 months, which coincided with the protection of nigral dopaminergic neurons and their striatal terminals. Also, the HSC-derived macrophages/microglia were recruited selectively to the neurodegenerative areas of the substantia nigra. The therapeutic benefits appear to involve two mechanisms: (1) macrophage/microglia release of GDNF-containing exosomes, which are transferred to target neurons, and (2) direct release of GDNF by macrophage/microglia, which diffuses to target neurons. Furthermore, the study found that plasma GDNF levels were significantly increased from baseline and remained stable over time, potentially serving as a convenient biomarker for future clinical trials. Notably, no weight loss, altered food intake, cerebellar pathology, or other adverse effects were observed. Overall, this study provides compelling evidence for the long-term therapeutic efficacy and safety of HSC-based MMC-GDNF delivery in the treatment of PD.

Churn in Supplemental Nutrition Assistance Program: Changes in Medicaid Expenditure and Acute Care Utilization.

BACKGROUND: The Supplemental Nutrition Assistance Program (SNAP) provides financial assistance to low-income individuals and families to help them purchase food. However, when participants experience short-term disenrollment from the program, known as churn, it can disrupt their health care usage patterns or result in acute health care needs due to the loss of financial benefits and time burden required to reapply for SNAP. OBJECTIVE: The objective of this study was to examine the changes in health care expenditures and acute care utilization during periods of SNAP churn compared with nonchurn periods among those who churn during the study period. RESEARCH DESIGN: Longitudinal analysis of Pennsylvania Medicaid claims data for enrollees participating in SNAP between 2016 and 2018 using individual fixed-effects models. We add to the literature by estimating whether these changes varied based on the amount of SNAP benefit lost, or differed between adults and children. RESULTS: We found that SNAP churn was associated with reductions in pharmacy and primary care spending across all SNAP benefit levels and age groups. Specifically, our findings indicate a reduction of 4%-6% in pharmacy expenditures for adults and 2%-4% for children. Moreover, there was a 3%-4% decrease in primary care expenditures for adults and a 4%-6% decrease for children. Acute care utilization did not significantly change during a SNAP churn period. CONCLUSION: Our findings of decreases in pharmacy and primary care spending suggest that preventing SNAP churn may help reduce instances where adult and child participants forgo necessary care.

Effectiveness of cannabis use and cannabis use disorder interventions: a European and international data synthesis.

This data synthesis examined the effectiveness of behavioural and pharmacological approaches for cannabis treatment. We integrated findings from high level evidence studies and prioritised data from Europe when available. The synthesis found that only a relatively small number of published behavioural and pharmacological studies on cannabis interventions have been conducted in Europe. Applying both European and non-European data, it was found that Cognitive Behavioural Therapy (CBT) and/or Motivational Enhancement Therapy (MET) improved short-term outcomes in the frequency of cannabis use and dependency severity, although abstinence outcomes were less consistent. These improvements were typically not maintained nine months after treatment. CBT and MET (or combined CBT + MET) treatments that extend beyond four sessions were more effective than fewer sessions over a shorter duration. Combining CBT or MET (or combined CBT + MET) with adjunctive Contingency Management (CM) improved therapeutic outcomes. No pharmacotherapies have been approved for the management of cannabis use, cannabis use disorders or cannabis withdrawal. Despite only weak evidence to support the use of pharmacological agents, some are used 'off-label' to manage withdrawal symptoms outside clinical trials.

The contribution of pain catastrophizing, depression and anxiety symptoms among patients with persistent pain and opioid misuse behaviours.

BACKGROUND: Anxiety, depression and pain catastrophizing are independently associated with risk of opioid misuse in patients with persistent pain but their relationship to current opioid misuse, when considered together, is poorly understood. This study will assess the relative contribution of these modifiable, and distinct psychological constructs to current opioid misuse in patients with persistent pain. METHODS: One hundred and twenty-seven patients referred to a specialized opioid management clinic for prescription opioid misuse within a tertiary pain service were recruited for this study. The Pain Catastrophizing Scale, Depression, Anxiety and Stress Scales and the Current Opioid Misuse Measure were administered pre-treatment. Pain severity and morphine equivalent dose based on independent registry data were also recorded. RESULTS: Higher levels of pain catastrophizing, depression, and anxiety were significantly associated with higher current opioid misuse (r = .475, 0.599, and 0.516 respectively, p < .01). Pain severity was significantly associated with pain catastrophizing (r = .301, p < .01). Catastrophizing, depression, and anxiety explained an additional 11.56% of the variance (R2 change = 0.34, p < .01) over and above age, gender, pain severity and morphine equivalent dose. Depression was the only significant variable at Step 2 (ß = 0.62, p < .01). CONCLUSION: Findings show that in a sample of people with persistent pain referred for treatment for opioid misuse, depression contributes over and above that of anxiety and pain catastrophizing. Theoretical and clinical practice implications are presented.

Vaping on TikTok: a systematic thematic analysis.

INTRODUCTION: The rising popularity of TikTok among adolescents may influence their awareness and perceptions of e-cigarette use via user-generated content. This study aimed to examine how e-cigarette/vaping-related videos are portrayed on TikTok. METHODS: The nine most viewed hashtag based keywords were used to identify popular e-cigarette/vaping-related videos on TikTok (n=1000) from its inception (earliest upload date: January 2019) to November 2020. Five researchers independently coded the number of views, likes, user category and theme. RESULTS: A final sample of 808 e-cigarette/vaping-related videos that met study criteria were included. Collectively, these videos were viewed over 1.5 billion times, with a median view count of 1 000 000 (range 112 900-78 600 000) and a median 'likes' count of 143 000 (range 10 000-1 000 000). A majority of the videos portrayed e-cigarette use positively (63%; collectively viewed over 1.1 billion times). Neutral depictions of e-cigarette use were viewed a total of 290 million times (24%) and negative depictions of e-cigarettes were viewed a total of 193 million times (13%). The video themes included (not mutually exclusively): 'comedy and joke' (52%; total of 618 million views), 'lifestyle and acceptability' (35%; 459 million), 'marketing' (29%; 392 million), 'vaping tricks' (20%; 487 million), 'nicotine and addiction' (20%; 194 million), 'creativity' (16%; 322 million) and 'warning' (11%; 131 million). CONCLUSION: Our findings illustrated that positively framed e-cigarette and vaping-related postings available without age restrictions on TikTok-a rising video-sharing platform that is popular among adolescents-have been viewed many times. Effective age restrictions are needed to reduce adolescents' potential exposure to videos that portray vaping positively.

Predicting the long-term effects of electronic cigarette use on population health: a systematic review of modelling studies.

OBJECTIVE: To systematically review and synthesise the findings of modelling studies on the population impacts of e-cigarette use and to identify potential gaps requiring future investigation. DATA SOURCE AND STUDY SELECTION: Four databases were searched for modelling studies of e-cigarette use on population health published between 2010 and 2023. A total of 32 studies were included. DATA EXTRACTION: Data on study characteristics, model attributes and estimates of population impacts including health outcomes and smoking prevalence were extracted from each article. The findings were synthesised narratively. DATA SYNTHESIS: The introduction of e-cigarettes was predicted to lead to decreased smoking-related mortality, increased quality-adjusted life-years and reduced health system costs in 29 studies. Seventeen studies predicted a lower prevalence of cigarette smoking. Models that predicted negative population impacts assumed very high e-cigarette initiation rates among non-smokers and that e-cigarette use would discourage smoking cessation by a large margin. The majority of the studies were based on US population data and few studies included factors other than smoking status, such as jurisdictional tobacco control policies or social influence. CONCLUSIONS: A population increase in e-cigarette use may result in lower smoking prevalence and reduced burden of disease in the long run, especially if their use can be restricted to assisting smoking cessation. Given the assumption-dependent nature of modelling outcomes, future modelling studies should consider incorporating different policy options in their projection exercises, using shorter time horizons and expanding their modelling to low-income and middle-income countries where smoking rates remain relatively high.

Randomized Trial of Three Anticonvulsant Medications for Status Epilepticus.

BACKGROUND: The choice of drugs for patients with status epilepticus that is refractory to treatment with benzodiazepines has not been thoroughly studied. METHODS: In a randomized, blinded, adaptive trial, we compared the efficacy and safety of three intravenous anticonvulsive agents - levetiracetam, fosphenytoin, and valproate - in children and adults with convulsive status epilepticus that was unresponsive to treatment with benzodiazepines. The primary outcome was absence of clinically evident seizures and improvement in the level of consciousness by 60 minutes after the start of drug infusion, without additional anticonvulsant medication. The posterior probabilities that each drug was the most or least effective were calculated. Safety outcomes included life-threatening hypotension or cardiac arrhythmia, endotracheal intubation, seizure recurrence, and death. RESULTS: A total of 384 patients were enrolled and randomly assigned to receive levetiracetam (145 patients), fosphenytoin (118), or valproate (121). Reenrollment of patients with a second episode of status epilepticus accounted for 16 additional instances of randomization. In accordance with a prespecified stopping rule for futility of finding one drug to be superior or inferior, a planned interim analysis led to the trial being stopped. Of the enrolled patients, 10% were determined to have had psychogenic seizures. The primary outcome of cessation of status epilepticus and improvement in the level of consciousness at 60 minutes occurred in 68 patients assigned to levetiracetam (47%; 95% credible interval, 39 to 55), 53 patients assigned to fosphenytoin (45%; 95% credible interval, 36 to 54), and 56 patients assigned to valproate (46%; 95% credible interval, 38 to 55). The posterior probability that each drug was the most effective was 0.41, 0.24, and 0.35, respectively. Numerically more episodes of hypotension and intubation occurred in the fosphenytoin group and more deaths occurred in the levetiracetam group than in the other groups, but these differences were not significant. CONCLUSIONS: In the context of benzodiazepine-refractory convulsive status epilepticus, the anticonvulsant drugs levetiracetam, fosphenytoin, and valproate each led to seizure cessation and improved alertness by 60 minutes in approximately half the patients, and the three drugs were associated with similar incidences of adverse events. (Funded by the National Institute of Neurological Disorders and Stroke; ESETT ClinicalTrials.gov number, NCT01960075.).

Development of the motivational thought frequency scale for alcohol abstinence (MTF-A).

BACKGROUND AND AIMS: For most treatment-seeking patients with severe Alcohol Use Disorder (AUD), abstinence is the clinically indicated goal. Existing AUD motivation scales are non-specific about treatment consumption goals, which limit their effectiveness. Desires and mental imagery are relevant in the motivation for AUD treatment engagement. The Motivational Thought Frequency Scale for an abstinence goal (MTF-A) was adapted from the MTF for controlled drinking (MTF-CD). This study psychometrically evaluated the MTF-A in an alcohol-dependent sample engaged in treatment with a goal of abstinence. To enhance the clinical utility of the scale, a secondary aim was to evaluate a psychometrically equivalent short version of the MTF-A. METHOD: A sample N of 329 treatment-seeking patients with AUD (mean age of 44.44 years, SD = 11.89 years, 72% male) who were undertaking a cognitive behavioral treatment (CBT) program for abstinence completed the Motivational Thought Frequency Scale for Abstinence (MTF-A) and the Severity of Alcohol Dependence Questionnaire (SADQ). The MTF-A measured motivation for abstinence through four factors: intensity, self-efficacy imagery, incentives imagery, and availability. Confirmatory factor analyses (CFAs) were conducted to examine factor structure and model fit. Cronbach's alpha assessed internal consistency. Predictive validity was determined by logistic regression predicting first-session treatment non-attendance and alcohol consumption between baseline assessment and commencement of treatment, controlling for potential confounds. RESULTS: A four-factor structure provided the best fit for the MTF-A, compared with one- and three-factor models. A shortened 9-item MTF-A scale (S-MTF-A) provided better fit than the 13-item MTF-A scale. Both MTF-A and S-MTF-A displayed good internal consistency. Although both MTF-A and S-MTF-A successfully predicted first-session treatment non-attendance, neither predicted alcohol consumption between the baseline assessment and commencement of treatment. CONCLUSIONS: The model fit of the four-factor, 9-item S-MTF-A was superior to the original 13-item MTF-A. Both scales were predictive of participation of AUD treatment. Desires and mental imagery play an important role in AUD treatment motivation.

Mood and Anxiety Symptoms in Persons Taking Prescription Opioids: A Systematic Review with Meta-Analyses of Longitudinal Studies.

OBJECTIVE: To review evidence from longitudinal studies on the association between prescription opioid use and common mood and anxiety symptoms. DESIGN: We conducted a systematic review and meta-analysis according to Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. METHODS: We searched PubMed, Embase, and PsycINFO for search terms related to opioids AND (depression OR bipolar OR anxiety OR post-traumatic stress disorder [PTSD]). Findings were summarized narratively, and random-effects meta-analyses were used to pool effect sizes. RESULTS: We identified 10,290 records and found 10 articles that met our inclusion criteria. Incidence studies showed that people who used prescription opioids had an elevated risk of any mood outcome (adjusted effect size [aES] = 1.80 [95% confidence interval = 1.40-2.30]) and of an anxiety outcome (aES = 1.40 [1.20-1.80]) compared with those who did not use prescription opioids. Associations with depression were small and not significant after adjustment for potential confounders (aES = 1.18 [0.98-1.41]). However, some studies reported an increased risk of depressive symptoms after increased (aES = 1.58 [1.30-1.93]) or prolonged opioid use (aES = 1.49 [1.19-1.86]). CONCLUSIONS: Mental health should be considered when opioids are prescribed because some patients could be vulnerable to adverse mental health outcomes.

Changes in patterns of youth multiple tobacco and/or e-cigarette product use in the US between 2014 and 2020: a multiple-group latent class analysis.

BACKGROUND: Multiple tobacco and e-cigarette product (MTEP) use, the concurrent use of two or more different types of tobacco and/or e-cigarettes products, is common among young people in the US. Changes in patterns of MTEP use among US youth between 2014 and 2020 were identified and the determinants of MTEP use were examined. METHODS: Four years of repeated cross-sectional data from the US National Youth Tobacco Survey of middle and high school students from grade 6 to 12 (Ntotal=77 402). Multigroup latent class analysis (LCA) was applied to the data series to allow for simultaneous identification of MTEP use patterns between 2014 and 2020. Logistic regression was used to predict class membership on demographic and tobacco-related variables. FINDINGS: Over the 7-year period, LCA identified three patterns: minimal/non-users (MNU: ~89.8%), mostly occasional e-cigarette and cigarette users (MOEC: ~9%) and polytobacco users (POLY: ~1.2%). From 2014 to 2020, MNU increased from 86.4% to 92% (p<0.05), while MOEC and POLY decreased from 11.2% to 7.9% and from 2.4% to 0.1%, respectively. The probability of regular e-cigarette use increased from 0 to 2.3% among MNU, 6% to 31.9% among MOEC and 29.6% to 67.6% among POLY (p<0.05). In binomial logistic regression, being male, in high school, non-heterosexual, living with someone who uses tobacco at home, having cognitive difficulties, having lower perceptions of tobacco's danger and exposure to tobacco marketing were associated with greater odds of MOEC and POLY than MNU. CONCLUSIONS: There was an increase in regular e-cigarette use in all three classes, but a corresponding decrease in the proportion of MTEP use. Public health interventions to discourage uptake of e-cigarettes, such as tighter restrictions on marketing to minors, are warranted and there is a need to consider disparities in the determinants of MTEP use.

Randomization to Treadmill Training Improves Physical and Metabolic Health in Association With Declines in Oxidative Stress in Stroke.

OBJECTIVE: To investigate the effect of aerobic exercise vs control (stretching/balance) on inflammatory and oxidative stress biomarkers in stroke survivors and whether these changes are associated with improvements in physical and metabolic health. DESIGN: Randomized controlled trial. SETTING: The general communities of Baltimore, Maryland, and Atlanta, Georgia. PARTICIPANTS: Two hundred forty-six older (>50 years), chronic (>6 months) survivors of stroke (N=246) with hemiparetic gait were recruited, with 51 completing pre-intervention testing and 39 completing postintervention testing. Participants were required to have completed all conventional physical therapy and be capable of walking 3 minutes on a treadmill (N=246). INTERVENTION: Participants completed 6 months of 2 times/wk stretching or balance (ST; n=19) or 3 times/wk aerobic treadmill rehabilitation (TM; n=20;). MAIN OUTCOME MEASURE(S): Peak oxygen uptake rate (V̇o2peak), 6-minute walking distance (6MWD), fasting plasma glucose, insulin, oxidative stress, and inflammatory biomarkers were assessed pre- and postintervention. Homeostatic Model Assessment of Insulin Resistance (HOMA-IR) was calculated. RESULTS: Physical function and metabolic health parameters tended to improve after TM but not ST (ST vs TM: V̇o2peak: -9% vs 24%, P<.01; 6MWD: 1% vs 15%, P=.05; insulin: -1% vs -31%, P=.05; HOMA-IR: -3% vs -29%, P=.06). Plasma concentrations of nitrotyrosine, protein carbonyls, and oxidized low-density lipoprotein (oxLDL) tended to decrease from pre-intervention concentrations in response to TM compared to ST (ST vs TM: nitrotyrosine: 2% vs -28%, P=.01; protein carbonyls: -4% vs -34%, P=.08; oxLDL: -3% vs -32%, P<.01). Changes in circulating concentrations of C-reactive protein, protein carbonyls, and oxLDL were negatively associated with changes in V̇o2peak and 6MWD (r's=-0.40 to -0.76) and positively associated with fasting plasma insulin and HOMA-IR (r's=0.52-0.81, Ps<.01). CONCLUSIONS: Six months of TM tends to be associated with increased functional capacity and reduced oxidative stress in chronic stroke survivors. Our findings identify potentially modifiable systemic markers of inflammation and oxidative stress important to stroke rehabilitation and provide potential targets for novel therapeutics in future studies.

Suicidal Ideation Across Three Timepoints in Patients Discharged from Psychiatric Hospitalization.

This article describes the rate of suicidal ideation (SI) across three timepoints among treatment-seeking patients recently discharged from psychiatric hospitalization-a group that is at ultrahigh-risk for suicide. Retrospective chart review was used to quantify the rate of SI in 252 consecutive patients discharged to a post-hospital mental health clinic. Data include patients' lifetime history of SI, SI at the time of hospital intake, and SI at post-hospital outpatient clinic intake, as well as demographics and diagnosis. Overall, 67% of the sample reported a lifetime history of SI, 49% reported SI during hospital intake, and 6% reported SI at post-hospital clinic intake. Age was the only variable associated with history of SI (p = .04), with younger patients more likely (OR = 1.85) to report a history of SI. These results may help inform the development of interventions for the population of ultrahigh-risk patients being discharged from hospital after psychiatric care.

Efficacy of levetiracetam, fosphenytoin, and valproate for established status epilepticus by age group (ESETT): a double-blind, responsive-adaptive, randomised controlled trial.

BACKGROUND: Benzodiazepine-refractory, or established, status epilepticus is thought to be of similar pathophysiology in children and adults, but differences in underlying aetiology and pharmacodynamics might differentially affect response to therapy. In the Established Status Epilepticus Treatment Trial (ESETT) we compared the efficacy and safety of levetiracetam, fosphenytoin, and valproate in established status epilepticus, and here we describe our results after extending enrolment in children to compare outcomes in three age groups. METHODS: In this multicentre, double-blind, response-adaptive, randomised controlled trial, we recruited patients from 58 hospital emergency departments across the USA. Patients were eligible for inclusion if they were aged 2 years or older, had been treated for a generalised convulsive seizure of longer than 5 min duration with adequate doses of benzodiazepines, and continued to have persistent or recurrent convulsions in the emergency department for at least 5 min and no more than 30 min after the last dose of benzodiazepine. Patients were randomly assigned in a response-adaptive manner, using Bayesian methods and stratified by age group (<18 years, 18-65 years, and >65 years), to levetiracetam, fosphenytoin, or valproate. All patients, investigators, study staff, and pharmacists were masked to treatment allocation. The primary outcome was absence of clinically apparent seizures with improved consciousness and without additional antiseizure medication at 1 h from start of drug infusion. The primary safety outcome was life-threatening hypotension or cardiac arrhythmia. The efficacy and safety outcomes were analysed by intention to treat. This study is registered in ClinicalTrials.gov, NCT01960075. FINDINGS: Between Nov 3, 2015, and Dec 29, 2018, we enrolled 478 patients and 462 unique patients were included: 225 children (aged <18 years), 186 adults (18-65 years), and 51 older adults (>65 years). 175 (38%) patients were randomly assigned to levetiracetam, 142 (31%) to fosphenyltoin, and 145 (31%) were to valproate. Baseline characteristics were balanced across treatments within age groups. The primary efficacy outcome was met in those treated with levetiracetam for 52% (95% credible interval 41-62) of children, 44% (33-55) of adults, and 37% (19-59) of older adults; with fosphenytoin in 49% (38-61) of children, 46% (34-59) of adults, and 35% (17-59) of older adults; and with valproate in 52% (41-63) of children, 46% (34-58) of adults, and 47% (25-70) of older adults. No differences were detected in efficacy or primary safety outcome by drug within each age group. With the exception of endotracheal intubation in children, secondary safety outcomes did not significantly differ by drug within each age group. INTERPRETATION: Children, adults, and older adults with established status epilepticus respond similarly to levetiracetam, fosphenytoin, and valproate, with treatment success in approximately half of patients. Any of the three drugs can be considered as a potential first-choice, second-line drug for benzodiazepine-refractory status epilepticus. FUNDING: National Institute of Neurological Disorders and Stroke, National Institutes of Health.

Oseltamivir plus usual care versus usual care for influenza-like illness in primary care: an open-label, pragmatic, randomised controlled trial.

BACKGROUND: Antivirals are infrequently prescribed in European primary care for influenza-like illness, mostly because of perceived ineffectiveness in real world primary care and because individuals who will especially benefit have not been identified in independent trials. We aimed to determine whether adding antiviral treatment to usual primary care for patients with influenza-like illness reduces time to recovery overall and in key subgroups. METHODS: We did an open-label, pragmatic, adaptive, randomised controlled trial of adding oseltamivir to usual care in patients aged 1 year and older presenting with influenza-like illness in primary care. The primary endpoint was time to recovery, defined as return to usual activities, with fever, headache, and muscle ache minor or absent. The trial was designed and powered to assess oseltamivir benefit overall and in 36 prespecified subgroups defined by age, comorbidity, previous symptom duration, and symptom severity, using a Bayesian piece-wise exponential primary analysis model. The trial is registered with the ISRCTN Registry, number ISRCTN 27908921. FINDINGS: Between Jan 15, 2016, and April 12, 2018, we recruited 3266 participants in 15 European countries during three seasonal influenza seasons, allocated 1629 to usual care plus oseltamivir and 1637 to usual care, and ascertained the primary outcome in 1533 (94%) and 1526 (93%). 1590 (52%) of 3059 participants had PCR-confirmed influenza infection. Time to recovery was shorter in participants randomly assigned to oseltamivir (hazard ratio 1·29, 95% Bayesian credible interval [BCrI] 1·20-1·39) overall and in 30 of the 36 prespecified subgroups, with estimated hazard ratios ranging from 1·13 to 1·72. The estimated absolute mean benefit from oseltamivir was 1·02 days (95% [BCrI] 0·74-1·31) overall, and in the prespecified subgroups, ranged from 0·70 (95% BCrI 0·30-1·20) in patients younger than 12 years, with less severe symptoms, no comorbidities, and shorter previous illness duration to 3·20 (95% BCrI 1·00-5·50) in patients aged 65 years or older who had more severe illness, comorbidities, and longer previous illness duration. Regarding harms, an increased burden of vomiting or nausea was observed in the oseltamivir group. INTERPRETATION: Primary care patients with influenza-like illness treated with oseltamivir recovered one day sooner on average than those managed by usual care alone. Older, sicker patients with comorbidities and longer previous symptom duration recovered 2-3 days sooner. FUNDING: European Commission's Seventh Framework Programme.

Integrating regional and local monitoring data and assessment tools to evaluate habitat conditions and inform river restoration.

Restoring degraded rivers requires initial assessment of the fluvial landscape to identify stressors and riverine features that can be enhanced. We associated local-scale river habitat data collected using standardized national monitoring tools with modeled regional water temperature and flow data on mid-sized northwest U.S. rivers (30-60 m wide). We grouped these rivers according to quartiles of their modeled mean August water temperature and examined their physical habitat structure and flow. We then used principal components analysis to summarize the variation in several dimensions of physical habitat. We also compared local conditions in the Priest River, a river targeted for restoration of native salmonid habitat in northern Idaho, with those in other rivers of the region to infer potential drivers controlling water temperature. The warmest rivers had physical structure and fluvial characteristics typical of thermally degraded rivers, whereas the coldest rivers had higher mean summer flows and greater channel planform complexity. The Priest River sites had approximately twice as many deep residual pools (>50, >75, and >100 cm) and incision that averaged approximately twice that in the coldest rivers. Percentage fines and natural cover in the Priest were also more typical of the higher-temperature river groups. We found generally low instream cover and low levels of large wood both across the region and within the Priest River. Our approach enabled us to consider the local habitat conditions of a river in the context of other similarly sized rivers in the surrounding region. Understanding this context is important for identifying potential influences on river water temperature within the focal basin and for defining attainable goals for management and restoration of thermal and habitat conditions.

Neuron-Derived Estrogen Regulates Synaptic Plasticity and Memory.

17ß-estradiol (E2) is produced from androgens via the action of the enzyme aromatase. E2 is known to be made in neurons in the brain, but its precise functions in the brain are unclear. Here, we used a forebrain-neuron-specific aromatase knock-out (FBN-ARO-KO) mouse model to deplete neuron-derived E2 in the forebrain of mice and thereby elucidate its functions. FBN-ARO-KO mice showed a 70-80% decrease in aromatase and forebrain E2 levels compared with FLOX controls. Male and female FBN-ARO-KO mice exhibited significant deficits in forebrain spine and synaptic density, as well as hippocampal-dependent spatial reference memory, recognition memory, and contextual fear memory, but had normal locomotor function and anxiety levels. Reinstating forebrain E2 levels via exogenous in vivo E2 administration was able to rescue both the molecular and behavioral defects in FBN-ARO-KO mice. Furthermore, in vitro studies using FBN-ARO-KO hippocampal slices revealed that, whereas induction of long-term potentiation (LTP) was normal, the amplitude was significantly decreased. Intriguingly, the LTP defect could be fully rescued by acute E2 treatment in vitro Mechanistic studies revealed that FBN-ARO-KO mice had compromised rapid kinase (AKT, ERK) and CREB-BDNF signaling in the hippocampus and cerebral cortex. In addition, acute E2 rescue of LTP in hippocampal FBN-ARO-KO slices could be blocked by administration of a MEK/ERK inhibitor, further suggesting a key role for rapid ERK signaling in neuronal E2 effects. In conclusion, the findings provide evidence of a critical role for neuron-derived E2 in regulating synaptic plasticity and cognitive function in the male and female brain.SIGNIFICANCE STATEMENT The steroid hormone 17ß-estradiol (E2) is well known to be produced in the ovaries in females. Intriguingly, forebrain neurons also express aromatase, the E2 biosynthetic enzyme, but the precise functions of neuron-derived E2 is unclear. Using a novel forebrain-neuron-specific aromatase knock-out mouse model to deplete neuron-derived E2, the current study provides direct genetic evidence of a critical role for neuron-derived E2 in the regulation of rapid AKT-ERK and CREB-BDNF signaling in the mouse forebrain and demonstrates that neuron-derived E2 is essential for normal expression of LTP, synaptic plasticity, and cognitive function in both the male and female brain. These findings suggest that neuron-derived E2 functions as a novel neuromodulator in the forebrain to control synaptic plasticity and cognitive function.

Branched-Chain Amino Acids Depletion during Hemodialysis Is Associated with Fatigue.

BACKGROUND: Fatigue is one of the most debilitating symptoms reported by maintenance hemodialysis (MHD) patients. Hemodialysis causes marked depletion in plasma essential amino acids. We studied the cross-sectional relationship of pre- and post-hemodialysis branched-chain amino acids (BCAAs) concentrations with fatigue in MHD patients. METHODS: MHD patients self-reported fatigue during a dialysis session using the Brief Fatigue Inventory. Pre- and post-dialysis plasma levels of BCAAs (valine, leucine, and isoleucine) were measured using HPLC-mass spectrometry. RESULTS: The mean age of study participants (n = 114) was 54.8 ± 12.8 years. Plasma levels of BCAAs decreased significantly post-dialysis compared to pre-dialysis (303.8 ± 9.4 vs. 392.1 ± 9.4 µM/L, p < 0.0001). Fatigue score increased as a function of age (p = 0.015). There was no association between pre-dialysis plasma levels of BCAAs and fatigue. A significant negative correlation was found between post-dialysis plasma levels of BCAAs and fatigue (p < 0.05). CONCLUSIONS: These preliminary findings suggest that disruption in BCAAs homeostasis may play a role in precipitating fatigue.

DsbA-L prevents obesity-induced inflammation and insulin resistance by suppressing the mtDNA release-activated cGAS-cGAMP-STING pathway.

Chronic inflammation in adipose tissue plays a key role in obesity-induced insulin resistance. However, the mechanisms underlying obesity-induced inflammation remain elusive. Here we show that obesity promotes mtDNA release into the cytosol, where it triggers inflammatory responses by activating the DNA-sensing cGAS-cGAMP-STING pathway. Fat-specific knockout of disulfide-bond A oxidoreductase-like protein (DsbA-L), a chaperone-like protein originally identified in the mitochondrial matrix, impaired mitochondrial function and promoted mtDNA release, leading to activation of the cGAS-cGAMP-STING pathway and inflammatory responses. Conversely, fat-specific overexpression of DsbA-L protected mice against high-fat diet-induced activation of the cGAS-cGAMP-STING pathway and inflammation. Taken together, we identify DsbA-L as a key molecule that maintains mitochondrial integrity. DsbA-L deficiency promotes inflammation and insulin resistance by activating the cGAS-cGAMP-STING pathway. Our study also reveals that, in addition to its well-characterized roles in innate immune surveillance, the cGAS-cGAMP-STING pathway plays an important role in mediating obesity-induced metabolic dysfunction.

Alexithymia and Alcohol Dependence: The Roles of Negative Mood and Alcohol Craving.

Background: Alexithymia is a personality trait associated with emotion regulation difficulties. Up to 67% of alcohol-dependent patients in treatment have alexithymia. Objectives: The objective of this study was to investigate the direct and indirect effects of alexithymia, negative mood (stress, anxiety, and depression) and alcohol craving on alcohol dependence severity. Methods: Three hundred and fifty-five outpatients (mean age = 38.70, SD = 11.00, 244 males, range 18-71 years) undergoing Cognitive-Behavioral Therapy for alcohol dependence completed the Toronto Alexithymia Scale (TAS-20), Depression Anxiety Stress Scales (DASS-21), Obsessive Compulsive Drinking Scale (OCDS), and Alcohol Use Disorders Identification Test (AUDIT) prior to the first treatment session. Results: Alexithymia had an indirect effect on alcohol dependence severity, via both negative mood and alcohol craving (b = 0.03, seb = 0.008, 95% CI: 0.02-0.05). An indirect effect of negative mood on alcohol dependence via alcohol craving was also observed (b = 0.12, seb = 0.03, 95% CI: 0.07-0.16). Conclusions/importance: Alexithymia worked through negative mood and alcohol craving leading to increased alcohol dependence severity, indicating that craving had an indirect effect on the relationship between alexithymia and alcohol dependence severity. Targeting alcohol craving and negative mood for alcohol-dependent patients with alexithymia seems warranted.

Why do children and adolescents bully their peers? A critical review of key theoretical frameworks.

Bullying is a significant public health problem for children and adolescents worldwide. Evidence suggests that both being bullied (bullying victimisation) and bullying others (bullying perpetration) are associated with concurrent and future mental health problems. The onset and course of bullying perpetration are influenced by individual as well as systemic factors. Identifying effective solutions to address bullying requires a fundamental understanding of why it occurs. Drawing from multi-disciplinary domains, this review provides a summary and synthesis of the key theoretical frameworks applied to understanding and intervening on the issue of bullying. A number of explanatory models have been used to elucidate the dynamics of bullying, and broadly these correspond with either system (e.g., social-ecological, family systems, peer-group socialisation) or individual-level (e.g., developmental psychopathology, genetic, resource control, social-cognitive) frameworks. Each theory adds a unique perspective; however, no single framework comprehensively explains why bullying occurs. This review demonstrates that the integration of theoretical perspectives achieves a more nuanced understanding of bullying which is necessary for strengthening evidence-based interventions. Future progress requires researchers to integrate both the systems and individual-level theoretical frameworks to further improve current interventions. More effective intervention across different systems as well as tailoring interventions to the specific needs of the individuals directly involved in bullying will reduce exposure to a key risk factor for mental health problems.